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  • 1
    Online Resource
    Online Resource
    Evolutionary and Biomedical Insights from the Rhesus Macaque Genome
    American Association for the Advancement of Science (AAAS) ; 2007
    In:  Science Vol. 316, No. 5822 ( 2007-04-13), p. 222-234
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 316, No. 5822 ( 2007-04-13), p. 222-234
    Abstract: The rhesus macaque ( Macaca mulatta ) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1139247
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2007
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  • 2
    Online Resource
    Online Resource
    Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 31 ( 2023-08)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 31 ( 2023-08)
    Abstract: Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2306399120
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 3
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    The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 372, No. 6549 ( 2021-06-25)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 372, No. 6549 ( 2021-06-25)
    Abstract: Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor–β–activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine-threonine protein kinase 1 (RIPK1)–dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide CRISPR screen to uncover mediators of caspase-8–dependent pyroptosis identified an unexpected role of the lysosomal folliculin (FLCN)–folliculin-interacting protein 2 (FNIP2)–Rag-Ragulator supercomplex, which regulates metabolic signaling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, Fas-associated death domain (FADD), RIPK1, and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag guanosine triphosphatase activity and lysosomal tethering of Rag-Ragulator but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia .
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg0269
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 4
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    In vivo metabolic labeling of sialoglycans in the mouse brain by using a liposome-assisted bioorthogonal reporter strategy
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 19 ( 2016-05-10), p. 5173-5178
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 19 ( 2016-05-10), p. 5173-5178
    Abstract: Mammalian brains are highly enriched with sialoglycans, which have been implicated in brain development and disease progression. However, in vivo labeling and visualization of sialoglycans in the mouse brain remain a challenge because of the blood−brain barrier. Here we introduce a liposome-assisted bioorthogonal reporter (LABOR) strategy for shuttling 9-azido sialic acid (9AzSia), a sialic acid reporter, into the brain to metabolically label sialoglycoconjugates, including sialylated glycoproteins and glycolipids. Subsequent bioorthogonal conjugation of the incorporated 9AzSia with fluorescent probes via click chemistry enabled fluorescence imaging of brain sialoglycans in living animals and in brain sections. Newly synthesized sialoglycans were found to widely distribute on neuronal cell surfaces, in particular at synaptic sites. Furthermore, large-scale proteomic profiling identified 140 brain sialylated glycoproteins, including a wealth of synapse-associated proteins. Finally, by performing a pulse−chase experiment, we showed that dynamic sialylation is spatially regulated, and that turnover of sialoglycans in the hippocampus is significantly slower than that in other brain regions. The LABOR strategy provides a means to directly visualize and monitor the sialoglycan biosynthesis in the mouse brain and will facilitate elucidating the functional role of brain sialylation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1516524113
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 5
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    “Perfect” designer chromosome V and behavior of a ring derivative
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 355, No. 6329 ( 2017-03-10)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 355, No. 6329 ( 2017-03-10)
    Abstract: Perfect matching of an assembled physical sequence to a specified designed sequence is crucial to verify design principles in genome synthesis. We designed and de novo synthesized 536,024–base pair chromosome synV in the “Build-A-Genome China” course. We corrected an initial isolate of synV to perfectly match the designed sequence using integrative cotransformation and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)–mediated editing in 22 steps; synV strains exhibit high fitness under a variety of culture conditions, compared with that of wild-type V strains. A ring synV derivative was constructed, which is fully functional in Saccharomyces cerevisiae under all conditions tested and exhibits lower spore viability during meiosis. Ring synV chromosome can extends Sc2.0 design principles and provides a model with which to study genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaf4704
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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  • 6
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    Pathogenic role of diabetes-induced PPAR-α down-regulation in microvascular dysfunction
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 38 ( 2013-09-17), p. 15401-15406
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 38 ( 2013-09-17), p. 15401-15406
    Abstract: Two independent clinical studies have reported that fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has robust therapeutic effects on microvascular complications of diabetes, including diabetic retinopathy (DR) in type 2 diabetic patients. However, the expression and function of PPARα in the retina are unclear. Here, we demonstrated that PPARα is expressed in multiple cell types in the retina. In both type 1 and type 2 diabetes models, expression of PPARα, but not PPARβ/δ or PPARγ, was significantly down-regulated in the retina. Furthermore, high-glucose medium was sufficient to down-regulate PPARα expression in cultured retinal cells. To further investigate the role of PPARα in DR, diabetes was induced in PPARα knockout (KO) mice and wild-type (WT) mice. Diabetic PPARα KO mice developed more severe DR, as shown by retinal vascular leakage, leukostasis, pericyte loss, capillary degeneration, and over-expression of inflammatory factors, compared with diabetic WT mice. In addition, overexpression of PPARα in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation. Furthermore, PPARα overexpression inhibited endothelial cell migration and proliferation. These findings revealed that diabetes-induced down-regulation of PPARα plays an important role in DR. Up-regulation or activation of PPARα may represent a novel therapeutic strategy for DR.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1307211110
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 7
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    Online Resource
    Cyclin-Dependent Kinase 5 Controls TRPV1 Membrane Trafficking and the Heat Sensitivity of Nociceptors through KIF13B
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 42 ( 2012-10-17), p. 14709-14721
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 42 ( 2012-10-17), p. 14709-14721
    Abstract: The number of functional transient receptor potential vanilloid 1 (TRPV1) channels at the surface, especially at the peripheral terminals of primary sensory neurons, regulates heat sensitivity, and increased surface localization of TRPV1s contributes to heat hyperalgesia. However, the mechanisms for regulating TRPV1 surface localization are essentially unknown. Here, we show that cyclin-dependent kinase 5 (Cdk5), a new player in thermal pain sensation, positively regulates TRPV1 surface localization. Active Cdk5 was found to promote TRPV1 anterograde transport in vivo , suggesting a regulatory role of Cdk5 in TRPV1 membrane trafficking. TRPV1-containing vesicles bind to the forkhead-associated (FHA) domain of the KIF13B (kinesin-3 family member 13B) and are thus delivered to the cell surface. Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B–TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor–cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor–cargo interaction and the cell-permeable TAT–T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. Moreover, complete Freund's adjuvant (CFA) injection-induced activation of Cdk5 increased the anterograde transport of TRPV1s, contributing to the development and possibly the maintenance of heat hyperalgesia, whereas intrathecal delivery of the TAT–T506 peptide alleviated CFA-induced heat hyperalgesia in rats. Thus, Cdk5 regulation of TRPV1 membrane trafficking is a fundamental mechanism controlling the heat sensitivity of nociceptors, and moderate inhibition of Thr-506 phosphorylation during inflammation might be helpful for the treatment of inflammatory thermal pain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1634-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
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  • 8
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    Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 26 ( 2020-06-30), p. 15047-15054
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 26 ( 2020-06-30), p. 15047-15054
    Abstract: Tamoxifen, a widely used modulator of the estrogen receptor (ER), targets ER-positive breast cancer preferentially. We used a powerful validation-based insertion mutagenesis method to find that expression of a dominant-negative, truncated form of the histone deacetylase ZIP led to resistance to tamoxifen. Consistently, increased expression of full-length ZIP gives the opposite phenotype, inhibiting the expression of genes whose products mediate resistance. An important example is JAK2 . By binding to two specific sequences in the promoter, ZIP suppresses JAK2 expression. Increased expression and activation of JAK2 when ZIP is inhibited lead to increased STAT3 phosphorylation and increased resistance to tamoxifen, both in cell culture experiments and in a mouse xenograft model. Furthermore, data from human tumors are consistent with the conclusion that decreased expression of ZIP leads to resistance to tamoxifen in ER-positive breast cancer.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1910278117
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 9
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    Solving independent set problems with photonic quantum circuits
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 22 ( 2023-05-30)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 22 ( 2023-05-30)
    Abstract: An independent set (IS) is a set of vertices in a graph such that no edge connects any two vertices. In adiabatic quantum computation [E. Farhi, et al ., Science 292, 472–475 (2001); A. Das, B. K. Chakrabarti, Rev. Mod. Phys. 80, 1061–1081 (2008)], a given graph G ( V , E ) can be naturally mapped onto a many-body Hamiltonian H IS G ( V , E ) , with edges E being the two-body interactions between adjacent vertices V . Thus, solving the IS problem is equivalent to finding all the computational basis ground states of H IS G ( V , E ) . Very recently, non-Abelian adiabatic mixing (NAAM) has been proposed to address this task, exploiting an emergent non-Abelian gauge symmetry of H IS G ( V , E ) [B. Wu, H. Yu, F. Wilczek, Phys. Rev. A 101, 012318 (2020)]. Here, we solve a representative IS problem G ( 8 , 7 ) by simulating the NAAM digitally using a linear optical quantum network, consisting of three C-Phase gates, four deterministic two-qubit gate arrays (DGA), and ten single rotation gates. The maximum IS has been successfully identified with sufficient Trotterization steps and a carefully chosen evolution path. Remarkably, we find IS with a total probability of 0.875(16), among which the nontrivial ones have a considerable weight of about 31.4%. Our experiment demonstrates the potential advantage of NAAM for solving IS-equivalent problems.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2212323120
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
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  • 10
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    Ferroelectricity in layered bismuth oxide down to 1 nanometer
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 379, No. 6638 ( 2023-03-24), p. 1218-1224
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6638 ( 2023-03-24), p. 1218-1224
    Abstract: A bismuth samarium oxide thin film on a substrate maintains its ferroelectricity at a thickness of only 1 nanometer.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abm5134
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
    detail.hit.zdb_id: 128410-1
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    detail.hit.zdb_id: 2060783-0
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