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  • American Association for the Advancement of Science (AAAS)  (12)
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  • American Association for the Advancement of Science (AAAS)  (12)
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  • 1
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 360, No. 6393 ( 2018-06-08), p. 1087-1092
    Abstract: A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3 ) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1 -deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 2
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 370, No. 6519 ( 2020-11-20)
    Abstract: Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those of mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick, and mice in response to different stimuli. We identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, reactivity, and neurogenesis. In zebrafish and chick, the transition from quiescence to reactivity is essential for retinal regeneration, whereas in mice, a dedicated network suppresses neurogenic competence and restores quiescence. Disruption of nuclear factor I transcription factors, which maintain and restore quiescence, induces Müller glia to proliferate and generate neurons in adult mice after injury. These findings may aid in designing therapies to restore retinal neurons lost to degenerative diseases.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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  • 3
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 363, No. 6431 ( 2019-03-08), p. 1085-1088
    Abstract: Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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    detail.hit.zdb_id: 2066996-3
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  • 4
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 355, No. 6329 ( 2017-03-10)
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 355, No. 6329 ( 2017-03-10)
    Abstract: Debugging a genome sequence is imperative for successfully building a synthetic genome. As part of the effort to build a designer eukaryotic genome, yeast synthetic chromosome X (synX), designed as 707,459 base pairs, was synthesized chemically. SynX exhibited good fitness under a wide variety of conditions. A highly efficient mapping strategy called pooled PCRTag mapping (PoPM), which can be generalized to any watermarked synthetic chromosome, was developed to identify genetic alterations that affect cell fitness (“bugs”). A series of bugs were corrected that included a large region bearing complex amplifications, a growth defect mapping to a recoded sequence in FIP1 , and a loxPsym site affecting promoter function of ATP2 . PoPM is a powerful tool for synthetic yeast genome debugging and an efficient strategy for phenotype-genotype mapping.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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  • 5
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2013
    In:  Science Vol. 342, No. 6165 ( 2013-12-20), p. 1518-1521
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 342, No. 6165 ( 2013-12-20), p. 1518-1521
    Abstract: The duration of a woman’s reproductive period is determined by the size and persistence of a dormant oocyte pool. Specific oocyte genes are essential for follicle maintenance and female fertility. The mechanisms that regulate the expression of these genes are poorly understood. We found that a cullin-ring finger ligase-4 (CRL4) complex was crucial in this process. Oocyte-specific deletion of the CRL4 linker protein DDB1 or its substrate adaptor VPRBP (also known as DCAF1) caused rapid oocyte loss, premature ovarian insufficiency, and silencing of fertility maintaining genes. CRL4 VPRBP activates the TET methylcytosine dioxygenases, which are involved in female germ cell development and zygote genome reprogramming. Hence, CRL4 VPRBP ubiquitin ligase is a guardian of female reproductive life in germ cells and a maternal reprogramming factor after fertilization.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2013
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    detail.hit.zdb_id: 2066996-3
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  • 6
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 370, No. 6522 ( 2020-12-11)
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 370, No. 6522 ( 2020-12-11)
    Abstract: Embryo polarization is critical for mouse development; however, neither the regulatory clock nor the molecular trigger that it activates is known. Here, we show that the embryo polarization clock reflects the onset of zygotic genome activation, and we identify three factors required to trigger polarization. Advancing the timing of transcription factor AP-2 gamma (Tfap2c) and TEA domain transcription factor 4 (Tead4) expression in the presence of activated Ras homolog family member A (RhoA) induces precocious polarization as well as subsequent cell fate specification and morphogenesis. Tfap2c and Tead4 induce expression of actin regulators that control the recruitment of apical proteins on the membrane, whereas RhoA regulates their lateral mobility, allowing the emergence of the apical domain. Thus, Tfap2c, Tead4, and RhoA are regulators for the onset of polarization and cell fate segregation in the mouse.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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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: 2066996-3
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  • 7
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6637 ( 2023-03-17)
    Abstract: Autoimmune diseases such as ankylosing spondylitis (AS) can be caused by emerging neoantigens that break immune tolerance in humans. Posttranslational modifications (PTMs) have been shown to be a critical mechanism that alters protein structure and function to generate neoantigens and induce subsequent autoimmune responses. Previous studies have confirmed that citrulline-modified peptides are a critical source of neoantigens in rheumatoid arthritis. However, the molecular mechanisms underlying neoantigen formation and pathogenic autoreactive responses for AS are largely unknown. There is an urgent need to develop a systematic approach to profiling the possible PTMs in patients with AS and identifying AS-associated PTMs responsible for autoreactive neoantigen production to better understand the etiology of autoimmune diseases. RATIONALE AS has been suggested to be an autoimmune disease because of its clear correlation with certain major histocompatibility complex (MHC) alleles, including HLA-B27. Neoantigens have been hypothesized to induce an aberrant immune response, leading to pathogenic autoreactive T cell responses and autoantibody generation in AS. Here, we developed a systematic open search approach to identify any possible amino acid residues and derivatives in the proteins that are different from the genomic coding sequences. We then applied this information to identify AS-related neoantigens with PTMs within a possible pool of PTM autoantigens and elucidate the pathogenesis of AS. RESULTS An open search approach was applied to identify any possible amino acid derivatives across the proteome of patients with AS. This approach generated a large set of noncoded amino acids representing the mass differences between the coded amino acids and actual residues. Among these, an amino acid derivative with a delta mass of 72.021 showed the greatest increase in patients with AS and resulted from a PTM called cysteine carboxyethylation. In vitro and in vivo experiments demonstrated that carboxyethylation at a cysteine residue of integrin αIIb [ITGA2B (CD41)] was catalyzed by cystathionine beta synthase (CBS) in a process that required 3-hydroxypropionic acid (3-HPA), a metabolite commonly released from gut microbes. Cysteine carboxyethylation induced the lysosomal degradation of ITGA2B and produced neoantigens that triggered MHC-II–dependent CD4 + T cell responses. Fluorescence polarization and enzyme-linked immunosorbent assay (ELISA) demonstrated that the identified carboxyethylated peptide (ITGA2B-ceC96) specifically interacted with HLA-DRA*01/HLA-DRB1*04 and was associated with autoantibody production and T cell responses in HLA-DRB1*04 patients. Additional in vitro assays showed that the neoantigen ITGA2B-ceC96 correlated with 3-HPA levels but was independent of CBS expression. HLA-DRB1 haplotype, the carboxyethylated peptide, specific autoantibodies, and 3-HPA levels in patients with AS all correlated with one another. 3-HPA–treated and ITGA2B-ceC96–immunized HLA-DR4 transgenic mice developed colitis and vertebral bone erosion. Thus, cysteine carboxyethylation induced by the metabolite 3-HPA generates a neoantigen that appears to be critical for autoimmune responses in patients with AS. CONCLUSION Cysteine carboxyethylation is an in vivo protein modification induced by the metabolite 3-HPA, which is commonly released from gut microbes. Carboxyethylated ITGA2B then induces autoantibody production and autoimmune response in AS. Our work provides a systematic workflow to identify differentially modified proteins that are important for neoantigen production in immune disorders. This approach furthers our understanding of AS pathogenesis and may aid in the development of neoantigen-based diagnosis and treatment for AS and other autoimmune diseases. Metabolite-induced cysteine carboxyethylation provokes HLA-restricted autoimmune responses in ankylosing spondylitis. 3-HPA, which is commonly obtained from food and gut microbes, induces carboxyethylation of cysteine residues in integrin αIIb (ITGA2B). Cysteine carboxyethylation requires CBS, and carboxyethylated ITGA2B (ITGA2B-ceC96) peptides are recruited to the HLA-DR4 complex and thereby stimulate CD4 + T cell responses closely related to AS.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 8
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 381, No. 6657 ( 2023-08-04)
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 381, No. 6657 ( 2023-08-04)
    Abstract: Gut microbiota can regulate the physiology and pathophysiology of the host by producing enzymes with functions similar to those of the host. However, it is difficult to identify these microbial-host isozymes through sequencing-based studies because enzymes with similar functions in different species may lack sequence conservation. An activity-based functional protein screening framework is more reliable for the discovery and characterization of such microbial-host isozymes, which will help yield deeper insights into the gut microbiota–host cross-talk. RATIONALE To identify potential microbial-host isozymes, we set up an enzyme activity screening platform, including activity assays for 110 enzymes that are functional in various human diseases. These enzyme activities were measured in stool-derived ex vivo bacteria communities. Dipeptidyl peptidase 4 (DPP4) was a prominent microbial-host isozyme identified in our screen, but little is known about its pathophysiological effects on the host. We sought to determine whether gut microbial–derived DPP4, like host DPP4 (hDPP4), could decrease active GLP-1 and thus affect blood glucose homeostasis. RESULTS We identified 71 enzymes with positive activity in the human gut bacteria communities through our enzyme activity screening platform, most of which were validated in the protein extracts obtained from feces of germ-free and specific pathogen–free mice. Among these identified enzymes, DPP4 activity had the highest statistical effect size ( Z factor) among the 10 human samples. Through human gut bacteria isolation and DPP4 activity screening, we discovered that microbial DPP4 was mainly produced by Bacteroides spp. Gut microbial DPP4 (mDPP4) could degrade active GLP-1(7-37) in vitro. However, mDPP4 could not affect active GLP-1 levels in chow-fed mice but could decrease active GLP-1 activity and impair glucose homeostasis in high-fat diet (HFD)–fed mice or dextran sulfate sodium/indomethacin–treated mice, suggesting that a damaged gut barrier is required for mDPP4 to affect the activity of host GLP-1. We discovered that the clinical DPP4 inhibitor sitagliptin failed to efficiently inhibit mDPP4. And by solving the co-crystal of mDPP4 with sitagliptin at 1.97-anstrom resolution, we found differences in the nature of the binding between the drug and mDPP4 compared with its binding to hDPP4 that may explain this difference in inhibitory effects. A sitagliptin clinical trial ( www.clinicaltrials.gov identifer NCT04495881) among patients with type 2 diabetes (T2D) ( n = 57) and a related fecal microbiota transplant of stool from high responders and low responders in the present study to HFD-fed mice demonstrated that mDPP4 could limit the efficacy of sitagliptin in individuals with T2D and in glucose-intolerant mice. To identify a selective inhibitor of mDPP4, we screened ~107,000 compounds, and using structural modification we identified Dau-d4, a derivative of daurisoline, that could selectively inhibit mDPP4 activity compared with hDPP4. Dau-d4 could increase active GLP-1 levels and improve glucose metabolism in diabetic mice, and co-administration of Dau-d4 with sitagliptin further improved blood glucose homeostasis. CONCLUSION Here, we developed an activity-based strategy to identify uncharacterized gut microbial-host isozymes that provides a deeper understanding of gut microbiota–host interactions. Gut microbial DPP4 isozyme can impair host glucose homeostasis, and variations in microbial DPP4 activities could possibly contribute to the heterogeneous responses to sitagliptin observed among patients with T2D. Our findings highlight the promise of developing therapies that target both host and gut microbial enzymes to achieve greater clinical efficacy. Discovery and inhibition of a gut microbial–host isozyme to regulate host metabolism. Differences in the gut microbiota may explain why some individuals respond to antidiabetic DPP4 inhibitors but others do not. An activity-based enzyme activity screening system identified gut microbial DPP4 isozymes that can decrease active GLP-1 but cannot be inhibited by sitagliptin. High-throughput screening identified Dau-d4 as a selective inhibitor of microbial DPP4 to increase GLP-1 activity and improve glucose tolerance.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 9
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6597 ( 2022-06-03)
    Abstract: Extreme evolution of animal organs, such as elongation of the giraffe’s neck, has been the focus of intensive research for many decades. Here, we describe a fossil giraffoid, Discokeryx xiezhi , from the early Miocene (~16.9 million years ago) of northern China. This previously unknown species has a thick-boned cranium with a large disklike headgear, a series of cervical vertebrae with extremely thickened centra, and the most complicated head-neck joints in mammals known to date. The peculiar head-neck morphology was most probably adapted for a fierce intermale head-butting behavior, comparable to neck-blowing in male giraffes but indicative of an extreme adaptation in a different direction within giraffoids. This newly identified giraffoid increases our understanding the actual triggers for the giraffe’s head-neck evolution. RATIONALE The comparative anatomical studies of osteological structures, including the bony labyrinth morphology, the headgear genesis and histology, and dentitions, provide the basis for the giraffoid affinity of D. xiezhi , which was further supported by phylogenetic analyses and reconstructions of the fauna. Finite element analyses explain the mechanical predominance for the peculiar head-neck morphology in various head-butting modeling. Tooth enamel isotope analyses indicate the distinctiveness of the ecological niche occupied by D. xiezhi . Diversity of headgear within different pecoran groups reveals the different evolutionary selection pressure on these groups. RESULTS Finite element analysis reveals that the enlarged atlanto-occipitalis and intercervical articulations are essential for high-speed head-to-head butting. D. xiezhi appears to exhibit the most optimized head-butting adaptation in vertebrate evolution when compared with the models of extant head-butters. Tooth enamel isotope data show that D. xiezhi had the second highest average δ 13 C value among all herbivores and a large range of δ 18 O values, with some individuals occupying an isotopic niche differing substantially from others in the fossil community. This indicates that D. xiezhi was an open-land grazer with multiple sources of water intake, and their habitats likely included areas that were difficult for other contemporary herbivores to make use of. CONCLUSION The morphology and inferred ecology of D. xiezhi provide another example for understanding the neck evolution in giraffoids. Fossil giraffoids exhibit a higher degree of diversity in headgear morphology than any other pecoran group; such a diversity, associated with the complex head-neck morphology, likely indicates the intensive sexual combats between males in the evolution of giraffoids. For interspecific relationship, one possible strategy of early giraffoids is that they might have avoided competition with coeval bovids and cervids by taking advantage of other niches in the ecosystem. Giraffa , with its long neck, did not appear until the early Pliocene in savannah areas, when C 4 ecosystems started being vastly established. “Necking” combat was likely the primary driving force for giraffes that have evolved a long neck, and high-level browsing was likely a compatible benefit of this evolution. The ecological positioning on the marginal niches promoted the intensive sexual competition, and the fierce sexual combats fostered extreme morphologies to occupy the special niches in giraffoids. Male combat in the representative giraffoids. D. xiezhi (head-to-head butting, top left) and the extant Giraffa camelopardalis (neck blowing, bottom left) show different combat styles and head-neck morphology. The right panel exhibits the accumulative number of headgears in various pecoran groups during their evolution. Note that giraffomorphs had evolved more types of headgear than other pecoran groups, which may be partly attributable to their various combat styles. ILLUSTRATION: Y. WANG AND X. GUO
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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    detail.hit.zdb_id: 2066996-3
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    SSG: 11
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  • 10
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6633 ( 2023-02-17)
    Abstract: Hou et al . challenged the giraffoid affinity of Discokeryx and its ecology and behavior. In our response we reiterate that Discokeryx is a giraffoid that, along with Giraffa , shows extreme evolution of head-neck morphologies that were presumably shaped by selective pressure from sexual competition and marginal environments.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
    Location Call Number Limitation Availability
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