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Proceedings of the National Academy of Sciences of... 78건

  1. [해외논문]   A neurochemical hypothesis for the origin of hominids   SCI SCIE

    Raghanti, Mary Ann (Department of Anthropology, Kent State University, Kent, OH 44242) , Edler, Melissa K. (Department of Anthropology, Kent State University, Kent, OH 44242) , Stephenson, Alexa R. (Department of Anthropology, Kent State University, Kent, OH 44242) , Munger, Emily L. (Department of Anthropology, Kent State University, Kent, OH 44242) , Jacobs, Bob (Laboratory of Quantitative Neuromorphology, Department of Psychology, Colorado College, Colorado Springs, CO 80903) , Hof, Patrick R. (Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029) , Sherwood, Chet C. (Department of Anthropology, The George Washington University, Washington, DC 20052) , Holloway, Ralph L. (Department of Anthropology, Columbia University, New York, NY 10027 ) , Lovejoy, C. Owen (Department of Anthropology, Kent State University, Kent, OH 44242;)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1108 - E1116 , 2018 , 0027-8424 ,

    초록

    Significance Two factors vital to the human clade are our unique demographic success and our social facilities including language, empathy, and altruism. These have always been difficult to reconcile with individual reproductive success. However, the striatum, a region of the basal ganglia, modulates social behavior and exhibits a unique neurochemical profile in humans. The human signature amplifies sensitivity to social cues that encourage social conformity and affiliative behavior and could have favored provisioning and monogamy in emergent hominids, consilient with the simultaneous origin of upright walking and elimination of the sectorial canine. Such exceptional neurochemistry would have favored individuals especially sensitive to social cues throughout later human evolution and may account for cerebral cortical expansion and the emergence of language. It has always been difficult to account for the evolution of certain human characters such as language, empathy, and altruism via individual reproductive success. However, the striatum, a subcortical region originally thought to be exclusively motor, is now known to contribute to social behaviors and “personality styles” that may link such complexities with natural selection. We here report that the human striatum exhibits a unique neurochemical profile that differs dramatically from those of other primates. The human signature of elevated striatal dopamine, serotonin, and neuropeptide Y, coupled with lowered acetylcholine, systematically favors externally driven behavior and greatly amplifies sensitivity to social cues that promote social conformity, empathy, and altruism. We propose that selection induced an initial form of this profile in early hominids, which increased their affiliative behavior, and that this shift either preceded or accompanied the adoption of bipedality and elimination of the sectorial canine. We further hypothesize that these changes were critical for increased individual fitness and promoted the adoption of social monogamy, which progressively increased cooperation as well as a dependence on tradition-based cultural transmission. These eventually facilitated the acquisition of language by elevating the reproductive advantage afforded those most sensitive to social cues.

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  2. [해외논문]   MYCN -amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling   SCI SCIE

    Dzieran, Johanna (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , SE-171 77 Stockholm, Sweden ) , Rodriguez Garcia, Aida , Westermark, Ulrica Kristina (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , SE-171 77 Stockholm, Sweden ) , Henley, Aine Brigette , Eyre Sá (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , SE-171 77 Stockholm, Sweden ) , nchez, Elena , Trä (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , SE-171 77 Stockholm, Sweden ) , ger, Catarina , Johansson, Henrik Johan (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , SE-171 77 Stockholm, Sweden ) , Lehtiö , , Janne (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , SE-171 77 Stockholm, Sweden ) , Arsenian-Henriksson, Marie
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1229 - E1238 , 2018 , 0027-8424 ,

    초록

    Significance High-risk neuroblastoma (NB), a cancer of the sympathetic nervous system, is challenging to treat. MYCN is frequently amplified in high-risk NB and is linked to an undifferentiated phenotype and poor prognosis. Estrogen and nerve growth factor (NGF) are inducers of neural differentiation, a process associated with a favorable disease. We show that MYCN suppresses estrogen receptor alpha (ERα) and thereby NGF signaling and neural differentiation. ERα overexpression is sufficient to interfere with different tumorigenic processes and tumor growth. In patients with NB, ERα expression correlates with several clinical markers for good prognosis. Importantly, not only ERα but also the majority of other nuclear hormone receptors are linked to favorable NB, suggesting a potential prognostic and therapeutic value for these proteins. Neuroblastoma (NB) is a remarkably heterogenic childhood tumor of the sympathetic nervous system with clinical behavior ranging from spontaneous regression to poorly differentiated tumors and metastasis. MYCN is amplified in 20% of cases and correlates with an undifferentiated, aggressive phenotype and poor prognosis. Estrogen receptor alpha (ERα) and the nerve growth factor (NGF) receptors TrkA and p75 NTR are involved in neuronal differentiation and survival. We have previously shown that MYCN, via miR-18a, targets ERα in NB cells. Here, we demonstrate that interference with miR-18a or overexpression of ERα is sufficient to induce NGF signaling and to modulate both basal and NGF-induced neuronal differentiation in MYCN -amplified NB cells. Proteomic analysis confirmed an increase of neuronal features and showed that processes linked to tumor initiation and progression were inhibited upon ERα overexpression. Indeed, ectopic ERα expression was sufficient to inhibit metabolic activity and tumorigenic processes, including glycolysis, oxidative phosphorylation, cell viability, migration, and anchorage independent growth. Importantly, ERα overexpression reduced tumor burden in NB mouse models and high ERα levels were linked to improved survival in patients. In addition to ERα, several other nuclear hormone receptors (NHRs), including the glucocorticoid and the retinoic acid receptors, correlated with clinical markers for favorable and low-stage NB disease. Our data suggest that MYCN targets ERα and thereby NGF signaling to maintain an undifferentiated and aggressive phenotype. Notably, we identified the estrogen–NGF crosstalk, as well as a set of other NHRs, as potential prognostic markers and targets for therapeutic strategies against NB.

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  3. [해외논문]   Evolutionary history of carbon monoxide dehydrogenase/acetyl-CoA synthase, one of the oldest enzymatic complexes   SCI SCIE

    Adam, Panagiotis S. (Unit Evolutionary Biology of the Microbial Cell, Department of Microbiology, Institut Pasteur, 75015 Paris, France) , Borrel, Guillaume (Unit Evolutionary Biology of the Microbial Cell, Department of Microbiology, Institut Pasteur, 75015 Paris, France) , Gribaldo, Simonetta (Unit Evolutionary Biology of the Microbial Cell, Department of Microbiology, Institut Pasteur, 75015 Paris, France;)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1166 - E1173 , 2018 , 0027-8424 ,

    초록

    Significance Before the emergence of oxygenic photosynthesis and the accumulation of oxygen on Earth, life was essentially composed of anaerobic microorganisms. However, very little is known about which metabolisms were present at the time. Anaerobic carbon fixation through the Wood–Ljungdahl pathway is believed to be among the most ancient, and still plays a pivotal role in modern ecosystems. However, its origin and evolutionary history has been disputed. We analysed the distribution and phylogeny of carbon monoxide dehydrogenase/acetyl-CoA synthase, the main enzymatic complex of the pathway in thousands of bacterial and archaeal genomes. We show that this complex was already at work in the last universal common ancestor and has been remarkably conserved in microorganisms over more than 3.5 billion years. Carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS) is a five-subunit enzyme complex responsible for the carbonyl branch of the Wood–Ljungdahl (WL) pathway, considered one of the most ancient metabolisms for anaerobic carbon fixation, but its origin and evolutionary history have been unclear. While traditionally associated with methanogens and acetogens, the presence of CODH/ACS homologs has been reported in a large number of uncultured anaerobic lineages. Here, we have carried out an exhaustive phylogenomic study of CODH/ACS in over 6,400 archaeal and bacterial genomes. The identification of complete and likely functional CODH/ACS complexes in these genomes significantly expands its distribution in microbial lineages. The CODH/ACS complex displays astounding conservation and vertical inheritance over geological times. Rare intradomain and interdomain transfer events might tie into important functional transitions, including the acquisition of CODH/ACS in some archaeal methanogens not known to fix carbon, the tinkering of the complex in a clade of model bacterial acetogens, or emergence of archaeal–bacterial hybrid complexes. Once these transfers were clearly identified, our results allowed us to infer the presence of a CODH/ACS complex with at least four subunits in the last universal common ancestor (LUCA). Different scenarios on the possible role of ancestral CODH/ACS are discussed. Despite common assumptions, all are equally compatible with an autotrophic, mixotrophic, or heterotrophic LUCA. Functional characterization of CODH/ACS from a larger spectrum of bacterial and archaeal lineages and detailed evolutionary analysis of the WL methyl branch will help resolve this issue.

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  4. [해외논문]   Evolution of vertical and oblique transmission under fluctuating selection   SCI SCIE

    Ram, Yoav (Department of Biology, Stanford University , Stanford, CA 94305-5020) , Liberman, Uri (School of Mathematical Sciences, Tel Aviv University , Tel Aviv 69978, Israel ) , Feldman, Marcus W. (Department of Biology, Stanford University , Stanford, CA 94305-5020;)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1174 - E1183 , 2018 , 0027-8424 ,

    초록

    Significance Evolutionary dynamics of phenotypes in populations depend on how the traits are transmitted across generations and how the environments that cause selection on the traits fluctuate over time. We show that, under periodically fluctuating selection, a gene that increases the rate of vertical transmission is disfavored when the periods are short but approaches an intermediate stable rate for longer periods. This stable rate differs markedly from the rate that maximizes the geometric mean fitness. The evolution of learning rules thus differs qualitatively from the evolution of genetically modified rules of genetic transmission. The evolution and maintenance of social learning, in competition with individual learning, under fluctuating selection have been well-studied in the theory of cultural evolution. Here, we study competition between vertical and oblique cultural transmission of a dichotomous phenotype under constant, periodically cycling, and randomly fluctuating selection. Conditions are derived for the existence of a stable polymorphism in a periodically cycling selection regime. Under such a selection regime, the fate of a genetic modifier of the rate of vertical transmission depends on the length of the cycle and the strength of selection. In general, the evolutionarily stable rate of vertical transmission differs markedly from the rate that maximizes the geometric mean fitness of the population. The evolution of rules of transmission has dramatically different dynamics from the more frequently studied modifiers of recombination, mutation, or migration.

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  5. [해외논문]   Shape-directed dynamics of active colloids powered by induced-charge electrophoresis   SCI SCIE

    Brooks, Allan M. (Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802) , Sabrina, Syeda (Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802) , Bishop, Kyle J. M. (Department of Chemical Engineering, Columbia University, New York, NY 10027)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1090 - E1099 , 2018 , 0027-8424 ,

    초록

    Significance Despite recent advances in the ability to “program” the self-assembly of colloidal components, the resulting structures are often static and therefore incapable of performing dynamic functions such as the ability to actuate, heal, replicate, and compute. The realization of colloidal machines that organize in space and time to perform such functions requires new strategies for encoding the dynamic behaviors of colloidal components. Focusing on active colloids powered by induced-charge electrophoresis, we use theory and simulation to show how the shape of a colloidal particle can be rationally tailored to specify complex motions powered by simple energy inputs. The symmetry and shape of colloidal particles can direct complex particle motions through fluid environments powered by simple energy inputs. The ability to rationally design or “program” the dynamics of such active colloids is an important step toward the realization of colloidal machines, in which components assemble spontaneously in space and time to perform dynamic (dissipative) functions such as actuation and transport. Here, we systematically investigate the dynamics of polarizable particles of different shapes moving in an oscillating electric field via induced-charge electrophoresis (ICEP). We consider particles from each point group in three dimensions (3D) and identify the different rotational and translational motions allowed by symmetry. We describe how the 3D shape of rigid particles can be tailored to achieve desired dynamics including oscillatory motions, helical trajectories, and complex periodic orbits. The methodology we develop is generally applicable to the design of shape-directed particle motions powered by other energy inputs.

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  6. [해외논문]   IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells   SCI SCIE

    Paré (Centre de Recherche du Centre Hospitalier Universitaire de Quéééééébec, Universitééééééé) , , Alexandre (Laval, Quéééééééébec, QC G1V 4G2, Canada) , Mailhot, Benoit (Centre de Recherche du Centre Hospitalier Universitaire de Quéééééébec, Universitééééééé) , Lé (Laval, Quéééééééébec, QC G1V 4G2, Canada) , é (Centre de Recherche du Centre Hospitalier Universitaire de Quéééééébec, Universitééééééé) , é (Laval, Quéééééééébec, QC G1V 4G2, Canada) , vesque, Sé (Montreal Neurological Institute, Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC H3A 2B4, Canada) , é (Centre de Rec) , bastien A. , Juzwik, Camille , Ignatius Arokia Doss, Prenitha Mercy , Lé , é , é , é , é , cuyer, Marc-André , é , é , é , , Prat, Alexandre , Rangachari, Manu , Fournier, Alyson , Lacroix, Steve
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1194 - E1203 , 2018 , 0027-8424 ,

    초록

    Significance Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelinating plaques in the brain and spinal cord, causing progressive loss of functions. While the causes of MS remain undefined, treatments that target immune cells or their functions greatly improve the clinical outcome. Our laboratory has previously shown that production of the inflammatory cytokine interleukin (IL)-1β by myeloid cells is required for the development of experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we show that activation of central nervous system (CNS) endothelial cells by IL-1β enables inflammatory monocytes to enter the CNS and differentiate into antigen-presenting cells. Additionally, we demonstrate that factors released from the interaction between IL-1β–producing myeloid cells and autoreactive CD4 + T cells are toxic to neurons. Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1β–knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1β/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1β expression by inflammatory CCR2 hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1β, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4 + T cells. Factors released from the interaction between IL-1β–competent myeloid cells and CD4 + T cells are highly toxic to neurons. Together, our results suggest that IL-1β signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.

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  7. [해외논문]   Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry   SCI SCIE

    Beer, Katharina B. (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg , 97080 Würzburg, Germany ) , Rivas-Castillo, Jennifer , Kuhn, Kenneth (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg , 97080 Würzburg, Germany ) , Fazeli, Gholamreza , Karmann, Birgit (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg , 97080 Würzburg, Germany ) , Nance, Jeremy F. , Stigloher, Christian (Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg , 97080 Würzburg, Germany ) , Wehman, Ann M.
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1127 - E1136 , 2018 , 0027-8424 ,

    초록

    Significance Cells must interact with their environment to survive. The lipids and proteins of the plasma membrane send and receive signals at the cell surface to respond to stimuli. When the lipid bilayer of the plasma membrane is damaged, cells release membrane-bound extracellular vesicles to repair the membrane. Cells also release signals on extracellular vesicles to communicate at a distance. Here, we identify proteins that regulate the formation of extracellular vesicles from the plasma membrane, providing additional tools to control their release that can be used to test potential functions of extracellular vesicles. Furthermore, we reveal that proteins regulating the asymmetric localization of the lipid phosphatidylethanolamine are critical for extracellular vesicle release, implicating this abundant but understudied lipid. Cells release extracellular vesicles (EVs) that mediate intercellular communication and repair damaged membranes. Despite the pleiotropic functions of EVs in vitro, their in vivo function is debated, largely because it is unclear how to induce or inhibit their formation. In particular, the mechanisms of EV release by plasma membrane budding or ectocytosis are poorly understood. We previously showed that TAT-5 phospholipid flippase activity maintains the asymmetric localization of the lipid phosphatidylethanolamine (PE) in the plasma membrane and inhibits EV budding by ectocytosis in Caenorhabditis elegans . However, no proteins that inhibit ectocytosis upstream of TAT-5 were known. Here, we identify TAT-5 regulators associated with retrograde endosomal recycling: PI3Kinase VPS-34, Beclin1 homolog BEC-1, DnaJ protein RME-8, and the uncharacterized Dopey homolog PAD-1. PI3Kinase, RME-8, and semiredundant sorting nexins are required for the plasma membrane localization of TAT-5, which is important to maintain PE asymmetry and inhibit EV release. PAD-1 does not directly regulate TAT-5 localization, but is required for the lipid flipping activity of TAT-5. PAD-1 also has roles in endosomal trafficking with the GEF-like protein MON-2, which regulates PE asymmetry and EV release redundantly with sorting nexins independent of the core retromer. Thus, in addition to uncovering redundant intracellular trafficking pathways, our study identifies additional proteins that regulate EV release. This work pinpoints TAT-5 and PE as key regulators of plasma membrane budding, further supporting the model that PE externalization drives ectocytosis.

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  8. [해외논문]   Structure and function of the archaeal response regulator CheY   SCI SCIE

    Quax, Tessa E. F. (Molecular Biology of Archaea, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany) , Altegoer, Florian (Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz Center for Synthetic Microbiology & Faculty of Chemistry, Philipps-University-Marburg, 35043 Marburg, Germany) , Rossi, Fernando (Molecular Biology of Archaea, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany) , Li, Zhengqun (Molecular Biology of Archaea, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany) , Rodriguez-Franco, Marta (Cell Biology, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany) , Kraus, Florian (Faculty of Chemistry, Philipps-University-Marburg, 35043 Marburg, Germany ) , Bange, Gert (Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz Center for Synthetic Microbiology & Faculty of Chemistry, Philipps-University-Marburg, 35043 Marburg, Germany) , Albers, Sonja-Verena (Molecular Biology of Archaea, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany;)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1259 - E1268 , 2018 , 0027-8424 ,

    초록

    Significance Motility is a key feature for the success of microorganisms, as it allows the movement to optimal growth environments. Bacteria and archaea possess filamentous motility structures capable of rotation. However, both molecular machines consist of fundamentally different proteins and lack structural similarity. Intriguingly, some archaea possess the chemotaxis system. This system allows bacteria to travel along chemical gradients and is dependent on interaction of the response regulator CheY with the motor of the motility structure. In this study, we map the changes of the CheY protein structure required for its interaction with components of the archaeal motility machinery. Motility is a central feature of many microorganisms and provides an efficient strategy to respond to environmental changes. Bacteria and archaea have developed fundamentally different rotary motors enabling their motility, termed flagellum and archaellum, respectively. Bacterial motility along chemical gradients, called chemotaxis, critically relies on the response regulator CheY, which, when phosphorylated, inverses the rotational direction of the flagellum via a switch complex at the base of the motor. The structural difference between archaellum and flagellum and the presence of functional CheY in archaea raises the question of how the CheY protein changed to allow communication with the archaeal motility machinery. Here we show that archaeal CheY shares the overall structure and mechanism of magnesium-dependent phosphorylation with its bacterial counterpart. However, bacterial and archaeal CheY differ in the electrostatic potential of the helix α4. The helix α4 is important in bacteria for interaction with the flagellar switch complex, a structure that is absent in archaea. We demonstrated that phosphorylation-dependent activation, and conserved residues in the archaeal CheY helix α4, are important for interaction with the archaeal-specific adaptor protein CheF. This forms a bridge between the chemotaxis system and the archaeal motility machinery. Conclusively, archaeal CheY proteins conserved the central mechanistic features between bacteria and archaea, but differ in the helix α4 to allow binding to an archaellum-specific interaction partner.

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  9. [해외논문]   Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function   SCI SCIE

    Sundararaj, Srinivasan (Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia) , Zhang, Jingjing (Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045) , Krovi, S. Harsha (Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045) , Bedel, Romain (Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045) , Tuttle, Kathryn D. (Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045) , Veerapen, Natacha (School of Biosciences, University of Birmingham, Birmingham B15 2TT, United Kingdom) , Besra, Gurdyal S. (School of Biosciences, University of Birmingham, Birmingham B15 2TT, United Kingdom) , Khandokar, Yogesh (Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia) , Praveena, T. (Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia) , Le Nours, Jé (Infection and Immunity Program, Biomedicine Discovery) , ré , ô , me , Matsuda, Jennifer L. , Rossjohn, Jamie , Gapin, Laurent
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1204 - E1213 , 2018 , 0027-8424 ,

    초록

    Significance Natural killer T (NKT) cells are selected by CD1d molecules in the thymus. Two homologous genes in the mouse genome encode for CD1d proteins. The two CD1d isoforms are not equivalent in their lipid antigen presentation capabilities, affecting the development and the T cell antigen receptor repertoire of NKT cells. MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 diversity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in CD1D1 −/− mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of α-galactosylceramide revealed that its A′-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells.

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  10. [해외논문]   Chemotherapy induces enrichment of CD47+/CD73+/PDL1+ immune evasive triple-negative breast cancer cells   SCI SCIE

    Samanta, Debangshu (McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Park, Youngrok (McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Ni, Xuhao (Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Li, Huili (Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Zahnow, Cynthia A. (Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Gabrielson, Edward (Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Pan, Fan (Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205) , Semenza, Gregg L. (McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1239 - E1248 , 2018 , 0027-8424 ,

    초록

    Significance Cytotoxic chemotherapy is frequently used in patients with triple-negative breast cancer (TNBC). Although patients initially respond to the treatment, the cancer often comes back and kills the patient. Recent studies have demonstrated that cancer cells express genes that protect them from killing by immune cells, but the stimulus that prompts this response is unknown. We show that when TNBC cells are treated with chemotherapy, the surviving cells turn on genes that enable them to escape killing by the immune system. We identify hypoxia-inducible factors (HIFs), which are known to promote metastasis of TNBC, as responsible for this countertherapeutic effect. We show that coadministration of an HIF inhibitor with chemotherapy blocks the ability of surviving TNBC cells to evade the immune system. Triple-negative breast cancer (TNBC) is treated with cytotoxic chemotherapy and is often characterized by early relapse and metastasis. To form a secondary (recurrent and/or metastatic) tumor, a breast cancer cell must evade the innate and adaptive immune systems. CD47 enables cancer cells to evade killing by macrophages, whereas CD73 and PDL1 mediate independent mechanisms of evasion of cytotoxic T lymphocytes. Here, we report that treatment of human or murine TNBC cells with carboplatin, doxorubicin, gemcitabine, or paclitaxel induces the coordinate transcriptional induction of CD47, CD73, and PDL1 mRNA and protein expression, leading to a marked increase in the percentage of CD47 + CD73 + PDL1 + breast cancer cells. Genetic or pharmacological inhibition of hypoxia-inducible factors (HIFs) blocked chemotherapy-induced enrichment of CD47 + CD73 + PDL1 + TNBC cells, which were also enriched in the absence of chemotherapy by incubation under hypoxic conditions, leading to T cell anergy or death. Treatment of mice with cytotoxic chemotherapy markedly increased the intratumoral ratio of regulatory/effector T cells, an effect that was abrogated by HIF inhibition. Our results delineate an HIF-dependent transcriptional mechanism contributing to TNBC progression and suggest that combining chemotherapy with an HIF inhibitor may prevent countertherapeutic induction of proteins that mediate evasion of innate and adaptive antitumor immunity.

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