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

  1. [해외논문]   Correction for Noh et al., ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons   SCI SCIE


    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1329 - E1329 , 2018 , 0027-8424 ,

    초록

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  2. [해외논문]   Correction for Ferrari et al., Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome   SCI SCIE


    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1330 - E1330 , 2018 , 0027-8424 ,

    초록

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  3. [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 (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden) , Westermark, Ulrica Kristina (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden) , Henley, Aine Brigette (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden) , Eyre Sá (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden) , nchez, Elena (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden) , Trager, Catarina (Department of Oncology-Pathology, Karolinska Institutet, SE-171 21 Solna, Sweden) , Johansson, Henrik Johan (Department of Oncology-Pathology, Karolinska Institutet, SE-171 21 Solna, Sweden) , Lehtio, 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.

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  4. [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.

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  5. [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.

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  6. [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 Wurzburg, 97080 Wurzburg, Germany) , Rivas-Castillo, Jennifer (Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, 97080 Wurzburg, Germany) , Kuhn, Kenneth (Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, 97080 Wurzburg, Germany) , Fazeli, Gholamreza (Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, 97080 Wurzburg, Germany) , Karmann, Birgit (Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, 97080 Wurzburg, Germany) , Nance, Jeremy F. (Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016) , Stigloher, Christian (Division of Electron Microscopy, Biocenter, University of Wurzburg, 97074 Wurzburg, Germany ) , Wehman, Ann M. (Rudolf Virchow Center for Experimental Biomedicine, University of Wurzburg, 97080 Wurzburg, Germany;)
    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.

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  7. [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.

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  8. [해외논문]   No strong evidence that authoritarian attitudes are driven by a lack of control   SCI SCIE

    Safra, Lou (Evolution and Social Cognition Group, Laboratoire de Neurosciences Cognitives, Département d'Etudes Cognitives, INSERM U960, Ecole Normale Supéérieure, Universitééé) , Baumard, Nicolas (de Recherche Paris Sciences et Lettres, F-75005 Paris, France) , Chevallier, Coralie (Evolution and Social Cognition Group, Institut Jean Nicod, Déééépartement d'Etudes Cognitives, CNRS UMR8129, Ecole Normale Supééééérieure, Universitéééééé)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1076 - E1077 , 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.

    원문보기

    원문보기
    무료다운로드 유료다운로드

    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.

    이미지

    Fig. 1 이미지
  9. [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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  10. [해외논문]   Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease   SCI SCIE

    Bennett, Rachel E. (Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129) , Robbins, Ashley B. (Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129) , Hu, Miwei (Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129) , Cao, Xinrui (Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115 ) , Betensky, Rebecca A. (Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115 ) , Clark, Tim (Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129) , Das, Sudeshna (Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129) , Hyman, Bradley T. (Department of Neurology)
    Proceedings of the National Academy of Sciences of the United States of America v.115 no.6 ,pp. E1289 - E1298 , 2018 , 0027-8424 ,

    초록

    Significance This work provides evidence that the protein tau induces changes in blood vessels distinct from the effects of amyloid beta on vasculature and indicates a previously unknown pathway by which pathological tau may accelerate cognitive decline in Alzheimer’s disease. Mixed pathology, with both Alzheimer’s disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer’s disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa , Serpine1 , and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain’s microvasculature.

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