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  • 1
    Publication Date: 2011-03-11
    Description: In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095821/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095821/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bock, Davi D -- Lee, Wei-Chung Allen -- Kerlin, Aaron M -- Andermann, Mark L -- Hood, Greg -- Wetzel, Arthur W -- Yurgenson, Sergey -- Soucy, Edward R -- Kim, Hyon Suk -- Reid, R Clay -- EY10115/EY/NEI NIH HHS/ -- EY18532/EY/NEI NIH HHS/ -- EY18742/EY/NEI NIH HHS/ -- F32 EY018532/EY/NEI NIH HHS/ -- F32 EY018532-01A1/EY/NEI NIH HHS/ -- P41 RR06009/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Mar 10;471(7337):177-82. doi: 10.1038/nature09802.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390124" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium Signaling ; Interneurons/physiology ; Male ; Mice ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Microtomy ; Nerve Net/*anatomy & histology/*cytology/physiology/ultrastructure ; Neural Inhibition/physiology ; Neurons/*physiology/ultrastructure ; Pyramidal Cells/physiology/ultrastructure ; Synapses/physiology ; Visual Cortex/*anatomy & histology/*cytology/physiology/ultrastructure
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-07-12
    Description: Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases. Although numerous probiotic microorganisms have been identified, there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4(+)FOXP3(+) regulatory T (Treg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in Treg-cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing Treg cell abundance and inducing important anti-inflammatory molecules--including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)--in Treg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-beta-rich environment to help expansion and differentiation of Treg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Atarashi, Koji -- Tanoue, Takeshi -- Oshima, Kenshiro -- Suda, Wataru -- Nagano, Yuji -- Nishikawa, Hiroyoshi -- Fukuda, Shinji -- Saito, Takuro -- Narushima, Seiko -- Hase, Koji -- Kim, Sangwan -- Fritz, Joelle V -- Wilmes, Paul -- Ueha, Satoshi -- Matsushima, Kouji -- Ohno, Hiroshi -- Olle, Bernat -- Sakaguchi, Shimon -- Taniguchi, Tadatsugu -- Morita, Hidetoshi -- Hattori, Masahira -- Honda, Kenya -- England -- Nature. 2013 Aug 8;500(7461):232-6. doi: 10.1038/nature12331. Epub 2013 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23842501" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Cell Proliferation ; Clostridium/classification/genetics/*immunology ; Colitis/microbiology/pathology ; Colon/immunology/microbiology ; Disease Models, Animal ; Feces/microbiology ; Germ-Free Life ; Humans ; Inducible T-Cell Co-Stimulator Protein/metabolism ; Interleukin-10/metabolism ; Male ; Metagenome/genetics/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, SCID ; RNA, Ribosomal, 16S/genetics ; Rats ; Rats, Inbred F344 ; T-Lymphocytes, Regulatory/cytology/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-12-20
    Description: Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ariey, Frederic -- Witkowski, Benoit -- Amaratunga, Chanaki -- Beghain, Johann -- Langlois, Anne-Claire -- Khim, Nimol -- Kim, Saorin -- Duru, Valentine -- Bouchier, Christiane -- Ma, Laurence -- Lim, Pharath -- Leang, Rithea -- Duong, Socheat -- Sreng, Sokunthea -- Suon, Seila -- Chuor, Char Meng -- Bout, Denis Mey -- Menard, Sandie -- Rogers, William O -- Genton, Blaise -- Fandeur, Thierry -- Miotto, Olivo -- Ringwald, Pascal -- Le Bras, Jacques -- Berry, Antoine -- Barale, Jean-Christophe -- Fairhurst, Rick M -- Benoit-Vical, Francoise -- Mercereau-Puijalon, Odile -- Menard, Didier -- 090770/Z/09/Z/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- G0600718/Medical Research Council/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2014 Jan 2;505(7481):50-5. doi: 10.1038/nature12876. Epub 2013 Dec 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unite de Recherche Associee 2581, 75724 Paris Cedex 15, France [3] Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Sante et de la Recherche Medicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Universite Toulouse III, 31024 Toulouse Cedex 3, France Institut Pasteur, Unite de Biologie et Genetique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.). ; Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia. ; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unite de Recherche Associee 2581, 75724 Paris Cedex 15, France. ; Institut Pasteur, Plate-forme Genomique, Departement Genomes et Genetique, 75724 Paris Cedex 15, France. ; 1] Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia [2] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [3] National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. ; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. ; SSA WHO, Drug Monitoring in Cambodia, National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. ; 1] Service de Parasitologie et Mycologie, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse Cedex 9, France [2] Institut Pasteur, Genetics and Genomics of Insect Vectors Unit, 75724 Paris Cedex 15, France (F.A.); Institut Pasteur, Functional Genetics of Infectious Diseases Unit, 75724 Paris Cedex 15, France (J.B.); Centre de Physiopathologie de Toulouse-Purpan, Institut National de la Sante et de la Recherche Medicale UMR1043, Centre National de la Recherche Scientifique UMR5282, Universite Toulouse III, 31024 Toulouse Cedex 3, France Institut Pasteur, Unite de Biologie et Genetique du Paludisme, Team Malaria Targets and Drug Development, 75724 Paris Cedex 15, France (J.-C.B.). ; Naval Medical Research Unit #2 Detachment, Phnom Penh, Cambodia. ; Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland. ; 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia. ; 1] MRC Centre for Genomics and Global Health, University of Oxford, Oxford OX3 7BN, UK [2] Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok 10400, Thailand [3] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; Global Malaria Program, World Health Organization, 1211 Geneva, Switzerland. ; Centre National de Reference du Paludisme, CHU Bichat-Claude Bernard, APHP, PRES Sorbonne Paris Cite, 75018 Paris, France. ; 1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2]. ; 1] Centre National de la Recherche Scientifique, Laboratoire de Chimie de Coordination UPR8241, 31077 Toulouse Cedex 4, France [2] Universite de Toulouse, UPS, Institut National Polytechnique de Toulouse, 31077 Toulouse Cedex 4, France [3]. ; 1] Institut Pasteur, Parasite Molecular Immunology Unit, 75724 Paris Cedex 15, France [2] Centre National de la Recherche Scientifique, Unite de Recherche Associee 2581, 75724 Paris Cedex 15, France [3]. ; 1] Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24352242" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Antimalarials/*pharmacology ; Artemisinins/*pharmacology ; Blood Cells/parasitology ; Cambodia ; Drug Resistance/drug effects/*genetics ; Genetic Markers/genetics ; Half-Life ; Humans ; Malaria, Falciparum/drug therapy/*parasitology ; Mutation/genetics ; Parasitic Sensitivity Tests ; Plasmodium falciparum/*drug effects/*genetics/growth & development/isolation & ; purification ; Polymorphism, Single Nucleotide/genetics ; Protein Structure, Tertiary/genetics ; Protozoan Proteins/chemistry/*genetics ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-02-25
    Description: V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Min-Sung -- Lapkouski, Mikalai -- Yang, Wei -- Gellert, Martin -- Z01 DK036147-01/Intramural NIH HHS/ -- Z01 DK036147-02/Intramural NIH HHS/ -- Z01 DK036167-01/Intramural NIH HHS/ -- Z01 DK036167-02/Intramural NIH HHS/ -- ZIA DK036147-03/Intramural NIH HHS/ -- ZIA DK036147-04/Intramural NIH HHS/ -- ZIA DK036147-05/Intramural NIH HHS/ -- ZIA DK036147-06/Intramural NIH HHS/ -- ZIA DK036147-07/Intramural NIH HHS/ -- ZIA DK036147-08/Intramural NIH HHS/ -- ZIA DK036167-03/Intramural NIH HHS/ -- ZIA DK036167-04/Intramural NIH HHS/ -- ZIA DK036167-05/Intramural NIH HHS/ -- ZIA DK036167-06/Intramural NIH HHS/ -- ZIA DK036167-07/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):507-11. doi: 10.1038/nature14174. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707801" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Homeodomain Proteins/*chemistry/genetics/metabolism ; Humans ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Multimerization ; Protein Structure, Quaternary ; Severe Combined Immunodeficiency/genetics ; Transposases/chemistry ; VDJ Recombinases/*chemistry/metabolism ; X-Linked Combined Immunodeficiency Diseases/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-07-07
    Description: Microbial populations stochastically generate variants with strikingly different properties, such as virulence or avirulence and antibiotic tolerance or sensitivity. Photorhabdus luminescens bacteria have a variable life history in which they alternate between pathogens to a wide variety of insects and mutualists to their specific host nematodes. Here, we show that the P. luminescens pathogenic variant (P form) switches to a smaller-cell variant (M form) to initiate mutualism in host nematode intestines. A stochastic promoter inversion causes the switch between the two distinct forms. M-form cells are much smaller (one-seventh the volume), slower growing, and less bioluminescent than P-form cells; they are also avirulent and produce fewer secondary metabolites. Observations of form switching by individual cells in nematodes revealed that the M form persisted in maternal nematode intestines, were the first cells to colonize infective juvenile (IJ) offspring, and then switched to P form in the IJ intestine, which armed these nematodes for the next cycle of insect infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006969/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Somvanshi, Vishal S -- Sloup, Rudolph E -- Crawford, Jason M -- Martin, Alexander R -- Heidt, Anthony J -- Kim, Kwi-suk -- Clardy, Jon -- Ciche, Todd A -- 1K99 GM097096-01/GM/NIGMS NIH HHS/ -- K99 GM097096/GM/NIGMS NIH HHS/ -- R00 GM097096/GM/NIGMS NIH HHS/ -- R01 GM086258/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2012 Jul 6;337(6090):88-93. doi: 10.1126/science.1216641.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22767929" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Fimbriae Proteins/genetics ; Gene Expression Regulation, Bacterial ; Genome, Bacterial ; Intestines/microbiology ; Moths/*microbiology ; Mutation ; Phenotype ; Photorhabdus/cytology/*genetics/growth & development/*pathogenicity ; *Promoter Regions, Genetic ; Rhabditoidea/*microbiology ; *Sequence Inversion ; *Symbiosis ; Virulence/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2011-08-16
    Description: CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T(H)2 cytokine-mediated inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263308/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263308/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siracusa, Mark C -- Saenz, Steven A -- Hill, David A -- Kim, Brian S -- Headley, Mark B -- Doering, Travis A -- Wherry, E John -- Jessup, Heidi K -- Siegel, Lori A -- Kambayashi, Taku -- Dudek, Emily C -- Kubo, Masato -- Cianferoni, Antonella -- Spergel, Jonathan M -- Ziegler, Steven F -- Comeau, Michael R -- Artis, David -- AI083480/AI/NIAID NIH HHS/ -- AI61570/AI/NIAID NIH HHS/ -- AI74878/AI/NIAID NIH HHS/ -- AI87990/AI/NIAID NIH HHS/ -- F31 GM082187/GM/NIGMS NIH HHS/ -- F32 AI085828/AI/NIAID NIH HHS/ -- R01 AI061570/AI/NIAID NIH HHS/ -- R01 AI061570-09/AI/NIAID NIH HHS/ -- R01 AI074878/AI/NIAID NIH HHS/ -- R01 AI074878-05/AI/NIAID NIH HHS/ -- R01 AI095466/AI/NIAID NIH HHS/ -- R01 AI095466-02/AI/NIAID NIH HHS/ -- R01 HL107589/HL/NHLBI NIH HHS/ -- R21 AI083480/AI/NIAID NIH HHS/ -- R21 AI083480-02/AI/NIAID NIH HHS/ -- T32 AI060516/AI/NIAID NIH HHS/ -- U01 AI095608/AI/NIAID NIH HHS/ -- U01 AI095608-02/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 14;477(7363):229-33. doi: 10.1038/nature10329.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21841801" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asthma/immunology ; Basophils/*cytology/metabolism ; Cytokines/genetics/immunology/*metabolism ; Dermatitis, Atopic/immunology ; Food Hypersensitivity/immunology ; *Hematopoiesis ; Humans ; Hypersensitivity, Immediate/*immunology ; Inflammation/*immunology/*metabolism ; *Interleukin-3/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Phenotype ; Receptors, Cytokine/metabolism ; Receptors, Interleukin-3/deficiency/genetics/metabolism ; Th2 Cells/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-05-09
    Description: How does the mammalian retina detect motion? This classic problem in visual neuroscience has remained unsolved for 50 years. In search of clues, here we reconstruct Off-type starburst amacrine cells (SACs) and bipolar cells (BCs) in serial electron microscopic images with help from EyeWire, an online community of 'citizen neuroscientists'. On the basis of quantitative analyses of contact area and branch depth in the retina, we find evidence that one BC type prefers to wire with a SAC dendrite near the SAC soma, whereas another BC type prefers to wire far from the soma. The near type is known to lag the far type in time of visual response. A mathematical model shows how such 'space-time wiring specificity' could endow SAC dendrites with receptive fields that are oriented in space-time and therefore respond selectively to stimuli that move in the outward direction from the soma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074887/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074887/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jinseop S -- Greene, Matthew J -- Zlateski, Aleksandar -- Lee, Kisuk -- Richardson, Mark -- Turaga, Srinivas C -- Purcaro, Michael -- Balkam, Matthew -- Robinson, Amy -- Behabadi, Bardia F -- Campos, Michael -- Denk, Winfried -- Seung, H Sebastian -- EyeWirers -- R01 NS076467/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 15;509(7500):331-6. doi: 10.1038/nature13240. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Brain & Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2]. ; Electrical Engineering and Computer Science Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Brain & Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Brain & Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] 601 N 42nd Street, Seattle, Washington 98103, USA (M.R.); Princeton Neuroscience Institute and Computer Science Deptartment, Princeton, New Jersey 08544, USA (H.S.S.); Gatsby Computational Neuroscience Unit, London WC1N 3AR, UK (S.C.T.). ; Qualcomm Research, 5775 Morehouse Drive, San Diego, California 92121, USA. ; Max-Planck Institute for Medical Research, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805243" target="_blank"〉PubMed〈/a〉
    Keywords: Amacrine Cells/cytology/physiology/ultrastructure ; Animals ; Artificial Intelligence ; *Brain Mapping ; Crowdsourcing ; Dendrites/metabolism ; Mice ; *Models, Neurological ; Motion ; Neural Pathways/*physiology ; Presynaptic Terminals/metabolism ; Retina/*cytology/*physiology ; Retinal Bipolar Cells/cytology/physiology/ultrastructure ; *Spatio-Temporal Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2013-06-04
    Description: Rev-Erb-alpha and Rev-Erb-beta are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Michael T Y -- Cho, Han -- Lesch, Hanna P -- Gosselin, David -- Heinz, Sven -- Tanaka-Oishi, Yumiko -- Benner, Christopher -- Kaikkonen, Minna U -- Kim, Aneeza S -- Kosaka, Mika -- Lee, Cindy Y -- Watt, Andy -- Grossman, Tamar R -- Rosenfeld, Michael G -- Evans, Ronald M -- Glass, Christopher K -- CA014195/CA/NCI NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- CA52599/CA/NCI NIH HHS/ -- DK057978/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- HL088093/HL/NHLBI NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 HL088093/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA052599/CA/NCI NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- T32 GM007198-37/GM/NIGMS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19DK62434/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 27;498(7455):511-5. doi: 10.1038/nature12209. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728303" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Base Sequence ; Binding Sites ; Down-Regulation/*genetics ; Enhancer Elements, Genetic/*genetics ; Gene Knockdown Techniques ; Macrophages/*metabolism ; Mice ; Nuclear Receptor Subfamily 1, Group D, Member 1/deficiency/genetics/*metabolism ; Organ Specificity ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics/metabolism ; Response Elements/genetics ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2013-03-15
    Description: Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regulates centriole duplication while restricting centriole elongation and ciliogenesis. Maintenance of normal CP110 levels is essential, as excessive CP110 drives centrosome over-duplication and suppresses ciliogenesis, whereas its depletion inhibits centriole amplification and leads to highly elongated centrioles and aberrant assembly of cilia in growing cells. CP110 levels are tightly controlled, partly through ubiquitination by the ubiquitin ligase complex SCF(cyclin F) during G2 and M phases of the cell cycle. Here, using human cells, we report a new mechanism for the regulation of centrosome duplication that requires USP33, a deubiquitinating enzyme that is able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily in S and G2/M phases, the periods during which centrioles duplicate and elongate. USP33 potently and specifically deubiquitinates CP110, but not other cyclin-F substrates. USP33 activity antagonizes SCF(cyclin F)-mediated ubiquitination and promotes the generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, we have identified the first centriolar deubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin-F-mediated destruction of a key substrate. Our results point towards potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815529/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815529/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ji -- D'Angiolella, Vincenzo -- Seeley, E Scott -- Kim, Sehyun -- Kobayashi, Tetsuo -- Fu, Wenxiang -- Campos, Eric I -- Pagano, Michele -- Dynlacht, Brian David -- 5R01HD069647-02/HD/NICHD NIH HHS/ -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01 HD069647/HD/NICHD NIH HHS/ -- R37 CA076584/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Mar 14;495(7440):255-9. doi: 10.1038/nature11941.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, 522 1st Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23486064" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle ; Cell Cycle Proteins/*metabolism ; Cell Line ; Centrioles/metabolism ; Centrosome/*metabolism ; Cyclins/metabolism ; Homeostasis ; Humans ; Microtubule-Associated Proteins/*metabolism ; Neoplasms/pathology/therapy ; Phosphoproteins/*metabolism ; Protein Stability ; SKP Cullin F-Box Protein Ligases/metabolism ; Ubiquitin Thiolesterase/*metabolism ; *Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-07-23
    Description: Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5-40-microm long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777791/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777791/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Tsai-Wen -- Wardill, Trevor J -- Sun, Yi -- Pulver, Stefan R -- Renninger, Sabine L -- Baohan, Amy -- Schreiter, Eric R -- Kerr, Rex A -- Orger, Michael B -- Jayaraman, Vivek -- Looger, Loren L -- Svoboda, Karel -- Kim, Douglas S -- T32 GM008042/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 18;499(7458):295-300. doi: 10.1038/nature12354.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23868258" target="_blank"〉PubMed〈/a〉
    Keywords: *Action Potentials ; Animals ; Calcium/metabolism ; Calcium-Binding Proteins/*chemistry/genetics ; Cells, Cultured ; Dendritic Spines/metabolism ; Fluorescent Dyes/*chemistry ; GABAergic Neurons/metabolism ; Luminescent Proteins/*chemistry/genetics ; Mice ; Molecular Imaging ; Mutagenesis ; Protein Engineering ; Pyramidal Cells/metabolism/physiology ; Visual Cortex/cytology/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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