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Sample records for human anaphase-promoting complex-cdh1

  1. RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex

    PubMed Central

    Brown, Nicholas G.; VanderLinden, Ryan; Watson, Edmond R.; Qiao, Renping; Grace, Christy R. R.; Yamaguchi, Masaya; Weissmann, Florian; Frye, Jeremiah J.; Dube, Prakash; Ei Cho, Shein; Actis, Marcelo L.; Rodrigues, Patrick; Fujii, Naoaki; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A.

    2015-01-01

    For many E3 ligases, a mobile RING (Really Interesting New Gene) domain stimulates ubiquitin (Ub) transfer from a thioester-linked E2∼Ub intermediate to a lysine on a remotely bound disordered substrate. One such E3 is the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), which controls cell division by ubiquitinating cell cycle regulators to drive their timely degradation. Intrinsically disordered substrates are typically recruited via their KEN-box, D-box, and/or other motifs binding to APC and a coactivator such as CDH1. On the opposite side of the APC, the dynamic catalytic core contains the cullin-like subunit APC2 and its RING partner APC11, which collaborates with the E2 UBCH10 (UBE2C) to ubiquitinate substrates. However, how dynamic RING–E2∼Ub catalytic modules such as APC11–UBCH10∼Ub collide with distally tethered disordered substrates remains poorly understood. We report structural mechanisms of UBCH10 recruitment to APCCDH1 and substrate ubiquitination. Unexpectedly, in addition to binding APC11’s RING, UBCH10 is corecruited via interactions with APC2, which we visualized in a trapped complex representing an APCCDH1–UBCH10∼Ub–substrate intermediate by cryo-electron microscopy, and in isolation by X-ray crystallography. To our knowledge, this is the first structural view of APC, or any cullin–RING E3, with E2 and substrate juxtaposed, and it reveals how tripartite cullin–RING–E2 interactions establish APC’s specificity for UBCH10 and harness a flexible catalytic module to drive ubiquitination of lysines within an accessible zone. We propose that multisite interactions reduce the degrees of freedom available to dynamic RING E3–E2∼Ub catalytic modules, condense the search radius for target lysines, increase the chance of active-site collision with conformationally fluctuating substrates, and enable regulation. PMID:25825779

  2. Human Papillomavirus Type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis

    PubMed Central

    Yu, Yueyang; Munger, Karl

    2013-01-01

    The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase complex that orchestrates mitotic progression by targeting key mitotic regulators for proteasomal degradation. APC/C dysfunction is a frequent event during cancer development and can give rise to genomic instability. Here we report that the HPV16 E7 oncoprotein interferes with the degradation of APC/C substrates and that the APC/C inhibitor, EMI1, is expressed at higher levels in HPV16 E7-expressing mitotic cells. HPV16 E7 expression causes increased EMI1 mRNA expression and also inhibits EMI1 degradation. The resulting abnormally high EMI1 levels in HPV16 E7-expressing mitotic cells may inhibit degradation of APC/C substrates and cause the prometaphase delay that we have previously observed in such cells. PMID:24074588

  3. Molecular architecture and mechanism of the anaphase-promoting complex

    PubMed Central

    Yang, Jing; McLaughlin, Stephen H.; Barford, David

    2015-01-01

    The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of G1. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C – substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-EM reconstruction of a human APC/C-coactivator-substrate complex at 7.4 Å resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that coactivator promotes a profound allosteric transition involving displacement of the cullin-RING catalytic subunits relative to the degron recognition module of coactivator and Apc10. This transition is accompanied by increased flexibility of the cullin-RING subunits and enhanced affinity for UbcH10~ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity. PMID:25043029

  4. The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior in C. elegans

    PubMed Central

    Wang, Julia; Jennings, Alexandra K.

    2016-01-01

    The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation in Caenorhabditis elegans by testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted. Animals with loss of function mutations in either of two alleles (g48 and ye143) of the gene encoding the APC subunit EMB-27 APC6 showed increased chemotaxis towards diacetyl and pyrazine, odorants sensed by AWA neurons, but exhibited normal chemotaxis to isoamyl alcohol, which is sensed by AWC neurons. The statistically significant increase in chemotaxis in the emb-27 APC6 mutants suggests that the APC inhibits AWA-mediated chemosensation in C. elegans. Increased chemotaxis to pyrazine was also seen with mutants lacking another essential APC subunit, MAT-2 APC1; however, mat-2 APC1 mutants exhibited wild type responses to diacetyl. The difference in responsiveness of these two APC subunit mutants may be due to differential strength of these hypomorphic alleles or may indicate the presence of functional sub-complexes of the APC at work in this process. These findings are the first evidence for APC-mediated regulation of chemosensation and lay the groundwork for further studies aimed at identifying the expression levels, function, and targets of the APC in specific sensory neurons. Because of the similarity between human and C. elegans nervous systems, the role of the APC in sensory neurons may also advance our understanding of human sensory function and disease. PMID

  5. The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior in C. elegans.

    PubMed

    Wang, Julia; Jennings, Alexandra K; Kowalski, Jennifer R

    2016-01-01

    The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation in Caenorhabditis elegans by testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted. Animals with loss of function mutations in either of two alleles (g48 and ye143) of the gene encoding the APC subunit EMB-27 APC6 showed increased chemotaxis towards diacetyl and pyrazine, odorants sensed by AWA neurons, but exhibited normal chemotaxis to isoamyl alcohol, which is sensed by AWC neurons. The statistically significant increase in chemotaxis in the emb-27 APC6 mutants suggests that the APC inhibits AWA-mediated chemosensation in C. elegans. Increased chemotaxis to pyrazine was also seen with mutants lacking another essential APC subunit, MAT-2 APC1; however, mat-2 APC1 mutants exhibited wild type responses to diacetyl. The difference in responsiveness of these two APC subunit mutants may be due to differential strength of these hypomorphic alleles or may indicate the presence of functional sub-complexes of the APC at work in this process. These findings are the first evidence for APC-mediated regulation of chemosensation and lay the groundwork for further studies aimed at identifying the expression levels, function, and targets of the APC in specific sensory neurons. Because of the similarity between human and C. elegans nervous systems, the role of the APC in sensory neurons may also advance our understanding of human sensory function and disease. PMID

  6. Functional Redundancy of Paralogs of an Anaphase Promoting Complex/Cyclosome Subunit in Caenorhabditis elegans Meiosis

    PubMed Central

    Stein, Kathryn K.; Nesmith, Jessica E.; Ross, Benjamin D.; Golden, Andy

    2010-01-01

    The anaphase promoting complex/cyclosome (APC/C) mediates the metaphase-to-anaphase transition by instructing the ubiquitination and turnover of key proteins at this stage of the cell cycle. We have recovered a gain-of-function allele in an APC5 subunit of the anaphase promoting complex/cyclosome. This finding led us to investigate further the role of APC5 in Caenorhabditis elegans, which contains two APC5 paralogs. We have shown that these two paralogs, such-1 and gfi-3, are coexpressed in the germline but have nonoverlapping expression patterns in other tissues. Depletion of such-1 or gfi-3 alone does not have a notable effect on the meiotic divisions; however, codepletion of these two factors results in meiotic arrest. In sum, the two C. elegans APC5 paralogs have a redundant function during the meiotic divisions. PMID:20944012

  7. Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells

    PubMed Central

    Lub, Susanne; Maes, Anke; Maes, Ken; De Veirman, Kim; De Bruyne, Elke; Menu, Eline; Fostier, Karel; Kassambara, Alboukadel; Moreaux, Jérôme; Hose, Dirk; Leleu, Xavier; King, Randall W.

    2016-01-01

    The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase involved in cell cycle. During the metaphase-anaphase transition the APC/C is activated by Cdc20. The aim of this study is to elucidate the importance and therapeutic potential of APC/C and its co-activator Cdc20 in multiple myeloma (MM). Gene expression analysis revealed that Cdc20 was expressed at higher levels in gene expression-based high-risk MM patients. Moreover, high Cdc20 expression correlated with poor prognosis. Treatment of human myeloma cell lines with proTAME, an APC/C inhibitor, resulted in an accumulation of APC/CCdc20 substrate cyclin B1 and an accumulation of cells in metaphase. Moreover we observed a significant dose-dependent decrease in viability and increase in apoptosis in MM cells upon proTAME treatment. The induction of apoptosis was accompanied with caspase 3, 8, 9 and PARP cleavage. A similar metaphase arrest and induction of apoptosis were obtained with specific knockdown of Cdc20. In addition, we demonstrated the accumulation of Bim was partially responsible for the observed cell death. Combining proTAME with another APC/C inhibitor apcin or the alkylating agent melphalan resulted in enhanced anti-MM activity. This study suggests that the APC/C and its co-activator Cdc20 could be a new and promising target especially in high-risk MM patients. PMID:26716651

  8. Structure of an APC3-APC16 complex: Insights into assembly of the Anaphase Promoting Complex/Cyclosome

    PubMed Central

    Yamaguchi, Masaya; Yu, Shanshan; Qiao, Renping; Weissmann, Florian; Miller, Darcie J.; VanderLinden, Ryan; Brown, Nicholas G.; Frye, Jeremiah J.; Peters, Jan-Michael; Schulman, Brenda A.

    2015-01-01

    The Anaphase Promoting Complex/Cyclosome (APC/C) is a massive E3 ligase that controls mitosis by catalyzing ubiquitination of key cell cycle regulatory proteins. The APC/C assembly contains two subcomplexes: the “Platform” centers around a cullin-RING-like E3 ligase catalytic core; the “Arc Lamp” is a hub that mediates transient association with regulators and ubiquitination substrates. The Arc Lamp contains the small subunits APC16, CDC26, and APC13, and tetratricopeptide repeat (TPR) proteins (APC7, APC3, APC6, and APC8) that homodimerize and stack with quasi-twofold symmetry. Within the APC/C complex, APC3 serves as center for regulation. APC3’s TPR motifs recruit substrate-binding coactivators, CDC20 and CDH1, via their C-terminal conserved Ile-Arg (IR) tail sequences. Human APC3 also binds APC16 and APC7, and contains a >200-residue loop that is heavily phosphorylated during mitosis, although the basis for APC3 interactions and whether loop phosphorylation is required for ubiquitination are unclear. Here, we map the basis for human APC3 assembly with APC16 and APC7, report crystal structures of APC3Δloop alone and in complex with the C-terminal domain of APC16, and test roles of APC3’s loop and IR-tail binding surfaces in APC/C-catalyzed ubiquitination. The structures show how one APC16 binds asymmetrically to the symmetric APC3 dimer, and together with biochemistry and prior data explain how APC16 recruits APC7 to APC3, show how APC3’s C-terminal domain is rearranged in the full APC/C assembly, and visualize residues in the IR-tail binding cleft important for coactivator-dependent ubiquitination. Overall, the results provide insights into assembly, regulation, and interactions of TPR proteins and the APC/C. PMID:25490258

  9. Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN

    SciTech Connect

    Stroschein, Shannon L.; Bonni, Shirin; Wrana, Jeffrey L.; Luo, Kunxin

    2001-09-11

    Smad proteins mediate transforming growth factor-b signaling to regulate cell growth and differentiation. SnoN is an important negative regulator of TGFb signaling that functions to maintain the repressed state of TGFb target genes in the absence of ligand. Upon TGFb stimulation, Smad3 and Smad2 translocate into the nucleus and induce a rapid degradation of SnoN, allowing activation of TGFb target genes. Here we show that Smad2- or Smad3-induced degradation of SnoN requires the ubiquitin-dependent proteasome and can be mediated by the anaphase promoting complex (APC) and the UbcH5 family of ubiquitin conjugating enzymes. Smad3 and to a lesser extent, Smad2, interact with both the APC and SnoN, resulting in the recruitment of the APC to SnoN and subsequent ubiquitination of SnoN in a destruction box-dependent manner. In addition to the destruction box, efficient degradation of SnoN also requires the Smad3 binding site in SnoN as well as key lysine residues necessary for ubiquitin attachment. Mutation of either the Smad3 binding site or lysine residues results in stabilization of SnoN and in enhanced antagonism of TGFb signaling. Our studies elucidate an important pathway for the degradation of SnoN and reveal a novel role of the APC in regulation of TGFb signaling.

  10. Building a pseudo-atomic model of the anaphase-promoting complex

    SciTech Connect

    Kulkarni, Kiran; Zhang, Ziguo; Chang, Leifu; Yang, Jing; Fonseca, Paula C. A. da; Barford, David

    2013-11-01

    This article describes an example of molecular replacement in which atomic models are used to interpret electron-density maps determined using single-particle electron-microscopy data. The anaphase-promoting complex (APC/C) is a large E3 ubiquitin ligase that regulates progression through specific stages of the cell cycle by coordinating the ubiquitin-dependent degradation of cell-cycle regulatory proteins. Depending on the species, the active form of the APC/C consists of 14–15 different proteins that assemble into a 20-subunit complex with a mass of approximately 1.3 MDa. A hybrid approach of single-particle electron microscopy and protein crystallography of individual APC/C subunits has been applied to generate pseudo-atomic models of various functional states of the complex. Three approaches for assigning regions of the EM-derived APC/C density map to specific APC/C subunits are described. This information was used to dock atomic models of APC/C subunits, determined either by protein crystallography or homology modelling, to specific regions of the APC/C EM map, allowing the generation of a pseudo-atomic model corresponding to 80% of the entire complex.

  11. Structural basis for the subunit assembly of the anaphase-promoting complex.

    PubMed

    Schreiber, Anne; Stengel, Florian; Zhang, Ziguo; Enchev, Radoslav I; Kong, Eric H; Morris, Edward P; Robinson, Carol V; da Fonseca, Paula C A; Barford, David

    2011-02-10

    The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates. PMID:21307936

  12. Spatial Regulation of the Spindle Assembly Checkpoint and Anaphase Promoting Complex in Aspergillus nidulans

    PubMed Central

    Edgerton, Heather; Paolillo, Vitoria; Oakley, Berl R.

    2014-01-01

    Summary The spindle assembly checkpoint (SAC) plays a critical role in preventing mitotic errors by inhibiting anaphase until all kinetochores are correctly attached to spindle microtubules. In spite of the economic and medical importance of filamentous fungi, relatively little is known about the behavior of SAC proteins in these organisms. In our efforts to understand the role of γ-tubulin in cell cycle regulation, we have created functional fluorescent protein fusions of four SAC proteins in Aspergillus nidulans, the homologs of Mad2, Mps1, Bub1/BubR1 and Bub3. Time-lapse imaging reveals that SAC proteins are in distinct compartments of the cell until early mitosis when they co-localize at the spindle pole body. SAC activity is, thus, spatially regulated in A. nidulans. Likewise, Cdc20, an activator of the anaphase promoting complex/cyclosome, is excluded from interphase nuclei, but enters nuclei at mitotic onset and accumulates to a higher level in mitotic nuclei than in the surrounding nucleoplasm before leaving in anaphase/telophase. The activity of this critical cell cycle regulatory complex is likely regulated by the location of Cdc20. Finally, the γ-tubulin mutation mipAD159 causes a nuclear-specific failure of nuclear localization of Mps1 and Bub1/R1 but not of Cdc20, Bub3 or Mad2. PMID:25417844

  13. Inhibitory factors associated with anaphase-promoting complex/cylosome in mitotic checkpoint

    PubMed Central

    Braunstein, Ilana; Miniowitz, Shirly; Moshe, Yakir; Hershko, Avram

    2007-01-01

    The mitotic (or spindle assembly) checkpoint system ensures accurate chromosome segregation by preventing anaphase initiation until all chromosomes are correctly attached to the mitotic spindle. It affects the activity of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets inhibitors of anaphase initiation for degradation. The mechanisms by which this system regulates APC/C remain obscure. Some models propose that the system promotes sequestration of the APC/C activator Cdc20 by binding to the checkpoint proteins Mad2 and BubR1. A different model suggests that a mitotic checkpoint complex (MCC) composed of BubR1, Bub3, Cdc20, and Mad2 inhibits APC/C in mitotic checkpoint [Sudakin V, Chan GKT, Yen TJ (2001) J Cell Biol 154:925–936]. We examined this problem by using extracts from nocodazole-arrested cells that reproduce some downstream events of the mitotic checkpoint system, such as lag kinetics of the degradation of APC/C substrate. Incubation of extracts with adenosine-5′-(γ-thio)triphosphate (ATP[γS]) stabilized the checkpoint-arrested state, apparently by stable thiophosphorylation of some proteins. By immunoprecipitation of APC/C from stably checkpoint-arrested extracts, followed by elution with increased salt concentration, we isolated inhibitory factors associated with APC/C. A part of the inhibitory material consists of Cdc20 associated with BubR1 and Mad2, and is thus similar to MCC. Contrary to the original MCC hypothesis, we find that MCC disassembles upon exit from the mitotic checkpoint. Thus, the requirement of the mitotic checkpoint system for the binding of Mad2 and BubR1 to Cdc20 may be for the assembly of the inhibitory complex rather than for Cdc20 sequestration. PMID:17360335

  14. Overexpression of the Arabidopsis anaphase promoting complex subunit CDC27a increases growth rate and organ size.

    PubMed

    Rojas, Cristian Antonio; Eloy, Nubia Barbosa; Lima, Marcelo de Freitas; Rodrigues, Roberta Lopes; Franco, Luciana Ozório; Himanen, Kristiina; Beemster, Gerrit T S; Hemerly, Adriana Silva; Ferreira, Paulo Cavalcanti Gomes

    2009-10-01

    The Anaphase Promoting Complex (APC) controls CDK activity by targeting the ubiquitin-dependent proteolysis of S-phase and mitosis-promoting cyclins. Here, we report that the ectopic expression of the Arabidopsis CDC27a, an APC subunit, accelerates plant growth and results in plants with increased biomass production. CDC27a overexpression was associated to apical meristem restructuration, protoplasts with higher (3)H-thimidine incorporation and altered cell-cycle marker expression. Total protein extracts immunoprecipitated with a CDC27a antibody showed ubiquitin ligase activity, indicating that the Arabidopsis CDC27a gets incorporated into APC complexes. These results indicate a role of AtCDC27a in regulation of plant growth and raise the possibility that the activity of the APC and the rates of plant cell division could be regulated by the concentration of the CDC27a subunit. PMID:19629716

  15. Structure of an APC3–APC16 Complex: Insights into Assembly of the Anaphase-Promoting Complex/Cyclosome

    SciTech Connect

    Yamaguchi, Masaya; Yu, Shanshan; Qiao, Renping; Weissmann, Florian; Miller, Darcie J.; VanderLinden, Ryan; Brown, Nicholas G.; Frye, Jeremiah J.; Peters, Jan-Michael; Schulman, Brenda A.

    2015-08-21

    The anaphase-promoting complex/cyclosome (APC/C) is a massive E3 ligase that controls mitosis by catalyzing ubiquitination of key cell cycle regulatory proteins. The APC/C assembly contains two subcomplexes: the “Platform” centers around a cullin-RING-like E3 ligase catalytic core; the “Arc Lamp” is a hub that mediates transient association with regulators and ubiquitination substrates. The Arc Lamp contains the small subunits APC16, CDC26, and APC13, and tetratricopeptide repeat (TPR) proteins (APC7, APC3, APC6, and APC8) that homodimerize and stack with quasi-2-fold symmetry. Within the APC/C complex, APC3 serves as center for regulation. APC3's TPR motifs recruit substrate-binding coactivators, CDC20 and CDH1, via their C-terminal conserved Ile-Arg (IR) tail sequences. Human APC3 also binds APC16 and APC7 and contains a > 200-residue loop that is heavily phosphorylated during mitosis, although the basis for APC3 interactions and whether loop phosphorylation is required for ubiquitination are unclear. Here, we map the basis for human APC3 assembly with APC16 and APC7, report crystal structures of APC3Δloop alone and in complex with the C-terminal domain of APC16, and test roles of APC3's loop and IR tail binding surfaces in APC/C-catalyzed ubiquitination. The structures show how one APC16 binds asymmetrically to the symmetric APC3 dimer and, together with biochemistry and prior data, explain how APC16 recruits APC7 to APC3, show how APC3's C-terminal domain is rearranged in the full APC/C assembly, and visualize residues in the IR tail binding cleft important for coactivator-dependent ubiquitination. Overall, the results provide insights into assembly, regulation, and interactions of TPR proteins and the APC/C.

  16. Histone H2B Ubiquitination Promotes the Function of the Anaphase-Promoting Complex/Cyclosome in Schizosaccharomyces pombe

    PubMed Central

    Elmore, Zachary C.; Beckley, Janel R.; Chen, Jun-Song; Gould, Kathleen L.

    2014-01-01

    Ubiquitination and deubiquitination of proteins are reciprocal events involved in many cellular processes, including the cell cycle. During mitosis, the metaphase to anaphase transition is regulated by the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C). Although the E3 ubiquitin ligase function of the APC/C has been well characterized, it is not clear whether deubiquitinating enzymes (DUBs) play a role in reversing APC/C substrate ubiquitination. Here we performed a genetic screen to determine what DUB, if any, antagonizes the function of the APC/C in the fission yeast Schizosaccharomyces pombe. We found that deletion of ubp8, encoding the Spt-Ada-Gcn5-Acetyl transferase (SAGA) complex associated DUB, suppressed temperature-sensitive phenotypes of APC/C mutants cut9-665, lid1-6, cut4-533, and slp1-362. Our analysis revealed that Ubp8 antagonizes APC/C function in a mechanism independent of the spindle assembly checkpoint and proteasome activity. Notably, suppression of APC/C mutants was linked to loss of Ubp8 catalytic activity and required histone H2B ubiquitination. On the basis of these data, we conclude that Ubp8 antagonizes APC/C function indirectly by modulating H2B ubiquitination status. PMID:24948786

  17. APC16 is a conserved subunit of the anaphase-promoting complex/cyclosome

    PubMed Central

    Kops, Geert J. P. L.; van der Voet, Monique; Manak, Michael S.; van Osch, Maria H. J.; Naini, Said M.; Brear, Andrea; McLeod, Ian X.; Hentschel, Dirk M.; Yates, John R.; van den Heuvel, Sander; Shah, Jagesh V.

    2010-01-01

    Error-free chromosome segregation depends on timely activation of the multi-subunit E3 ubiquitin ligase APC/C. Activation of the APC/C initiates chromosome segregation and mitotic exit by targeting critical cell-cycle regulators for destruction. The APC/C is the principle target of the mitotic checkpoint, which prevents segregation while chromosomes are unattached to spindle microtubules. We now report the identification and characterization of APC16, a conserved subunit of the APC/C. APC16 was found in association with tandem-affinity-purified mitotic checkpoint complex protein complexes. APC16 is a bona fide subunit of human APC/C: it is present in APC/C complexes throughout the cell cycle, the phenotype of APC16-depleted cells copies depletion of other APC/C subunits, and APC16 is important for APC/C activity towards mitotic substrates. APC16 sequence homologues can be identified in metazoans, but not fungi, by four conserved primary sequence stretches. We provide evidence that the C. elegans gene K10D2.4 and the D. rerio gene zgc:110659 are functional equivalents of human APC16. Our findings show that APC/C is composed of previously undescribed subunits, and raise the question of why metazoan APC/C is molecularly different from unicellular APC/C. PMID:20392738

  18. Intermediates in the assembly of mitotic checkpoint complexes and their role in the regulation of the anaphase-promoting complex

    PubMed Central

    Kaisari, Sharon; Sitry-Shevah, Danielle; Miniowitz-Shemtov, Shirly; Hershko, Avram

    2016-01-01

    The mitotic (or spindle assembly) checkpoint system prevents premature separation of sister chromatids in mitosis and thus ensures the fidelity of chromosome segregation. Kinetochores that are not attached properly to the mitotic spindle produce an inhibitory signal that prevents progression into anaphase. The checkpoint system acts on the Anaphase-Promoting Complex/Cyclosome (APC/C) ubiquitin ligase, which targets for degradation inhibitors of anaphase initiation. APC/C is inhibited by the Mitotic Checkpoint Complex (MCC), which assembles when the checkpoint is activated. MCC is composed of the checkpoint proteins BubR1, Bub3, and Mad2, associated with the APC/C coactivator Cdc20. The intermediary processes in the assembly of MCC are not sufficiently understood. It is also not clear whether or not some subcomplexes of MCC inhibit the APC/C and whether Mad2 is required only for MCC assembly and not for its action on the APC/C. We used purified subcomplexes of mitotic checkpoint proteins to examine these problems. Our results do not support a model in which Mad2 catalytically generates a Mad2-free APC/C inhibitor. We also found that the release of Mad2 from MCC caused a marked (although not complete) decrease in inhibitory action, suggesting a role of Mad2 in MCC for APC/C inhibition. A previously unknown species of MCC, which consists of Mad2, BubR1, and two molecules of Cdc20, contributes to the inhibition of APC/C by the mitotic checkpoint system. PMID:26755599

  19. ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint

    PubMed Central

    Miniowitz-Shemtov, Shirly; Teichner, Adar; Sitry-Shevah, Danielle; Hershko, Avram

    2010-01-01

    The mitotic (or spindle assembly) checkpoint system ensures accurate segregation of chromosomes by delaying anaphase until all chromosomes are correctly attached to the mitotic spindle. This system acts by inhibiting the activity of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase to target securin for degradation. APC/C is inhibited by a mitotic checkpoint complex (MCC) composed of BubR1, Bub3, Mad2, and Cdc20. The molecular mechanisms of the inactivation of the mitotic checkpoint, including the release of APC/C from inhibition, remain obscure. It has been reported that polyubiquitylation by the APC/C is required for the inactivation of the mitotic checkpoint [Reddy SK, Rape M, Margansky WA, Kirschner MW (2007) Nature, 446:921–924]. We confirmed the involvement of polyubiquitylation, but found that another process, which requires ATP cleavage at the β–γ position (as opposed to α–β bond scission involved in ubiquitylation), is essential for the release of APC/C from checkpoint inhibition. ATP (β–γ) cleavage is required both for the dissociation of MCC components from APC/C and for the disassembly of free MCC, whereas polyubiquitylation is involved only in the former process. We find that the requirement for ATP (β–γ) cleavage is not due to the involvement of the 26S proteasome and that the phenomena observed are not due to sustained activity of protein kinase Cdk1/cyclin B, caused by inhibition of the degradation of cyclin B. Thus, some other energy-consuming process is needed for the inactivation of the mitotic checkpoint. PMID:20212161

  20. Roles of the anaphase-promoting complex/cyclosome and of its activator Cdc20 in functional substrate binding

    PubMed Central

    Eytan, Esther; Moshe, Yakir; Braunstein, Ilana; Hershko, Avram

    2006-01-01

    The anaphase-promoting complex/cyclosome (APC/C) is a multisubunit ubiquitin-protein ligase that targets for degradation cell-cycle regulatory proteins during exit from mitosis and in the G1 phase of the cell cycle. The activity of APC/C in mitosis and in G1 requires interaction with the activator proteins Cdc20 and Cdh1, respectively. Substrates of APC/C–Cdc20 contain a recognition motif called the “destruction box” (D-box). The mode of the action of APC/C activators and their possible role in substrate binding remain poorly understood. Several investigators suggested that Cdc20 and Cdh1 mediate substrate recognition, whereas others proposed that substrates bind to APC/C or to APC/C–activator complexes. All these studies used binding assays, which do not necessarily indicate that substrate binding is functional and leads to product formation. In the present investigation we examined this problem by an “isotope-trapping” approach that directly demonstrates productive substrate binding. With this method we found that the simultaneous presence of both APC/C and Cdc20 is required for functional substrate binding. By contrast, with conventional binding assays we found that either Cdc20 or APC/C can bind substrate by itself, but only at low affinity and relaxed selectivity for D-box. Our results are consistent with models in which interaction of substrate with specific binding sites on both APC/C and Cdc20 is involved in selective and productive substrate binding. PMID:16455800

  1. A Specific Form of Phospho Protein Phosphatase 2 Regulates Anaphase-promoting Complex/Cyclosome Association with Spindle Poles

    PubMed Central

    Ban, Kenneth H.

    2010-01-01

    In early mitosis, the END (Emi1/NuMA/Dynein-dynactin) network anchors the anaphase-promoting complex/cyclosome (APC/C) to the mitotic spindle and poles. Spindle anchoring restricts APC/C activity, thereby limiting the destruction of spindle-associated cyclin B and ensuring maintenance of spindle integrity. Emi1 binds directly to hypophosphorylated APC/C, linking the APC/C to the spindle via NuMA. However, whether the phosphorylation state of the APC/C is important for its association with the spindle and what kinases and phosphatases are necessary for regulating this event remain unknown. Here, we describe the regulation of APC/C-mitotic spindle pole association by phosphorylation. We find that only hypophosphorylated APC/C associates with microtubule asters, suggesting that phosphatases are important. Indeed, a specific form of PPP2 (CA/R1A/R2B) binds APC/C, and PPP2 activity is necessary for Cdc27 dephosphorylation. Screening by RNA interference, we find that inactivation of CA, R1A, or R2B leads to delocalization of APC/C from spindle poles, early mitotic spindle defects, a failure to congress chromosomes, and decreased levels of cyclin B on the spindle. Consistently, inhibition of cyclin B/Cdk1 activity increased APC/C binding to microtubules. Thus, cyclin B/Cdk1 and PPP2 regulate the dynamic association of APC/C with spindle poles in early mitosis, a step necessary for proper spindle formation. PMID:20089842

  2. Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance

    PubMed Central

    Malo, Mackenzie E.; Postnikoff, Spike D.L.; Arnason, Terra G.; Harkness, Troy A.A.

    2016-01-01

    The Saccharomyces cerevisiae Forkhead Box (Fox) orthologs, Forkheads (Fkh) 1 and 2, are conserved transcription factors required for stress response, cell cycle progression and longevity. These yeast proteins play a key role in mitotic progression through activation of the ubiquitin E3 ligase Anaphase Promoting Complex (APC) via transcriptional control. Here, we used genetic and molecular analyses to demonstrate that the APC E3 activity is necessary for mitotic Fkh1 protein degradation and subsequent cell cycle progression. We report that Fkh1 protein degradation occurs specifically during mitosis, requires APCCdc20 and proteasome activity, and that a stable Fkh1 mutant reduces normal chronological lifespan, increases genomic instability, and increases sensitivity to stress. Our data supports a model whereby cell cycle progression through mitosis and G1 requires the targeted degradation of Fkh1 by the APC. This is significant to many fields as these results impact our understanding of the mechanisms underpinning the control of aging and cancer. PMID:27099939

  3. The Anaphase-Promoting Complex Is a Dual Integrator That Regulates Both MicroRNA-Mediated Transcriptional Regulation of Cyclin B1 and Degradation of Cyclin B1 during Arabidopsis Male Gametophyte Development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The anaphase-promoting complex/cyclosome (APC/C), an essential ubiquitin protein ligase, regulates mitotic progression and exit by enhancing degradation of cell cycle regulatory proteins, such as CYCB1;1, whose transcripts are upregulated by DUO POLLEN1 (DUO1). DUO1 is required for cell division in ...

  4. The Anaphase-Promoting Complex is a dual integrator that regulates both microRNA-mediated transcriptional regulation of Cyclin B1 and degradation of Cyclin B1 during Arabidopsis male gametophyte development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The anaphase-promoting complex/cyclosome (APC/C), an essential ubiquitin protein ligase, regulates mitotic progression and exit by enhancing degradation of cell cycle regulatory proteins, such as CYCB1;1, whose transcripts are upregulated by DUO POLLEN1 (DUO1). DUO1 is required for cell division in ...

  5. Orthologues of the Anaphase-Promoting Complex/Cyclosome Coactivators Cdc20p and Cdh1p Are Important for Mitotic Progression and Morphogenesis in Candida albicans ▿ †

    PubMed Central

    Chou, Hsini; Glory, Amandeep; Bachewich, Catherine

    2011-01-01

    The conserved anaphase-promoting complex/cyclosome (APC/C) system mediates protein degradation during mitotic progression. Conserved coactivators Cdc20p and Cdh1p regulate the APC/C during early to late mitosis and G1 phase. Candida albicans is an important fungal pathogen of humans, and it forms highly polarized cells when mitosis is blocked through depletion of the polo-like kinase Cdc5p or other treatments. However, the mechanisms governing mitotic progression and associated polarized growth in the pathogen are poorly understood. In order to gain insights into these processes, we characterized C. albicans orthologues of Cdc20p and Cdh1p. Cdc20p-depleted cells were blocked in early or late mitosis with elevated levels of Cdc5p and the mitotic cyclin Clb2p, suggesting that Cdc20p is essential and has some conserved functions during mitosis. However, the yeast cells formed highly polarized buds in contrast to the large doublets of S. cerevisiae cdc20 mutants, implying a distinct role in morphogenesis. In comparison, cdh1Δ/cdh1Δ cells were viable but showed enrichment of Clb2p and Cdc5p, suggesting that Cdh1p may influence mitotic exit. The cdh1Δ/cdh1Δ phenotype was pleiotropic, consisting of normal or enlarged yeast, pseudohyphae, and some elongated buds, whereas S. cerevisiae cdh1Δ yeast cells were reduced in size. Thus, C. albicans Cdh1p may have some distinct functions. Finally, absence of Cdh1p or Cdc20p had a minor or no effect on hyphal development, respectively. Overall, the results suggest that Cdc20p and Cdh1p may be APC/C activators that are important for mitosis but also morphogenesis in C. albicans. Their novel features imply additional variations in function and underscore rewiring in the emerging mitotic regulatory networks of the pathogen. PMID:21398510

  6. In silico spatial simulations reveal that MCC formation and excess BubR1 are required for tight inhibition of the anaphase-promoting complex.

    PubMed

    Ibrahim, Bashar

    2015-11-01

    In response to the activation of the mitotic spindle assembly checkpoint (SAC), distinct inhibitory pathways control the activity of the anaphase-promoting complex (APC/C). It remains unclear whether the different regulatory mechanisms function in separate pathways or as part of an integrated signalling system. Here, five variant models of APC/C regulation were constructed and analysed. The simulations showed that all variant models were able to reproduce the wild type behaviour of the APC. However, only one model, which included both the mitotic checkpoint complex (MCC) as well as BubR1 as direct inhibitors of the APC/C, was able to reproduce both wild and mutant type behaviour of APC/C regulation. Interestingly, in this model, the MCC as well as the BubR1 binding rate to the APC/C was comparable to the known Cdc20-Mad2 binding rate and could not be made higher. Mad2 active transport towards the spindle mid-zone accelerated the inhibition speed of the APC/C but not its concentration level. The presented study highlights the principle that a systems biology approach is critical for the SAC mechanism and could also be used for predicting hypotheses to design future experiments. The presented work has successfully distinguished between five potent inhibitors of the APC/C using a systems biology approach. Here, the favoured model contains both BubR1 and MCC as direct inhibitors of the APC/C. PMID:26256776

  7. Regulation of the Action of Early Mitotic Inhibitor 1 on the Anaphase-promoting Complex/Cyclosome by Cyclin-dependent Kinases*

    PubMed Central

    Moshe, Yakir; Bar-On, Ortal; Ganoth, Dvora; Hershko, Avram

    2011-01-01

    Cell cycle regulation is characterized by alternating activities of cyclin-dependent kinases (CDKs) and of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). During S-phase APC/C is inhibited by early mitotic inhibitor 1 (Emi1) to allow the accumulation of cyclins A and B and to prevent re-replication. Emi1 is degraded at prophase by a Plk1-dependent pathway. Recent studies in which the degradation pathway of Emi1 was disrupted have shown that APC/C is activated at mitotic entry despite stabilization of Emi1. These results suggested the possibility of additional mechanisms other than degradation of Emi1, which release APC/C from inhibition by Emi1 upon entry into mitosis. In this study we report one such mechanism, by which the ability of Emi1 to inhibit APC/C is negatively regulated by CDKs. We show that in Plk1-inhibited cells Emi1 is stabilized and phosphorylated, that Emi1 is phosphorylated by CDKs in mitotic but not S-phase cell extracts, and that Emi1 phosphorylation by mitotic cell extracts or purified CDKs markedly reduces the ability of Emi1 to bind and to inhibit APC/C. Finally, we show that the addition of extracts from S-phase cells to extracts from mitotic cells protects Emi1 from CDK-mediated inactivation. PMID:21454540

  8. Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

    PubMed Central

    Nath, Somsubhra; Chowdhury, Abhishek; Dey, Sanjib; Roychoudhury, Anirban; Ganguly, Abira; Bhattacharyya, Dibyendu

    2014-01-01

    The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells. PMID:25368385

  9. A role for the anaphase-promoting complex inhibitor Emi2/XErp1, a homolog of early mitotic inhibitor 1, in cytostatic factor arrest of Xenopus eggs

    PubMed Central

    Tung, Jeffrey J.; Hansen, David V.; Ban, Kenneth H.; Loktev, Alexander V.; Summers, Matthew K.; Adler, John R.; Jackson, Peter K.

    2005-01-01

    Unfertilized vertebrate eggs are arrested in metaphase of meiosis II with high cyclin B/Cdc2 activity to prevent parthenogenesis. Until fertilization, exit from metaphase is blocked by an activity called cytostatic factor (CSF), which stabilizes cyclin B by inhibiting the anaphase-promoting complex (APC) ubiquitin ligase. The APC inhibitor early mitotic inhibitor 1 (Emi1) was recently found to be required for maintenance of CSF arrest. We show here that exogenous Emi1 is unstable in CSF-arrested Xenopus eggs and is destroyed by the SCFβTrCP ubiquitin ligase, suggesting that endogenous Emi1, an apparent 44-kDa protein, requires a stabilizing factor. However, anti-Emi1 antibodies crossreact with native Emi2/Erp1/FBXO43, a homolog of Emi1 and conserved APC inhibitor. Emi2 is stable in CSF-arrested eggs, is sufficient to prevent CSF release, and is rapidly degraded in a Polo-like kinase 1-dependent manner in response to calcium-mediated egg activation. These results identify Emi2 as a candidate CSF maintenance protein. PMID:15753281

  10. Anillin is a substrate of anaphase-promoting complex/cyclosome (APC/C) that controls spatial contractility of myosin during late cytokinesis.

    PubMed

    Zhao, Wei-Meng; Fang, Guowei

    2005-09-30

    Anillin, an actin-binding protein localized at the cleavage furrow, is required for cytokinesis. Through an in vitro expression screen, we identified anillin as a substrate of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that controls mitotic progression. We found that the levels of anillin fluctuate in the cell cycle, peaking in mitosis and dropping drastically during mitotic exit. Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin. Functionally, anillin was required for the completion of cytokinesis. In anillin knockdown cells, the cleavage furrow ingressed but failed to complete the ingression. At late cytokinesis, the cytosol and DNA in knockdown cells underwent rapid myosin-based oscillatory movement across the furrow. During this movement, RhoA and active myosin were absent from the cleavage furrow, and myosin was redistributed to cortical patches, which powers the random oscillatory movement. We concluded that anillin functions to maintain the localization of active myosin, thereby ensuring the spatial control of concerted contraction during cytokinesis. PMID:16040610

  11. Arabidopsis ULTRAVIOLET-B-INSENSITIVE4 Maintains Cell Division Activity by Temporal Inhibition of the Anaphase-Promoting Complex/Cyclosome[C][W

    PubMed Central

    Heyman, Jefri; Van den Daele, Hilde; De Wit, Kevin; Boudolf, Véronique; Berckmans, Barbara; Verkest, Aurine; Kamei, Claire Lessa Alvim; De Jaeger, Geert; Koncz, Csaba; De Veylder, Lieven

    2011-01-01

    The anaphase-promoting complex/cyclosome (APC/C) is a multisubunit ubiquitin ligase that regulates progression through the cell cycle by marking key cell division proteins for destruction. To ensure correct cell cycle progression, accurate timing of APC/C activity is important, which is obtained through its association with both activating and inhibitory subunits. However, although the APC/C is highly conserved among eukaryotes, no APC/C inhibitors are known in plants. Recently, we have identified ULTRAVIOLET-B-INSENSITIVE4 (UVI4) as a plant-specific component of the APC/C. Here, we demonstrate that UVI4 uses conserved APC/C interaction motifs to counteract the activity of the CELL CYCLE SWITCH52 A1 (CCS52A1) activator subunit, inhibiting the turnover of the A-type cyclin CYCA2;3. UVI4 is expressed in an S phase-dependent fashion, likely through the action of E2F transcription factors. Correspondingly, uvi4 mutant plants failed to accumulate CYCA2;3 during the S phase and prematurely exited the cell cycle, triggering the onset of the endocycle. We conclude that UVI4 regulates the temporal inactivation of APC/C during DNA replication, allowing CYCA2;3 to accumulate above the level required for entering mitosis, and thereby regulates the meristem size and plant growth rate. PMID:22167059

  12. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome

    PubMed Central

    Moshe, Yakir; Boulaire, Jérôme; Pagano, Michele; Hershko, Avram

    2004-01-01

    Early mitotic inhibitor 1 (Emi1) inhibits the activity of the anaphase promoting complex/cyclosome (APC/C), which is a multisubunit ubiquitin ligase that targets mitotic regulators for degradation in exit from mitosis. Levels of Emi1 oscillate in the cell cycle: it accumulates in the S phase and is rapidly degraded in prometaphase. The degradation of Emi1 in early mitosis is necessary for the activation of APC/C in late mitosis. Previous studies have shown that Emi1 is targeted for degradation in mitosis by a Skp1–Cullin1 F-box protein (SCF) ubiquitin ligase complex that contains the F-box protein β-TrCP. As with other substrates of SCFβ-TrCP, the phosphorylation of Emi1 on a DSGxxS sequence is required for this process. However, the protein kinase(s) involved has not been identified. We find that Polo-like kinase 1 (Plk1), a protein kinase that accumulates in mitosis, markedly stimulates the ligation of Emi1 to ubiquitin by purified SCFβ-TrCP. Cdk1-cyclin B, another major mitotic protein kinase, has no influence on this process by itself but stimulates the action of Plk1 at low, physiological concentrations. Plk1 phosphorylates serine residues in the DSGxxS sequence of Emi1, as suggested by the reduced phosphorylation of a derivative in which the two serines were mutated to nonphosphorylatable amino acids. Transfection with an small interfering RNA duplex directed against Plk1 caused the accumulation of Emi1 in mitotically arrested HeLa cells. It is suggested that phosphorylation of Emi1 by Plk1 is involved in its degradation in mitosis. PMID:15148369

  13. Two different mitotic checkpoint inhibitors of the anaphase-promoting complex/cyclosome antagonize the action of the activator Cdc20

    PubMed Central

    Eytan, Esther; Braunstein, Ilana; Ganoth, Dvora; Teichner, Adar; Hittle, James C.; Yen, Tim J.; Hershko, Avram

    2008-01-01

    The mitotic checkpoint system ensures the fidelity of chromosome segregation by preventing the completion of mitosis in the presence of any misaligned chromosome. When activated, it blocks the initiation of anaphase by inhibiting the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). Little is known about the biochemical mechanisms by which this system inhibits APC/C, except for the existence of a mitotic checkpoint complex (MCC) inhibitor of APC/C composed of the APC/C activator Cdc20 associated with the checkpoint proteins Mad2, BubR1, and Bub3. We have been studying the mechanisms of the mitotic checkpoint system in extracts that reproduce its downstream events. We found that inhibitory factors are associated with APC/C in the checkpoint-arrested state, which can be recovered from immunoprecipitates. Only a part of the inhibitory activity was caused by MCC [Braunstein I, Miniowitz S, Moshe Y, Hershko A (2007) Proc Natl Acad Sci USA 104:4870–4875]. Here, we show that during exit from checkpoint, rapid disassembly of MCC takes place while APC/C is still inactive. This observation suggested the possible involvement of multiple factors in the regulation of APC/C by the mitotic checkpoint. We have separated a previously unknown inhibitor of APC/C from MCC. This inhibitor, called mitotic checkpoint factor 2 (MCF2), is associated with APC/C only in the checkpoint-arrested state. The inhibition of APC/C by both MCF2 and MCC was decreased at high concentrations of Cdc20. We propose that both MCF2 and MCC inhibit APC/C by antagonizing Cdc20, possibly by interaction with the Cdc20-binding site of APC/C. PMID:18591651

  14. The Spo12 protein of Saccharomyces cerevisiae: a regulator of mitotic exit whose cell cycle-dependent degradation is mediated by the anaphase-promoting complex.

    PubMed Central

    Shah, R; Jensen, S; Frenz, L M; Johnson, A L; Johnston, L H

    2001-01-01

    The Spo12 protein plays a regulatory role in two of the most fundamental processes of biology, mitosis and meiosis, and yet its biochemical function remains elusive. In this study we concentrate on the genetic and biochemical analysis of its mitotic function. Since high-copy SPO12 is able to suppress a wide variety of mitotic exit mutants, all of which arrest with high Clb-Cdc28 activity, we speculated whether SPO12 is able to facilitate exit from mitosis when overexpressed by antagonizing mitotic kinase activity. We show, however, that Spo12 is not a potent regulator of Clb-Cdc28 activity and can function independently of either the cyclin-dependent kinase inhibitor (CDKi), Sic1, or the anaphase-promoting complex (APC) regulator, Hct1. Spo12 protein level is regulated by the APC and the protein is degraded in G1 by an Hct1-dependent mechanism. We also demonstrate that in addition to localizing to the nucleus Spo12 is a nucleolar protein. We propose a model where overexpression of Spo12 may lead to the delocalization of a small amount of Cdc14 from the nucleolus, resulting in a sufficient lowering of mitotic kinase levels to facilitate mitotic exit. Finally, site-directed mutagenesis of highly conserved residues in the Spo12 protein sequence abolishes both its mitotic suppressor activity as well as its meiotic function. This result is the first indication that Spo12 may carry out the same biochemical function in mitosis as it does in meiosis. PMID:11729145

  15. Study of Cyclin Proteolysis in Anaphase-Promoting Complex (APC) Mutant Cells Reveals the Requirement for APC Function in the Final Steps of the Fission Yeast Septation Initiation Network

    PubMed Central

    Chang, Louise; Morrell, Jennifer L.; Feoktistova, Anna; Gould, Kathleen L.

    2001-01-01

    Cytokinesis in eukaryotic cells requires the inactivation of mitotic cyclin-dependent kinase complexes. An apparent exception to this relationship is found in Schizosaccharomyces pombe mutants with mutations of the anaphase-promoting complex (APC). These conditional lethal mutants arrest with unsegregated chromosomes because they cannot degrade the securin, Cut2p. Although failing at nuclear division, these mutants septate and divide. Since septation requires Cdc2p inactivation in wild-type S. pombe, it has been suggested that Cdc2p inactivation occurs in these mutants by a mechanism independent of cyclin degradation. In contrast to this prediction, we show that Cdc2p kinase activity fluctuates in APC cut mutants due to Cdc13/cyclin B destruction. In APC-null mutants, however, septation and cutting do not occur and Cdc13p is stable. We conclude that APC cut mutants are hypomorphic with respect to Cdc13p degradation. Indeed, overproduction of nondestructible Cdc13p prevents septation in APC cut mutants and the normal reorganization of septation initiation network components during anaphase. PMID:11533255

  16. Mes1 controls the meiosis I to meiosis II transition by distinctly regulating the anaphase-promoting complex/cyclosome coactivators Fzr1/Mfr1 and Slp1 in fission yeast

    PubMed Central

    Kimata, Yuu; Kitamura, Kenji; Fenner, Nicola; Yamano, Hiroyuki

    2011-01-01

    Meiosis is a specialized form of cell division generating haploid gametes and is dependent upon protein ubiquitylation by the anaphase-promoting complex/cyclosome (APC/C). Accurate control of the APC/C during meiosis is important in all eukaryotic cells and is in part regulated by the association of coactivators and inhibitors. We previously showed that the fission yeast meiosis-specific protein Mes1 binds to a coactivator and inhibits APC/C; however, regulation of the Mes1-mediated APC/C inhibition remains elusive. Here we show how Mes1 distinctively regulates different forms of the APC/C. We study all the coactivators present in the yeast genome and find that only Slp1/Cdc20 is essential for meiosis I progression. However, Fzr1/Mfr1 is a critical target for Mes1 inhibition because fzr1Δ completely rescues the defect on the meiosis II entry in mes1Δ cells. Furthermore, cell-free studies suggest that Mes1 behaves as a pseudosubstrate for Fzr1/Mfr1 but works as a competitive substrate for Slp1. Intriguingly, mutations in the D-box or KEN-box of Mes1 increase its recognition as a substrate by Fzr1, but not by Slp1. Thus Mes1 interacts with two coactivators in a different way to control the activity of the APC/C required for the meiosis I/meiosis II transition. PMID:21389117

  17. Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

    PubMed Central

    2015-01-01

    Abstract Correct DNA segregation is a fundamental process that ensures the precise and reliable inheritance of genomic information for the propagation of cell life. Eukaryotic cells have evolved a conserved surveillance control mechanism for DNA segregation named the Spindle Assembly Checkpoint (SAC).The SAC ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome whose activation by Cdc20 is required for sister-chromatid separation; this marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. However, the underlying regulatory pathways remain largely elusive. In this study, five possible model variants of APC/C regulation were constructed, namely BubR1, Mad2, MCC, MCF2, and an all-pathways model variant. These models were validated with experimental data from the literature. A wide range of parameter values has been tested to find the critical values of the APC/C binding rate. The results show that all variants are able to capture the wild-type behavior of the APC/C. However, only one model variant, which included both MCC as well as BubR1 as potent inhibitors of the APC/C, was able to reproduce both wild-type and mutant type behavior of APC/C regulation. In conclusion, the presented work informs the regulation of fundamental processes such as SAC and APC/C in cell biology and has successfully distinguished between five competing dynamical models using a systems biology approach. The results attest that systems-level approaches are vital for molecular and cell biology. PMID:25871779

  18. Systematic Characterization of Human Protein Complexes Identifies Chromosome Segregation Proteins

    PubMed Central

    Hutchins, James R.A.; Toyoda, Yusuke; Hegemann, Björn; Poser, Ina; Hériché, Jean-Karim; Sykora, Martina M.; Augsburg, Martina; Hudecz, Otto; Buschhorn, Bettina A.; Bulkescher, Jutta; Conrad, Christian; Comartin, David; Schleiffer, Alexander; Sarov, Mihail; Pozniakovsky, Andrei; Slabicki, Mikolaj Michal; Schloissnig, Siegfried; Steinmacher, Ines; Leuschner, Marit; Ssykor, Andrea; Lawo, Steffen; Pelletier, Laurence; Stark, Holger; Nasmyth, Kim; Ellenberg, Jan; Durbin, Richard; Buchholz, Frank; Mechtler, Karl; Hyman, Anthony A.; Peters, Jan-Michael

    2010-01-01

    Chromosome segregation and cell division are essential, highly ordered processes that depend on numerous protein complexes. Results from recent RNA interference (RNAi) screens indicate that the identity and composition of these protein complexes is incompletely understood. Using gene tagging on bacterial artificial chromosomes, protein localization and tandem affinity purification-mass spectrometry, the MitoCheck consortium has analyzed about 100 human protein complexes, many of which had not or only incompletely been characterized. This work has led to the discovery of previously unknown, evolutionarily conserved subunits of the anaphase-promoting complex (APC/C) and the γ-tubulin ring complex (γ-TuRC), large complexes which are essential for spindle assembly and chromosome segregation. The approaches we describe here are generally applicable to high throughput follow-up analyses of phenotypic screens in mammalian cells. PMID:20360068

  19. Systematic analysis of human protein complexes identifies chromosome segregation proteins.

    PubMed

    Hutchins, James R A; Toyoda, Yusuke; Hegemann, Björn; Poser, Ina; Hériché, Jean-Karim; Sykora, Martina M; Augsburg, Martina; Hudecz, Otto; Buschhorn, Bettina A; Bulkescher, Jutta; Conrad, Christian; Comartin, David; Schleiffer, Alexander; Sarov, Mihail; Pozniakovsky, Andrei; Slabicki, Mikolaj Michal; Schloissnig, Siegfried; Steinmacher, Ines; Leuschner, Marit; Ssykor, Andrea; Lawo, Steffen; Pelletier, Laurence; Stark, Holger; Nasmyth, Kim; Ellenberg, Jan; Durbin, Richard; Buchholz, Frank; Mechtler, Karl; Hyman, Anthony A; Peters, Jan-Michael

    2010-04-30

    Chromosome segregation and cell division are essential, highly ordered processes that depend on numerous protein complexes. Results from recent RNA interference screens indicate that the identity and composition of these protein complexes is incompletely understood. Using gene tagging on bacterial artificial chromosomes, protein localization, and tandem-affinity purification-mass spectrometry, the MitoCheck consortium has analyzed about 100 human protein complexes, many of which had not or had only incompletely been characterized. This work has led to the discovery of previously unknown, evolutionarily conserved subunits of the anaphase-promoting complex and the gamma-tubulin ring complex--large complexes that are essential for spindle assembly and chromosome segregation. The approaches we describe here are generally applicable to high-throughput follow-up analyses of phenotypic screens in mammalian cells. PMID:20360068

  20. The Anaphase Promoting Complex Is Required for Memory Function in Mice

    ERIC Educational Resources Information Center

    Kuczera, Tanja; Stilling, Roman Manuel; Hsia, Hung-En; Bahari-Javan, Sanaz; Irniger, Stefan; Nasmyth, Kim; Sananbenesi, Farahnaz; Fischer, Andre

    2011-01-01

    Learning and memory processes critically involve the orchestrated regulation of de novo protein synthesis. On the other hand it has become clear that regulated protein degradation also plays a major role in neuronal plasticity and learning behavior. One of the key pathways mediating protein degradation is proteosomal protein destruction. The…

  1. Dissecting the roles of human BUB1 in the spindle assembly checkpoint.

    PubMed

    Vleugel, Mathijs; Hoek, Tim A; Tromer, Eelco; Sliedrecht, Tale; Groenewold, Vincent; Omerzu, Manja; Kops, Geert J P L

    2015-08-15

    Mitotic chromosome segregation is initiated by the anaphase promoting complex/cyclosome (APC/C) and its co-activator CDC20 (forming APC/C(CDC20)). APC/C(CDC20) is inhibited by the spindle assembly checkpoint (SAC) when chromosomes have not attached to spindle microtubules. Unattached kinetochores catalyze the formation of a diffusible APC/C(CDC20) inhibitor that comprises BUBR1 (also known as BUB1B), BUB3, MAD2 (also known as MAD2L1) and a second molecule of CDC20. Recruitment of these proteins to the kinetochore, as well as SAC activation, rely on the mitotic kinase BUB1, but the molecular mechanism by which BUB1 accomplishes this in human cells is unknown. We show that kinetochore recruitment of BUBR1 and BUB3 by BUB1 is dispensable for SAC activation. Unlike its yeast and nematode orthologs, human BUB1 does not associate stably with the MAD2 activator MAD1 (also known as MAD1L1) and, although required for accelerating the loading of MAD1 onto kinetochores, BUB1 is dispensable for the maintenance of steady-state levels of MAD1 there. Instead, we identify a 50-amino-acid segment that harbors the recently reported ABBA motif close to a KEN box as being crucial for the role of BUB1 in SAC signaling. The presence of this segment correlates with SAC activity and efficient binding of CDC20 but not of MAD1 to kinetochores. PMID:26148513

  2. The ubiquitin ligase APC(Cdh1) is required to maintain genome integrity in primary human cells.

    PubMed

    Engelbert, D; Schnerch, D; Baumgarten, A; Wäsch, R

    2008-02-01

    Ensuring precise DNA replication and chromosome segregation is essential during cell division in order to provide genomic stability and avoid malignant growth. Proteolytic control of cell cycle regulators by the anaphase-promoting complex, activated by Cdh1 (APC(Cdh1)), is responsible for a stable G1 phase after mitotic exit allowing accurate preparation for DNA replication in the following S phase. APC(Cdh1) target proteins are frequently upregulated in tumor cells and the inactivation of human Cdh1 might interfere with genome integrity by target stabilization. Here we show that APC(Cdh1) is required for maintaining genomic integrity in primary human cells. Lentiviral-delivered strong and stable suppression of Cdh1 by RNA interference (RNAi) causes aberrant accumulation of several APC(Cdh1) target proteins, such as cyclin A, B, Aurora A or Plk1, which control accurate and equal distribution of the genetic information to daughter cells. This induces a premature and prolonged S phase, mitotic-entry delay and defects in chromosome separation and cytokinesis. Cell cycle deregulation by stable knockdown of Cdh1 leads to activation of p53/p21 and genomic instability, which is further increased by codepletion of p53. Thus, stabilization of APC(Cdh1) targets may initiate aberrant DNA replication and chromosome separation, and trigger a p53 response by deregulating G1 in primary human cells. PMID:17700535

  3. Structure and Substrate Recruitment of the Human Spindle Checkpoint Kinase Bub1

    SciTech Connect

    Kang, Jungseog; Yang, Maojun; Li, Bing; Qi, Wei; Zhang, Chao; Shokat, Kevan M.; Tomchick, Diana R.; Machius, Mischa; Yu, Hongtao

    2009-11-10

    In mitosis, the spindle checkpoint detects a single unattached kinetochore, inhibits the anaphase-promoting complex or cyclosome (APC/C), and prevents premature sister chromatid separation. The checkpoint kinase Bub1 contributes to checkpoint sensitivity through phosphorylating the APC/C activator, Cdc20, and inhibiting APC/C catalytically. We report here the crystal structure of the kinase domain of Bub1, revealing the requirement of an N-terminal extension for its kinase activity. Though the activation segment of Bub1 is ordered and has structural features indicative of active kinases, the C-terminal portion of this segment sterically restricts substrate access to the active site. Bub1 uses docking motifs, so-called KEN boxes, outside its kinase domain to recruit Cdc20, one of two known KEN box receptors. The KEN boxes of Bub1 are required for the spindle checkpoint in human cells. Therefore, its unusual active-site conformation and mode of substrate recruitment suggest that Bub1 has an exquisitely tuned specificity for Cdc20.

  4. In silico analysis of deleterious single nucleotide polymorphisms in human BUB1 mitotic checkpoint serine/threonine kinase B gene.

    PubMed

    Akhoundi, Fatemeh; Parvaneh, Nikpour; Modjtaba, Emadi-Baygi

    2016-09-01

    One of the major challenges in the analysis of human genetic variation is to distinguish mutations that are functionally neutral from those that contribute to disease. BubR1 is a key protein mediating spindle-checkpoint activation that plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Owing to the importance of BUB1B gene in mitotic checkpoint a functional analysis using different in silico approaches was undertaken to explore the possible associations between genetic mutations and phenotypic variation. In this work we found that 3 nsSNPs I82N, P334L and R814H have a functional effect on protein function and stability. A literature search revealed that R814H was already implicated in human diseases. Additionally, 2 SNPs in the 5' UTR region was predicted to exhibit a pattern change in the internal ribosome entry site (IRES), and eight MicroRNA binding sites were found to be highly affected due to 3' UTR SNPs. These in silico predictions will provide useful information in selecting the target SNPs that are likely to have functional impact on the BUB1B gene. PMID:27331020

  5. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint.

    PubMed

    Brito, Daniela A; Rieder, Conly L

    2006-06-20

    In the presence of unattached/weakly attached kinetochores, the spindle assembly checkpoint (SAC) delays exit from mitosis by preventing the anaphase-promoting complex (APC)-mediated proteolysis of cyclin B, a regulatory subunit of cyclin-dependent kinase 1 (Cdk1). Like all checkpoints, the SAC does not arrest cells permanently, and escape from mitosis in the presence of an unsatisfied SAC requires that cyclin B/Cdk1 activity be inhibited. In yeast , and likely Drosophila, this occurs through an "adaptation" process involving an inhibitory phosphorylation on Cdk1 and/or activation of a cyclin-dependent kinase inhibitor (Cdki). The mechanism that allows vertebrate cells to escape mitosis when the SAC cannot be satisfied is unknown. To explore this issue, we conducted fluorescence microscopy studies on rat kangaroo (PtK) and human (RPE1) cells dividing in the presence of nocodazole. We find that in the absence of microtubules (MTs), escape from mitosis occurs in the presence of an active SAC and requires cyclin B destruction. We also find that cyclin B is progressively destroyed during the block by a proteasome-dependent mechanism. Thus, vertebrate cells do not adapt to the SAC. Rather, our data suggest that in normal cells, the SAC cannot prevent a slow but continuous degradation of cyclin B that ultimately drives the cell out of mitosis. PMID:16782009

  6. The Spindle Assembly Checkpoint Is Not Essential for Viability of Human Cells with Genetically Lowered APC/C Activity

    PubMed Central

    Wild, Thomas; Larsen, Marie Sofie Yoo; Narita, Takeo; Schou, Julie; Nilsson, Jakob; Choudhary, Chunaram

    2016-01-01

    Summary The anaphase-promoting complex/cyclosome (APC/C) and the spindle assembly checkpoint (SAC), which inhibits the APC/C, are essential determinants of mitotic timing and faithful division of genetic material. Activation of the APC/C is known to depend on two APC/C-interacting E2 ubiquitin-conjugating enzymes—UBE2C and UBE2S. We show that APC/C activity in human cells is tuned by the combinatorial use of three E2s, namely UBE2C, UBE2S, and UBE2D. Genetic deletion of UBE2C and UBE2S, individually or in combination, leads to discriminative reduction in APC/C function and sensitizes cells to UBE2D depletion. Reduction of APC/C activity results in loss of switch-like metaphase-to-anaphase transition and, strikingly, renders cells insensitive to chemical inhibition of MPS1 and genetic ablation of MAD2, both of which are essential for the SAC. These results provide insights into the regulation of APC/C activity and demonstrate that the essentiality of the SAC is imposed by the strength of the APC/C. PMID:26904940

  7. EM Structure of human APC/CCDH1-EMI1 reveals multimodal mechanism of E3 ligase shutdown

    PubMed Central

    Frye, Jeremiah J.; Brown, Nicholas G.; Petzold, Georg; Watson, Edmond R.; Grace, Christy R. R.; Nourse, Amanda; Jarvis, Marc A.; Kriwacki, Richard W.; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A.

    2013-01-01

    The Anaphase Promoting Complex/Cyclosome (APC/C) is a ~1.5 MDa multiprotein E3 ligase enzyme that regulates cell division by promoting timely ubiquitin-mediated proteolysis of key cell cycle regulatory proteins. Inhibition of human APC/CCDH1 during interphase by Early Mitotic Inhibitor 1 (EMI1) is essential for accurate coordination of DNA synthesis and mitosis. Here, we report a hybrid structural approach involving NMR, electron microscopy, and enzymology, which reveal that EMI1’s 143-residue C-terminal domain inhibits multiple APC/CCDH1 functions. The intrinsically disordered D-box, Linker, and Tail elements, together with a structured zinc-binding domain, bind distinct regions of APC/CCDH1 to synergistically both block the substrate-binding site and inhibit ubiquitin chain elongation. The functional importance of intrinsic structural disorder is explained by enabling a small inhibitory domain to bind multiple sites to shut down multiple functions of a “molecular machine” nearly 100 times its size. PMID:23708605

  8. The RZZ complex requires the N-terminus of KNL1 to mediate optimal Mad1 kinetochore localization in human cells

    PubMed Central

    Caldas, Gina V.; Lynch, Tina R.; Anderson, Ryan; Afreen, Sana; Varma, Dileep; DeLuca, Jennifer G.

    2015-01-01

    The spindle assembly checkpoint is a surveillance mechanism that blocks anaphase onset until all chromosomes are properly attached to microtubules of the mitotic spindle. Checkpoint activity requires kinetochore localization of Mad1/Mad2 to inhibit activation of the anaphase promoting complex/cyclosome in the presence of unattached kinetochores. In budding yeast and Caenorhabditis elegans, Bub1, recruited to kinetochores through KNL1, recruits Mad1/Mad2 by direct linkage with Mad1. However, in human cells it is not yet established which kinetochore protein(s) function as the Mad1/Mad2 receptor. Both Bub1 and the RZZ complex have been implicated in Mad1/Mad2 kinetochore recruitment; however, their specific roles remain unclear. Here, we investigate the contributions of Bub1, RZZ and KNL1 to Mad1/Mad2 kinetochore recruitment. We find that the RZZ complex localizes to the N-terminus of KNL1, downstream of Bub1, to mediate robust Mad1/Mad2 kinetochore localization. Our data also point to the existence of a KNL1-, Bub1-independent mechanism for RZZ and Mad1/Mad2 kinetochore recruitment. Based on our results, we propose that in humans, the primary mediator for Mad1/Mad2 kinetochore localization is the RZZ complex. PMID:26581576

  9. The RZZ complex requires the N-terminus of KNL1 to mediate optimal Mad1 kinetochore localization in human cells.

    PubMed

    Caldas, Gina V; Lynch, Tina R; Anderson, Ryan; Afreen, Sana; Varma, Dileep; DeLuca, Jennifer G

    2015-11-01

    The spindle assembly checkpoint is a surveillance mechanism that blocks anaphase onset until all chromosomes are properly attached to microtubules of the mitotic spindle. Checkpoint activity requires kinetochore localization of Mad1/Mad2 to inhibit activation of the anaphase promoting complex/cyclosome in the presence of unattached kinetochores. In budding yeast and Caenorhabditis elegans, Bub1, recruited to kinetochores through KNL1, recruits Mad1/Mad2 by direct linkage with Mad1. However, in human cells it is not yet established which kinetochore protein(s) function as the Mad1/Mad2 receptor. Both Bub1 and the RZZ complex have been implicated in Mad1/Mad2 kinetochore recruitment; however, their specific roles remain unclear. Here, we investigate the contributions of Bub1, RZZ and KNL1 to Mad1/Mad2 kinetochore recruitment. We find that the RZZ complex localizes to the N-terminus of KNL1, downstream of Bub1, to mediate robust Mad1/Mad2 kinetochore localization. Our data also point to the existence of a KNL1-, Bub1-independent mechanism for RZZ and Mad1/Mad2 kinetochore recruitment. Based on our results, we propose that in humans, the primary mediator for Mad1/Mad2 kinetochore localization is the RZZ complex. PMID:26581576

  10. The Four Canonical TPR Subunits of Human APC/C Form Related Homo-Dimeric Structures and Stack in Parallel to Form a TPR Suprahelix☆

    PubMed Central

    Zhang, Ziguo; Chang, Leifu; Yang, Jing; Conin, Nora; Kulkarni, Kiran; Barford, David

    2013-01-01

    The anaphase-promoting complex or cyclosome (APC/C) is a large E3 RING-cullin ubiquitin ligase composed of between 14 and 15 individual proteins. A striking feature of the APC/C is that only four proteins are involved in directly recognizing target proteins and catalyzing the assembly of a polyubiquitin chain. All other subunits, which account for > 80% of the mass of the APC/C, provide scaffolding functions. A major proportion of these scaffolding subunits are structurally related. In metazoans, there are four canonical tetratricopeptide repeat (TPR) proteins that form homo-dimers (Apc3/Cdc27, Apc6/Cdc16, Apc7 and Apc8/Cdc23). Here, we describe the crystal structure of the N-terminal homo-dimerization domain of Schizosaccharomyces pombe Cdc23 (Cdc23Nterm). Cdc23Nterm is composed of seven contiguous TPR motifs that self-associate through a related mechanism to those of Cdc16 and Cdc27. Using the Cdc23Nterm structure, we generated a model of full-length Cdc23. The resultant “V”-shaped molecule docks into the Cdc23-assigned density of the human APC/C structure determined using negative stain electron microscopy (EM). Based on sequence conservation, we propose that Apc7 forms a homo-dimeric structure equivalent to those of Cdc16, Cdc23 and Cdc27. The model is consistent with the Apc7-assigned density of the human APC/C EM structure. The four canonical homo-dimeric TPR proteins of human APC/C stack in parallel on one side of the complex. Remarkably, the uniform relative packing of neighboring TPR proteins generates a novel left-handed suprahelical TPR assembly. This finding has implications for understanding the assembly of other TPR-containing multimeric complexes. PMID:23583778

  11. PUL21a-Cyclin A2 Interaction is Required to Protect Human Cytomegalovirus-Infected Cells from the Deleterious Consequences of Mitotic Entry

    PubMed Central

    Eifler, Martin; Uecker, Ralf; Weisbach, Henry; Bogdanow, Boris; Richter, Ellen; König, Lydia; Vetter, Barbara; Lenac-Rovis, Tihana; Jonjic, Stipan; Neitzel, Heidemarie; Hagemeier, Christian; Wiebusch, Lüder

    2014-01-01

    Entry into mitosis is accompanied by dramatic changes in cellular architecture, metabolism and gene expression. Many viruses have evolved cell cycle arrest strategies to prevent mitotic entry, presumably to ensure sustained, uninterrupted viral replication. Here we show for human cytomegalovirus (HCMV) what happens if the viral cell cycle arrest mechanism is disabled and cells engaged in viral replication enter into unscheduled mitosis. We made use of an HCMV mutant that, due to a defective Cyclin A2 binding motif in its UL21a gene product (pUL21a), has lost its ability to down-regulate Cyclin A2 and, therefore, to arrest cells at the G1/S transition. Cyclin A2 up-regulation in infected cells not only triggered the onset of cellular DNA synthesis, but also promoted the accumulation and nuclear translocation of Cyclin B1-CDK1, premature chromatin condensation and mitotic entry. The infected cells were able to enter metaphase as shown by nuclear lamina disassembly and, often irregular, metaphase spindle formation. However, anaphase onset was blocked by the still intact anaphase promoting complex/cyclosome (APC/C) inhibitory function of pUL21a. Remarkably, the essential viral IE2, but not the related chromosome-associated IE1 protein, disappeared upon mitotic entry, suggesting an inherent instability of IE2 under mitotic conditions. Viral DNA synthesis was impaired in mitosis, as demonstrated by the abnormal morphology and strongly reduced BrdU incorporation rates of viral replication compartments. The prolonged metaphase arrest in infected cells coincided with precocious sister chromatid separation and progressive fragmentation of the chromosomal material. We conclude that the Cyclin A2-binding function of pUL21a contributes to the maintenance of a cell cycle state conducive for the completion of the HCMV replication cycle. Unscheduled mitotic entry during the course of the HCMV replication has fatal consequences, leading to abortive infection and cell death. PMID

  12. A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain

    PubMed Central

    Huang, Ju; Ikeuchi, Yoshiho; Malumbres, Marcos; Bonni, Azad

    2015-01-01

    SUMMARY Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligase Cdh1-anaphase promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1-APC forms a complex with endogenous FMRP, and knockout of Cdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin-signaling pathway that regulates mGluR-LTD in the brain. PMID:25913861

  13. Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner.

    PubMed

    Liu, Jia; Wan, Lixin; Liu, Jing; Yuan, Zhu; Zhang, Jinfang; Guo, Jianfeng; Malumbres, Marcos; Liu, Jiankang; Zou, Weiguo; Wei, Wenyi

    2016-01-01

    Anaphase-promoting complex/cyclosome/Cdh1 is a multi-subunit ubiquitin E3 ligase that drives M to G1 cell cycle progression through primarily earmarking various substrates for ubiquitination and subsequent degradation by the 26S proteasome. Notably, emerging evidence suggested that Cdh1 could also function in various cellular processes independent of anaphase-promoting complex/cyclosome. To this end, we recently identified an anaphase-promoting complex/cyclosome-independent function of Cdh1 in modulating osteoblast differentiation through activating Smurf1, one of the NEDD4 family of HECT domain-containing E3 ligases. However, it remains largely unknown whether Cdh1 could exert its tumor suppressor role through similarly modulating the E3 ligase activities of other NEDD4 family members, most of which have characterized important roles in tumorigenesis. Here we report that in various tumor cells, Cdh1, conversely, suppresses the E3 ligase activity of WWP2, another NEDD4 family protein, in an anaphase-promoting complex/cyclosome-independent manner. As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K/Akt oncogenic signaling to facilitate tumorigenesis. This study expands the non-anaphase-promoting complex/cyclosome function of Cdh1 in regulating the NEDD4 family E3 ligases, and further suggested that enhancing Cdh1 to inhibit the E3 ligase activity of WWP2 could be a promising strategy for treating human cancers. PMID:27462441

  14. Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner

    PubMed Central

    Liu, Jia; Wan, Lixin; Liu, Jing; Yuan, Zhu; Zhang, Jinfang; Guo, Jianfeng; Malumbres, Marcos; Liu, Jiankang; Zou, Weiguo; Wei, Wenyi

    2016-01-01

    Anaphase-promoting complex/cyclosome/Cdh1 is a multi-subunit ubiquitin E3 ligase that drives M to G1 cell cycle progression through primarily earmarking various substrates for ubiquitination and subsequent degradation by the 26S proteasome. Notably, emerging evidence suggested that Cdh1 could also function in various cellular processes independent of anaphase-promoting complex/cyclosome. To this end, we recently identified an anaphase-promoting complex/cyclosome-independent function of Cdh1 in modulating osteoblast differentiation through activating Smurf1, one of the NEDD4 family of HECT domain-containing E3 ligases. However, it remains largely unknown whether Cdh1 could exert its tumor suppressor role through similarly modulating the E3 ligase activities of other NEDD4 family members, most of which have characterized important roles in tumorigenesis. Here we report that in various tumor cells, Cdh1, conversely, suppresses the E3 ligase activity of WWP2, another NEDD4 family protein, in an anaphase-promoting complex/cyclosome-independent manner. As such, loss of Cdh1 activates WWP2, leading to reduced abundance of WWP2 substrates including PTEN, which subsequently activates PI3K/Akt oncogenic signaling to facilitate tumorigenesis. This study expands the non-anaphase-promoting complex/cyclosome function of Cdh1 in regulating the NEDD4 family E3 ligases, and further suggested that enhancing Cdh1 to inhibit the E3 ligase activity of WWP2 could be a promising strategy for treating human cancers. PMID:27462441

  15. The ubiquitin ligase APC/CCdh1 puts the brakes on DNA-end resection

    PubMed Central

    Lafranchi, Lorenzo; Sartori, Alessandro A

    2015-01-01

    DNA double-strand breaks (DSBs) are highly deleterious lesions and their misrepair can promote genomic instability, a hallmark of cancer. DNA-end resection is a cell cycle-regulated mechanism that is required for the faithful repair of DSBs. We recently discovered that the anaphase-promoting complex/cyclosome-Cdh1 (APC/CCdh1) ubiquitin ligase is responsible for the timely degradation of CtBP-interacting protein (CtIP), a key DNA-end resection factor, providing a new layer of regulation of DSB repair in human cells. PMID:27308488

  16. Human See, Human Do.

    ERIC Educational Resources Information Center

    Tomasello, Michael

    1997-01-01

    A human demonstrator showed human children and captive chimpanzees how to drag food or toys closer using a rakelike tool. One side of the rake was less efficient than the other for dragging. Chimps tried to reproduce results rather than methods while children imitated and used the more efficient rake side. Concludes that imitation leads to…

  17. Human Development, Human Evolution.

    ERIC Educational Resources Information Center

    Smillie, David

    One of the truly remarkable events in human evolution is the unprecedented increase in the size of the brain of "Homo" over a brief span of 2 million years. It would appear that some significant selective pressure or opportunity presented itself to this branch of the hominid line and caused a rapid increase in the brain, introducing a wholly new…

  18. Human Health

    MedlinePlus

    ... effects of climate change Video not supported Human Health Climate change threatens human health and well-being ... Copy link to clipboard Key Message: Wide-ranging Health Impacts Climate change threatens human health and well- ...

  19. Human Trafficking

    MedlinePlus

    ... to debt bondage or peonage in which traffickers demand labor as a means repayment for a real ... human smuggling are two separate crimes under federal law. There are several important differences between them. Human ...

  20. Human Trafficking

    MedlinePlus

    ... TRAFFICKING (English) Listen < Back to Search FACT SHEET: HUMAN TRAFFICKING (English) Published: August 2, 2012 Topics: Public Awareness , ... organizations that protect and serve trafficking victims. National Human Trafficking Resource Center at 1.888.373.7888 Last ...

  1. Human Issues in Human Rights

    ERIC Educational Resources Information Center

    Kates, Robert W.

    1978-01-01

    Presents the report of the National Academy of Sciences' Committee in Human Rights which seeks to ease the plight of individual scientists, engineers, and medical personnel suffering severe repression. Case studies of instances of negligence of human rights are provided. (CP)

  2. Action, human.

    PubMed

    Russo, M T

    2010-01-01

    The term "human action" designates the intentional and deliberate movement that is proper and exclusive to mankind. Human action is a unified structure: knowledge, intention or volition, deliberation, decision or choice of means and execution. The integration between these dimensions appears as a task that demands strength of will to achieve the synthesis of self-possession and self-control that enables full personal realisation. Recently, the debate about the dynamism of human action has been enriched by the contribution of neurosciences. Thanks to techniques of neuroimaging, neurosciences have expanded the field of investigation to the nature of volition, to the role of the brain in decision-making processes and to the notion of freedom and responsibility. PMID:20393686

  3. Classical Humanities

    ERIC Educational Resources Information Center

    Goodwin, Donn; And Others

    1975-01-01

    This article reports on a pilot course in humanities team-taught by three teachers, two from a senior high-school and one from a junior high-school, in Brookfield, Wisconsin. The specific subject matter is Greek and Roman culture. The curriculum is outlined and the basic reading list is included. (CLK)

  4. [Human monkeypox].

    PubMed

    Chastel, C

    2009-03-01

    Unlike other recent viral emergences, which were in majority caused by RNA viruses, the monkeypox results from infection by a DNA virus, an orthopoxvirus closely related to both vaccine and smallpox viruses and whose two genomic variants are known. Unexpectedly isolated from captive Asiatic monkeys and first considered as an laboratory curiosity, this virus was recognised in 1970 as an human pathogen in tropical Africa. Here it was responsible for sporadic cases following intrusions (for hunting) into tropical rain forests or rare outbreak with human-to-human transmission as observed in 1996 in Democratic Republic of Congo. As monkeypox in humans is not distinguishable from smallpox (a disease globally eradicated in 1977) it was only subjected to vigilant epidemiological surveillance and not considered as a potential threat outside Africa. This point of view radically changed in 2003 when monkeypox was introduced in the USA by African wild rodents and spread to 11 different states of this country. Responsible for 82 infections in American children and adults, this outbreak led to realize the sanitary hazards resulting from international trade of exotic animals and scientific investigations increasing extensively our knowledge of this zoonosis. PMID:18394820

  5. Humanizing Calculus

    ERIC Educational Resources Information Center

    Cirillo, Michelle

    2007-01-01

    In this article, the author explores the history and the mathematics used by Newton and Leibniz in their invention of calculus. The exploration of this topic is intended to show students that mathematics is a human invention. Suggestions are made to help teachers incorporate the mathematics and the history into their own lessons. (Contains 3…

  6. Human Trafficking

    ERIC Educational Resources Information Center

    Wilson, David McKay

    2011-01-01

    The shadowy, criminal nature of human trafficking makes evaluating its nature and scope difficult. The U.S. State Department and anti-trafficking groups estimate that worldwide some 27 million people are caught in a form of forced servitude today. Public awareness of modern-day slavery is gaining momentum thanks to new abolitionist efforts. Among…

  7. Nothing Human

    ERIC Educational Resources Information Center

    Wharram, C. C.

    2014-01-01

    In this essay C. C. Wharram argues that Terence's concept of translation as a form of "contamination" anticipates recent developments in philosophy, ecology, and translation studies. Placing these divergent fields of inquiry into dialogue enables us read Terence's well-known statement "I am a human being--I deem nothing…

  8. Human Rights in the Humanities

    ERIC Educational Resources Information Center

    Harpham, Geoffrey

    2012-01-01

    Human rights are rapidly entering the academic curriculum, with programs appearing all over the country--including at Duke, Harvard, Northeastern, and Stanford Universities; the Massachusetts Institute of Technology; the Universities of Chicago, of Connecticut, of California at Berkeley, and of Minnesota; and Trinity College. Most of these…

  9. Human Protothecosis

    PubMed Central

    Lass-Flörl, Cornelia; Mayr, Astrid

    2007-01-01

    Human protothecosis is a rare infection caused by members of the genus Prototheca. Prototheca species are generally considered to be achlorophyllic algae and are ubiquitous in nature. The occurrence of protothecosis can be local or disseminated and acute or chronic, with the latter being more common. Diseases have been classified as (i) cutaneous lesions, (ii) olecranon bursitis, or (iii) disseminated or systemic manifestations. Infections can occur in both immunocompetent and immunosuppressed patients, although more severe and disseminated infections tend to occur in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii have been associated with human disease. Usually, treatment involves medical and surgical approaches; treatment failure is not uncommon. Antifungals such as ketoconazole, itraconazole, fluconazole, and amphotericin B are the most commonly used drugs to date. Among them, amphotericin B displays the best activity against Prototheca spp. Diagnosis is largely made upon detection of characteristic structures observed on histopathologic examination of tissue. PMID:17428884

  10. Human genetics

    SciTech Connect

    Carlson, E.A.

    1984-01-01

    This text provides full and balanced coverage of the concepts requisite for a thorough understanding of human genetics. Applications to both the individual and society are integrated throughout the lively and personal narrative, and the essential principles of heredity are clearly presented to prepare students for informed participation in public controversies. High-interest, controversial topics, including recombinant DNA technology, oncogenes, embryo transfer, environmental mutagens and carcinogens, IQ testing, and eugenics encourage understanding of important social issues.

  11. Human evolution.

    PubMed

    Wood, B

    1996-12-01

    The common ancestor of modern humans and the great apes is estimated to have lived between 5 and 8 Myrs ago, but the earliest evidence in the human, or hominid, fossil record is Ardipithecus ramidus, from a 4.5 Myr Ethiopian site. This genus was succeeded by Australopithecus, within which four species are presently recognised. All combine a relatively primitive postcranial skeleton, a dentition with expanded chewing teeth and a small brain. The most primitive species in our own genus, Homo habilis and Homo rudolfensis, are little advanced over the australopithecines and with hindsight their inclusion in Homo may not be appropriate. The first species to share a substantial number of features with later Homo is Homo ergaster, or 'early African Homo erectus', which appears in the fossil record around 2.0 Myr. Outside Africa, fossil hominids appear as Homo erectus-like hominids, in mainland Asia and in Indonesia close to 2 Myr ago; the earliest good evidence of 'archaic Homo' in Europe is dated at between 600-700 Kyr before the present. Anatomically modern human, or Homo sapiens, fossils are seen first in the fossil record in Africa around 150 Kyr ago. Taken together with molecular evidence on the extent of DNA variation, this suggests that the transition from 'archaic' to 'modern' Homo may have taken place in Africa. PMID:8976151

  12. Human Capital, (Human) Capabilities and Higher Education

    ERIC Educational Resources Information Center

    Le Grange, L.

    2011-01-01

    In this article I initiate a debate into the (de)merits of human capital theory and human capability theory and discuss implications of the debate for higher education. Human capital theory holds that economic growth depends on investment in education and that economic growth is the basis for improving the quality of human life. Human capable…

  13. Cell cycle: proteomics gives it a spin.

    PubMed

    Archambault, Vincent

    2005-08-01

    The eukaryotic cell division cycle has been studied at the molecular level for over 30 years, most fruitfully in model organisms. In the past 5 years, developments in mass spectrometry-based proteomics have been applied to the study of protein interactions and post-translational modifications involving key cell cycle regulators such as cyclin-dependent kinases and the anaphase-promoting complex, as well as effectors such as centrosomes, the kinetochore and DNA replication forks. In addition, innovations in chemical biology, functional proteomics and bioinformatics have been employed to study the cell cycle at the proteome level. This review surveys the contributions of proteomics to cell cycle research. The near future should see the application of more quantitative proteomic approaches to probe the dynamic aspects of the molecular system that underlie the cell cycle in model organisms and in human cells. PMID:16097893

  14. Human Heredity: Genetic Mechanisms in Humans.

    ERIC Educational Resources Information Center

    Blank, C. E.

    1988-01-01

    Discussed are some of the uncertainties in human genetic mechanisms that are often presented as dogma in Biology textbooks. Presented is a brief historical background and illustrations involving chromosome abnormality in humans and linkage studies in humans. (CW)

  15. Human Astroviruses

    PubMed Central

    Pintó, Rosa M.; Guix, Susana

    2014-01-01

    SUMMARY Human astroviruses (HAtVs) are positive-sense single-stranded RNA viruses that were discovered in 1975. Astroviruses infecting other species, particularly mammalian and avian, were identified and classified into the genera Mamastrovirus and Avastrovirus. Through next-generation sequencing, many new astroviruses infecting different species, including humans, have been described, and the Astroviridae family shows a high diversity and zoonotic potential. Three divergent groups of HAstVs are recognized: the classic (MAstV 1), HAstV-MLB (MAstV 6), and HAstV-VA/HMO (MAstV 8 and MAstV 9) groups. Classic HAstVs contain 8 serotypes and account for 2 to 9% of all acute nonbacterial gastroenteritis in children worldwide. Infections are usually self-limiting but can also spread systemically and cause severe infections in immunocompromised patients. The other groups have also been identified in children with gastroenteritis, but extraintestinal pathologies have been suggested for them as well. Classic HAstVs may be grown in cells, allowing the study of their cell cycle, which is similar to that of caliciviruses. The continuous emergence of new astroviruses with a potential zoonotic transmission highlights the need to gain insights on their biology in order to prevent future health threats. This review focuses on the basic virology, pathogenesis, host response, epidemiology, diagnostic assays, and prevention strategies for HAstVs. PMID:25278582

  16. Human schistosomiasis

    PubMed Central

    Colley, Daniel G; Bustinduy, Amaya L; Secor, W Evan; King, Charles H

    2015-01-01

    Human schistosomiasis—or bilharzia—is a parasitic disease caused by trematode flukes of the genus Schistosoma. By conservative estimates, at least 230 million people worldwide are infected with Schistosoma spp. Adult schistosome worms colonise human blood vessels for years, successfully evading the immune system while excreting hundreds to thousands of eggs daily, which must either leave the body in excreta or become trapped in nearby tissues. Trapped eggs induce a distinct immune-mediated granulomatous response that causes local and systemic pathological effects ranging from anaemia, growth stunting, impaired cognition, and decreased physical fitness, to organ-specific effects such as severe hepatosplenism, periportal fibrosis with portal hypertension, and urogenital inflammation and scarring. At present, preventive public health measures in endemic regions consist of treatment once every 1 or 2 years with the isoquinolinone drug, praziquantel, to suppress morbidity. In some locations, elimination of transmission is now the goal; however, more sensitive diagnostics are needed in both the field and clinics, and integrated environmental and health-care management will be needed to ensure elimination. PMID:24698483

  17. Human abilities.

    PubMed

    Sternberg, R J; Kaufman, J C

    1998-01-01

    This chapter reviews recent literature, primarily from the 1990s, on human abilities. The review opens with a consideration of the question of what intelligence is, and then considers some of the major definitions of intelligence, as well as implicit theories of intelligence around the world. Next, the chapter considers cognitive approaches to intelligence, and then biological approaches. It proceeds to psychometric or traditional approaches to intelligence, and then to broad, recent approaches. The different approaches raise somewhat different questions, and hence produce somewhat different answers. They have in common, however, the attempt to understand what kinds of mechanisms lead some people to adapt to, select, and shape environments in ways that match particularly well the demands of those environments. PMID:9496630

  18. Structural Basis for the Catalytic Activity of Human Serine/Threonine Protein Phosphatase type 5 (PP5)

    NASA Technical Reports Server (NTRS)

    Swingle, Mark R.; Ciszak, Ewa M.; Honkanen, Richard E.

    2004-01-01

    Serine/threonine protein phosphatase-5 (PP5) is a member of the PPP-gene family of protein phosphatases that is widely expressed in mammalian tissues and is highly conserved among eukaryotes. PP5 associates with several proteins that affect signal transduction networks, including the glucocorticoid receptor (GR)-heat shock protein-90 (Hsp90)-heterocomplex, the CDC16 and CDC27 subunits of the anaphase-promoting complex, elF2alpha kinase, the A subunit of PP2A, the G12-alpha / G13-alpha subunits of heterotrimeric G proteins and DNA-PK. The catalytic domain of PP5 (PP5c) shares 35-45% sequence identity with the catalytic domains of other PPP-phosphatases, including protein phosphatase-1 (PP1), -2A (PP2A), -2B / calcineurin (PP2B), -4 (PP4), -6 (PP6), and -7 (PP7). Like PP1, PP2A and PP4, PP5 is also sensitive to inhibition by okadaic acid, microcystin, cantharidin, tautomycin, and calyculin A. Here we report the crystal structure of the PP5 catalytic domain (PP5c) at a resolution of 1.6 angstroms. From this structure we propose a mechanism for PP5-mediated hydrolysis of phosphoprotein substrates, which requires the precise positioning of two metal ions within a conserved Asp(sup 271)-M(sub 1):M(sub 2)-W(sup 1)-His(sup 304)-Asp(sup 274) catalytic motif. The structure of PP5c provides a possible structural basis for explaining the exceptional catalytic proficiency of protein phosphatases, which are among the most powerful known catalysts. Resolution of the entire C-terminus revealed a novel subdomain, and the structure of the PP5c should also aid development of type-specific inhibitors.

  19. NATO Human View Architecture and Human Networks

    NASA Technical Reports Server (NTRS)

    Handley, Holly A. H.; Houston, Nancy P.

    2010-01-01

    The NATO Human View is a system architectural viewpoint that focuses on the human as part of a system. Its purpose is to capture the human requirements and to inform on how the human impacts the system design. The viewpoint contains seven static models that include different aspects of the human element, such as roles, tasks, constraints, training and metrics. It also includes a Human Dynamics component to perform simulations of the human system under design. One of the static models, termed Human Networks, focuses on the human-to-human communication patterns that occur as a result of ad hoc or deliberate team formation, especially teams distributed across space and time. Parameters of human teams that effect system performance can be captured in this model. Human centered aspects of networks, such as differences in operational tempo (sense of urgency), priorities (common goal), and team history (knowledge of the other team members), can be incorporated. The information captured in the Human Network static model can then be included in the Human Dynamics component so that the impact of distributed teams is represented in the simulation. As the NATO militaries transform to a more networked force, the Human View architecture is an important tool that can be used to make recommendations on the proper mix of technological innovations and human interactions.

  20. The Digital Humanities as a Humanities Project

    ERIC Educational Resources Information Center

    Svensson, Patrik

    2012-01-01

    This article argues that the digital humanities can be seen as a humanities project in a time of significant change in the academy. The background is a number of scholarly, educational and technical challenges, the multiple epistemic traditions linked to the digital humanities, the potential reach of the field across and outside the humanities,…

  1. Human oestrus

    PubMed Central

    Gangestad, Steven W; Thornhill, Randy

    2008-01-01

    For several decades, scholars of human sexuality have almost uniformly assumed that women evolutionarily lost oestrus—a phase of female sexuality occurring near ovulation and distinct from other phases of the ovarian cycle in terms of female sexual motivations and attractivity. In fact, we argue, this long-standing assumption is wrong. We review evidence that women's fertile-phase sexuality differs in a variety of ways from their sexuality during infertile phases of their cycles. In particular, when fertile in their cycles, women are particularly sexually attracted to a variety of features that likely are (or, ancestrally, were) indicators of genetic quality. As women's fertile-phase sexuality shares with other vertebrate females' fertile-phase sexuality a variety of functional and physiological features, we propose that the term oestrus appropriately applies to this phase in women. We discuss the function of women's non-fertile or extended sexuality and, based on empirical findings, suggest ways that fertile-phase sexuality in women has been shaped to partly function in the context of extra-pair mating. Men are particularly attracted to some features of fertile-phase women, but probably based on by-products of physiological changes males have been selected to detect, not because women signal their cycle-based fertility status. PMID:18252670

  2. Human Rhinoviruses

    PubMed Central

    Lamson, Daryl M.; St. George, Kirsten; Walsh, Thomas J.

    2013-01-01

    Human rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genus Enterovirus and the family Picornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs. PMID:23297263

  3. [Human papillomaviruses].

    PubMed

    Gross, G

    2003-10-01

    Human papillomaviruses (HPV) infect exclusively the basal cells of the skin and of mucosal epithelia adjacent to the skin such as the mouth, the upper respiratory tract, the lower genital tract and the anal canal. HPV does not lead to a viremia. Basically there are three different types of HPV infection: Clinically visible lesions, subclinical HPV infections and latent HPV infections. Distinct HPV types induce morphologically and prognostically different clinical pictures. The most common HPV associated benign tumor of the skin is the common wart. Infections of the urogenitoanal tract with specific HPV-types are recognised as the most frequent sexually transmitted viral infections. So-called "high-risk" HPV-types (HPV16, 18 and others) are regarded by the world health organisation as important risk-factors for the development of genital cancer (mainly cervical cancer), anal cancer and upper respiratory tract cancer in both genders. Antiviral substances with a specific anti-HPV effect are so far unknown. Conventional therapies of benign skin warts and of mucosal warts are mainly nonspecific. They comprise tissue-destroying therapies such as electrocautery, cryotherapy and laser. In addition cytotoxic substances such as podophyllotoxin and systemic therapy with retinoids are in use. Systemically and topically administered immunotherapies represent a new approach for treatment. Both interferons and particularly the recently developed imiquimod, an interferon-alpha and cytokine-inductor lead to better results and are better tolerated then conventional therapies. HPV-specific vaccines have been developed in the last 5 years and will be used in future for prevention and treatment of benign and malignant HPV-associated tumors of the genitoanal tract in both sexes. PMID:14610898

  4. Human Factors in Human-Systems Integration

    NASA Technical Reports Server (NTRS)

    Fitts, David J.; Sandor, Aniko; Litaker, Harry L., Jr.; Tillman, Barry

    2008-01-01

    Any large organization whose mission is to design and develop systems for humans, and train humans needs a well-developed integration and process plan to deal with the challenges that arise from managing multiple subsystems. Human capabilities, skills, and needs must be considered early in the design and development process, and must be continuously considered throughout the development lifecycle. This integration of human needs within system design is typically formalized through a Human-Systems Integration (HSI) program. By having an HSI program, an institution or organization can reduce lifecycle costs and increase the efficiency, usability, and quality of its products because human needs have been considered from the beginning.

  5. Human Research Roadmap

    NASA Video Gallery

    Crew health and performance is critical to successful human exploration beyond low Earth orbit. The Human Research Program (HRP) investigates and mitigates the highest risks to human health and per...

  6. Engineered human vaccines

    SciTech Connect

    Sandhu, J.S. . Div. of Immunology and Neurobiology)

    1994-01-01

    The limitations of human vaccines in use at present and the design requirements for a new generation of human vaccines are discussed. The progress in engineering of human vaccines for bacteria, viruses, parasites, and cancer is reviewed, and the data from human studies with the engineered vaccines are discussed, especially for cancer and AIDS vaccines. The final section of the review deals with the possible future developments in the field of engineered human vaccines and the requirement for effective new human adjuvants.

  7. Human-machine interactions

    DOEpatents

    Forsythe, J. Chris; Xavier, Patrick G.; Abbott, Robert G.; Brannon, Nathan G.; Bernard, Michael L.; Speed, Ann E.

    2009-04-28

    Digital technology utilizing a cognitive model based on human naturalistic decision-making processes, including pattern recognition and episodic memory, can reduce the dependency of human-machine interactions on the abilities of a human user and can enable a machine to more closely emulate human-like responses. Such a cognitive model can enable digital technology to use cognitive capacities fundamental to human-like communication and cooperation to interact with humans.

  8. Visualizing Humans by Computer.

    ERIC Educational Resources Information Center

    Magnenat-Thalmann, Nadia

    1992-01-01

    Presents an overview of the problems and techniques involved in visualizing humans in a three-dimensional scene. Topics discussed include human shape modeling, including shape creation and deformation; human motion control, including facial animation and interaction with synthetic actors; and human rendering and clothing, including textures and…

  9. Cooperation in human teaching.

    PubMed

    Kruger, Ann Cale

    2015-01-01

    Kline's evolutionary analysis of teaching provides welcome reframing for cross-species comparisons. However, theory based on competition cannot explain the transmission of human cultural elements that were collectively created. Humans evolved in a cultural niche and teaching-learning coevolved to transmit culture. To study human cultural variation in teaching, we need a more articulated theory of this distinctively human engagement. PMID:26786392

  10. Humanism: A Christian Perspective.

    ERIC Educational Resources Information Center

    Kaasa, Harris; And Others

    As part of a four-college project to integrate the religious tradition with humanities teaching, humanism is discussed from a Christian perspective. Definitions of the terms humanism, religion, Christianity, and Christian humanism are provided. The latter is viewed as the issues surrounding the Christian approach to the dichotomy of good and evil…

  11. The Humanities: Interconnections.

    ERIC Educational Resources Information Center

    Salomone, Ronald E., Ed.

    1985-01-01

    Focusing on a wide range of interdisciplinary themes and ideas for humanities instruction, the 17 articles in this journal issue discuss the following topics: (1) literature, humanities, and the adult learner; (2) the role of the humanities in educating for a democracy; (3) humanities in the marketplace; (4) literature versus "great books" in high…

  12. Human Research Program Opportunities

    NASA Technical Reports Server (NTRS)

    Kundrot, Craig E.

    2014-01-01

    The goal of HRP is to provide human health and performance countermeasures, knowledge, technologies, and tools to enable safe, reliable, and productive human space exploration. The Human Research Program was designed to meet the needs of human space exploration, and understand and reduce the risk to crew health and performance in exploration missions.

  13. ISS Payload Human Factors

    NASA Technical Reports Server (NTRS)

    Ellenberger, Richard; Duvall, Laura; Dory, Jonathan

    2016-01-01

    The ISS Payload Human Factors Implementation Team (HFIT) is the Payload Developer's resource for Human Factors. HFIT is the interface between Payload Developers and ISS Payload Human Factors requirements in SSP 57000. ? HFIT provides recommendations on how to meet the Human Factors requirements and guidelines early in the design process. HFIT coordinates with the Payload Developer and Astronaut Office to find low cost solutions to Human Factors challenges for hardware operability issues.

  14. Boundaries of Humanities: Writing Medical Humanities

    ERIC Educational Resources Information Center

    Bolton, Gillie

    2008-01-01

    Literature and medicine is a discipline within medical humanities, which challenges medicine to reconfigure its scientific model to become interdisciplinary, and be disciplined by arts and humanities as well as science. The psychological, emotional, spiritual and physical are inextricably linked in people, inevitably entailing provisionality,…

  15. Virtual Human Project

    SciTech Connect

    Ward, RD

    2001-06-12

    This paper describes the development of a comprehensive human modeling environment, the Virtual Human, which will be used initially to model the human respiratory system for purposes of predicting pulmonary disease or injury using lung sounds. The details of the computational environment, including the development of a Virtual Human Thorax, a database for storing models, model parameters, and experimental data, and a Virtual Human web interface are outlined. Preliminary progress in developing this environment will be presented. A separate paper at the conference describes the modeling of sound generation using computational fluid dynamics and the modeling of sound propagation in the human respiratory system.

  16. Virtual Human project

    NASA Astrophysics Data System (ADS)

    Ward, Richard C.; Kruse, Kara L.; Allgood, Glenn O.; Hively, Lee M.; Fischer, K. N.; Munro, Nancy B.; Easterly, Clay E.

    2001-08-01

    This paper describes the development of a comprehensive human modeling environment, the Virtual Human, which will be used initially to model the human respiratory system for purposes of predicting pulmonary disease or injury using lung sounds. The details of the computational environment, including the development of a Virtual Human Thorax, a database for storing models, model parameters, and experimental data, and a Virtual Human web interface are outlined. Preliminary progress in developing this environment will be presented. A separate paper at the conference describes the modeling of sound generation using computational fluid dynamics and the modeling of sound propagation in the human respiratory system.

  17. Telling the Human Story.

    ERIC Educational Resources Information Center

    Richardson, Miles

    1987-01-01

    Proposes that one of the fundamental human attributes is telling stories. Explores the debate on whether Neanderthals possessed language ability. Discusses the role of the "human story" in teaching anthropology. (DH)

  18. Human bites (image)

    MedlinePlus

    Human bites present a high risk of infection. Besides the bacteria which can cause infection, there is ... the wound extends below the skin. Anytime a human bite has broken the skin, seek medical attention.

  19. Human Resource Accounting System

    ERIC Educational Resources Information Center

    Cerullo, Michael J.

    1974-01-01

    Main objectives of human resource accounting systems are to satisfy the informational demands made by investors and by operating managers. The paper's main concern is with the internal uses of a human asset system. (Author)

  20. Pathfinder: Humans in space

    NASA Technical Reports Server (NTRS)

    Anderson, John L.

    1988-01-01

    Viewgraphs are presented on the Pathfinder program. Information is given on human exploration of the solar system, technical requirements interfaces, program objectives, space suits, human performance, man-machine systems, space habitats, life support systems, and artificial gravity

  1. Whose Human Rights?

    ERIC Educational Resources Information Center

    Rendel, Margherita

    During the last 50 years, principles, institutions, and policies of human rights have been developed worldwide. This book brings together European and international conventions on human rights, the rights of women, and the users and uses of education, and places them in their wider context. It examines issues in how human rights work, the ways in…

  2. HUMAN USE INDEX (FUTURE)

    EPA Science Inventory

    Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the percentage of human land use in an area, including agriculture, urban and suburban development, and mining. Low values ...

  3. HUMAN USE INDEX

    EPA Science Inventory

    Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the percentage of human land use in an area, including agriculture, urban and suburban development, and mining. Low values ...

  4. Visible Human Project

    MedlinePlus

    ... Mobile Gallery Site Navigation Home The Visible Human Project ® Overview The Visible Human Project ® is an outgrowth of the NLM's 1986 Long- ... The long-term goal of the Visible Human Project ® is to produce a system of knowledge structures ...

  5. Human Rights Educational Resources.

    ERIC Educational Resources Information Center

    Flowers, Nancy

    1998-01-01

    Gives a variety of educational resources on human rights that include videos, resource notebooks, books, publications, and websites along with short descriptions of the materials. Provides the contact information for a list of human-rights organizations, such as the Center for Human Rights Education and the Franklin and Eleanor Roosevelt…

  6. Expanding Human Intelligence.

    ERIC Educational Resources Information Center

    Galyean, Beverly-Colleene

    1983-01-01

    The human brain is capable of mastering skills far beyond those it is now used for. Three questions about the further evolution of human intelligence are raised: What will be the next step in human intelligence? How is the next step manifesting itself? How can we prepare for those changes? (IS)

  7. Human Rights Resource Catalogue.

    ERIC Educational Resources Information Center

    Zambrano, Elias, Comp.

    This document provides information about 25 programs/brochures which focus on human rights topics. Specific topics include: (1) counselor preparation; (2) multicultural awareness; (3) abuse and neglect; (4) Acquired Immune Deficiency Syndrome; (5) self-awareness; (6) human rights awareness and human rights of students; (7) cultural diversity; (8)…

  8. Production Of Human Antibodies

    NASA Technical Reports Server (NTRS)

    Sammons, David W.; Neil, Garry A.

    1993-01-01

    Process for making human monoclonal antibodies based on combination of techniques. Antibodies made active against specific antigen. Process involves in vivo immunization of human B lymphocyte cells in mice. B cells of interest enriched in vitro before fusion. Method potentially applicable to any antigen. Does not rely on use of Epstein-Barr virus at any step. Human lymphocytes taken from any source.

  9. HUMAN EXPOSURE ACTIVITY PATTERNS

    EPA Science Inventory

    Human activity/uptake rate data are necessary to estimate potential human exposure and intake dose to environmental pollutants and to refine human exposure models. Personal exposure monitoring studies have demonstrated the critical role that activities play in explaining and pre...

  10. Some Criteria for Humanizing.

    ERIC Educational Resources Information Center

    Read, Charlotte S.

    Patterns for humanizing the information sciences include recognizing essential "humanness," taking a holistic approach to the subject field, and being aware of the epistemological nature of how people communicate and relate to others and themselves. The complete inclusion of the human factor in information theory researches can only amplify the…

  11. Esprit: A Humanities Magazine.

    ERIC Educational Resources Information Center

    Parker, Donald G.; Capella, Barry John

    In March 1984, the first issue of "Esprit," a semi-annual humanities magazine for the 56 two-year colleges in New York State, was published. The magazine seeks to confront the apparent decline of student interest in the humanities, community doubts about the relevance of the humanities, and the seeming indifference to the special truths inherent…

  12. Financing Human Capital.

    ERIC Educational Resources Information Center

    Juffras, Jason; Sawhill, Isabel V.

    This paper examines the government's role in financing human capital investments. It first examines why private investments in education, training, and other forms of human capital are likely to fall short of socially desirable levels. It then reviews past trends in public support for human resource investments. Finally, it discusses current…

  13. Has Human Evolution Stopped?

    PubMed Central

    Templeton, Alan R.

    2010-01-01

    It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important implications for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool, thereby enhancing the potential for human evolution. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences. PMID:23908778

  14. Human Mitochondrial Protein Database

    National Institute of Standards and Technology Data Gateway

    SRD 131 Human Mitochondrial Protein Database (Web, free access)   The Human Mitochondrial Protein Database (HMPDb) provides comprehensive data on mitochondrial and human nuclear encoded proteins involved in mitochondrial biogenesis and function. This database consolidates information from SwissProt, LocusLink, Protein Data Bank (PDB), GenBank, Genome Database (GDB), Online Mendelian Inheritance in Man (OMIM), Human Mitochondrial Genome Database (mtDB), MITOMAP, Neuromuscular Disease Center and Human 2-D PAGE Databases. This database is intended as a tool not only to aid in studying the mitochondrion but in studying the associated diseases.

  15. Humanism in emergency medicine.

    PubMed

    Rosenzweig, S

    1993-09-01

    Emergency medicine has not yet appropriated "humanism" as a term of its own. Medical humanism needs to be interpreted in a way that is consistent with the practical goals of emergency medicine. In this essay, humanism in emergency medicine is defined by identifying the dehumanizing aspects of sudden illness and exploring of ways for sustaining the humanity of emergency department patients. Excerpts from Dr Oliver Sacks' autobiographical work A Leg to Stand On give voice to the human needs created by sudden illness and its treatment. PMID:8363690

  16. Human-technology Integration

    NASA Astrophysics Data System (ADS)

    Mullen, Katharine M.

    Human-technology integration is the replacement of human parts and extension of human capabilities with engineered devices and substrates. Its result is hybrid biological-artificial systems. We discuss here four categories of products furthering human-technology integration: wearable computers, pervasive computing environments, engineered tissues and organs, and prosthetics, and introduce examples of currently realized systems in each category. We then note that realization of a completely artificial sytem via the path of human-technology integration presents the prospect of empirical confirmation of an aware artificially embodied system.

  17. Biological races in humans.

    PubMed

    Templeton, Alan R

    2013-09-01

    Races may exist in humans in a cultural sense, but biological concepts of race are needed to access their reality in a non-species-specific manner and to see if cultural categories correspond to biological categories within humans. Modern biological concepts of race can be implemented objectively with molecular genetic data through hypothesis-testing. Genetic data sets are used to see if biological races exist in humans and in our closest evolutionary relative, the chimpanzee. Using the two most commonly used biological concepts of race, chimpanzees are indeed subdivided into races but humans are not. Adaptive traits, such as skin color, have frequently been used to define races in humans, but such adaptive traits reflect the underlying environmental factor to which they are adaptive and not overall genetic differentiation, and different adaptive traits define discordant groups. There are no objective criteria for choosing one adaptive trait over another to define race. As a consequence, adaptive traits do not define races in humans. Much of the recent scientific literature on human evolution portrays human populations as separate branches on an evolutionary tree. A tree-like structure among humans has been falsified whenever tested, so this practice is scientifically indefensible. It is also socially irresponsible as these pictorial representations of human evolution have more impact on the general public than nuanced phrases in the text of a scientific paper. Humans have much genetic diversity, but the vast majority of this diversity reflects individual uniqueness and not race. PMID:23684745

  18. Biological Races in Humans

    PubMed Central

    Templeton, Alan R.

    2013-01-01

    Races may exist in humans in a cultural sense, but biological concepts of race are needed to access their reality in a non-species-specific manner and to see if cultural categories correspond to biological categories within humans. Modern biological concepts of race can be implemented objectively with molecular genetic data through hypothesis-testing. Genetic data sets are used to see if biological races exist in humans and in our closest evolutionary relative, the chimpanzee. Using the two most commonly used biological concepts of race, chimpanzees are indeed subdivided into races but humans are not. Adaptive traits, such as skin color, have frequently been used to define races in humans, but such adaptive traits reflect the underlying environmental factor to which they are adaptive and not overall genetic differentiation, and different adaptive traits define discordant groups. There are no objective criteria for choosing one adaptive trait over another to define race. As a consequence, adaptive traits do not define races in humans. Much of the recent scientific literature on human evolution portrays human populations as separate branches on an evolutionary tree. A tree-like structure among humans has been falsified whenever tested, so this practice is scientifically indefensible. It is also socially irresponsible as these pictorial representations of human evolution have more impact on the general public than nuanced phrases in the text of a scientific paper. Humans have much genetic diversity, but the vast majority of this diversity reflects individual uniqueness and not race. PMID:23684745

  19. Office for Human Research Protections

    MedlinePlus

    ... Office for Human Research Protections The Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and wellbeing of human subjects involved in ...

  20. Human research subjects as human research workers.

    PubMed

    Lynch, Holly Fernandez

    2014-01-01

    Biomedical research involving human subjects has traditionally been treated as a unique endeavor, presenting special risks and demanding special protections. But in several ways, the regulatory scheme governing human subjects research is counter-intuitively less protective than the labor and employment laws applicable to many workers. This Article relies on analogical and legal reasoning to demonstrate that this should not be the case; in a number of ways, human research subjects ought to be fundamentally recast as human research workers. Like other workers protected under worklaw, biomedical research subjects often have interests that diverge from those in positions of control but little bargaining power for change. Bearing these important similarities in mind, the question becomes whether there is any good reason to treat subjects and protected workers differently as a matter of law. With regard to unrestricted payment, eligibility for a minimum wage, compensation for injury, and rights to engage in concerted activity, the answer is no and human subjects regulations ought to be revised accordingly. PMID:25051653

  1. Integrated Environmental Modelling: human decisions, human challenges

    USGS Publications Warehouse

    Glynn, Pierre D.

    2015-01-01

    Integrated Environmental Modelling (IEM) is an invaluable tool for understanding the complex, dynamic ecosystems that house our natural resources and control our environments. Human behaviour affects the ways in which the science of IEM is assembled and used for meaningful societal applications. In particular, human biases and heuristics reflect adaptation and experiential learning to issues with frequent, sharply distinguished, feedbacks. Unfortunately, human behaviour is not adapted to the more diffusely experienced problems that IEM typically seeks to address. Twelve biases are identified that affect IEM (and science in general). These biases are supported by personal observations and by the findings of behavioural scientists. A process for critical analysis is proposed that addresses some human challenges of IEM and solicits explicit description of (1) represented processes and information, (2) unrepresented processes and information, and (3) accounting for, and cognizance of, potential human biases. Several other suggestions are also made that generally complement maintaining attitudes of watchful humility, open-mindedness, honesty and transparent accountability. These suggestions include (1) creating a new area of study in the behavioural biogeosciences, (2) using structured processes for engaging the modelling and stakeholder communities in IEM, and (3) using ‘red teams’ to increase resilience of IEM constructs and use.

  2. Human organ markets and inherent human dignity.

    PubMed

    MacKellar, Calum

    2014-01-01

    It has been suggested that human organs should be bought and sold on a regulated market as any other material property belongingto an individual. This would have the advantage of both addressing the grave shortage of organs available for transplantation and respecting the freedom of individuals to choose to do whatever they want with their body parts. The old arguments against such a market in human organs are, therefore, being brought back into question. The article examines the different arguments both in favour and against the sale of human organs. It concludes that the body and any of its elements is a full expression of the whole person. As such, they cannot have a price if the individual is to retain his or her full inherent dignity and if society is to retain and protect this very important concept. PMID:24979876

  3. Human Performance in Space

    NASA Technical Reports Server (NTRS)

    Jones, Patricia M.; Fiedler, Edna

    2010-01-01

    Human factors is a critical discipline for human spaceflight. Nearly every human factors research area is relevant to space exploration -- from the ergonomics of hand tools used by astronauts, to the displays and controls of a spacecraft cockpit or mission control workstation, to levels of automation designed into rovers on Mars, to organizational issues of communication between crew and ground. This chapter focuses more on the ways in which the space environment (especially altered gravity and the isolated and confined nature of long-duration spaceflight) affects crew performance, and thus has specific novel implications for human factors research and practice. We focus on four aspects of human performance: neurovestibular integration, motor control and musculo-skeletal effects, cognitive effects, and behavioral health. We also provide a sampler of recent human factors studies from NASA.

  4. Human reliability analysis

    SciTech Connect

    Dougherty, E.M.; Fragola, J.R.

    1988-01-01

    The authors present a treatment of human reliability analysis incorporating an introduction to probabilistic risk assessment for nuclear power generating stations. They treat the subject according to the framework established for general systems theory. Draws upon reliability analysis, psychology, human factors engineering, and statistics, integrating elements of these fields within a systems framework. Provides a history of human reliability analysis, and includes examples of the application of the systems approach.

  5. Human target acquisition performance

    NASA Astrophysics Data System (ADS)

    Teaney, Brian P.; Du Bosq, Todd W.; Reynolds, Joseph P.; Thompson, Roger; Aghera, Sameer; Moyer, Steven K.; Flug, Eric; Espinola, Richard; Hixson, Jonathan

    2012-06-01

    The battlefield has shifted from armored vehicles to armed insurgents. Target acquisition (identification, recognition, and detection) range performance involving humans as targets is vital for modern warfare. The acquisition and neutralization of armed insurgents while at the same time minimizing fratricide and civilian casualties is a mounting concern. U.S. Army RDECOM CERDEC NVESD has conducted many experiments involving human targets for infrared and reflective band sensors. The target sets include human activities, hand-held objects, uniforms & armament, and other tactically relevant targets. This paper will define a set of standard task difficulty values for identification and recognition associated with human target acquisition performance.

  6. The psychology of humanness.

    PubMed

    Haslam, Nick; Loughnan, Steve; Holland, Elise

    2013-01-01

    This chapter explores the ways in which the concept of "humanness" illuminates a wide and fascinating variety of psychological phenomena. After introducing the concept--everyday understandings of what it is to be human--we present a model of the diverse ways in which humanness can be denied to people. According to this model people may be perceived as lacking uniquely human characteristics, and thus likened to animals, or as lacking human nature, and thus likened to inanimate objects. Both of these forms of dehumanization occur with varying degrees of subtlety, from the explicit uses of derogatory animal metaphors, to stereotypes that ascribe lesser humanness or simpler minds to particular groups, to nonconscious associations between certain humans and nonhumans. After reviewing research on dehumanization through the lens of our model we examine additional topics that the psychology of humanness clarifies, notably the perception of nonhuman animals and the objectification of women. Humanness emerges as a concept that runs an integrating thread through a variety of research literatures. PMID:23947277

  7. Artificial human vision camera

    NASA Astrophysics Data System (ADS)

    Goudou, J.-F.; Maggio, S.; Fagno, M.

    2014-10-01

    In this paper we present a real-time vision system modeling the human vision system. Our purpose is to inspire from human vision bio-mechanics to improve robotic capabilities for tasks such as objects detection and tracking. This work describes first the bio-mechanical discrepancies between human vision and classic cameras and the retinal processing stage that takes place in the eye, before the optic nerve. The second part describes our implementation of these principles on a 3-camera optical, mechanical and software model of the human eyes and associated bio-inspired attention model.

  8. Robotics for Human Exploration

    NASA Technical Reports Server (NTRS)

    Fong, Terrence; Deans, Mathew; Bualat, Maria

    2013-01-01

    Robots can do a variety of work to increase the productivity of human explorers. Robots can perform tasks that are tedious, highly repetitive or long-duration. Robots can perform precursor tasks, such as reconnaissance, which help prepare for future human activity. Robots can work in support of astronauts, assisting or performing tasks in parallel. Robots can also perform "follow-up" work, completing tasks designated or started by humans. In this paper, we summarize the development and testing of robots designed to improve future human exploration of space.

  9. Developing Human Resources through Actualizing Human Potential

    ERIC Educational Resources Information Center

    Clarken, Rodney H.

    2012-01-01

    The key to human resource development is in actualizing individual and collective thinking, feeling and choosing potentials related to our minds, hearts and wills respectively. These capacities and faculties must be balanced and regulated according to the standards of truth, love and justice for individual, community and institutional development,…

  10. Health and Humanity: Humanities 401 Syllabus.

    ERIC Educational Resources Information Center

    Snowden, Fraser; Taylor, Maxine

    A syllabus for the "Health and Humanities" interdisciplinary course at Northwestern State University, Louisiana, is presented. An introduction suggests that with the proliferation of technological advances in the field of health care, there is a need for reconsideration of many moral, ethical, legal, and humanistic questions. Information is…

  11. The Humanities' Value

    ERIC Educational Resources Information Center

    Harpham, Geoffrey Galt

    2009-01-01

    Why should society support the humanities when so many people are suffering from the effects of the economic crisis? What claim do the humanities, or scholarship generally, have on increasingly limited resources? Shouldn't such pursuits be considered luxuries at a time when people should be focusing on essentials? The alleviation of human…

  12. Human Pythiosis, Brazil

    PubMed Central

    Bosco, Sandra de Moraes Gimenes; Araújo, João Pessoa; Candeias, João Manuel Grisi; Fabiano de Franco, Marcello; Marques, Mariangela Esther Alencar; Mendoza, Leonel; Pires de Camargo, Rosangela; Marques, Silvio Alencar

    2005-01-01

    Pythiosis, caused by Pythium insidiosum, occurs in humans and animals and is acquired from aquatic environments that harbor the emerging pathogen. Diagnosis is difficult because clinical and histopathologic features are not pathognomonic. We report the first human case of pythiosis from Brazil, diagnosed by using culture and rDNA sequencing. PMID:15890126

  13. Human Mind Maps

    ERIC Educational Resources Information Center

    Glass, Tom

    2016-01-01

    When students generate mind maps, or concept maps, the maps are usually on paper, computer screens, or a blackboard. Human Mind Maps require few resources and little preparation. The main requirements are space where students can move around and a little creativity and imagination. Mind maps can be used for a variety of purposes, and Human Mind…

  14. Human Powered Centrifuge

    NASA Technical Reports Server (NTRS)

    Mulenburg, Gerald M. (Inventor); Vernikos, Joan (Inventor)

    1997-01-01

    A human powered centrifuge has independently established turntable angular velocity and human power input. A control system allows excess input power to be stored as electric energy in a battery or dissipated as heat through a resistors. In a mechanical embodiment, the excess power is dissipated in a friction brake.

  15. Human Sociobiology: Wilson's Fallacy.

    ERIC Educational Resources Information Center

    Lehrman, Nathaniel S.

    1981-01-01

    Presents an introduction to and a critique of E.O. Wilson's new science of sociobiology, which focuses on explaining the social behavior of species as diverse as ants, apes, and humans. Suggests that Wilson has gone beyond his data in claiming that complex human behaviors such as altruism are caused to any extent by genetic, as opposed to…

  16. Manage "Human Capital" Strategically

    ERIC Educational Resources Information Center

    Odden, Allan

    2011-01-01

    To strategically manage human capital in education means restructuring the entire human resource system so that schools not only recruit and retain smart and capable individuals, but also manage them in ways that support the strategic directions of the organization. These management practices must be aligned with a district's education improvement…

  17. Quantification of human responses

    NASA Technical Reports Server (NTRS)

    Steinlage, R. C.; Gantner, T. E.; Lim, P. Y. W.

    1992-01-01

    Human perception is a complex phenomenon which is difficult to quantify with instruments. For this reason, large panels of people are often used to elicit and aggregate subjective judgments. Print quality, taste, smell, sound quality of a stereo system, softness, and grading Olympic divers and skaters are some examples of situations where subjective measurements or judgments are paramount. We usually express what is in our mind through language as a medium but languages are limited in available choices of vocabularies, and as a result, our verbalizations are only approximate expressions of what we really have in mind. For lack of better methods to quantify subjective judgments, it is customary to set up a numerical scale such as 1, 2, 3, 4, 5 or 1, 2, 3, ..., 9, 10 for characterizing human responses and subjective judgments with no valid justification except that these scales are easy to understand and convenient to use. But these numerical scales are arbitrary simplifications of the complex human mind; the human mind is not restricted to such simple numerical variations. In fact, human responses and subjective judgments are psychophysical phenomena that are fuzzy entities and therefore difficult to handle by conventional mathematics and probability theory. The fuzzy mathematical approach provides a more realistic insight into understanding and quantifying human responses. This paper presents a method for quantifying human responses and subjective judgments without assuming a pattern of linear or numerical variation for human responses. In particular, quantification and evaluation of linguistic judgments was investigated.

  18. IMMUNOASSAY HUMAN EXPOSURE STUDIES

    EPA Science Inventory

    The Human Exposure Research Branch has developed several enzyme-linked immunosorbent assay (ELISA) methods to support human exposure assessment studies. Immunoassays to detect low levels (<10 ng/mL) of chlorpyrifos in food, track-in dirt and house dust have been applied to sam...

  19. Human Simulated Diving Experiments.

    ERIC Educational Resources Information Center

    Bruce, David S.; Speck, Dexter F.

    1979-01-01

    This report details several simulated divinq experiments on the human. These are suitable for undergraduate or graduate laboratories in human or environmental physiology. The experiment demonstrates that a diving reflex is precipitated by both facial cooling and apnea. (Author/RE)

  20. Assessment of Human Factors

    NASA Technical Reports Server (NTRS)

    Mount, Frances; Foley, Tico

    1999-01-01

    Human Factors Engineering, often referred to as Ergonomics, is a science that applies a detailed understanding of human characteristics, capabilities, and limitations to the design, evaluation, and operation of environments, tools, and systems for work and daily living. Human Factors is the investigation, design, and evaluation of equipment, techniques, procedures, facilities, and human interfaces, and encompasses all aspects of human activity from manual labor to mental processing and leisure time enjoyments. In spaceflight applications, human factors engineering seeks to: (1) ensure that a task can be accomplished, (2) maintain productivity during spaceflight, and (3) ensure the habitability of the pressurized living areas. DSO 904 served as a vehicle for the verification and elucidation of human factors principles and tools in the microgravity environment. Over six flights, twelve topics were investigated. This study documented the strengths and limitations of human operators in a complex, multifaceted, and unique environment. By focusing on the man-machine interface in space flight activities, it was determined which designs allow astronauts to be optimally productive during valuable and costly space flights. Among the most promising areas of inquiry were procedures, tools, habitat, environmental conditions, tasking, work load, flexibility, and individual control over work.

  1. Introduction to human factors

    SciTech Connect

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems. (LEW)

  2. Evaluating the Humanities

    ERIC Educational Resources Information Center

    Brody, Howard

    2013-01-01

    How can one measure the value of teaching the humanities? The problem of assessment and accountability is prominent today, of course, in secondary and higher education. It is perhaps even more acute for those who teach the humanities in nontraditional settings, such as medical and other professional schools. The public assumes that academes can…

  3. Environment and the Humanities.

    ERIC Educational Resources Information Center

    Allen, Rodney F., Ed.; And Others

    As a conference report, the booklet is primarily devoted to abstracts of papers presented at a Conference on Environment and Humanities held in Tallahassee, Florida, April 25-27, 1976. Dr. Huston Smith of Syracuse University, the main speaker, addressed the issue of "Humanities and Environmental Awareness." Other topics discussed included: (1)…

  4. Teaching Human Rights Law.

    ERIC Educational Resources Information Center

    Berman, Howard R.

    1985-01-01

    The international community has developed a system of human rights law relevant to many areas of legal encounter, which American law schools have been slow to incorporate into curricula. Teaching human rights law provides an opportunity for law schools to enrich the learning process and contribute creatively to the respect for rights in society.…

  5. Neurobehavioral testing in humans.

    PubMed

    Anger, W K; Rohlman, D S; Storzbach, D

    2001-05-01

    The evaluation of the effects of chemical exposures on humans is a worldwide concern, and most chemicals have not been evaluated for neurotoxic effect. Human neurobehavioral research or clinical evaluations of populations exposed to chemicals must be carefully planned and structured. This unit describes the steps required to create such a study, select the appropriate measures, and evaluate the results. PMID:20957644

  6. Humanism within Globalization

    ERIC Educational Resources Information Center

    Weber, Jennifer E.

    2014-01-01

    The complexity of adult learning connects it to almost all other facets of human endeavor. Consequently, the future of adult education depends, to a large extent on who participates and the quality of such participation. Quality participation, when teamed with environments committed to a concern for humanity, launches opportunities for varied…

  7. Methods in human cytogenetics

    SciTech Connect

    1993-12-31

    Chapter 4, discusses the various techniques used in the study human cytogenetics. The methods are discussed in historical order, from direct methods to tissue culture techniques, prenatal studies, meiotic studies, sex chromatin techniques, banding techniques, prophase banding and replication studies. Nomenclature of human chromosomes and quantitative methods are also mentioned. 60 refs., 3 figs.

  8. Humane Education Projects Handbook.

    ERIC Educational Resources Information Center

    Junior League of Ogden, UT.

    This handbook was developed to promote interest in humane education and to encourage the adoption of humane education projects. Although specifically designed to assist Junior Leagues in developing such projects, the content should prove valuable to animal welfare organizations, zoos, aquariums, nature centers, and other project-oriented groups…

  9. HSI in Human Spaceflight

    NASA Technical Reports Server (NTRS)

    Baggerman, Susan D.

    2007-01-01

    This viewgraph document examines the scope of Human Systems Integration (HSI) at NASA, and the implementation of HSI in the human space flight programs. Two areas of interest are the Responsibilities and the lessons learned from the International Space Station and the strategy and approach for the Crew Exploration Vehicle.

  10. Human Granulocytic Anaplasmosis, Japan

    PubMed Central

    Gaowa; Wuritu; Kawamori, Fumihiko; Wu, Dongxing; Yoshikawa, Yuko; Chiya, Seizou; Fukunaga, Kazutoshi; Funato, Toyohiko; Shiojiri, Masaaki; Nakajima, Hideki; Hamauzu, Yoshiji; Takano, Ai; Kawabata, Hiroki; Ando, Shuji; Kishimoto, Toshio

    2013-01-01

    We retrospectively confirmed 2 cases of human Anaplasma phagocytophilum infection. Patient blood samples contained unique p44/msp2 for the pathogen, and antibodies bound to A. phagocytophilum antigens propagated in THP-1 rather than HL60 cells. Unless both cell lines are used for serodiagnosis of rickettsiosis-like infections, cases of human granulocytic anaplasmosis could go undetected. PMID:23460988

  11. Human Space Flight

    NASA Technical Reports Server (NTRS)

    Woolford, Barbara; Mount, Frances

    2004-01-01

    The first human space flight, in the early 1960s, was aimed primarily at determining whether humans could indeed survive and function in micro-gravity. Would eating and sleeping be possible? What mental and physical tasks could be performed? Subsequent programs increased the complexity of the tasks the crew performed. Table 1 summarizes the history of U.S. space flight, showing the projects, their dates, crew sizes, and mission durations. With over forty years of experience with human space flight, the emphasis now is on how to design space vehicles, habitats, and missions to produce the greatest returns to human knowledge. What are the roles of the humans in space flight in low earth orbit, on the moon, and in exploring Mars?

  12. Mars Human Exploration Objectives

    NASA Technical Reports Server (NTRS)

    Briggs, Geoff

    1998-01-01

    This paper reviews the objectives and other considerations of Human exploration of Mars. The objectives of human exploration of Mars are: (1) to learn how Mars is similar to, and different from, Earth; (2) to explore possible life, past and present; (3) to discover what Mars is like now from the perspective of Geoscience and geologic history; and (4) how did Mars form and how did its formation differ from Earth. Considerations of human Martian exploration involve: (1) having a capable base laboratory; (2) having long range transportation; (3) having operational autonomy of the crew, and the requirement of the crew to possess a range of new cognitive processes along with easy communications with terrestrial colleagues; and finally (4) creating the human habitat along with human factors which involve more than just survivability.

  13. Humanization of immunotoxins.

    PubMed

    Rybak, S M; Hoogenboom, H R; Meade, H M; Raus, J C; Schwartz, D; Youle, R J

    1992-04-15

    The construction and expression of a chimeric gene encoding a mouse/human antibody to the human transferrin receptor fused to the gene for angiogenin, a human homolog of pancreatic RNase, are described. F(ab')2-like antibody-enzyme fusions were prepared by linking the gene for human angiogenin to a chimeric anti-transferrin receptor heavy chain gene. The antibody-enzyme fusion gene was introduced into a transfectoma that secretes the chimeric light chain of the same antibody, and cell lines were cloned that synthesize and secrete the antibody-enzyme fusion protein of the expected size at a concentration of 1-5 ng/ml. Culture supernatants from clones secreting the fusion protein caused inhibition of growth and protein synthesis of K562 cells that express the human transferrin receptor but not toward a non-human-derived cell line that lacks this receptor. Whereas excess antibody to the same receptor did not itself inhibit protein synthesis, it was able to completely prevent the protein synthesis inhibition caused by the fusion protein. These results indicate that the cytotoxicity is due to a transferrin receptor-mediated mechanism involving the angiogenin portion of the fusion protein and demonstrate the feasibility of constructing recombinant antibody-RNase molecules capable of killing tumor cells bearing the transferrin receptor. The significance of the acquired cytotoxicity of a mouse/human chimeric antibody linked to a human protein may bear importantly in human therapeutic strategies that use mouse antibodies linked to toxins from plants or bacteria to target tumor cells. It is expected that the humanization of immunotoxins will lead to less toxicity and immunogenicity than currently available reagents. PMID:1565609

  14. Novel human astroviruses: Novel human diseases?

    PubMed

    Vu, Diem-Lan; Cordey, Samuel; Brito, Francisco; Kaiser, Laurent

    2016-09-01

    Astroviruses are small, non-enveloped, single-stranded positive RNA viruses that belong to the Astroviridae family. While classical human astroviruses (HAstV) are a well-recognized cause of acute non-bacterial diarrhea among young children worldwide, novel astroviruses, named HAstV-MLB and HAstV-VA/HMO, have been identified recently in humans by molecular assays. They are phylogenetically more related to animal astroviruses than to classical human astroviruses, thus suggesting cross-species transmission. Serological studies demonstrated a surprisingly high seroprevalence in certain populations and highlighted a high infection rate in the early years of life. Although their pathogenic role has not yet been clearly determined, novel astrovirus RNA sequences have been identified in different biological specimens of symptomatic patients, including the feces, plasma, cerebrospinal fluid, and brain biopsies. Thus, there is evidence that they could contribute not only to digestive tract infection, but also to unexpected clinical syndromes, notably encephalitis and meningitis. Severe infections affect mainly immunocompromised patients. These findings indicate that novel astroviruses should be considered in the differential diagnosis of immunocompromised patients with meningitis or encephalitis of unknown origin. PMID:27434149

  15. Archaea on human skin.

    PubMed

    Probst, Alexander J; Auerbach, Anna K; Moissl-Eichinger, Christine

    2013-01-01

    The recent era of exploring the human microbiome has provided valuable information on microbial inhabitants, beneficials and pathogens. Screening efforts based on DNA sequencing identified thousands of bacterial lineages associated with human skin but provided only incomplete and crude information on Archaea. Here, we report for the first time the quantification and visualization of Archaea from human skin. Based on 16 S rRNA gene copies Archaea comprised up to 4.2% of the prokaryotic skin microbiome. Most of the gene signatures analyzed belonged to the Thaumarchaeota, a group of Archaea we also found in hospitals and clean room facilities. The metabolic potential for ammonia oxidation of the skin-associated Archaea was supported by the successful detection of thaumarchaeal amoA genes in human skin samples. However, the activity and possible interaction with human epithelial cells of these associated Archaea remains an open question. Nevertheless, in this study we provide evidence that Archaea are part of the human skin microbiome and discuss their potential for ammonia turnover on human skin. PMID:23776475

  16. Human Space Exploration

    NASA Technical Reports Server (NTRS)

    Jeevarajan, Antony

    2014-01-01

    The Mars probe, launched by India a few months ago, is on its way to Mars. At this juncture, it is appropriate to talk about the opportunities presented to us for the Human Exploration of Mars. I am planning to highlight some of the challenges to take humans to Mars, descend, land, stay, ascend and return home safely. The logistics of carrying the necessary accessories to stay at Mars will be delivered in multiple stages using robotic missions. The primary ingredients for human survival is air, water, food and shelter and the necessity to recycle the primary ingredients will be articulated. Humans have to travel beyond the van Allen radiation belt under microgravity condition during this inter-planetary travel for about 6 months minimum one way. The deconditioning of human system under microgravity conditions and protection of humans from Galactic cosmic radiation during the travel should be taken into consideration. The multi-disciplinary effort to keep the humans safe and functional during this journey will be addressed.

  17. The human genome project

    SciTech Connect

    Bell, G.I.

    1991-06-01

    The Human Genome Project will obtain high-resolution genetic and physical maps of each human chromosome and, somewhat later, of the complete nucleotide sequence of the deoxyribonucleic acid (DNA) in a human cell. The talk will begin with an extended introduction to explain the Project to nonbiologists and to show that map construction and sequence determination require extensive computation in order to determine the correct order of the mapped entities and to provide estimates of uncertainty. Computational analysis of the sequence data will become an increasingly important part of the project, and some computational challenges are described. 5 refs.

  18. Human Computer Interaction

    NASA Astrophysics Data System (ADS)

    Bhagwani, Akhilesh; Sengar, Chitransh; Talwaniper, Jyotsna; Sharma, Shaan

    2012-08-01

    The paper basically deals with the study of HCI (Human computer interaction) or BCI(Brain-Computer-Interfaces) Technology that can be used for capturing brain signals and translating them into commands that allow humans to control (just by thinking) devices such as computers, robots, rehabilitation technology and virtual reality environments. The HCI is based as a direct communication pathway between the brain and an external device. BCIs are often aimed at assisting, augmenting, or repairing human cognitive or sensory-motor functions.The paper also deals with many advantages of BCI Technology along with some of its applications and some major drawbacks.

  19. Managing human bites

    PubMed Central

    Patil, Pradnya D; Panchabhai, Tanmay S; Galwankar, Sagar C

    2009-01-01

    Human bites are frequently overlooked in making a diagnosis in the emergency room. They are particularly notorious due to the polymicrobial nature of human saliva inoculated in the wound and the risk they pose for transmission of infectious diseases. Early treatment, appropriate prophylaxis and surgical evaluation are the key to achieving desired treatment outcomes. Through this article, we have tried to summarize the diagnostic features, complications as well as the recommended treatment alternatives for human bites based on the current available evidence. PMID:20009309

  20. Human Genome Project

    SciTech Connect

    Block, S.; Cornwall, J.; Dally, W.; Dyson, F.; Fortson, N.; Joyce, G.; Kimble, H. J.; Lewis, N.; Max, C.; Prince, T.; Schwitters, R.; Weinberger, P.; Woodin, W. H.

    1998-01-04

    The study reviews Department of Energy supported aspects of the United States Human Genome Project, the joint National Institutes of Health/Department of Energy program to characterize all human genetic material, to discover the set of human genes, and to render them accessible for further biological study. The study concentrates on issues of technology, quality assurance/control, and informatics relevant to current effort on the genome project and needs beyond it. Recommendations are presented on areas of the genome program that are of particular interest to and supported by the Department of Energy.

  1. Human Photoreactivating Enzyme

    PubMed Central

    Sutherland, J. C.; Sutherland, B. M.

    1975-01-01

    The action spectrum for photoreactivation by enzymes from human leukocytes and fibroblasts extends from 300 to approximately 600 nm with a maximum near 400 nm. The ability of the human enzymes to utilize light of wavelengths greater than 500 nm suggested that yellow or gold lights conventionally used as safelights for photoreactivation might serve as sources of photoreactivating light for these enzymes. Experiments using lights with a range of spectral outputs confirm that the standard yellow “safe” lights do produce photoreactivation by the human but not the Escherichia coli enzyme. PMID:19211015

  2. Human pancreas development.

    PubMed

    Jennings, Rachel E; Berry, Andrew A; Strutt, James P; Gerrard, David T; Hanley, Neil A

    2015-09-15

    A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes. PMID:26395141

  3. The Concept of Being Human.

    ERIC Educational Resources Information Center

    Purcell, Royal

    This analysis of the relationship between humanism and humanitarianism outlines educational goals that should lead to a more humane world. Section 1, an outline of human life examines six substructures--human life, individuality, amenity, contact, actualization, and problems. A definition and examples of humanism in section 2 are elaborated into a…

  4. Human Reliability Program Overview

    SciTech Connect

    Bodin, Michael

    2012-09-25

    This presentation covers the high points of the Human Reliability Program, including certification/decertification, critical positions, due process, organizational structure, program components, personnel security, an overview of the US DOE reliability program, retirees and academia, and security program integration.

  5. Sociobiology and Humanism.

    ERIC Educational Resources Information Center

    Hoult, Thomas Ford

    1979-01-01

    Describes the fundamental conflict between the implications of sociobiology and the aspirations of humanists. Sociobiology tends to rationalize and defend special privileges for the powerful few, while humanism stresses equality of opportunity. Journal availability: see SO 507 272. (Author)

  6. Aerospace Human Factors

    NASA Technical Reports Server (NTRS)

    Jordan, Kevin

    1999-01-01

    The following contains the final report on the activities related to the Cooperative Agreement between the human factors research group at NASA Ames Research Center and the Psychology Department at San Jose State University. The participating NASA Ames division has been, as the organization has changed, the Aerospace Human Factors Research Division (ASHFRD and Code FL), the Flight Management and Human Factors Research Division (Code AF), and the Human Factors Research and Technology Division (Code IH). The inclusive dates for the report are November 1, 1984 to January 31, 1999. Throughout the years, approximately 170 persons worked on the cooperative agreements in one capacity or another. The Cooperative Agreement provided for research personnel to collaborate with senior scientists in ongoing NASA ARC research. Finally, many post-MA/MS and post-doctoral personnel contributed to the projects. It is worth noting that 10 former cooperative agreement personnel were hired into civil service positions directly from the agreements.

  7. Human Biomass Consumption

    NASA Video Gallery

    Humans are using an increasing amount of Earth’s annual production of plants. Research shows that, from 1995 to 2005, consumption rose from 20 to 25 percent of the planet's annual production. Wha...

  8. Creativity: The Human Resource.

    ERIC Educational Resources Information Center

    Lewis, Richard W.

    1979-01-01

    The author discusses an exhibition entitled "Creativity--The Human Resource." The exhibition examines the work of 15 Americans, such as designer Buckminster Fuller and artist Judy Chicago, who have contributed in special ways to the arts and sciences. (PHR)

  9. Pesticides and Human Health

    MedlinePlus

    ... Control a pest Integrated Pest Management What are pesticides? Herbicides Disinfectants Fungicides Insecticides Natural and Biological Pesticides ... Rodenticides Other types of pesticides Disponible en español Pesticides and Human Health Pesticides have a specific purpose ...

  10. Teaching about Human Geography.

    ERIC Educational Resources Information Center

    Schlene, Vickie J.

    1991-01-01

    Presents a sampling of items from the ERIC database concerning the teaching of human geography. Includes documents dealing with Africa, Asia, the United States, Canada, Antarctica, and geographic concepts. Explains how to obtain ERIC documents. (SG)

  11. Approaches to Human Communication.

    ERIC Educational Resources Information Center

    Budd, Richard W., Ed.; Ruben, Brent D., Ed.

    This anthology of essays approaches human communication from the points of view of: anthropology, art biology, economics, encounter groups, semantics, general system theory, history, information theory, international behavior, journalism, linguistics, mass media, neurophysiology, nonverbal behavior, organizational behavior, philosophy, political…

  12. HPV (Human Papillomavirus)

    MedlinePlus

    ... Health Topics Mammography Women and Diabetes HPV, HIV, Birth Control Heart Health for Women Pregnancy Menopause More Women's Health Topics Resources for You Human Papillomavirus Vaccine HPV Information in Other Languages Women ...

  13. Statement on Human Cloning

    MedlinePlus

    ... form Search American Association for the Advancement of Science Statement on Human Cloning Print Email Tweet The American Association for the Advancement of Science (AAAS) recognizes the intense debates within our society ...

  14. Human Resource Planning

    ERIC Educational Resources Information Center

    Hoffman, W. H.; Wyatt, L. L.

    1977-01-01

    By using the total resource approach, we have focused attention on the need to integrate human resource planning with other business plans and highlighted the importance of a productivity strategy. (Author)

  15. Human Systems Integration Introduction

    NASA Video Gallery

    This lecture provides an overview of Human Systems Integration (HSI), its implementation cost and return on investment, HSI domains, how HSI fits into the NASA organization structure, HSI roles and...

  16. Human Computers 1947

    NASA Technical Reports Server (NTRS)

    1947-01-01

    Langley's human computers at work in 1947. The female presence at Langley, who performed mathematical computations for male staff. Photograph published in Winds of Change, 75th Anniversary NASA publication (page 48), by James Schultz.

  17. The Human Hazard.

    ERIC Educational Resources Information Center

    Tickell, Crispin

    1995-01-01

    Examines the plight of environmental refugees and the adequacy of political responses to the situation. Discusses the consequences of accelerated environmental change, particularly the impact of global warming on human migration. (LZ)

  18. Habitability and Human Factors Contributions to Human Space Flight

    NASA Technical Reports Server (NTRS)

    Sumaya, Jennifer Boyer

    2011-01-01

    This slide presentation reviews the work of the Habitability and Human Factors Branch in support of human space flight in two main areas: Applied support to major space programs, and Space research. The field of Human Factors applies knowledge of human characteristics for the design of safer, more effective, and more efficient systems. This work is in several areas of the human space program: (1) Human-System Integration (HSI), (2) Orion Crew Exploration Vehicle, (3) Extravehicular Activity (EVA), (4) Lunar Surface Systems, (5) International Space Station (ISS), and (6) Human Research Program (HRP). After detailing the work done in these areas, the facilities that are available for human factors work are shown.

  19. Human Assisted Assembly Processes

    SciTech Connect

    CALTON,TERRI L.; PETERS,RALPH R.

    2000-01-01

    Automatic assembly sequencing and visualization tools are valuable in determining the best assembly sequences, but without Human Factors and Figure Models (HFFMs) it is difficult to evaluate or visualize human interaction. In industry, accelerating technological advances and shorter market windows have forced companies to turn to an agile manufacturing paradigm. This trend has promoted computerized automation of product design and manufacturing processes, such as automated assembly planning. However, all automated assembly planning software tools assume that the individual components fly into their assembled configuration and generate what appear to be a perfectly valid operations, but in reality the operations cannot physically be carried out by a human. Similarly, human figure modeling algorithms may indicate that assembly operations are not feasible and consequently force design modifications; however, if they had the capability to quickly generate alternative assembly sequences, they might have identified a feasible solution. To solve this problem HFFMs must be integrated with automated assembly planning to allow engineers to verify that assembly operations are possible and to see ways to make the designs even better. Factories will very likely put humans and robots together in cooperative environments to meet the demands for customized products, for purposes including robotic and automated assembly. For robots to work harmoniously within an integrated environment with humans the robots must have cooperative operational skills. For example, in a human only environment, humans may tolerate collisions with one another if they did not cause much pain. This level of tolerance may or may not apply to robot-human environments. Humans expect that robots will be able to operate and navigate in their environments without collisions or interference. The ability to accomplish this is linked to the sensing capabilities available. Current work in the field of cooperative

  20. Pushing Human Frontiers

    NASA Technical Reports Server (NTRS)

    Zubrin, Robert

    2005-01-01

    With human colonization of Mars, I think you will see a higher standard of civilization, just as America set a higher standard of civilization which then promulgated back into Europe. I think that if you want to maximize human potential, you need a higher standard of civilization, and that becomes an example that benefits everyone. Without an open frontier, closed world ideologies, such as the Malthus Theory, tend to come to the forefront. It is that there are limited resources; therefore, we are all in deadly competition with each other for the limited pot. The result is tyrannical and potentially genocidal regimes, and we've already seen this in the twentieth century. There s no truth in the Malthus Theory, because human beings are the creators of their resources. With every mouth comes a pair of hands and a brain. But if it seems to be true, you have a vector in this direction, and it is extremely unfortunate. It is only in a universe of infinite resources that all humans can be brothers and sisters. The fundamental question which affects humanity s sense of itself is whether the world is changeable or fixed. Are we the makers of our world or just its inhabitants? Some people have a view that they re living at the end of history within a world that s already defined, and there is no fundamental purpose to human life because there is nothing humans can do that matters. On the other hand, if humans understand their own role as the creators of their world, that s a much more healthy point of view. It raises the dignity of humans. Indeed, if we do establish a new branch of human civilization on Mars that grows in time and potency to the point where it cannot really settle Mars, but transforms Mars, and brings life to Mars, we will prove to everyone and for all time the precious and positive nature of the human species and every member of it.

  1. Humans in space.

    PubMed

    White, R J; Averner, M

    2001-02-22

    Many successful space missions over the past 40 years have highlighted the advantages and necessity of humans in the exploration of space. But as space travel becomes ever more feasible in the twenty-first century, the health and safety of future space explorers will be paramount. In particular, understanding the risks posed by exposure to radiation and extended weightlessness will be crucial if humans are to travel far from Earth. PMID:11234026

  2. Mapping the human genome

    SciTech Connect

    Annas, G.C.; Elias, S.

    1992-01-01

    This article is a review of the book Mapping the Human Genome: Using Law and Ethics as Guides, edited by George C. Annas and Sherman Elias. The book is a collection of essays on the subject of using ethics and laws as guides to justify human gene mapping. It addresses specific issues such problems related to eugenics, patents, insurance as well as broad issues such as the societal definitions of normality.

  3. Meeting human needs

    NASA Technical Reports Server (NTRS)

    Nicogossian, Arnauld E.

    1992-01-01

    The degree of autonomy of future long duration manned missions will emphasize interactions between human operators and automated systems aimed at the most effective allocations of tasks between humans and machines. Knowledge of crewmembers' physical status, encompassing both capabilities and limitations, will also be critical during EVA and planetary roving missions; psychological evaluation and support, with a view to both individual health and group cohesion and productivity, may become a critical consideration. Attention is here given to crewmembers' medical and psychological vulnerabilities.

  4. Human ocular anatomy.

    PubMed

    Kels, Barry D; Grzybowski, Andrzej; Grant-Kels, Jane M

    2015-01-01

    We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes. PMID:25704934

  5. Human exploration mission studies

    NASA Technical Reports Server (NTRS)

    Cataldo, Robert L.

    1990-01-01

    This paper describes several case studies of human space exploration, considered by the NASA's Office of Exploration in 1988. Special attention is given to the mission scenarios, the critical technology required in these expeditions, and the extraterrestrial power requirements of significant system elements. The cases examined include a manned expedition to Phobos, the inner Martian moon; a human expedition to Mars; the Lunar Observatory; and a lunar outpost to early Mars evolution.

  6. The human oncogenic viruses

    SciTech Connect

    Luderer, A.A.; Weetall, H.H

    1986-01-01

    This book contains eight selections. The titles are: Cytogenetics of the Leukemias and Lymphomas; Cytogenetics of Solid Tumors: Renal Cell Carcinoma, Malignant Melanoma, Retinoblastoma, and Wilms' Tumor; Elucidation of a Normal Function for a Human Proto-Oncogene; Detection of HSV-2 Genes and Gene Products in Cervical Neoplasia; Papillomaviruses in Anogennital Neoplasms; Human Epstein-Barr Virus and Cancer; Hepatitis B Virus and Hepatocellular Carcinoma; and Kaposi's Sarcoma: Acquired Immunodeficiency Syndrome (AIDS) and Associated Viruses.

  7. Evolution and human sexuality.

    PubMed

    Gray, Peter B

    2013-12-01

    The aim of this review is to put core features of human sexuality in an evolutionary light. Toward that end, I address five topics concerning the evolution of human sexuality. First, I address theoretical foundations, including recent critiques and developments. While much traces back to Darwin and his view of sexual selection, more recent work helps refine the theoretical bases to sex differences and life history allocations to mating effort. Second, I consider central models attempting to specify the phylogenetic details regarding how hominin sexuality might have changed, with most of those models honing in on transitions from a possible chimpanzee-like ancestor to the slightly polygynous and long-term bonded sociosexual partnerships observed among most recently studied hunter-gatherers. Third, I address recent genetic and physiological data contributing to a refined understanding of human sexuality. As examples, the availability of rapidly increasing genomic information aids comparative approaches to discern signals of selection in sexuality-related phenotypes, and neuroendocrine studies of human responses to sexual stimuli provide insight into homologous and derived mechanisms. Fourth, I consider some of the most recent, large, and rigorous studies of human sexuality. These provide insights into sexual behavior across other national samples and on the Internet. Fifth, I discuss the relevance of a life course perspective to understanding the evolution of human sexuality. Most research on the evolution of human sexuality focuses on young adults. Yet humans are sexual beings from gestation to death, albeit in different ways across the life course, and in ways that can be theoretically couched within life history theory. PMID:24151100

  8. Human immunoglobulin allotypes

    PubMed Central

    Lefranc, Marie-Paule

    2009-01-01

    More than twenty recombinant monoclonal antibodies are approved as therapeutics. Almost all of these are based on the whole IgG isotype format, but vary in the origin of the variable regions between mouse (chimeric), humanized mouse and fully human sequences; all of those with whole IgG format employ human constant region sequences. Currently, the opposing merits of the four IgG subclasses are considered with respect to the in vivo biological activities considered to be appropriate to the disease indication being treated. Human heavy chain genes also exhibit extensive structural polymorphism(s) and, being closely linked, are inherited as a haplotype. Polymorphisms (allotypes) within the IgG isotype were originally discovered and described using serological reagents derived from humans; demonstrating that allotypic variants can be immunogenic and provoke antibody responses as a result of allo-immunization. The serologically defined allotypes differ widely within and between population groups; therefore, a mAb of a given allotype will, inevitably, be delivered to a cohort of patients homozygous for the alternative allotype. This publication reviews the serologically defined human IgG allotypes and considers the potential for allotype differences to contribute to or potentiate immunogenicity. PMID:20073133

  9. Human Factors Review Plan

    SciTech Connect

    Paramore, B.; Peterson, L.R.

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

  10. The human telomere

    SciTech Connect

    Moyzis, R.K.

    1989-01-01

    An ultimate goal of human genetics is the generation of a complete physical and ''functional'' map of the human genome. Twenty-five percent of human DNA, however, consists of repetitive DNA sequences. These repetitive DNA sequences are thought to arise by many mechanisms, from direct sequence amplification by the unequal recombination of homologous DNA regions to the reverse flow of genetic information. A general outline of the chromosomal organization of these repetitive sequences will be discussed. Our working hypothesis is that certain classes of human repetitive DNA sequences ''encode'' the information necessary for defining long-range genomic structure. Evidence will be presented that the first goal of this research, the identification and cloning of the human telomere, has been achieved. A human repetitive DNA library was constructed from randomly sheared, reassociated, and oligo(G/center dot/C)-tailed DNA, a method that minimizes the potential loss of sequences devoid of a given restriction enzyme site. Sequences too large to clone efficiently in cosmid or /lambda/ vectors, such as centromeric repeats, or telomeric sequences with an end incompatible for cloning, should be present in this library. In order to isolate highly conserved repetitive DNA sequences, this library was screened with radiolabeled hamster Cot50 repetitive DNA. Two clones, containing tandem arrays of the sequence (TTAGGG), were isolated by this method. 30 refs., 1 fig., 2 tabs.

  11. Human bites - self-care

    MedlinePlus

    Bites - human - self-care ... Human bites can occur in two ways: If someone bites you If your hand comes into contact ... bite to express anger or other negative feelings. Human bites may be more dangerous than animal bites. ...

  12. Human behavior and human performance: Psychomotor demands

    NASA Technical Reports Server (NTRS)

    1992-01-01

    The results of several experiments are presented in abstract form. These studies are critical for the interpretation and acceptance of flight based science to be conducted by the Behavior and Performance project. Some representative titles are as follow: External audio for IBM/PC compatible computers; A comparative assessment of psychomotor performance (target prediction by humans and macaques); Response path (a dependent measure for computer maze solving and other tasks); Behavioral asymmetries of psychomotor performance in Rhesus monkey (a dissociation between hand preference and skill); Testing primates with joystick based automated apparatus; and Environmental enrichment and performance assessment for ground or flight based research with primates;

  13. Developing Human Performance Measures

    SciTech Connect

    Jeffrey Joe; Bruce Hallbert; Larry Blackwood; Donald Dudehoeffer; Kent Hansen

    2006-05-01

    Through the reactor oversight process (ROP), the U.S. Nuclear Regulatory Commission (NRC) monitors the performance of utilities licensed to operate nuclear power plants. The process is designed to assure public health and safety by providing reasonable assurance that licensees are meeting the cornerstones of safety and designated crosscutting elements. The reactor inspection program, together with performance indicators (PIs), and enforcement activities form the basis for the NRC’s risk-informed, performance based regulatory framework. While human performance is a key component in the safe operation of nuclear power plants and is a designated cross-cutting element of the ROP, there is currently no direct inspection or performance indicator for assessing human performance. Rather, when human performance is identified as a substantive cross cutting element in any 1 of 3 categories (resources, organizational or personnel), it is then evaluated for common themes to determine if follow-up actions are warranted. However, variability in human performance occurs from day to day, across activities that vary in complexity, and workgroups, contributing to the uncertainty in the outcomes of performance. While some variability in human performance may be random, much of the variability may be attributed to factors that are not currently assessed. There is a need to identify and assess aspects of human performance that relate to plant safety and to develop measures that can be used to successfully assure licensee performance and indicate when additional investigation may be required. This paper presents research that establishes a technical basis for developing human performance measures. In particular, we discuss: 1) how historical data already gives some indication of connection between human performance and overall plant performance, 2) how industry led efforts to measure and model human performance and organizational factors could serve as a data source and basis for a

  14. Meeting human needs

    NASA Technical Reports Server (NTRS)

    Nicogossian, Arnauld E.

    1992-01-01

    Manned space flight can be viewed as an interaction of three general elements: the human crewmember, spacecraft systems, and the environment. While the human crewmember is a crucial element in the system, certain physiological, psychological, environ- mental and spacecraft systems factors can compromise human performance in space. These factors include atmospheric pressure, physiology, uncertainties associated with space radiation, the potential for exposure to toxic materials in the closed environment, and spacecraft habitability. Health protection in space, for current and future missions, relies on a philosophy of risk reduction, which in the space program is achieved in four ways-through health maintenance, health care, design criteria, an selection and training. Emphasis is place upon prevention, through selection criteria and careful screening. Spacecraft health care systems must be absolutely reliable, and they will be automated and computerized to the maximum extent possible, but still designed with the human crewmember's capabilities in mind. The autonomy and technological sophistication of future missions will require a greater emphasis on high-level interaction between the human operator and automated systems, with effective allocation of tasks between humans and machines. Performance in space will include complex tasks during extravehicular activity (EVA) and on planetary surfaces, and knowledge of crewmembers' capability and limitations during such operations will be critical to mission success. Psychological support will become increasingly important on space missions, as crews spend long periods in remote and potentially hazardous environments. The success of future missions will depend on both individual psychological health and group cohesion and productivity, particularly as crew profiles become more heterogeneous. Thus, further human factors are needed in the area of small-group dynamics and performance.

  15. Spaceflight Human System Standards

    NASA Technical Reports Server (NTRS)

    Holubec, Keith; Tillman, Barry; Connolly, Jan

    2009-01-01

    NASA created a new approach for human system integration and human performance standards. NASA created two documents a standard and a reference handbook. The standard is titled NASA Space Flight Human-System Standard (SFHSS) and consists of two-volumes: Volume 1- Crew Health This volume covers standards needed to support astronaut health (medical care, nutrition, sleep, exercise, etc.) Volume 2 Human Factors, Habitability and Environmental Health This volume covers the standards for system design that will maintain astronaut performance (ie., environmental factors, design of facilities, layout of workstations, and lighting requirements). It includes classic human factors requirements. The new standards document is written in terms so that it is applicable to a broad range of present and future NASA systems. The document states that all new programs prepare system-specific requirements that will meet the general standards. For example, the new standard does not specify a design should accommodate specific percentiles of a defined population. Rather, NASA-STD-3001, Volume 2 states that all programs shall prepare program-specific requirements that define the user population and their size ranges. The design shall then accommodate the full size range of those users. The companion reference handbook, Human Integration Design Handbook (HIDH), was developed to capture the design consideration information from NASA-STD-3000, and adds spaceflight lessons learned, gaps in knowledge, example solutions, and suggests research to further mature specific disciplines. The HIDH serves two major purposes: HIDH is the reference document for writing human factors requirements for specific systems. HIDH contains design guidance information that helps insure that designers create systems which safely and effectively accommodate the capabilities and limitations of space flight crews.

  16. Human Milk Fortification.

    PubMed

    Simmer, Karen

    2015-01-01

    Human milk is the feed of choice for preterm infants. However, human milk does not provide enough nutrition, especially protein, for preterm infants to achieve target growth rates similar to those in utero (15-20 g/kg per day). Fortifiers for human milk, manufactured from bovine milk, are commercially available and routinely used for patients born <32 weeks' gestation prior to discharge home. Recent recommended dietary intakes (RDI) have been revised. Up to 4.2 g of protein and 135 kcal/kg per day is recommended for infants born very preterm. Additional supplements are needed to current commercial fortifiers to achieve these RDI and reduce the incidence of ex-uterine growth failure. A human milk fortifier that is manufactured from donor human milk is available in some developed countries and may confer some clinical benefits, including a reduction in necrotizing enterocolitis. Fortification can be added in a standardized protocol as per manufacturers' instructions. Human milk composition can be analyzed and fortification individualized to take into account the large variation from mother to mother. Alternatively, fortification can be increased in a stepwise manner based on assumed composition while monitoring blood urea levels for safety. The current aim is to prevent preterm infants dropping percentiles and falling below the 10th percentile at 36 weeks' corrected gestational age or discharge home. More data are required on how best to fortify human milk for preterm infants to achieve optimal growth, development and health outcomes in the long term. There is an urgent need for well-designed and informed randomized clinical trials in this vulnerable preterm population. PMID:26111568

  17. Infants' Responses to Real Humans and Representations of Humans

    ERIC Educational Resources Information Center

    Heron, Michelle; Slaughter, Virginia

    2010-01-01

    Infants' responses to typical and scrambled human body shapes were assessed in relation to the realism of the human body stimuli presented. In four separate experiments, infants were familiarized to typical human bodies and then shown a series of scrambled human bodies on the test. Looking behaviour was assessed in response to a range of different…

  18. Archaic human genomics.

    PubMed

    Disotell, Todd R

    2012-01-01

    For much of the 20th century, the predominant view of human evolutionary history was derived from the fossil record. Homo erectus was seen arising in Africa from an earlier member of the genus and then spreading throughout the Old World and into the Oceania. A regional continuity model of anagenetic change from H. erectus via various intermediate archaic species into the modern humans in each of the regions inhabited by H. erectus was labeled the multiregional model of human evolution (MRE). A contrasting model positing a single origin, in Africa, of anatomically modern H. sapiens with some populations later migrating out of Africa and replacing the local archaic populations throughout the world with complete replacement became known as the recent African origin (RAO) model. Proponents of both models used different interpretations of the fossil record to bolster their views for decades. In the 1980s, molecular genetic techniques began providing evidence from modern human variation that allowed not only the different models of modern human origins to be tested but also the exploration demographic history and the types of selection that different regions of the genome and even specific traits had undergone. The majority of researchers interpreted these data as strongly supporting the RAO model, especially analyses of mitochondrial DNA (mtDNA). Extrapolating backward from modern patterns of variation and using various calibration points and substitution rates, a consensus arose that saw modern humans evolving from an African population around 200,000 years ago. Much later, around 50,000 years ago, a subset of this population migrated out of Africa replacing Neanderthals in Europe and western Asia as well as archaics in eastern Asia and Oceania. mtDNA sequences from more than two-dozen Neanderthals and early modern humans re-enforced this consensus. In 2010, however, the complete draft genomes of Neanderthals and of heretofore unknown hominins from Siberia, called

  19. Why Geo-Humanities

    NASA Astrophysics Data System (ADS)

    Graells, Robert Casals i.; Sibilla, Anna; Bohle, Martin

    2016-04-01

    Anthropogenic global change is a composite process. It consists of societal processes (in the 'noosphere') and natural processes (in the 'bio-geosphere'). The 'noosphere' is the ensemble of social, cultural or political insights ('shared subjective mental concepts') of people. Understanding the composite of societal and natural processes ('human geo-biosphere intersections'), which shapes the features of anthropogenic global change, would benefit from a description that draws equally on natural sciences, social sciences and humanities. To that end it is suggested to develop a concept of 'geo-humanities': This essay presents some aspects of its scope, discussing "knowledge that is to manage", "intentions that are to shape", "choices that are to justify" and "complexity that is to handle". Managing knowledge: That people understand anthropogenic global change requires their insights into how 'human geosphere intersections' function. Insights are formed ('processed') in the noosphere by means of interactions between people. Understanding how 'human geosphere intersections' functions combines scientific, engineering and economic studies with studies of the dynamics of the noosphere. Shaping intentions: During the last century anthropogenic global change developed as the collateral outcome of humankind's accumulated actions. It is caused by the number of people, the patterns of their consumption of resources, and the alterations of their environments. Nowadays, anthropogenic global chance is either an intentional negligence or a conscious act. Justifying choices: Humanity has alternatives how to alter Earth at planetary scale consciously. For example, there is a choice to alter the geo-biosphere or to adjust the noosphere. Whatever the choice, it will depend on people's world-views, cultures and preferences. Thus beyond issues whether science and technology are 'sound' overarching societal issues are to tackle, such as: (i) how to appropriate and distribute natural

  20. Human and murine erythropoiesis

    PubMed Central

    An, Xiuli; Schulz, Vincent P.; Mohandas, Narla; Gallagher, Patrick G.

    2015-01-01

    Purpose of review Research into the fundamental mechanisms of erythropoiesis has provided critical insights into inherited and acquired disorders of the erythrocyte. Studies of human erythropoiesis have primarily utilized in-vitro systems, whereas murine models have provided insights from in-vivo studies. This report reviews recent insights into human and murine erythropoiesis gained from transcriptome-based analyses. Recent findings The availability of high-throughput genomic methodologies has allowed attainment of detailed gene expression data from cells at varying developmental and differentiation stages of erythropoiesis. Transcriptome analyses of human and murine reveal both stage and species-specific similarities and differences across terminal erythroid differentiation. Erythroid-specific long noncoding RNAs exhibit poor sequence conservation between human and mouse. Genome-wide analyses of alternative splicing reveal that complex, dynamic, stage-specific programs of alternative splicing program are utilized during terminal erythroid differentiation. Transcriptome data provide a significant resource for understanding mechanisms of normal and perturbed erythropoiesis. Understanding these processes will provide innovative strategies to detect, diagnose, prevent, and treat hematologic disease. Summary Understanding the shared and different mechanisms controlling human and murine erythropoiesis will allow investigators to leverage the best model system to provide insights in normal and perturbed erythropoiesis. PMID:25719574

  1. The Human Serum Metabolome

    PubMed Central

    Psychogios, Nikolaos; Hau, David D.; Peng, Jun; Guo, An Chi; Mandal, Rupasri; Bouatra, Souhaila; Sinelnikov, Igor; Krishnamurthy, Ramanarayan; Eisner, Roman; Gautam, Bijaya; Young, Nelson; Xia, Jianguo; Knox, Craig; Dong, Edison; Huang, Paul; Hollander, Zsuzsanna; Pedersen, Theresa L.; Smith, Steven R.; Bamforth, Fiona; Greiner, Russ; McManus, Bruce; Newman, John W.; Goodfriend, Theodore; Wishart, David S.

    2011-01-01

    Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca. PMID:21359215

  2. Human herpesvirus 6.

    PubMed Central

    Braun, D K; Dominguez, G; Pellett, P E

    1997-01-01

    Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation. PMID:9227865

  3. Human occupancy detection

    NASA Astrophysics Data System (ADS)

    Brown, David A.

    1994-10-01

    In the area of security and surveillance technologies, the problem of the arrival in Canada of illegal and undesirable ship and truck cargo loads is steadily increasing. As the volumes of cargo arrivals increase so do the Immigration and Customs problems related to the determination of the validity of those cargo contents. Of special concern to Immigration Control Authorities around the world is the emerging and increasing trend of illegal smuggling of human beings hidden inside of shipping containers. Beginning in 1992, Immigration Control Authorities in Canada observed an escalation of alien people smuggling through the use of cargo shipping containers arriving in the Port of Montreal. This paper will present to the audience the recently completed Immigration Canada Human Occupancy Detection project by explaining the design, development and testing of human occupancy detectors. The devices are designed to electronically detect the presence of persons hiding inside of shipping containers, without the requirement of opening the container doors. The human occupancy detection concepts are based upon the presence of carbon dioxide or other human waste characteristics commonly found inside of shipping containers.

  4. Human Spinal Motor Control.

    PubMed

    Nielsen, Jens Bo

    2016-07-01

    Human studies in the past three decades have provided us with an emerging understanding of how cortical and spinal networks collaborate to ensure the vast repertoire of human behaviors. Humans have direct cortical connections to spinal motoneurons, which bypass spinal interneurons and exert a direct (willful) muscle control with the aid of a context-dependent integration of somatosensory and visual information at cortical level. However, spinal networks also play an important role. Sensory feedback through spinal circuitries is integrated with central motor commands and contributes importantly to the muscle activity underlying voluntary movements. Regulation of spinal interneurons is used to switch between motor states such as locomotion (reciprocal innervation) and stance (coactivation pattern). Cortical regulation of presynaptic inhibition of sensory afferents may focus the central motor command by opening or closing sensory feedback pathways. In the future, human studies of spinal motor control, in close collaboration with animal studies on the molecular biology of the spinal cord, will continue to document the neural basis for human behavior. PMID:27023730

  5. [Human genetics and ethics].

    PubMed

    Zergollern, L

    1990-01-01

    Many new problems and dilemmas have occurred in the practice of medical geneticists with the development of human genetics and its subdisciplines--molecular genetics, ethic genetics and juridical genetics. Devoid of the possibility to get adequate education, genetic informer or better to say, counsellor, although a scientist and a professional who has already formed his ethic attitudes, often finds himself in a dilemma when he has to decide whether a procedure made possible by progress of science is ethical or not. Thus, due to different attitudes, same decision is ethical for some, while for the others it is not. Ethic committees are groups of moral and good people trying to find an objective approach to certain genetic and ethic problems. There are more and more ethically unanswered questions in modern human genetics, and particularly in medical genetics. Medical geneticist-ethicist still encounters numerous problems in his work. These are, for example, experiments with human gametes and embryos, possibilities of hybridization of human gametes with animal gametes, in vitro fertilization, detection of heterozygotes and homozygotes for monogene diseases. early detection of chromosomopathies, substitute mothers, homo and hetero insemination, transplantation of fetal and cadeveric organs, uncontrolled consumption of alcohol and drugs, environmental pollution, etc. It is almost impossible to create a single attitude which shall be shared by all those engaged in human health protection. Therefore, it is best to have a neutral eugenetic attitude which allows free ethical choice of each individual, in any case, for the well-being of man. PMID:2366624

  6. Healthy human gut phageome.

    PubMed

    Manrique, Pilar; Bolduc, Benjamin; Walk, Seth T; van der Oost, John; de Vos, Willem M; Young, Mark J

    2016-09-13

    The role of bacteriophages in influencing the structure and function of the healthy human gut microbiome is unknown. With few exceptions, previous studies have found a high level of heterogeneity in bacteriophages from healthy individuals. To better estimate and identify the shared phageome of humans, we analyzed a deep DNA sequence dataset of active bacteriophages and available metagenomic datasets of the gut bacteriophage community from healthy individuals. We found 23 shared bacteriophages in more than one-half of 64 healthy individuals from around the world. These shared bacteriophages were found in a significantly smaller percentage of individuals with gastrointestinal/irritable bowel disease. A network analysis identified 44 bacteriophage groups of which 9 (20%) were shared in more than one-half of all 64 individuals. These results provide strong evidence of a healthy gut phageome (HGP) in humans. The bacteriophage community in the human gut is a mixture of three classes: a set of core bacteriophages shared among more than one-half of all people, a common set of bacteriophages found in 20-50% of individuals, and a set of bacteriophages that are either rarely shared or unique to a person. We propose that the core and common bacteriophage communities are globally distributed and comprise the HGP, which plays an important role in maintaining gut microbiome structure/function and thereby contributes significantly to human health. PMID:27573828

  7. Abortion and human rights.

    PubMed

    Shaw, Dorothy

    2010-10-01

    Abortion has been a reality in women's lives since the beginning of recorded history, typically with a high risk of fatal consequences, until the last century when evolutions in the field of medicine, including techniques of safe abortion and effective methods of family planning, could have ended the need to seek unsafe abortion. The context of women's lives globally is an important but often ignored variable, increasingly recognised in evolving human rights especially related to gender and reproduction. International and regional human rights instruments are being invoked where national laws result in violations of human rights such as health and life. The individual right to conscientious objection must be respected and better understood, and is not absolute. Health professional organisations have a role to play in clarifying responsibilities consistent with national laws and respecting reproductive rights. Seeking common ground using evidence rather than polarised opinion can assist the future focus. PMID:20303830

  8. Classifying human manipulation behavior.

    PubMed

    Bullock, Ian M; Dollar, Aaron M

    2011-01-01

    This paper presents a taxonomy for detailed classification of human and anthropomorphic manipulation behavior. This hand-centric, motion-centric taxonomy differentiates tasks based on criteria such as object contact, prehension, and the nature of object motion relative to a hand frame. A sub-classification of the most dexterous categories, within-hand manipulation, is also presented, based on the principal axis of object rotation or translation in the hand frame. Principles for categorizing complex, multi-faceted tasks are also presented, along with illustrative examples. We hope that the proposed taxonomy will both establish a standard language around human and anthropomorphic manipulation as well as enable improved understanding of the differences in hand use for a wide variety of behavior. Although designed for human and anthropomorphic hands, the taxonomy might easily be extended to a wide range of robot manipulators and end-effectors. PMID:22275611

  9. Autophagy and human diseases

    PubMed Central

    Jiang, Peidu; Mizushima, Noboru

    2014-01-01

    Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized. PMID:24323045

  10. Helicopter human factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.

    1988-01-01

    The state-of-the-art helicopter and its pilot are examined using the tools of human-factors analysis. The significant role of human error in helicopter accidents is discussed; the history of human-factors research on helicopters is briefly traced; the typical flight tasks are described; and the noise, vibration, and temperature conditions typical of modern military helicopters are characterized. Also considered are helicopter controls, cockpit instruments and displays, and the impact of cockpit design on pilot workload. Particular attention is given to possible advanced-technology improvements, such as control stabilization and augmentation, FBW and fly-by-light systems, multifunction displays, night-vision goggles, pilot night-vision systems, night-vision displays with superimposed symbols, target acquisition and designation systems, and aural displays. Diagrams, drawings, and photographs are provided.

  11. The human toxome project.

    PubMed

    Bouhifd, Mounir; Andersen, Melvin E; Baghdikian, Christina; Boekelheide, Kim; Crofton, Kevin M; Fornace, Albert J; Kleensang, Andre; Li, Henghong; Livi, Carolina; Maertens, Alexandra; McMullen, Patrick D; Rosenberg, Michael; Thomas, Russell; Vantangoli, Marguerite; Yager, James D; Zhao, Liang; Hartung, Thomas

    2015-01-01

    The Human Toxome Project, funded as an NIH Transformative Research grant 2011-2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectroscopy-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies. PMID:25742299

  12. Discounting human lives

    SciTech Connect

    Cropper, M.L. ); Portney, P.R.

    1992-09-01

    The future costs of regulatory programs to protect human health are routinely discounted, but the lives they save in the future are not. To shed light on the public's attitude toward the discounting of human lives, researchers at Resources for the Future asked 2,600 individuals to choose between one hypothetical program that would save lives immediately and another that would save lives in 5, 10, 25, 50, or 100 years. From the responses, they inferred the number of lives that must be saved in the future to make people as content as saving one life today, compared this implicit discount rate to the respondents' discount rate for money, and identified several factors that affect discount rates for human lives.

  13. Human factors in aviation

    NASA Technical Reports Server (NTRS)

    Wiener, Earl L. (Editor); Nagel, David C. (Editor)

    1988-01-01

    The fundamental principles of human-factors (HF) analysis for aviation applications are examined in a collection of reviews by leading experts, with an emphasis on recent developments. The aim is to provide information and guidance to the aviation community outside the HF field itself. Topics addressed include the systems approach to HF, system safety considerations, the human senses in flight, information processing, aviation workloads, group interaction and crew performance, flight training and simulation, human error in aviation operations, and aircrew fatigue and circadian rhythms. Also discussed are pilot control; aviation displays; cockpit automation; HF aspects of software interfaces; the design and integration of cockpit-crew systems; and HF issues for airline pilots, general aviation, helicopters, and ATC.

  14. Human nutrition: evolutionary perspectives.

    PubMed

    Barnicot, N A

    2005-01-01

    In recent decades, much new evidence relating to the ape forerunners of modern humans has come to hand and diet appears to be an important factor. At some stage, there must have been a transition from a largely vegetarian ape diet to a modern human hunting economy providing significant amounts of meat. On an even longer evolutionary time scale the change was more complex. The mechanisms of evolutionary change are now better understood than they were in Darwin's time, thanks largely to great advances in genetics, both experimental and theoretical. It is virtually certain that diet, as a major component of the human environment, must have exerted evolutionary effects, but researchers still have little good evidence. PMID:17393680

  15. The Human Toxome Project

    PubMed Central

    Bouhifd, Mounir; Andersen, Melvin E.; Baghdikian, Christina; Boekelheide, Kim; Crofton, Kevin M.; Fornace, Albert J.; Kleensang, Andre; Li, Henghong; Livi, Carolina; Maertens, Alexandra; McMullen, Patrick D.; Rosenberg, Michael; Thomas, Russell; Vantangoli, Marguerite; Yager, James D.; Zhao, Liang; Hartung, Thomas

    2016-01-01

    Summary The Human Toxome Project, funded as an NIH Transformative Research grant 2011–2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectrometry-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies. PMID:25742299

  16. Is humanity suicidal?

    PubMed

    Wilson, E O

    1993-01-01

    The world's fauna and flora has entered a crisis unparalleled since the end of the Mesozoic Era, with the extinction rate of species now elevated to more than a thousand times that existing before the coming of humanity. Scientists and policy makers are ill-prepared to moderate this hemorrhaging, because so little is known of the biology of the Earth's millions of species and because so little effort has been directed toward conservation thus far. With the vanished species will go great potential wealth in scientific knowledge, new products, ecosystems services, and part of the natural world in which the human species originated. The need for new research and improved management is thus urgent. If it is not met, humanity will likely survive, but in a world biologically impoverished for all time. PMID:8155855

  17. Scientists and Human Rights

    NASA Astrophysics Data System (ADS)

    Makdisi, Yousef

    2012-02-01

    The American Physical Society has a long history of involvement in defense of human rights. The Committee on International Freedom of Scientists was formed in the mid seventies as a subcommittee within the Panel On Public Affairs ``to deal with matters of an international nature that endangers the abilities of scientists to function as scientists'' and by 1980 it was established as an independent committee. In this presentation I will describe some aspects of the early history and the impetus that led to such an advocacy, the methods employed then and how they evolved to the present CIFS responsibility ``for monitoring concerns regarding human rights for scientists throughout the world''. I will also describe the current approach and some sample cases the committee has pursued recently, the interaction with other human rights organizations, and touch upon some venues through which the community can engage to help in this noble cause.

  18. Human-Robot Interaction

    NASA Technical Reports Server (NTRS)

    Rochlis-Zumbado, Jennifer; Sandor, Aniko; Ezer, Neta

    2012-01-01

    Risk of Inadequate Design of Human and Automation/Robotic Integration (HARI) is a new Human Research Program (HRP) risk. HRI is a research area that seeks to understand the complex relationship among variables that affect the way humans and robots work together to accomplish goals. The DRP addresses three major HRI study areas that will provide appropriate information for navigation guidance to a teleoperator of a robot system, and contribute to the closure of currently identified HRP gaps: (1) Overlays -- Use of overlays for teleoperation to augment the information available on the video feed (2) Camera views -- Type and arrangement of camera views for better task performance and awareness of surroundings (3) Command modalities -- Development of gesture and voice command vocabularies

  19. Preparing for Human Exploration

    NASA Technical Reports Server (NTRS)

    Drake, Bret G.; Joosten, B. Kent

    1998-01-01

    NASA's Human Exploration and Development of Space (HEDS) Enterprise is defining architectures and requirements for human exploration that radically reduce the costs of such missions through the use of advanced technologies, commercial partnerships and innovative systems strategies. In addition, the HEDS Enterprise is collaborating with the Space Science Enterprise to acquire needed early knowledge about Mars and to demonstrate critical technologies via robotic missions. This paper provides an overview of the technological challenges facing NASA as it prepares for human exploration. Emphasis is placed on identifying the key technologies including those which will provide the most return in terms of reducing total mission cost and/or reducing potential risk to the mission crew. Top-level requirements are provided for those critical enabling technology options currently under consideration.

  20. Whither medical humanities?

    PubMed

    Singh, Navjeevan

    2012-01-01

    Understanding the medical humanities (MH) and their role in medical education is in its infancy in India. Students are initiated into professional (medical) education too early in life, usually at the expense of a basic grounding in the humanities, resulting in warped intellectual growth. The author, arguing against the wholesale import of foreign systems, advocates free inquiry by medical educators to evolve a humanities programme for medical students derived from our own cultural context. This essay describes the early experiences of efforts to make a beginning at the University College of Medical Sciences, Delhi. The author reviews the various strategies used and the challenges of introducing the subject to the current generation of medical students. PMID:22864074

  1. Teleoperator Human Factors Study

    NASA Technical Reports Server (NTRS)

    1986-01-01

    An investigation of the spectrum of space teleoperation activities likely in the 1985 to 1995 decade focused on the resolution of critical human engineering issues and characterization of the technology effect on performance of remote human operators. The study began with the identification and documentation of a set of representative reference teleoperator tasks. For each task, technology, development, and design options, issues, and alternatives that bear on human operator performance were defined and categorized. A literature survey identified existing studies of man/machine issues. For each teleoperations category, an assessment was made of the state of knowledge on a scale from adequate to void. The tests, experiments, and analyses necessary to provide the missing elements of knowledge were then defined. A limited set of tests were actually performed, including operator selection, baseline task definition, control mode study, lighting study, camera study, and preliminary time delay study.

  2. The Exploration of Mars by Humans: Why Mars? Why Humans?

    NASA Technical Reports Server (NTRS)

    Levine, Joel S.

    2011-01-01

    As we commemorate the 50th anniversary of Yuri Gagarin's historic flight in 1961, the first flight of a human in space, plans are underway for another historic human mission. Plans are being developed for a human mission to Mars. Once we reach Mars, the human species will become the first two-planet species. Both the Bush Administration (in 2004) and the Obama Administration (in 2010) proposed a human mission to Mars as a national goal of the United States.

  3. Human Modeling For Ground Processing Human Factors Engineering Analysis

    NASA Technical Reports Server (NTRS)

    Tran, Donald; Stambolian, Damon; Henderson, Gena; Barth, Tim

    2011-01-01

    There have been many advancements and accomplishments over that last few years using human modeling for human factors engineering analysis for design of spacecraft and launch vehicles. The key methods used for this are motion capture and computer generated human models. The focus of this paper is to explain the different types of human modeling used currently and in the past at Kennedy Space Center (KSC) currently, and to explain the future plans for human modeling for future spacecraft designs.

  4. Human Modeling for Ground Processing Human Factors Engineering Analysis

    NASA Technical Reports Server (NTRS)

    Stambolian, Damon B.; Lawrence, Brad A.; Stelges, Katrine S.; Steady, Marie-Jeanne O.; Ridgwell, Lora C.; Mills, Robert E.; Henderson, Gena; Tran, Donald; Barth, Tim

    2011-01-01

    There have been many advancements and accomplishments over the last few years using human modeling for human factors engineering analysis for design of spacecraft. The key methods used for this are motion capture and computer generated human models. The focus of this paper is to explain the human modeling currently used at Kennedy Space Center (KSC), and to explain the future plans for human modeling for future spacecraft designs

  5. Cardiovascular Deconditioning in Humans: Human Studies Core

    NASA Technical Reports Server (NTRS)

    Williams, Gordon

    1999-01-01

    Major cardiovascular problems, secondary to cardiovascular deconditioning, may occur on extended space missions. While it is generally assumed that the microgravity state is the primary cause of cardiovascular deconditioning, sleep deprivation and disruption of diurnal rhythms may also play an important role. Factors that could be modified by either or both of these perturbations include: autonomic function and short-term cardiovascular reflexes, vasoreactivity, circadian rhythm of cardiovascular hormones (specifically the renin-angiotensin system) and renal sodium handling and hormonal influences on that process, venous compliance, cardiac mass, and cardiac conduction processes. The purpose of the Human Studies Core is to provide the infrastructure to conduct human experiments which will allow for the assessment of the likely role of such factors in the space travel associated cardiovascular deconditioning process and to develop appropriate countermeasures. The Core takes advantage of a newly-created Intensive Physiologic Monitoring (IPM) Unit at the Brigham and Women's Hospital, Boston, MA, to perform these studies. The Core includes two general experimental protocols. The first protocol involves a head down tilt bed-rest study to simulate microgravity. The second protocol includes the addition of a disruption of circadian rhythms to the simulated microgravity environment. Before and after each of these environmental manipulations, the subjects will undergo acute stressors simulating changes in volume and/or stress, which could occur in space and on return to Earth. The subjects are maintained in a rigidly controlled environment with fixed light/dark cycles, activity pattern, and dietary intake of nutrients, fluids, ions and calories.

  6. [Human reservoirs of Pneumocystis].

    PubMed

    Wissmann, Gustavo; Morilla, Ruben; Friaza, Vicente; Calderón, Enrique; Varela, Jose M

    2010-01-01

    Pneumocystis jirovecii, the fungal agent that causes Pneumocystis pneumonia (PCP), is known to exclusively infect humans. Molecular studies have enabled detection of this fungus in individuals who have been colonized by P. jirovecii. Such colonization, found in several populations, seems to act as a human reservoir for the fungus. Various studies have reported mutations associated with sulfa resistance in P. jirovecii strains isolated from colonized patients, who can transmit the mutant genotype to PCP-susceptible individuals. The growing interest in P. jirovecii colonization may prompt the design of new prevention and management strategies for PCP. PMID:19403207

  7. Human variation databases

    PubMed Central

    Küntzer, Jan; Eggle, Daniela; Klostermann, Stefan; Burtscher, Helmut

    2010-01-01

    More than 100 000 human genetic variations have been described in various genes that are associated with a wide variety of diseases. Such data provides invaluable information for both clinical medicine and basic science. A number of locus-specific databases have been developed to exploit this huge amount of data. However, the scope, format and content of these databases differ strongly and as no standard for variation databases has yet been adopted, the way data is presented varies enormously. This review aims to give an overview of current resources for human variation data in public and commercial resources. PMID:20639550

  8. Human MSH2 protein

    DOEpatents

    Chapelle, A. de la; Vogelstein, B.; Kinzler, K.W.

    1997-01-07

    The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error{sup +} (RER{sup +}) tumor cells. 19 figs.

  9. Human MSH2 protein

    DOEpatents

    de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

    1997-01-01

    The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

  10. Memristance in human skin

    NASA Astrophysics Data System (ADS)

    Martinsen, Ø. G.; Grimnes, S.; Lütken, C. A.; Johnsen, G. K.

    2010-04-01

    The memristor is basically a resistor with memory, so that the resistance is dependent on the net amount of charge having passed through the device. It is the regarded the fourth fundamental component, in addition to the resistor, capacitor and inductor, that can be deduced from the four basic circuit variables; current, voltage, charge and magnetic flux. We show that memristors can be used for modelling electrical properties of human skin. In particular is electro-osmosis in human sweat ducts of memristive nature.

  11. Disorders of Human Hemoglobin

    NASA Astrophysics Data System (ADS)

    Bank, Arthur; Mears, J. Gregory; Ramirez, Francesco

    1980-02-01

    Studies of the human hemoglobin system have provided new insights into the regulation of expression of a group of linked human genes, the γ -δ -β globin gene complex in man. In particular, the thalassemia syndromes and related disorders of man are inherited anemias that provide mutations for the study of the regulation of globin gene expression. New methods, including restriction enzyme analysis and cloning of cellular DNA, have made it feasible to define more precisely the structure and organization of the globin genes in cellular DNA. Deletions of specific globin gene fragments have already been found in certain of these disorders and have been applied in prenatal diagnosis.

  12. Human Factors Model

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Jack is an advanced human factors software package that provides a three dimensional model for predicting how a human will interact with a given system or environment. It can be used for a broad range of computer-aided design applications. Jack was developed by the computer Graphics Research Laboratory of the University of Pennsylvania with assistance from NASA's Johnson Space Center, Ames Research Center and the Army. It is the University's first commercial product. Jack is still used for academic purposes at the University of Pennsylvania. Commercial rights were given to Transom Technologies, Inc.

  13. We Are Human Beings.

    PubMed

    McGee, Andrew

    2016-04-01

    In this paper, I examine Jeff McMahan's arguments for his claim that we are not human organisms, and the arguments of Derek Parfit to the same effect in a recent paper. McMahan uses these arguments to derive conclusions concerning the moral status of embryos and permanent vegetative state (PVS) patients. My claim will be that neither thinker has successfully shown that we are not human beings, and therefore these arguments do not establish the ethical conclusions that McMahan has sought to draw from the arguments in respect of the moral status of embryos and PVS patients. PMID:26810918

  14. Making IBM's Computer, Watson, Human

    ERIC Educational Resources Information Center

    Rachlin, Howard

    2012-01-01

    This essay uses the recent victory of an IBM computer (Watson) in the TV game, "Jeopardy," to speculate on the abilities Watson would need, in addition to those it has, to be human. The essay's basic premise is that to be human is to behave as humans behave and to function in society as humans function. Alternatives to this premise are considered…

  15. Human Challenges in Exploration Missions

    NASA Technical Reports Server (NTRS)

    Lloyd, Charles W.

    2007-01-01

    This viewgraph presents an overview using pictures some of the history of human exploration of the new frontiers of Earth and then examines some of the challenges to human exploration of space. Particular attention is given to the environmental factors and to the social and human factors that effect humans in space environments.

  16. Human thimet oligopeptidase.

    PubMed Central

    Dando, P M; Brown, M A; Barrett, A J

    1993-01-01

    We have purified human thimet oligopeptidase to homogeneity from erythrocytes, and compared it with the enzyme from rat testis and chicken liver. An antiserum raised against rat thimet oligopeptidase also recognized the human and chicken enzymes, suggesting that the structure of the enzyme has been strongly conserved in evolution. Consistent with this, the properties of the human enzyme were very similar to those for the other species. Thus human thimet oligopeptidase also is a thiol-dependent metallo-oligopeptidase with M(r) about 75,000. Specificity for cleavage of a number of peptides was indistinguishable from that of the rat enzyme, but Ki values for the four potent reversible inhibitors tested were lower. In discussing the results, we consider the determinants of the complex substrate specificity of thimet oligopeptidase. We question whether substrates containing more than 17 amino acid residues are cleaved, as has been suggested. We also point out that the favourable location of a proline residue and a free C-terminus in the substrate may be as important as the hydrophobic residues in the P2, P1 and P3' positions that have been emphasized in the past. Images Figure 1 PMID:8373360

  17. Humans as Lie Detectors.

    ERIC Educational Resources Information Center

    DePaulo, Bella; And Others

    1980-01-01

    Discusses several studies of whether and how well humans can detect lies. Examines the accuracy of such persons as well as the process of how they actually detect lies, how they think they detect lies, and whether the actual and perceived processes of lie detection correspond to one another. (JMF)

  18. Trends in Humanities Programming.

    ERIC Educational Resources Information Center

    Vavrek, Bernard, Ed.; Whitney, Loralyn, Ed.

    Proceedings from this workshop sponsored by the Center for the Study of Rural Librarianship are intended to disseminate information to assist rural librarians engaged in planning and conducting public programs that explore issues related to the humanities. This report of the proceedings includes the texts of three presented papers, reactions from…

  19. Humanizing the Workplace.

    ERIC Educational Resources Information Center

    Fairfield, Roy P., Ed.

    A series of essays discussing ideas about humanizing work are presented in the document. Three major sections divide the essays, and each includes a preface with comments suggesting the central focus and questions with which the authors are concerned. The first section deals with the history, philosophy, and issues related to work and contains…

  20. Television's New Humane Collectivity.

    ERIC Educational Resources Information Center

    Schrag, Robert L.; And Others

    1981-01-01

    Analyzes "Taxi,""Barney Miller,""Lou Grant," and "M*A*S*H" in terms of three fantasy themes: the realization of significant others, the alliance in action, and membership into personhood. From these themes emerges a rhetorical vision of the new humane collectivity. (PD)

  1. Strategic Human Resource Development.

    ERIC Educational Resources Information Center

    Garavan, Thomas N.

    1991-01-01

    Reviews literature on strategic human resource development (HRD) focusing on the characteristics of such activities, conditions necessary for the promotion of HRD, and the benefits to an organization pursuing such activities. Empirical evidence is presented on HRD policy formation and planning processes in Irish high technology companies. (JOW)

  2. Grass and human nutrition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Food products from animals that graze grasslands and consume diets high in forages are often better for human health than livestock fed diets with forages and concentrates. Meat from livestock that graze pastures in the United States frequently has less fat and higher concentrations of omega-3 fatty...

  3. Humanism in Education

    ERIC Educational Resources Information Center

    Armstrong, Michael

    2015-01-01

    This is the text of Michael Armstrong's address to the Brian Simon Centenary conference, held at the Institute of Education on 26 March 2015. Michael Armstrong celebrates the humanism that underlay Brian's belief in a common system of education, democratic and non-selective, and finds its counterpart in the creative practice of school children.

  4. Futures of Human Communication.

    ERIC Educational Resources Information Center

    Harms, L. S.

    There are several research areas basic to the long-range future of human communications. Telecommunication and transportation offer the possiblity of two worldwide communications networks whose interrelationships need to be explored in terms of the needs of the individual, the community, and the world at large. Expanding possibilities of…

  5. Human Papilloma Virus Infections

    PubMed Central

    Wright, V. Cecil

    1989-01-01

    Genital warts are believed to be caused by human papilloma viruses and to be sexually transmitted. The viruses are classified by DNA types, which appear to cause different types of disease. The choice of treatment, and usually its success rate, vary according to the type of disease and its location. PMID:21248973

  6. Marketing Human Resource Development.

    ERIC Educational Resources Information Center

    Frank, Eric, Ed.

    1994-01-01

    Describes three human resource development activities: training, education, and development. Explains marketing from the practitioners's viewpoint in terms of customer orientation; external and internal marketing; and market analysis, research, strategy, and mix. Shows how to design, develop, and implement strategic marketing plans and identify…

  7. Strengthening Career Human Agency

    ERIC Educational Resources Information Center

    Chen, Charles P.

    2006-01-01

    Rooted in A. Bandura's (1982, 2001b) social cognitive theory, the notion of human agency has received considerable attention in vocational and career psychology for the last 2 decades, especially with the recent emergence of social constructivist thinking in the field. This article continues in the same direction. In reviewing the notion of human…

  8. Human performance measuring device

    NASA Technical Reports Server (NTRS)

    Michael, J.; Scow, J.

    1970-01-01

    Complex coordinator, consisting of operator control console, recorder, subject display panel, and limb controls, measures human performance by testing perceptual and motor skills. Device measures psychophysiological functions in drug and environmental studies, and is applicable to early detection of psychophysiological body changes.

  9. Independent Human Studies.

    ERIC Educational Resources Information Center

    Kaplan, Suzanne; Wilson, Gordon

    1978-01-01

    The Independent Human Studies program at Schoolcraft College offers an alternative method of earning academic credits. Students delineate an area of study, pose research questions, gather resources, synthesize the information, state the thesis, choose the method of presentation, set schedules, and take responsibility for meeting deadlines. (MB)

  10. Human Learning and Memory

    ERIC Educational Resources Information Center

    Lieberman, David A.

    2012-01-01

    This innovative textbook is the first to integrate learning and memory, behaviour, and cognition. It focuses on fascinating human research in both memory and learning (while also bringing in important animal studies) and brings the reader up to date with the latest developments in the subject. Students are encouraged to think critically: key…