FEZ2 Has Acquired Additional Protein Interaction Partners Relative to FEZ1: Functional and Evolutionary Implications

PubMed Central

Alborghetti, Marcos R.; Furlan, Ariane S.; Kobarg, Jörg

2011-01-01

Background The FEZ (fasciculation and elongation protein zeta) family designation was purposed by Bloom and Horvitz by genetic analysis of C. elegans unc-76. Similar human sequences were identified in the expressed sequence tag database as FEZ1 and FEZ2. The unc-76 function is necessary for normal axon fasciculation and is required for axon-axon interactions. Indeed, the loss of UNC-76 function results in defects in axonal transport. The human FEZ1 protein has been shown to rescue defects caused by unc-76 mutations in nematodes, indicating that both UNC-76 and FEZ1 are evolutionarily conserved in their function. Until today, little is known about FEZ2 protein function. Methodology/Principal Findings Using the yeast two-hybrid system we demonstrate here conserved evolutionary features among orthologs and non-conserved features between paralogs of the FEZ family of proteins, by comparing the interactome profiles of the C-terminals of human FEZ1, FEZ2 and UNC-76 from C. elegans. Furthermore, we correlate our data with an analysis of the molecular evolution of the FEZ protein family in the animal kingdom. Conclusions/Significance We found that FEZ2 interacted with 59 proteins and that of these only 40 interacted with FEZ1. Of the 40 FEZ1 interacting proteins, 36 (90%), also interacted with UNC-76 and none of the 19 FEZ2 specific proteins interacted with FEZ1 or UNC-76. This together with the duplication of unc-76 gene in the ancestral line of chordates suggests that FEZ2 is in the process of acquiring new additional functions. The results provide also an explanation for the dramatic difference between C. elegans and D. melanogaster unc-76 mutants on one hand, which cause serious defects in the nervous system, and the mouse FEZ1 -/- knockout mice on the other, which show no morphological and no strong behavioural phenotype. Likely, the ubiquitously expressed FEZ2 can completely compensate the lack of neuronal FEZ1, since it can interact with all FEZ1 interacting proteins and additional 19 proteins. PMID:21408165

An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1

PubMed Central

Konze, Kyle D.; Ma, Anqi; Li, Fengling; Barsyte-Lovejoy, Dalia; Parton, Trevor; MacNevin°, Christopher J.; Liu, Feng; Gao, Cen; Huang, Xi-Ping; Kuznetsova, Ekaterina; Rougie°, Marie; Jiang, Alice; Pattenden, Samantha G.; Norris, Jacqueline L.; James, Lindsey I.; Roth, Bryan L.; Brown, Peter J.; Frye, Stephen V.; Arrowsmith, Cheryl H.; Hahn°, Klaus M.; Wang, Gang Greg; Vedadi, Masoud; Jin, Jian

2013-01-01

EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression of EZH2 and hypertrimethylation of H3K27 have been implicated in a number of cancers. Several selective inhibitors of EZH2 have been reported recently. Herein we disclose UNC1999, the first orally bioavailable inhibitor that has high in vitro potency for wild-type and mutant EZH2 as well as EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their respective catalytic domains. UNC1999 was highly selective for EZH2 and EZH1 over a broad range of epigenetic and non-epigenetic targets, competitive with the cofactor SAM, and non-competitive with the peptide substrate. This inhibitor potently reduced H3K27me3 levels in cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2Y641N mutant. Importantly, UNC1999 was orally bioavailable in mice, making this inhibitor a valuable tool for investigating the role of EZH2 and EZH1 in chronic animal studies. We also designed and synthesized UNC2400, a close analog of UNC1999 with >1,000-fold lower potency than UNC1999 as a negative control for cell-based studies. Finally, we created a biotin-tagged UNC1999 (UNC2399) which enriched EZH2 in pull-down studies, and a UNC1999 – dye conjugate (UNC2239) for co-localization studies with EZH2 in live cells. Taken together, these compounds represent a set of useful tools for the biomedical community to investigate the role of EZH2 and EZH1 in health and disease. PMID:23614352

EVA-1 functions as an UNC-40 Co-receptor to enhance attraction to the MADD-4 guidance cue in Caenorhabditis elegans.

PubMed

Chan, Kevin Ka Ming; Seetharaman, Ashwin; Bagg, Rachel; Selman, Guillermo; Zhang, Yuqian; Kim, Joowan; Roy, Peter J

2014-08-01

We recently discovered a secreted and diffusible midline cue called MADD-4 (an ADAMTSL) that guides migrations along the dorsoventral axis of the nematode Caenorhabditis elegans. We showed that the transmembrane receptor, UNC-40 (DCC), whose canonical ligand is the UNC-6 (netrin) guidance cue, is required for extension towards MADD-4. Here, we demonstrate that MADD-4 interacts with an EVA-1/UNC-40 co-receptor complex to attract cell extensions. EVA-1 is a conserved transmembrane protein with predicted galactose-binding lectin domains. EVA-1 functions in the same pathway as MADD-4, physically interacts with both MADD-4 and UNC-40, and enhances UNC-40's sensitivity to the MADD-4 cue. This enhancement is especially important in the presence of UNC-6. In EVA-1's absence, UNC-6 interferes with UNC-40's responsiveness to MADD-4; in UNC-6's absence, UNC-40's responsiveness to MADD-4 is less dependent on EVA-1. By enabling UNC-40 to respond to MADD-4 in the presence of UNC-6, EVA-1 may increase the precision by which UNC-40-directed processes can reach their MADD-4-expressing targets within a field of the UNC-6 guidance cue.

EVA-1 Functions as an UNC-40 Co-receptor to Enhance Attraction to the MADD-4 Guidance Cue in Caenorhabditis elegans

PubMed Central

Bagg, Rachel; Selman, Guillermo; Zhang, Yuqian; Kim, Joowan; Roy, Peter J.

2014-01-01

We recently discovered a secreted and diffusible midline cue called MADD-4 (an ADAMTSL) that guides migrations along the dorsoventral axis of the nematode Caenorhabditis elegans. We showed that the transmembrane receptor, UNC-40 (DCC), whose canonical ligand is the UNC-6 (netrin) guidance cue, is required for extension towards MADD-4. Here, we demonstrate that MADD-4 interacts with an EVA-1/UNC-40 co-receptor complex to attract cell extensions. EVA-1 is a conserved transmembrane protein with predicted galactose-binding lectin domains. EVA-1 functions in the same pathway as MADD-4, physically interacts with both MADD-4 and UNC-40, and enhances UNC-40's sensitivity to the MADD-4 cue. This enhancement is especially important in the presence of UNC-6. In EVA-1's absence, UNC-6 interferes with UNC-40's responsiveness to MADD-4; in UNC-6's absence, UNC-40's responsiveness to MADD-4 is less dependent on EVA-1. By enabling UNC-40 to respond to MADD-4 in the presence of UNC-6, EVA-1 may increase the precision by which UNC-40-directed processes can reach their MADD-4-expressing targets within a field of the UNC-6 guidance cue. PMID:25122090

Position-dependent and neuron-specific splicing regulation by the CELF family RNA-binding protein UNC-75 in Caenorhabditis elegans

PubMed Central

Kuroyanagi, Hidehito; Watanabe, Yohei; Suzuki, Yutaka; Hagiwara, Masatoshi

2013-01-01

A large fraction of protein-coding genes in metazoans undergo alternative pre-mRNA splicing in tissue- or cell-type-specific manners. Recent genome-wide approaches have identified many putative-binding sites for some of tissue-specific trans-acting splicing regulators. However, the mechanisms of splicing regulation in vivo remain largely unknown. To elucidate the modes of splicing regulation by the neuron-specific CELF family RNA-binding protein UNC-75 in Caenorhabditis elegans, we performed deep sequencing of poly(A)+ RNAs from the unc-75(+)- and unc-75-mutant worms and identified more than 20 cassette and mutually exclusive exons repressed or activated by UNC-75. Motif searches revealed that (G/U)UGUUGUG stretches are enriched in the upstream and downstream introns of the UNC-75-repressed and -activated exons, respectively. Recombinant UNC-75 protein specifically binds to RNA fragments carrying the (G/U)UGUUGUG stretches in vitro. Bi-chromatic fluorescence alternative splicing reporters revealed that the UNC-75-target exons are regulated in tissue-specific and (G/U)UGUUGUG element-dependent manners in vivo. The unc-75 mutation affected the splicing reporter expression specifically in the nervous system. These results indicate that UNC-75 regulates alternative splicing of its target exons in neuron-specific and position-dependent manners through the (G/U)UGUUGUG elements in C. elegans. This study thus reveals the repertoire of target events for the CELF family in the living organism. PMID:23416545

A Co-operative Regulation of Neuronal Excitability by UNC-7 Innexin and NCA/NALCN Leak Channel

PubMed Central

2011-01-01

Gap junctions mediate the electrical coupling and intercellular communication between neighboring cells. Some gap junction proteins, namely connexins and pannexins in vertebrates, and innexins in invertebrates, may also function as hemichannels. A conserved NCA/Dmα1U/NALCN family cation leak channel regulates the excitability and activity of vertebrate and invertebrate neurons. In the present study, we describe a genetic and functional interaction between the innexin UNC-7 and the cation leak channel NCA in Caenorhabditis elegans neurons. While the loss of the neuronal NCA channel function leads to a reduced evoked postsynaptic current at neuromuscular junctions, a simultaneous loss of the UNC-7 function restores the evoked response. The expression of UNC-7 in neurons reverts the effect of the unc-7 mutation; moreover, the expression of UNC-7 mutant proteins that are predicted to be unable to form gap junctions also reverts this effect, suggesting that UNC-7 innexin regulates neuronal activity, in part, through gap junction-independent functions. We propose that, in addition to gap junction-mediated functions, UNC-7 innexin may also form hemichannels to regulate C. elegans' neuronal activity cooperatively with the NCA family leak channels. PMID:21489288

The Caenorhabditis elegans gene unc-89, required fpr muscle M-line assembly, encodes a giant modular protein composed of Ig and signal transduction domains

PubMed Central

1996-01-01

Mutations in the Caenorhabditis elegans gene unc-89 result in nematodes having disorganized muscle structure in which thick filaments are not organized into A-bands, and there are no M-lines. Beginning with a partial cDNA from the C. elegans sequencing project, we have cloned and sequenced the unc-89 gene. An unc-89 allele, st515, was found to contain an 84-bp deletion and a 10-bp duplication, resulting in an in- frame stop codon within predicted unc-89 coding sequence. Analysis of the complete coding sequence for unc-89 predicts a novel 6,632 amino acid polypeptide consisting of sequence motifs which have been implicated in protein-protein interactions. UNC-89 begins with 67 residues of unique sequences, SH3, dbl/CDC24, and PH domains, 7 immunoglobulins (Ig) domains, a putative KSP-containing multiphosphorylation domain, and ends with 46 Ig domains. A polyclonal antiserum raised to a portion of unc-89 encoded sequence reacts to a twitchin-sized polypeptide from wild type, but truncated polypeptides from st515 and from the amber allele e2338. By immunofluorescent microscopy, this antiserum localizes to the middle of A-bands, consistent with UNC-89 being a structural component of the M-line. Previous studies indicate that myofilament lattice assembly begins with positional cues laid down in the basement membrane and muscle cell membrane. We propose that the intracellular protein UNC-89 responds to these signals, localizes, and then participates in assembling an M-line. PMID:8603916

UNC93B1 mediates differential trafficking of endosomal TLRs

PubMed Central

Lee, Bettina L; Moon, Joanne E; Shu, Jeffrey H; Yuan, Lin; Newman, Zachary R; Schekman, Randy; Barton, Gregory M

2013-01-01

UNC93B1, a multipass transmembrane protein required for TLR3, TLR7, TLR9, TLR11, TLR12, and TLR13 function, controls trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes. The mechanisms by which UNC93B1 mediates these regulatory effects remain unclear. Here, we demonstrate that UNC93B1 enters the secretory pathway and directly controls the packaging of TLRs into COPII vesicles that bud from the ER. Unlike other COPII loading factors, UNC93B1 remains associated with the TLRs through post-Golgi sorting steps. Unexpectedly, these steps are different among endosomal TLRs. TLR9 requires UNC93B1-mediated recruitment of adaptor protein complex 2 (AP-2) for delivery to endolysosomes while TLR7, TLR11, TLR12, and TLR13 utilize alternative trafficking pathways. Thus, our study describes a mechanism for differential sorting of endosomal TLRs by UNC93B1, which may explain the distinct roles played by these receptors in certain autoimmune diseases. DOI: http://dx.doi.org/10.7554/eLife.00291.001 PMID:23426999

UNC5B receptor deletion exacerbates tissue injury in response to AKI.

PubMed

Ranganathan, Punithavathi; Jayakumar, Calpurnia; Navankasattusas, Sutip; Li, Dean Y; Kim, Il-man; Ramesh, Ganesan

2014-02-01

Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. We investigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B(-/flox)) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B(-/flox/GGT-cre)). Mice were subjected to two different models of organ injury: ischemia reperfusion injury of the kidney and cisplatin-induced nephrotoxicity. Both mouse models of UNC5B depletion had normal organ function and histology under basal conditions. After AKI, however, UNC5B(-/flox/GGT-cre) mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B(-/flox) and wild-type mice. shRNA-mediated suppression of UNC5B expression in cultured tubular epithelial cells exacerbated cisplatin-induced cell death in a p53-dependent manner and blunted Akt phosphorylation. Inhibition of PI3 kinase similarly exacerbated cisplatin-induced apoptosis; in contrast, overexpression of UNC5B reduced cisplatin-induced apoptosis in these cells. Taken together, these results show that the netrin-1 receptor UNC5B plays a critical role in cell survival and kidney injury through Akt-mediated inactivation of p53 in response to stress.

Differential Regulation of Synaptic Vesicle Tethering and Docking by UNC-18 and TOM-1.

PubMed

Gracheva, Elena O; Maryon, Ed B; Berthelot-Grosjean, Martine; Richmond, Janet E

2010-01-01

The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18), unc-64(syntaxin) and tom-1(tomosyn). We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25 nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin.

Strain-dependent airway hyperresponsiveness and a chromosome 7 locus of elevated lymphocyte numbers in cystic fibrosis transmembrane conductance regulator-deficient mice.

PubMed

Bazett, Mark; Stefanov, Anguel N; Paun, Alexandra; Paradis, Josee; Haston, Christina K

2012-03-01

We previously observed the lungs of naive BALB/cJ Cftr(tm1UNC) mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftr(tm1UNC) mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftr(tm1UNC) mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftr(tm1UNC) mice had more CD3(+) (both CD4(+) and CD8(+)) cells than did littermates or C57BL/6J Cftr(tm1UNC) mice. Cftr(tm1UNC) and littermate mice of either strain did not differ in anti-CD3-stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftr(tm1UNC) mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftr(tm1UNC) mice demonstrated increased Il-17 secretion. BALB Cftr(tm1UNC) mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftr(tm1UNC) mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftr(tm1UNC) mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

Drosophila UNC-45 prevents heat-induced aggregation of skeletal muscle myosin and facilitates refolding of citrate synthase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melkani, Girish C.; Lee, Chi F.; Cammarato, Anthony

2010-05-28

UNC-45 belongs to the UCS (UNC-45, CRO1, She4p) domain protein family, whose members interact with various classes of myosin. Here we provide structural and biochemical evidence that Escherichia coli-expressed Drosophila UNC-45 (DUNC-45) maintains the integrity of several substrates during heat-induced stress in vitro. DUNC-45 displays chaperone function in suppressing aggregation of the muscle myosin heavy meromyosin fragment, the myosin S-1 motor domain, {alpha}-lactalbumin and citrate synthase. Biochemical evidence is supported by electron microscopy, which reveals the first structural evidence that DUNC-45 prevents inter- or intra-molecular aggregates of skeletal muscle heavy meromyosin caused by elevated temperatures. We also demonstrate for themore » first time that UNC-45 is able to refold a denatured substrate, urea-unfolded citrate synthase. Overall, this in vitro study provides insight into the fate of muscle myosin under stress conditions and suggests that UNC-45 protects and maintains the contractile machinery during in vivo stress.« less

Genetic organization of the unc-22 IV gene and the adjacent region in Caenorhabditis elegans.

PubMed

Rogalski, T M; Baillie, D L

1985-01-01

The genetic organization of the region immediately adjacent to the unc-22 IV gene in Caenorhabditis elegans has been studied. We have identified twenty essential genes in this interval of approximately 1.5-map units on Linkage Group IV. The mutations that define these genes were positioned by recombination mapping and complementation with several deficiencies. With few exceptions, the positions obtained by these two methods agreed. Eight of the twenty essential genes identified are represented by more than one allele. Three possible internal deletions of the unc-22 gene have been located by intra-genic mapping. In addition, the right end point of a deficiency or an inversion affecting the adjacent genes let-56 and unc-22 has been positioned inside the unc-22 gene.

Improving the UNC Passive Aerosol Sampler Model Based on Comparison with Commonly Used Aerosol Sampling Methods.

PubMed

Shirdel, Mariam; Andersson, Britt M; Bergdahl, Ingvar A; Sommar, Johan N; Wingfors, Håkan; Liljelind, Ingrid E

2018-03-12

In an occupational environment, passive sampling could be an alternative to active sampling with pumps for sampling of dust. One passive sampler is the University of North Carolina passive aerosol sampler (UNC sampler). It is often analysed by microscopic imaging. Promising results have been shown for particles above 2.5 µm, but indicate large underestimations for PM2.5. The aim of this study was to evaluate, and possibly improve, the UNC sampler for stationary sampling in a working environment. Sampling was carried out at 8-h intervals during 24 h in four locations in an open pit mine with UNC samplers, respirable cyclones, PM10 and PM2.5 impactors, and an aerodynamic particle sizer (APS). The wind was minimal. For quantification, two modifications of the UNC sampler analysis model, UNC sampler with hybrid model and UNC sampler with area factor, were compared with the original one, UNC sampler with mesh factor derived from wind tunnel experiments. The effect of increased resolution for the microscopic imaging was examined. Use of the area factor and a higher resolution eliminated the underestimation for PM10 and PM2.5. The model with area factor had the overall lowest deviation versus the impactor and the cyclone. The intraclass correlation (ICC) showed that the UNC sampler had a higher precision and better ability to distinguish between different exposure levels compared to the cyclone (ICC: 0.51 versus 0.24), but lower precision compared to the impactor (PM10: 0.79 versus 0.99; PM2.5: 0.30 versus 0.45). The particle size distributions as calculated from the different UNC sampler analysis models were visually compared with the distributions determined by APS. The distributions were obviously different when the UNC sampler with mesh factor was used but came to a reasonable agreement when the area factor was used. High resolution combined with a factor based on area only, results in no underestimation of small particles compared to impactors and cyclones and a better agreement with the APS's particle size distributions. The UNC sampler had lower precision than the impactors, but higher than the respirable cyclone. The UNC sampler with area factor could be used for PM2.5, PM10 and respirable fraction measurements in this working environment without wind.

Improving the UNC Passive Aerosol Sampler Model Based on Comparison with Commonly Used Aerosol Sampling Methods

PubMed Central

Shirdel, Mariam; Andersson, Britt M; Bergdahl, Ingvar A; Sommar, Johan N; Wingfors, Håkan; Liljelind, Ingrid E

2018-01-01

Abstract Objectives In an occupational environment, passive sampling could be an alternative to active sampling with pumps for sampling of dust. One passive sampler is the University of North Carolina passive aerosol sampler (UNC sampler). It is often analysed by microscopic imaging. Promising results have been shown for particles above 2.5 µm, but indicate large underestimations for PM2.5. The aim of this study was to evaluate, and possibly improve, the UNC sampler for stationary sampling in a working environment. Methods Sampling was carried out at 8-h intervals during 24 h in four locations in an open pit mine with UNC samplers, respirable cyclones, PM10 and PM2.5 impactors, and an aerodynamic particle sizer (APS). The wind was minimal. For quantification, two modifications of the UNC sampler analysis model, UNC sampler with hybrid model and UNC sampler with area factor, were compared with the original one, UNC sampler with mesh factor derived from wind tunnel experiments. The effect of increased resolution for the microscopic imaging was examined. Results Use of the area factor and a higher resolution eliminated the underestimation for PM10 and PM2.5. The model with area factor had the overall lowest deviation versus the impactor and the cyclone. The intraclass correlation (ICC) showed that the UNC sampler had a higher precision and better ability to distinguish between different exposure levels compared to the cyclone (ICC: 0.51 versus 0.24), but lower precision compared to the impactor (PM10: 0.79 versus 0.99; PM2.5: 0.30 versus 0.45). The particle size distributions as calculated from the different UNC sampler analysis models were visually compared with the distributions determined by APS. The distributions were obviously different when the UNC sampler with mesh factor was used but came to a reasonable agreement when the area factor was used. Conclusions High resolution combined with a factor based on area only, results in no underestimation of small particles compared to impactors and cyclones and a better agreement with the APS’s particle size distributions. The UNC sampler had lower precision than the impactors, but higher than the respirable cyclone. The UNC sampler with area factor could be used for PM2.5, PM10 and respirable fraction measurements in this working environment without wind. PMID:29300818

Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis.

PubMed

Larrivée, Bruno; Freitas, Catarina; Trombe, Marc; Lv, Xiang; Delafarge, Benjamin; Yuan, Li; Bouvrée, Karine; Bréant, Christiane; Del Toro, Raquel; Bréchot, Nicolas; Germain, Stéphane; Bono, Françoise; Dol, Frédérique; Claes, Filip; Fischer, Christian; Autiero, Monica; Thomas, Jean-Léon; Carmeliet, Peter; Tessier-Lavigne, Marc; Eichmann, Anne

2007-10-01

Netrins are secreted molecules with roles in axonal growth and angiogenesis. The Netrin receptor UNC5B is required during embryonic development for vascular patterning, suggesting that it may also contribute to postnatal and pathological angiogenesis. Here we show that unc5b is down-regulated in quiescent adult vasculature, but re-expressed during sprouting angiogenesis in matrigel and tumor implants. Stimulation of UNC5B-expressing neovessels with an agonist (Netrin-1) inhibits sprouting angiogenesis. Genetic loss of function of unc5b reduces Netrin-1-mediated angiogenesis inhibition. Expression of UNC5B full-length receptor also triggers endothelial cell repulsion in response to Netrin-1 in vitro, whereas a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion. These data show that UNC5B activation inhibits sprouting angiogenesis, thus identifying UNC5B as a potential anti-angiogenic target.

Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis

PubMed Central

Larrivée, Bruno; Freitas, Catarina; Trombe, Marc; Lv, Xiang; DeLafarge, Benjamin; Yuan, Li; Bouvrée, Karine; Bréant, Christiane; Del Toro, Raquel; Bréchot, Nicolas; Germain, Stéphane; Bono, Françoise; Dol, Frédérique; Claes, Filip; Fischer, Christian; Autiero, Monica; Thomas, Jean-Léon; Carmeliet, Peter; Tessier-Lavigne, Marc; Eichmann, Anne

2007-01-01

Netrins are secreted molecules with roles in axonal growth and angiogenesis. The Netrin receptor UNC5B is required during embryonic development for vascular patterning, suggesting that it may also contribute to postnatal and pathological angiogenesis. Here we show that unc5b is down-regulated in quiescent adult vasculature, but re-expressed during sprouting angiogenesis in matrigel and tumor implants. Stimulation of UNC5B-expressing neovessels with an agonist (Netrin-1) inhibits sprouting angiogenesis. Genetic loss of function of unc5b reduces Netrin-1-mediated angiogenesis inhibition. Expression of UNC5B full-length receptor also triggers endothelial cell repulsion in response to Netrin-1 in vitro, whereas a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion. These data show that UNC5B activation inhibits sprouting angiogenesis, thus identifying UNC5B as a potential anti-angiogenic target. PMID:17908930

UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans

PubMed Central

Hu, Zhitao; Tong, Xia-Jing; Kaplan, Joshua M

2013-01-01

Synaptic transmission consists of fast and slow components of neurotransmitter release. Here we show that these components are mediated by distinct exocytic proteins. The Caenorhabditis elegans unc-13 gene is required for SV exocytosis, and encodes long and short isoforms (UNC-13L and S). Fast release was mediated by UNC-13L, whereas slow release required both UNC-13 proteins and was inhibited by Tomosyn. The spatial location of each protein correlated with its effect. Proteins adjacent to the dense projection mediated fast release, while those controlling slow release were more distal or diffuse. Two UNC-13L domains accelerated release. C2A, which binds RIM (a protein associated with calcium channels), anchored UNC-13 at active zones and shortened the latency of release. A calmodulin binding site accelerated release but had little effect on UNC-13’s spatial localization. These results suggest that UNC-13L, UNC-13S, and Tomosyn form a molecular code that dictates the timing of neurotransmitter release. DOI: http://dx.doi.org/10.7554/eLife.00967.001 PMID:23951547

A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor

PubMed Central

Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G

2015-01-01

Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

Genes affecting sensitivity to serotonin in Caenorhabditis elegans.

PubMed

Schafer, W R; Sanchez, B M; Kenyon, C J

1996-07-01

Regulating the response of a postsynaptic cell to neurotransmitter is an important mechanism for controlling synaptic strength, a process critical to learning. We have begun to define and characterize genes that may control sensitivity to the neurotransmitter serotonin in the nematode Caenorhabditis elegans by identifying serotonin-hypersensitive mutants. We reported previously that mutations in the gene unc-2, which encodes a putative calcium channel subunit, result in hypersensitivity to serotonin. Here we report that mutants defective in the unc-36 gene, which encodes a homologue of a calcium channel auxiliary subunit, are also serotonin-hypersensitive. Moreover, the unc-36 gene appears to be required in the same cells as unc-2 for control of the same behaviors. Mutations in several other genes, including unc-8, unc-10, unc-20, unc-35, unc-75, unc-77, and snt-1 also result in hypersensitivity to serotonin. Several of these mutations have previously been shown to confer resistance to acetylcholinesterase inhibitors, suggesting that they may affect acetylcholine release. Moreover, we found that mutations that decrease acetylcholine synthesis cause defective egg-laying and serotonin hypersensitivity. Thus, acetylcholine appears to negatively regulate the response to serotonin and may participate in the process of serotonin desensitization.

Genes Affecting Sensitivity to Serotonin in Caenorhabditis Elegans

PubMed Central

Schafer, W. R.; Sanchez, B. M.; Kenyon, C. J.

1996-01-01

Regulating the response of a postsynaptic cell to neurotransmitter is an important mechanism for controlling synaptic strength, a process critical to learning. We have begun to define and characterize genes that may control sensitivity to the neurotransmitter serotonin in the nematode Caenorhabditis elegans by identifying serotonin-hypersensitive mutants. We reported previously that mutations in the gene unc-2, which encodes a putative calcium channel subunit, result in hypersensitivity to serotonin. Here we report that mutants defective in the unc-36 gene, which encodes a homologue of a calcium channel auxiliary subunit, are also serotonin-hypersensitive. Moreover, the unc-36 gene appears to be required in the same cells as unc-2 for control of the same behaviors. Mutations in several other genes, including unc-8, unc-10, unc-20, unc-35, unc-75, unc-77, and snt-1 also result in hypersensitivity to serotonin. Several of these mutations have previously been shown to confer resistance to acetylcholinesterase inhibitors, suggesting that they may affect acetylcholine release. Moreover, we found that mutations that decrease acetylcholine synthesis cause defective egg-laying and serotonin hypersensitivity. Thus, acetylcholine appears to negatively regulate the response to serotonin and may participate in the process of serotonin desensitization. PMID:8807295

UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons

PubMed Central

Edwards, Stacey L.; Morrison, Logan M.; Yorks, Rosalina M.; Hoover, Christopher M.; Boominathan, Soorajnath; Miller, Kenneth G.

2015-01-01

The conserved protein UNC-16 (JIP3) inhibits the active transport of some cell soma organelles, such as lysosomes, early endosomes, and Golgi, to the synaptic region of axons. However, little is known about UNC-16’s organelle transport regulatory function, which is distinct from its Kinesin-1 adaptor function. We used an unc-16 suppressor screen in Caenorhabditis elegans to discover that UNC-16 acts through CDK-5 (Cdk5) and two conserved synapse assembly proteins: SAD-1 (SAD-A Kinase), and SYD-2 (Liprin-α). Genetic analysis of all combinations of double and triple mutants in unc-16(+) and unc-16(−) backgrounds showed that the three proteins (CDK-5, SAD-1, and SYD-2) are all part of the same organelle transport regulatory system, which we named the CSS system based on its founder proteins. Further genetic analysis revealed roles for SYD-1 (another synapse assembly protein) and STRADα (a SAD-1-interacting protein) in the CSS system. In an unc-16(−) background, loss of the CSS system improved the sluggish locomotion of unc-16 mutants, inhibited axonal lysosome accumulation, and led to the dynein-dependent accumulation of lysosomes in dendrites. Time-lapse imaging of lysosomes in CSS system mutants in unc-16(+) and unc-16(−) backgrounds revealed active transport defects consistent with the steady-state distributions of lysosomes. UNC-16 also uses the CSS system to regulate the distribution of early endosomes in neurons and, to a lesser extent, Golgi. The data reveal a new and unprecedented role for synapse assembly proteins, acting as part of the newly defined CSS system, in mediating UNC-16’s organelle transport regulatory function. PMID:26354976

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy

PubMed Central

Shamseldin, Hanan E.; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S.; Gleeson, Joseph G.; Alkuraya, Fowzan S.

2016-01-01

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. PMID:26708753

Uncoordinated (UNC)119: coordinating the trafficking of myristoylated proteins.

PubMed

Constantine, Ryan; Zhang, Houbin; Gerstner, Cecilia D; Frederick, Jeanne M; Baehr, Wolfgang

2012-12-15

The mechanism by which myristoylated proteins are targeted to specific subcellular membrane compartments is poorly understood. Two novel acyl-binding proteins, UNC119A and UNC119B, have been shown recently to function as chaperones/co-factors in the transport of myristoylated G protein α-subunits and src-type tyrosine kinases. UNC119 polypeptides feature an immunoglobulin-like β-sandwich fold that forms a hydrophobic pocket capable of binding lauroyl (C12) and myristoyl (C14) side chains. UNC119A in rod photoreceptors facilitates the transfer of transducin α subunits (Tα) from inner segment to outer segment membranes by forming an intermediate diffusible UNC119-Tα complex. Similar complexes are formed in other sensory neurons, as the G proteins ODR-3 and GPA-13 in Caenorhabditis elegans unc-119 mutants traffic inappropriately. UNC119B knockdown in IMCD3 cells prevents trafficking ofmyristoylated nephrocystin-3 (NPHP3), a protein associated with nephronophthisis, to cilia. Further, UNC119A was shown to transport myristoylated src-type tyrosine kinases to cell membranes and to affect T-cell receptor (TCR) and interleukin-5 receptor (IL-5R) activities. These interactions establish UNC119 polypeptides as novel lipid-binding chaperones with specificity for a diverse subset of myristoylated proteins. Copyright © 2012 Elsevier Ltd. All rights reserved.

Uncoordinated (UNC)119: Coordinating the Trafficking of Myristoylated Proteins

PubMed Central

Constantine, Ryan; Zhang, Houbin; Gerstner, Cecilia D.; Frederick, Jeanne M.; Baehr, Wolfgang

2012-01-01

The mechanism by which myristoylated proteins are targeted to specific subcellular membrane compartments is poorly understood. Two novel acyl-binding proteins, UNC119A and UNC119B, have been shown recently to function as chaperones/co-factors in the transport of myristoylated G protein α-subunits and src-type tyrosine kinases. UNC119 polypeptides feature an immunoglobulin-like β-sandwich fold that forms a hydrophobic pocket capable of binding lauroyl (C12) and myristoyl (C14) side chains. UNC119A in rod photoreceptors facilitates the transfer of transducin α subunits (Tα) from inner segment to outer segment membranes by forming an intermediate diffusible UNC119-Tα complex. Similar complexes are formed in other sensory neurons, as the G proteins ODR-3 and GPA-13 in C. elegans unc-119 mutants traffic inappropriately. UNC119B knockdown in IMCD3 cells prevents trafficking of myristoylated nephrocystin-3 (NPHP3), a protein associated with nephronophthisis, to cilia. Further, UNC119A was shown to transpot myristoylated src-type tyrosine kinases to cell membranes and to affect T-cell receptor (TCR) and interleukin-5 receptor (IL-5R) activities. These interactions establish UNC119 polypeptides as novel lipid-binding chaperones with specificity for a diverse subset of myristoylated proteins. PMID:23000199

The UNC-45 Chaperone Is Critical for Establishing Myosin-Based Myofibrillar Organization and Cardiac Contractility in the Drosophila Heart Model

PubMed Central

Melkani, Girish C.; Bodmer, Rolf; Ocorr, Karen; Bernstein, Sanford I.

2011-01-01

UNC-45 is a UCS (UNC-45/CRO1/She4P) class chaperone necessary for myosin folding and/or accumulation, but its requirement for maintaining cardiac contractility has not been explored. Given the prevalence of myosin mutations in eliciting cardiomyopathy, chaperones like UNC-45 are likely to be equally critical in provoking or modulating myosin-associated cardiomyopathy. Here, we used the Drosophila heart model to examine its role in cardiac physiology, in conjunction with RNAi-mediated gene silencing specifically in the heart in vivo. Analysis of cardiac physiology was carried out using high-speed video recording in conjunction with movement analysis algorithms. unc-45 knockdown resulted in severely compromised cardiac function in adults as evidenced by prolonged diastolic and systolic intervals, and increased incidence of arrhythmias and extreme dilation; the latter was accompanied by a significant reduction in muscle contractility. Structural analysis showed reduced myofibrils, myofibrillar disarray, and greatly decreased cardiac myosin accumulation. Cardiac unc-45 silencing also dramatically reduced life-span. In contrast, third instar larval and young pupal hearts showed mild cardiac abnormalities, as severe cardiac defects only developed during metamorphosis. Furthermore, cardiac unc-45 silencing in the adult heart (after metamorphosis) led to less severe phenotypes. This suggests that UNC-45 is mostly required for myosin accumulation/folding during remodeling of the forming adult heart. The cardiac defects, myosin deficit and decreased life-span in flies upon heart-specific unc-45 knockdown were significantly rescued by UNC-45 over-expression. Our results are the first to demonstrate a cardiac-specific requirement of a chaperone in Drosophila, suggestive of a critical role of UNC-45 in cardiomyopathies, including those associated with unfolded proteins in the failing human heart. The dilated cardiomyopathy phenotype associated with UNC-45 deficiency is mimicked by myosin knockdown suggesting that UNC-45 plays a crucial role in stabilizing myosin and possibly preventing human cardiomyopathies associated with functional deficiencies of myosin. PMID:21799905

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.

PubMed

Shamseldin, Hanan E; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S; Gleeson, Joseph G; Alkuraya, Fowzan S

2016-01-07

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

The UNC-45 Myosin Chaperone: From Worms to Flies to Vertebrates

PubMed Central

Lee, Chi F.; Melkani, Girish C.; Bernstein, Sanford I.

2014-01-01

UNC-45 is a UCS domain protein that is critical for myosin stability and function. It likely aides in folding myosin during cellular differentiation and maintenance and protects myosin from denaturation during stress. Invertebrates have a single unc-45 gene that is expressed in both muscle and non-muscle tissues. Vertebrates possess one gene expressed in striated muscle (unc-45b) and one that is more generally expressed (unc-45a). Structurally, UNC-45 is composed of a series of alpha-helices connected by loops. It has an N-terminal TPR domain that binds to Hsp90 and a central domain composed of armadillo repeats. Its C-terminal UCS domain, which is also comprised of helical armadillo repeats, interacts with myosin. In this review, we present biochemical, structural and genetic analyses of UNC-45 in Caenorhabditis elegans, Drosophila melanogaster and various vertebrates. Further, we provide insights into UNC-45 functions, its potential mechanism of action and its roles in human disease. PMID:25376491

Effects of MERTK Inhibitors UNC569 and UNC1062 on the Growth of Acute Myeloid Leukaemia Cells.

PubMed

Koda, Yuki; Itoh, Mai; Tohda, Shuji

2018-01-01

MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells. Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated. Treatment with the inhibitors suppressed cell growth and induced apoptosis in all cell lines. OCI/AML5 and TMD7 cells, in which MERTK was constitutively phosphorylated by autocrine mechanisms, were highly susceptible to these inhibitors. The treatment reduced the phosphorylation of MERTK and its down-stream signalling molecules, v-akt murine thymoma viral oncogene homolog 1 (AKT) and extracellular signal-regulated kinase (ERK). Similar effects were observed after MERTK knockdown. The inhibitors and the knockdown caused similar changes in mRNA expression. These MERTK inhibitors are potential molecular-targeted drugs for treating AML expressing constitutively phosphorylated MERTK. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans.

PubMed

Jang, Heeun; Levy, Sagi; Flavell, Steven W; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I

2017-02-14

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9-containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9 -based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits.

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans

PubMed Central

Jang, Heeun; Levy, Sagi; Flavell, Steven W.; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I.

2017-01-01

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans. The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9–containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9–based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits. PMID:28143932

The minus-end actin capping protein, UNC-94/tropomodulin, regulates development of the Caenorhabditis elegans intestine

PubMed Central

Cox-Paulson, Elisabeth; Cannataro, Vincent; Gallagher, Thomas; Hoffman, Corey; Mantione, Gary; McIntosh, Matthew; Silva, Malan; Vissichelli, Nicole; Walker, Rachel; Simske, Jeffrey; Ono, Shoichiro; Hoops, Harold

2014-01-01

Background Tropomodulins are actin capping proteins that regulate the stability of the slow growing, minus-ends of actin filaments. The C. elegans tropomodulin homolog, UNC-94 has sequence and functional similarity to vertebrate tropomodulins. We investigated the role of UNC-94 in C. elegans intestinal morphogenesis. Results In the embryonic C. elegans intestine, UNC-94 localizes to the terminal web, an actin and intermediate filament rich structure that underlies the apical membrane. Loss of UNC-94 function results in areas of flattened intestinal lumen. In worms homozygous for the strong loss-of-function allele, unc-94(tm724), the terminal web is thinner and the amount of F-actin is reduced, pointing to a role for UNC-94 in regulating the structure of the terminal web. The non-muscle myosin, NMY-1, also localizes to the terminal web; and we present evidence that increasing actomyosin contractility by depleting the myosin phosphatase regulatory subunit, mel-11, can rescue the flattened lumen phenotype of unc-94 mutants. Conclusions The data support a model in which minus-end actin capping by UNC-94 promotes proper F-actin structure and contraction in the terminal web, yielding proper shape of the intestinal lumen. This establishes a new role for a tropomodulin in regulating lumen shape during tubulogenesis. PMID:24677443

Readmissions, unplanned emergency room visits, and surgical retreatment rates after anti-reflux procedures.

PubMed

Wang, Hsin-Hsiao S; Tejwani, Rohit; Wolf, Steven; Wiener, John S; Routh, Jonathan C

2017-10-01

The choice between endoscopic injection (EI) and ureteroneocystotomy (UNC) for surgical correction of vesicoureteral reflux (VUR) is controversial. To compare postoperative outcomes of EI vs UNC. This study reviewed linked inpatient (SID), ambulatory surgery (SASD), and emergency department (SEDD) data from five states in the United States (2007-10) to identify pediatric patients with primary VUR undergoing EI or UNC as an initial surgical intervention. Unplanned readmissions, additional procedures, and emergency room (ER) visits were extracted. Statistical analysis was performed using multivariate logistic regression using generalized estimating equation (GEE) to adjust for hospital-level clustering. The study identified 2556 UNC and 1997 EI procedures. Compared with patients undergoing EI, those who underwent UNC were more likely to be younger (4.6 vs 6.0 years, P < 0.001), male (30 vs 20%, P < 0.001), and publicly insured (34 vs 29%, P < 0.001). As shown in Summary Figure, compared with EI, UNC patients had lower rates of additional anti-reflux procedures within 12 months (25 (1.0) vs 121 (6.1%), P < 0.001), but a higher rate of 30-day and 90-day readmissions and ER visits. On multivariate analysis, patients treated by UNC remained at higher odds of being readmitted (OR = 4.45; 2.69 in 30 days; 90 days, P < 0.001) and to have postoperative ER visits (OR = 3.33; 2.26 in 30 days; 90 days, P < 0.001); however, EI had significantly higher odds of repeat anti-reflux procedures in the subsequent year (OR = 7.12, P < 0.001). Endoscopic injection constituted nearly half of initial anti-reflux procedures in children. However, patients treated with UNC had significantly lower odds of requiring re-treatment in the first year relative to those treated with EI. By contrast, patients treated with UNC had more than twice the odds of being readmitted or visiting an ER postoperatively. Although the available data were amongst the largest and most well validated, the major limitation was the retrospective nature of the administrative database. The practice setting may not be generalizable to states not included in the analysis. Postoperative readmissions and ER visits were uncommon after any surgical intervention for VUR, but were more common among children undergoing UNC. The EI patients had a more than seven-fold increased risk of surgical re-treatment within 1 year. Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Mutation of the Ser18 phosphorylation site on the sole Saccharomyces cerevisiae UCS protein, She4, can compromise high-temperature survival.

PubMed

Gomez-Escalante, Susana; Piper, Peter W; Millson, Stefan H

2017-01-01

Folding of the myosin head often requires the joint actions of Hsp90 and a dedicated UNC45, Cro1, She4 (UCS) domain-containing cochaperone protein. Relatively weak sequence conservation exists between the single UCS protein of simple eukaryotes (She4 in budding yeast) and the two UCS proteins of higher organisms (the general cell and smooth muscle UNC45s; UNC45-GC and UNC45-SM respectively). In vertebrates, UNC45-GC facilitates cytoskeletal function whereas the 55% identical UNC45-SM assists in the assembly of the contractile apparatus of cardiac and skeletal muscles. UNC45-SM, unlike UNC45-GC, shares with yeast She4 an IDSL sequence motif known to be a site of in vivo serine phosphorylation in yeast. Investigating this further, we found that both a non-phosphorylatable (S18A) and a phosphomimetic (S18E) mutant form of She4 could rescue the type 1 myosin localisation and endocytosis defects of the yeast she4Δ mutant at 39 °C. Nevertheless, at higher temperature (45 °C), only She4 (S18A), not She4(S18E), could substantially rescue the cell lysis defect of she4Δ mutant cells. In the yeast two-hybrid system, the non-phosphorylatable S18A and S251A mutant forms of She4 and UNC45-SM still displayed the stress-enhanced in vivo interaction with Hsp90 seen with the wild-type She4 and UNC45-SM. Such high-temperature enforcement to interaction was though lost with the phosphomimetic mutant forms (She4(S18E) and UNC45-SM (S251E)), an indication that phosphorylation might suppress these increases in She4/Hsp90 and UNC45-SM/Hsp90 interaction with stress.

Transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 control anterior-posterior neuroblast migration with left-right functional asymmetry in Caenorhabditis elegans.

PubMed

Sundararajan, Lakshmi; Lundquist, Erik A

2012-12-01

Migration of neurons and neural crest cells is of central importance to the development of nervous systems. In Caenorhabditis elegans, the QL neuroblast on the left migrates posteriorly, and QR on the right migrates anteriorly, despite similar lineages and birth positions with regard to the left-right axis. Initial migration is independent of a Wnt signal that controls later anterior-posterior Q descendant migration. Previous studies showed that the transmembrane proteins UNC-40/DCC and MIG-21, a novel thrombospondin type I repeat containing protein, act redundantly in left-side QL posterior migration. Here we show that the LAR receptor protein tyrosine phosphatase PTP-3 acts with MIG-21 in parallel to UNC-40 in QL posterior migration. We also show that in right-side QR, the UNC-40 and PTP-3/MIG-21 pathways mutually inhibit each other's role in posterior migration, allowing anterior QR migration. Finally, we present evidence that these proteins act autonomously in the Q neuroblasts. These studies indicate an inherent left-right asymmetry in the Q neuroblasts with regard to UNC-40, PTP-3, and MIG-21 function that results in posterior vs. anterior migration.

Regulation of Gap Junction Dynamics by UNC-44/ankyrin and UNC-33/CRMP through VAB-8 in C. elegans Neurons

PubMed Central

Yan, Dong

2016-01-01

Gap junctions are present in both vertebrates and invertebrates from nematodes to mammals. Although the importance of gap junctions has been documented in many biological processes, the molecular mechanisms underlying gap junction dynamics remain unclear. Here, using the C. elegans PLM neurons as a model, we show that UNC-44/ankyrin acts upstream of UNC-33/CRMP in regulation of a potential kinesin VAB-8 to control gap junction dynamics, and loss-of-function in the UNC-44/UNC-33/VAB-8 pathway suppresses the turnover of gap junction channels. Therefore, we first show a signal pathway including ankyrin, CRMP, and kinesin in regulating gap junctions. PMID:27015090

The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract

PubMed Central

Hansen, Lars; Comyn, Sophie; Mang, Yuan; Lind-Thomsen, Allan; Myhre, Layne; Jean, Francesca; Eiberg, Hans; Tommerup, Niels; Rosenberg, Thomas; Pilgrim, David

2014-01-01

Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles in this region, in ACACA and UNC45B. As alterations of the UNC45B protein have been shown to affect eye development in model organisms, effort was focused on the heterozygous UNC45B missense mutation. UNC45B encodes a myosin-specific chaperone that, together with the general heat shock protein HSP90, is involved in myosin assembly. The mutation changes p.Arg805 to Trp in the UCS domain, an amino acid that is highly conserved from yeast to human. UNC45B is strongly expressed in the heart and skeletal muscle tissue, but here we show expression in human embryo eye and zebrafish lens. The zebrafish mutant steif, carrying an unc45b nonsense mutation, has smaller eyes than wild-type embryos and shows accumulation of nuclei in the lens. Injection of RNA encoding the human wild-type UNC45B protein into the steif homozygous embryo reduced the nuclei accumulation and injection of human mutant UNC45B cDNA in wild-type embryos resulted in development of a phenotype similar to the steif mutant. The p.Arg805Trp alteration in the mammalian UNC45B gene suggests that developmental cataract may be caused by a defect in non-muscle myosin assembly during maturation of the lens fiber cells. PMID:24549050

The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract.

PubMed

Hansen, Lars; Comyn, Sophie; Mang, Yuan; Lind-Thomsen, Allan; Myhre, Layne; Jean, Francesca; Eiberg, Hans; Tommerup, Niels; Rosenberg, Thomas; Pilgrim, David

2014-11-01

Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles in this region, in ACACA and UNC45B. As alterations of the UNC45B protein have been shown to affect eye development in model organisms, effort was focused on the heterozygous UNC45B missense mutation. UNC45B encodes a myosin-specific chaperone that, together with the general heat shock protein HSP90, is involved in myosin assembly. The mutation changes p.Arg805 to Trp in the UCS domain, an amino acid that is highly conserved from yeast to human. UNC45B is strongly expressed in the heart and skeletal muscle tissue, but here we show expression in human embryo eye and zebrafish lens. The zebrafish mutant steif, carrying an unc45b nonsense mutation, has smaller eyes than wild-type embryos and shows accumulation of nuclei in the lens. Injection of RNA encoding the human wild-type UNC45B protein into the steif homozygous embryo reduced the nuclei accumulation and injection of human mutant UNC45B cDNA in wild-type embryos resulted in development of a phenotype similar to the steif mutant. The p.Arg805Trp alteration in the mammalian UNC45B gene suggests that developmental cataract may be caused by a defect in non-muscle myosin assembly during maturation of the lens fiber cells.

The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

PubMed Central

Miller-Fleming, Tyne W; Petersen, Sarah C; Manning, Laura; Matthewman, Cristina; Gornet, Megan; Beers, Allison; Hori, Sayaka; Mitani, Shohei; Bianchi, Laura; Richmond, Janet; Miller, David M

2016-01-01

Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons. DOI: http://dx.doi.org/10.7554/eLife.14599.001 PMID:27403890

Phenotypic Evolution of UNC80 Loss of Function

PubMed Central

Valkanas, Elise; Schaffer, Katherine; Dunham, Christopher; Maduro, Valerie; du Souich, Christèle; Rupps, Rosemarie; Adams, David R.; Baradaran-Heravi, Alireza; Flynn, Elise; Malicdan, May C.; Gahl, William A.; Toro, Camilo; Boerkoel, Cornelius F.

2017-01-01

Failure to thrive arises as a complication of a heterogeneous group of disorders. We describe two female siblings with spastic paraplegia and global developmental delay but also, atypically for the HSPs, poor weight gain classified as failure to thrive. After extensive clinical and biochemical investigations failed to identify the etiology, we used exome sequencing to identify biallelic UNC80 mutations (NM_032504.1:c.[3983-3_3994delinsA];[2431C>T]. The paternally inherited NM_032504.1:c.3983-3_3994delinsA is predicted to encode p.Ser1328Argfs*19 and the maternally inherited NM_032504.1:c.2431C>T is predicted to encode p.Arg811*. No UNC80 mRNA was detectable in patient cultured skin fibroblasts, suggesting UNC80 loss of function by nonsense mediated mRNA decay. Further supporting the UNC80 mutations as causative of these siblings disorder, biallelic mutations in UNC80 have recently been described among individuals with an overlapping phenotype. This report expands the disease spectrum associated with UNC80 mutations. PMID:27513830

Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104

PubMed Central

Asghari Adib, Elham; Stanchev, Doychin T; Xiong, Xin; Klinedinst, Susan; Soppina, Pushpanjali; Jahn, Thomas Robert; Hume, Richard I

2017-01-01

The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104’s transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104’s function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon. PMID:28925357

Validation of a Glucocorticoid Receptor Effects-Based Environmental Sample Screening Tool

EPA Science Inventory

Abstract describing study and results that will be presented in a seminar presentation to members of UNC-Chapel Hill Curriculum in Toxicology. This seminar presentation will be fulfilling the requirements of the USEPA-UNC Toxicology Cooperative Postdoctoral Training program.

The ENU-3 protein family members function in the Wnt pathway parallel to UNC-6/Netrin to promote motor neuron axon outgrowth in C. elegans.

PubMed

Florica, Roxana Oriana; Hipolito, Victoria; Bautista, Stephen; Anvari, Homa; Rapp, Chloe; El-Rass, Suzan; Asgharian, Alimohammad; Antonescu, Costin N; Killeen, Marie T

2017-10-01

The axons of the DA and DB classes of motor neurons fail to reach the dorsal cord in the absence of the guidance cue UNC-6/Netrin or its receptor UNC-5 in C. elegans. However, the axonal processes usually exit their cell bodies in the ventral cord in the absence of both molecules. Strains lacking functional versions of UNC-6 or UNC-5 have a low level of DA and DB motor neuron axon outgrowth defects. We found that mutations in the genes for all six of the ENU-3 proteins function to enhance the outgrowth defects of the DA and DB axons in strains lacking either UNC-6 or UNC-5. A mutation in the gene for the MIG-14/Wntless protein also enhances defects in a strain lacking either UNC-5 or UNC-6, suggesting that the ENU-3 and Wnt pathways function parallel to the Netrin pathway in directing motor neuron axon outgrowth. Our evidence suggests that the ENU-3 proteins are novel members of the Wnt pathway in nematodes. Five of the six members of the ENU-3 family are predicted to be single-pass trans-membrane proteins. The expression pattern of ENU-3.1 was consistent with plasma membrane localization. One family member, ENU-3.6, lacks the predicted signal peptide and the membrane-spanning domain. In HeLa cells ENU-3.6 had a cytoplasmic localization and caused actin dependent processes to appear. We conclude that the ENU-3 family proteins function in a pathway parallel to the UNC-6/Netrin pathway for motor neuron axon outgrowth, most likely in the Wnt pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

UNC-108/Rab2 Regulates Postendocytic Trafficking in Caenorhabditis elegans

PubMed Central

Chun, Denise K.; McEwen, Jason M.; Burbea, Michelle

2008-01-01

After endocytosis, membrane proteins are often sorted between two alternative pathways: a recycling pathway and a degradation pathway. Relatively little is known about how trafficking through these alternative pathways is differentially regulated. Here, we identify UNC-108/Rab2 as a regulator of postendocytic trafficking in both neurons and coelomocytes. Mutations in the Caenorhabditis elegans Rab2 gene unc-108, caused the green fluorescent protein (GFP)-tagged glutamate receptor GLR-1 (GLR-1::GFP) to accumulate in the ventral cord and in neuronal cell bodies. In neuronal cell bodies of unc-108/Rab2 mutants, GLR-1::GFP was found in tubulovesicular structures that colocalized with markers for early and recycling endosomes, including Syntaxin-13 and Rab8. GFP-tagged Syntaxin-13 also accumulated in the ventral cord of unc-108/Rab2 mutants. UNC-108/Rab2 was not required for ubiquitin-mediated sorting of GLR-1::GFP into the multivesicular body (MVB) degradation pathway. Mutations disrupting the MVB pathway and unc-108/Rab2 mutations had additive effects on GLR-1::GFP levels in the ventral cord. In coelomocytes, postendocytic trafficking of the marker Texas Red-bovine serum albumin was delayed. These results demonstrate that UNC-108/Rab2 regulates postendocytic trafficking, most likely at the level of early or recycling endosomes, and that UNC-108/Rab2 and the MVB pathway define alternative postendocytic trafficking mechanisms that operate in parallel. These results define a new function for Rab2 in protein trafficking. PMID:18434599

Transcriptional profiling reveals regulated genes in the hippocampus during memory formation

NASA Technical Reports Server (NTRS)

Donahue, Christine P.; Jensen, Roderick V.; Ochiishi, Tomoyo; Eisenstein, Ingrid; Zhao, Mingrui; Shors, Tracey; Kosik, Kenneth S.

2002-01-01

Transcriptional profiling (TP) offers a powerful approach to identify genes activated during memory formation and, by inference, the molecular pathways involved. Trace eyeblink conditioning is well suited for the study of regional gene expression because it requires the hippocampus, whereas the highly parallel task, delay conditioning, does not. First, we determined when gene expression was most regulated during trace conditioning. Rats were exposed to 200 trials per day of paired and unpaired stimuli each day for 4 days. Changes in gene expression were most apparent 24 h after exposure to 200 trials. Therefore, we profiled gene expression in the hippocampus 24 h after 200 trials of trace eyeblink conditioning, on multiple arrays using additional animals. Of 1,186 genes on the filter array, seven genes met the statistical criteria and were also validated by real-time polymerase chain reaction. These genes were growth hormone (GH), c-kit receptor tyrosine kinase (c-kit), glutamate receptor, metabotropic 5 (mGluR5), nerve growth factor-beta (NGF-beta), Jun oncogene (c-Jun), transmembrane receptor Unc5H1 (UNC5H1), and transmembrane receptor Unc5H2 (UNC5H2). All these genes, except for GH, were downregulated in response to trace conditioning. GH was upregulated; therefore, we also validated the downregulation of the GH inhibitor, somatostatin (SST), even though it just failed to meet criteria on the arrays. By during situ hybridization, GH was expressed throughout the cell layers of the hippocampus in response to trace conditioning. None of the genes regulated in trace eyeblink conditioning were similarly affected by delay conditioning, a task that does not require the hippocampus. These findings demonstrate that transcriptional profiling can exhibit a repertoire of genes sensitive to the formation of hippocampal-dependent associative memories.

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.

PubMed

van Eijk, Ruben P A; Jones, Ashley R; Sproviero, William; Shatunov, Aleksey; Shaw, Pamela J; Leigh, P Nigel; Young, Carolyn A; Shaw, Christopher E; Mora, Gabriele; Mandrioli, Jessica; Borghero, Giuseppe; Volanti, Paolo; Diekstra, Frank P; van Rheenen, Wouter; Verstraete, Esther; Eijkemans, Marinus J C; Veldink, Jan H; Chio, Adriano; Al-Chalabi, Ammar; van den Berg, Leonard H; van Es, Michael A

2017-10-31

To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers ( p = 0.027), but not for C9orf72 carriers ( p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Transmembrane Proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 Control Anterior–Posterior Neuroblast Migration with Left–Right Functional Asymmetry in Caenorhabditis elegans

PubMed Central

Sundararajan, Lakshmi; Lundquist, Erik A.

2012-01-01

Migration of neurons and neural crest cells is of central importance to the development of nervous systems. In Caenorhabditis elegans, the QL neuroblast on the left migrates posteriorly, and QR on the right migrates anteriorly, despite similar lineages and birth positions with regard to the left–right axis. Initial migration is independent of a Wnt signal that controls later anterior–posterior Q descendant migration. Previous studies showed that the transmembrane proteins UNC-40/DCC and MIG-21, a novel thrombospondin type I repeat containing protein, act redundantly in left-side QL posterior migration. Here we show that the LAR receptor protein tyrosine phosphatase PTP-3 acts with MIG-21 in parallel to UNC-40 in QL posterior migration. We also show that in right-side QR, the UNC-40 and PTP-3/MIG-21 pathways mutually inhibit each other’s role in posterior migration, allowing anterior QR migration. Finally, we present evidence that these proteins act autonomously in the Q neuroblasts. These studies indicate an inherent left–right asymmetry in the Q neuroblasts with regard to UNC-40, PTP-3, and MIG-21 function that results in posterior vs. anterior migration. PMID:23051647

Neil Hayes, M.D., M.P.H., Explains TCGA Findings on GBM Subtypes - TCGA

Cancer.gov

New findings by researchers at UNC Lineberger Comprehensive Cancer Center suggest that the most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is probably not a single disease but a set of diseases, each with a distinct underlying molecular disease process. The study was published by Cell Press in the January issue of the journal Cancer Cell and the researchers are part of the The Cancer Genome Atlas.

Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lv, Jianwei; Tianjin Institute of Orthopedics in Traditional Chinese and Western Medicine, No. 155, Munan Road, Tianjin 300050; Sun, Xiaolei

2015-08-14

Schwann cells (SCs) play an essentially supportive role in the regeneration of injured peripheral nerve system (PNS). As Netrin-1 is crucial for the normal development of nervous system (NS) and can direct the process of damaged PNS regeneration, our study was designed to determine the role of Netrin-1 in RSC96 Schwann cells (an immortalized rat Schwann cell line) proliferation and migration. Our studies demonstrated that Netrin-1 had no effect on RSC96 cells proliferation, while significantly promoted RSC96 cells migration. The Netrin-1-induced RSC96 cells migration was significantly attenuated by inhibition of p38 and PI3K through pretreatment with SB203580 and LY294002 respectively,more » but not inhibition of MEK1/2 and JNK by U0126-EtOH and SP600125 individually. Treatment with Netrin-1 enhanced the phosphorylation of p38 and Akt. QRT-PCR indicated that Netrin-1 and only its receptors Unc5a, Unc5b and Neogenin were expressed in RSC96 cells, among which Unc5b expressed the most. And UNC5B protein was significantly increased after stimulated by Netrin-1. In conclusion, we show here that Netrin-1-enhanced SCs migration is mediated by activating p38 MAPK and PI3K-Akt signal cascades via receptor UNC5B, which suggests that Netrin-1 could serve as a new therapeutic strategy and has potential application value for PNS regeneration. - Highlights: • Netrin-1 attracts RSC96 Schwann cells migration in a dose dependent manner. • Netrin-1 induced Schwann cells migration is p38 and PI3K-Akt signaling dependent. • UNC5B may be dominant receptor mediating Netrin-1′ effect on RSC96 cells motility. • Netrin-1 may promote peripheral nerve repair by enhancing Schwann cells motility.« less

Targeted mutagenesis in a human-parasitic nematode

PubMed Central

Gang, Spencer S.; Castelletto, Michelle L.

2017-01-01

Parasitic nematodes infect over 1 billion people worldwide and cause some of the most common neglected tropical diseases. Despite their prevalence, our understanding of the biology of parasitic nematodes has been limited by the lack of tools for genetic intervention. In particular, it has not yet been possible to generate targeted gene disruptions and mutant phenotypes in any parasitic nematode. Here, we report the development of a method for introducing CRISPR-Cas9-mediated gene disruptions in the human-parasitic threadworm Strongyloides stercoralis. We disrupted the S. stercoralis twitchin gene unc-22, resulting in nematodes with severe motility defects. Ss-unc-22 mutations were resolved by homology-directed repair when a repair template was provided. Omission of a repair template resulted in deletions at the target locus. Ss-unc-22 mutations were heritable; we passed Ss-unc-22 mutants through a host and successfully recovered mutant progeny. Using a similar approach, we also disrupted the unc-22 gene of the rat-parasitic nematode Strongyloides ratti. Our results demonstrate the applicability of CRISPR-Cas9 to parasitic nematodes, and thereby enable future studies of gene function in these medically relevant but previously genetically intractable parasites. PMID:29016680

A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans.

PubMed

Schafer, W R; Kenyon, C J

1995-05-04

Processing and storage of information by the nervous system requires the ability to modulate the response of excitable cells to neurotransmitter. A simple process of this type, known as adaptation or desensitization, occurs when prolonged stimulation triggers processes that attenuate the response to neurotransmitter. Here we report that the Caenorhabditis elegans gene unc-2 is required for adaptation to two neurotransmitters, dopamine and serotonin. A loss-of-function mutation in unc-2 resulted in failure to adapt either to paralysis by dopamine or to stimulation of egg laying by serotonin. In addition, unc-2 mutants displayed behaviours similar to those induced by serotonin treatment. We found that unc-2 encodes a homologue of a voltage-sensitive calcium-channel alpha-1 subunit. Expression of unc-2 occurs in two types of neurons implicated in the control of egg laying, a behaviour regulated by serotonin. Unc-2 appears to be required in modulatory neurons to downregulate the response of the egg-laying muscles to serotonin. We propose that adaptation to serotonin occurs through activation of an Unc-2-dependent calcium influx, which modulates the postsynaptic response to serotonin, perhaps by inhibiting the release of a potentiating neuropeptide.

Biallelic mutation of UNC50, encoding a protein involved in AChR trafficking, is responsible for arthrogryposis.

PubMed

Abiusi, Emanuela; D'Alessandro, Manuela; Dieterich, Klaus; Quevarec, Loic; Turczynski, Sandrina; Valfort, Aurore-Cecile; Mezin, Paulette; Jouk, Pierre Simon; Gut, Marta; Gut, Ivo; Bessereau, Jean Louis; Melki, Judith

2017-10-15

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Homozygosity mapping of disease loci combined with whole exome sequencing in a consanguineous family presenting with lethal AMC allowed the identification of a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4) in the index case. To assess the effect of the mutation, an equivalent mutation in the Caenorhabditis elegans orthologous gene was created using CRISPR/Cas9. We demonstrated that unc-50(kr331) modification caused the loss of acetylcholine receptor (AChR) expression in C. elegans muscle. unc-50(kr331) animals were as resistant to the cholinergic agonist levamisole as unc-50 null mutants suggesting that AChRs were no longer expressed in this animal model. This was confirmed by using a knock-in strain in which a red fluorescent protein was inserted into the AChR locus: no signal was detected in unc-50(kr331) background, suggesting that UNC-50, a protein known to be involved in AChR trafficking, was no longer functional. These data indicate that biallelic mutation in the UNC50 gene underlies AMC through a probable loss of AChR expression at the neuromuscular junction which is essential for the cholinergic transmission during human muscle development. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Thiocyanate complexes of uranium in multiple oxidation states: a combined structural, magnetic, spectroscopic, spectroelectrochemical, and theoretical study.

PubMed

Hashem, Emtithal; Platts, James A; Hartl, František; Lorusso, Giulia; Evangelisti, Marco; Schulzke, Carola; Baker, Robert J

2014-08-18

A comprehensive study of the complexes A4[U(NCS)8] (A = Cs, Et4N, (n)Bu4N) and A3[UO2(NCS)5] (A = Cs, Et4N) is described, with the crystal structures of [(n)Bu4N]4[U(NCS)8]·2MeCN and Cs3[UO2(NCS)5]·O0.5 reported. The magnetic properties of square antiprismatic Cs4[U(NCS)8] and cubic [Et4N]4[U(NCS)8] have been probed by SQUID magnetometry. The geometry has an important impact on the low-temperature magnetic moments: at 2 K, μeff = 1.21 μB and 0.53 μB, respectively. Electronic absorption and photoluminescence spectra of the uranium(IV) compounds have been measured. The redox chemistry of [Et4N]4[U(NCS)8] has been explored using IR and UV-vis spectroelectrochemical methods. Reversible 1-electron oxidation of one of the coordinated thiocyanate ligands occurs at +0.22 V vs Fc/Fc(+), followed by an irreversible oxidation to form dithiocyanogen (NCS)2 which upon back reduction regenerates thiocyanate anions coordinating to UO2(2+). NBO calculations agree with the experimental spectra, suggesting that the initial electron loss of [U(NCS)8](4-) is delocalized over all NCS(-) ligands. Reduction of the uranyl(VI) complex [Et4N]3[UO2(NCS)5] to uranyl(V) is accompanied by immediate disproportionation and has only been studied by DFT methods. The bonding in [An(NCS)8](4-) (An = Th, U) and [UO2(NCS)5](3-) has been explored by a combination of DFT and QTAIM analysis, and the U-N bonds are predominantly ionic, with the uranyl(V) species more ionic that the uranyl(VI) ion. Additionally, the U(IV)-NCS ion is more ionic than what was found for U(IV)-Cl complexes.

A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans

PubMed Central

2011-01-01

Background An essential stage of neural development involves the assembly of neural circuits via formation of inter-neuronal connections. Early steps in neural circuit formation, including cell migration, axon guidance, and the localization of synaptic components, are well described. However, upon reaching their target region, most neurites still contact many potential partners. In order to assemble functional circuits, it is critical that within this group of cells, neurons identify and form connections only with their appropriate partners, a process we call synaptic partner recognition (SPR). To understand how SPR is mediated, we previously developed a genetically encoded fluorescent trans-synaptic marker called NLG-1 GRASP, which labels synaptic contacts between individual neurons of interest in dense cellular environments in the genetic model organism Caenorhabditis elegans. Results Here, we describe the first use of NLG-1 GRASP technology, to identify SPR genes that function in this critical process. The NLG-1 GRASP system allows us to assess synaptogenesis between PHB sensory neurons and AVA interneurons instantly in live animals, making genetic analysis feasible. Additionally, we employ a behavioral assay to specifically test PHB sensory circuit function. Utilizing this approach, we reveal a new role for the secreted UNC-6/Netrin ligand and its transmembrane receptor UNC-40/Deleted in colorectal cancer (DCC) in SPR. Synapses between PHB and AVA are severely reduced in unc-6 and unc-40 animals despite normal axon guidance and subcellular localization of synaptic components. Additionally, behavioral defects indicate a complete disruption of PHB circuit function in unc-40 mutants. Our data indicate that UNC-40 and UNC-6 function in PHB and AVA, respectively, to specify SPR. Strikingly, overexpression of UNC-6 in postsynaptic neurons is sufficient to promote increased PHB-AVA synaptogenesis and to potentiate the behavioral response beyond wild-type levels. Furthermore, an artificially membrane-tethered UNC-6 expressed in the postsynaptic neurons promotes SPR, consistent with a short-range signal between adjacent synaptic partners. Conclusions These results indicate that the conserved UNC-6/Netrin-UNC-40/DCC ligand-receptor pair has a previously unknown function, acting in a juxtacrine manner to specify recognition of individual postsynaptic neurons. Furthermore, they illustrate the potential of this new approach, combining NLG-1 GRASP and behavioral analysis, in gene discovery and characterization. PMID:21663630

An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.

PubMed

Hashimoto, Yuichi; Toyama, Yuka; Kusakari, Shinya; Nawa, Mikiro; Matsuoka, Masaaki

2016-06-03

A missense mutation (T835M) in the uncoordinated-5C (UNC5C) netrin receptor gene increases the risk of late-onset Alzheimer disease (AD) and also the vulnerability of neurons harboring the mutation to various insults. The molecular mechanisms underlying T835M-UNC5C-induced death remain to be elucidated. In this study, we show that overexpression of wild-type UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M. An AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1, inhibit this death. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of death-associated protein kinase 1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid β precursor protein (APP). Notably, netrin1 also binds to APP and partially inhibits the death-signaling cascade, induced by APP. These results may provide new insight into the amyloid β-independent pathomechanism of AD. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A Cys-loop Mutation in the Caenorhabditis elegans Nicotinic Receptor Subunit UNC-63 Impairs but Does Not Abolish Channel Function*

PubMed Central

Jones, Andrew K.; Rayes, Diego; Al-Diwani, Adam; Maynard, Thomas P. R.; Jones, Rachel; Hernando, Guillermina; Buckingham, Steven D.; Bouzat, Cecilia; Sattelle, David B.

2011-01-01

The nematode Caenorhabditis elegans is an established model organism for studying neurobiology. UNC-63 is a C. elegans nicotinic acetylcholine receptor (nAChR) α-subunit. It is an essential component of the levamisole-sensitive muscle nAChR (L-nAChR) and therefore plays an important role in cholinergic transmission at the nematode neuromuscular junction. Here, we show that worms with the unc-63(x26) allele, with its αC151Y mutation disrupting the Cys-loop, have deficient muscle function reflected by impaired swimming (thrashing). Single-channel recordings from cultured muscle cells from the mutant strain showed a 100-fold reduced frequency of opening events and shorter channel openings of L-nAChRs compared with those of wild-type worms. Anti-UNC-63 antibody staining in both cultured adult muscle and embryonic cells showed that L-nAChRs were expressed at similar levels in the mutant and wild-type cells, suggesting that the functional changes in the receptor, rather than changes in expression, are the predominant effect of the mutation. The kinetic changes mimic those reported in patients with fast-channel congenital myasthenic syndromes. We show that pyridostigmine bromide and 3,4-diaminopyridine, which are drugs used to treat fast-channel congenital myasthenic syndromes, partially rescued the motility defect seen in unc-63(x26). The C. elegans unc-63(x26) mutant may therefore offer a useful model to assist in the development of therapies for syndromes produced by altered function of human nAChRs. PMID:20966081

The vesicle protein SAM-4 regulates the processivity of synaptic vesicle transport.

PubMed

Zheng, Qun; Ahlawat, Shikha; Schaefer, Anneliese; Mahoney, Tim; Koushika, Sandhya P; Nonet, Michael L

2014-10-01

Axonal transport of synaptic vesicles (SVs) is a KIF1A/UNC-104 mediated process critical for synapse development and maintenance yet little is known of how SV transport is regulated. Using C. elegans as an in vivo model, we identified SAM-4 as a novel conserved vesicular component regulating SV transport. Processivity, but not velocity, of SV transport was reduced in sam-4 mutants. sam-4 displayed strong genetic interactions with mutations in the cargo binding but not the motor domain of unc-104. Gain-of-function mutations in the unc-104 motor domain, identified in this study, suppress the sam-4 defects by increasing processivity of the SV transport. Genetic analyses suggest that SAM-4, SYD-2/liprin-α and the KIF1A/UNC-104 motor function in the same pathway to regulate SV transport. Our data support a model in which the SV protein SAM-4 regulates the processivity of SV transport.

The Vesicle Protein SAM-4 Regulates the Processivity of Synaptic Vesicle Transport

PubMed Central

Zheng, Qun; Ahlawat, Shikha; Schaefer, Anneliese; Mahoney, Tim; Koushika, Sandhya P.; Nonet, Michael L.

2014-01-01

Axonal transport of synaptic vesicles (SVs) is a KIF1A/UNC-104 mediated process critical for synapse development and maintenance yet little is known of how SV transport is regulated. Using C. elegans as an in vivo model, we identified SAM-4 as a novel conserved vesicular component regulating SV transport. Processivity, but not velocity, of SV transport was reduced in sam-4 mutants. sam-4 displayed strong genetic interactions with mutations in the cargo binding but not the motor domain of unc-104. Gain-of-function mutations in the unc-104 motor domain, identified in this study, suppress the sam-4 defects by increasing processivity of the SV transport. Genetic analyses suggest that SAM-4, SYD-2/liprin-α and the KIF1A/UNC-104 motor function in the same pathway to regulate SV transport. Our data support a model in which the SV protein SAM-4 regulates the processivity of SV transport. PMID:25329901

FEZ2 has acquired additional protein interaction partners relative to FEZ1: functional and evolutionary implications.

PubMed

Alborghetti, Marcos R; Furlan, Ariane S; Kobarg, Jörg

2011-03-08

The FEZ (fasciculation and elongation protein zeta) family designation was purposed by Bloom and Horvitz by genetic analysis of C. elegans unc-76. Similar human sequences were identified in the expressed sequence tag database as FEZ1 and FEZ2. The unc-76 function is necessary for normal axon fasciculation and is required for axon-axon interactions. Indeed, the loss of UNC-76 function results in defects in axonal transport. The human FEZ1 protein has been shown to rescue defects caused by unc-76 mutations in nematodes, indicating that both UNC-76 and FEZ1 are evolutionarily conserved in their function. Until today, little is known about FEZ2 protein function. Using the yeast two-hybrid system we demonstrate here conserved evolutionary features among orthologs and non-conserved features between paralogs of the FEZ family of proteins, by comparing the interactome profiles of the C-terminals of human FEZ1, FEZ2 and UNC-76 from C. elegans. Furthermore, we correlate our data with an analysis of the molecular evolution of the FEZ protein family in the animal kingdom. We found that FEZ2 interacted with 59 proteins and that of these only 40 interacted with FEZ1. Of the 40 FEZ1 interacting proteins, 36 (90%), also interacted with UNC-76 and none of the 19 FEZ2 specific proteins interacted with FEZ1 or UNC-76. This together with the duplication of unc-76 gene in the ancestral line of chordates suggests that FEZ2 is in the process of acquiring new additional functions. The results provide also an explanation for the dramatic difference between C. elegans and D. melanogaster unc-76 mutants on one hand, which cause serious defects in the nervous system, and the mouse FEZ1 -/- knockout mice on the other, which show no morphological and no strong behavioural phenotype. Likely, the ubiquitously expressed FEZ2 can completely compensate the lack of neuronal FEZ1, since it can interact with all FEZ1 interacting proteins and additional 19 proteins.

The Fat-like Cadherin CDH-4 Acts Cell-Non-Autonomously in Anterior-Posterior Neuroblast Migration

PubMed Central

Sundararajan, Lakshmi; Norris, Megan L.; Schöneich, Sebastian; Ackley, Brian D.; Lundquist, Erik A.

2014-01-01

Directed migration of neurons is critical in the normal and pathological development of the brain and central nervous system. In C. elegans, the bilateral Q neuroblasts, QR on the right and QL on the left, migrate anteriorly and posteriorly, respectively. Initial protrusion and migration of the Q neuroblasts is autonomously controlled by the transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21. As QL migrates posteriorly, it encounters and EGL-20/Wnt signal that induces MAB-5/Hox expression that drives QL descendant posterior migration. QR migrates anteriorly away from EGL-20/Wnt and does not activate MAB-5/Hox, resulting in anterior QR descendant migration. A forward genetic screen for new mutations affecting initial Q migrations identified alleles of cdh-4, which caused defects in both QL and QR directional migration similar to unc-40, ptp-3, and mig-21. Previous studies showed that in QL, PTP-3/LAR and MIG-21 act in a pathway in parallel to UNC-40/DCC to drive posterior QL migration. Here we show genetic evidence that CDH-4 acts in the PTP-3/MIG-21 pathway in parallel to UNC-40/DCC to direct posterior QL migration. In QR, the PTP-3/MIG-21 and UNC-40/DCC pathways mutually inhibit each other, allowing anterior QR migration. We report here that CDH-4 acts in both the PTP-3/MIG-21 and UNC-40/DCC pathways in mutual inhibition in QR, and that CDH-4 acts cell-non-autonomously. Interaction of CDH-4 with UNC-40/DCC in QR but not QL represents an inherent left-right asymmetry in the Q cells, the nature of which is not understood. We conclude that CDH-4 might act as a permissive signal for each Q neuroblast to respond differently to anterior-posterior guidance information based upon inherent left-right asymmetries in the Q neuroblasts. PMID:24954154

ALTERED RA SIGNALING IN THE GENESIS OF ETHANOL-INDUCED LIMB DEFECTS

EPA Science Inventory

Altered RA Signaling in the Genesis of Ethanol-Induced Limb Defects

Johnson CS(1), Sulik KK(1,2) Hunter, ES III(3)
(1) Dept of Cell and Developmental Biology, UNC-Chapel Hill (2) Bowles Center for Alcohol Studies, UNC-CH (3) NHEERL, ORD, US EPA, RTP, NC

Administr...

Reasons and Determinants for Perceiving Unmet Needs for Mental Health in Primary Care in Quebec

PubMed Central

Dezetter, Anne; Duhoux, Arnaud; Menear, Matthew; Roberge, Pasquale; Chartrand, Elise; Fournier, Louise

2015-01-01

Objective: To evaluate the mental health care needs perceived as unmet by adults in Quebec who had experienced depressive and (or) anxious symptomatology (DAS) in the previous 2 years and who used primary care services, and to identify the reasons associated with different types of unmet needs for care (UNCs) and the determinants of reporting UNCs. Method: Longitudinal data from the Dialogue Project were used. The sample consisted of 1288 adults who presented a common mental disorder and who consulted a general practitioner. The Hospital Anxiety and Depression Scale was used to measure DAS, and the Perceived Need for Care Questionnaire facilitated the assessment of the different types of UNCs and their motives. Results: About 40% of the participants perceived UNCs. Psychotherapy, help to improve ability to work, as well as general information on mental health and services were the most mentioned UNCs. The main reasons associated with reporting UNCs for psychotherapy and psychosocial interventions are “couldn’t afford to pay” and “didn’t know how or where to get help,” respectively. The factors associated with mentioning UNCs (compared with met needs) are to present a high DAS or a DAS that increased during the past 12 months, to perceive oneself as poor or to not have private health insurance. Conclusions: To reduce the UNCs and, further, to reduce DAS, it is necessary to improve the availability and affordability of psychotherapy and psychosocial intervention services, and to inform users on the types of services available and how to access them. PMID:26175326

Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing.

PubMed

Fukui, Ryutaro; Saitoh, Shin-ichiroh; Matsumoto, Fumi; Kozuka-Hata, Hiroko; Oyama, Masaaki; Tabeta, Koichi; Beutler, Bruce; Miyake, Kensuke

2009-06-08

Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.

UNESCO: Agenda 21 and UNCED Follow-Up.

ERIC Educational Resources Information Center

United Nations Educational, Scientific, and Cultural Organization, Paris (France). Bureau for the Coordination of Environmental Programme.

The United Nations Conference on Environment and Development (UNCED) took place in Rio de Janeiro in June, 1992. The main results of UNCED were the Rio Declaration, Agenda 21, Convention on Biological Diversity, Framework Convention on Climate Change, and Statement of Forest Principles. Agenda 21 is the international program of action for global…

Faculty Teaching Loads in the UNC System

ERIC Educational Resources Information Center

Schalin, Jay

2014-01-01

This paper explores the teaching loads of faculty in the University of North Carolina (UNC) system. Salaries for faculty members are the single largest cost of higher education in the UNC system, accounting for approximately half of expenditures. The system's funding formula for its 16 college campuses is largely dependent upon the number of…

Super-complexes of adhesion GPCRs and neural guidance receptors

NASA Astrophysics Data System (ADS)

Jackson, Verity A.; Mehmood, Shahid; Chavent, Matthieu; Roversi, Pietro; Carrasquero, Maria; Del Toro, Daniel; Seyit-Bremer, Goenuel; Ranaivoson, Fanomezana M.; Comoletti, Davide; Sansom, Mark S. P.; Robinson, Carol V.; Klein, Rüdiger; Seiradake, Elena

2016-04-01

Latrophilin adhesion-GPCRs (Lphn1-3 or ADGRL1-3) and Unc5 cell guidance receptors (Unc5A-D) interact with FLRT proteins (FLRT1-3), thereby promoting cell adhesion and repulsion, respectively. How the three proteins interact and function simultaneously is poorly understood. We show that Unc5D interacts with FLRT2 in cis, controlling cell adhesion in response to externally presented Lphn3. The ectodomains of the three proteins bind cooperatively. Crystal structures of the ternary complex formed by the extracellular domains reveal that Lphn3 dimerizes when bound to FLRT2:Unc5, resulting in a stoichiometry of 1:1:2 (FLRT2:Unc5D:Lphn3). This 1:1:2 complex further dimerizes to form a larger `super-complex' (2:2:4), using a previously undescribed binding motif in the Unc5D TSP1 domain. Molecular dynamics simulations, point-directed mutagenesis and mass spectrometry demonstrate the stability and molecular properties of these complexes. Our data exemplify how receptors increase their functional repertoire by forming different context-dependent higher-order complexes.

Tropomyosin inhibits ADF/cofilin-dependent actin filament dynamics.

PubMed

Ono, Shoichiro; Ono, Kanako

2002-03-18

Tropomyosin binds to actin filaments and is implicated in stabilization of actin cytoskeleton. We examined biochemical and cell biological properties of Caenorhabditis elegans tropomyosin (CeTM) and obtained evidence that CeTM is antagonistic to ADF/cofilin-dependent actin filament dynamics. We purified CeTM, actin, and UNC-60B (a muscle-specific ADF/cofilin isoform), all of which are derived from C. elegans, and showed that CeTM and UNC-60B bound to F-actin in a mutually exclusive manner. CeTM inhibited UNC-60B-induced actin depolymerization and enhancement of actin polymerization. Within isolated native thin filaments, actin and CeTM were detected as major components, whereas UNC-60B was present at a trace amount. Purified UNC-60B was unable to interact with the native thin filaments unless CeTM and other associated proteins were removed by high-salt extraction. Purified CeTM was sufficient to restore the resistance of the salt-extracted filaments from UNC-60B. In muscle cells, CeTM and UNC-60B were localized in different patterns. Suppression of CeTM by RNA interference resulted in disorganized actin filaments and paralyzed worms in wild-type background. However, in an ADF/cofilin mutant background, suppression of CeTM did not worsen actin organization and worm motility. These results suggest that tropomyosin is a physiological inhibitor of ADF/cofilin-dependent actin dynamics.

Poverty and Early Childhood Intervention. FPG Snapshot #42

ERIC Educational Resources Information Center

FPG Child Development Institute, 2007

2007-01-01

In the spring of 2006, the University of North Carolina's (UNC) Center on Poverty, Work and Opportunity hosted a competitive process to support original research by UNC faculty members in the form of policy briefs. Each brief was authored by a UNC faculty member and was reviewed by an academic and a practitioner in the field that the brief…

A Common-Sense Look at UNC Faculty Workloads

ERIC Educational Resources Information Center

Schalin, Jay

2011-01-01

This paper measures the teaching loads of faculty in the University of North Carolina (UNC) system. The impetus for the paper was a statistic provided by the UNC system to the North Carolina legislature's Fiscal Research Division. It claimed that the system-wide average teaching load is 3.37 courses per professor per semester. Based on the Pope…

LncRNA TNRC6C-AS1 regulates UNC5B in thyroid cancer to influence cell proliferation, migration, and invasion as a competing endogenous RNA of miR-129-5p.

PubMed

Hou, Sen; Lin, Qiuyu; Guan, Feng; Lin, Chenghe

2018-06-12

To investigate the biological functions and regulatory mechanism of lncRNA TNRC6C-AS1 in thyroid cancer (TC). TNRC6C-AS1, miR-129-5p, and UNC5B expression levels were investigated by qRT-PCR and Western blot. CCK-8 assay was conducted to determine cell proliferation, while transwell assay was for inspection of cell migration and invasion. Through bioinformatic analysis, the interactions among TNRC6C-AS1, miR-129-5p, and UNC5B were predicted. Dual luciferase reporter gene assay and RNA pull-down assay confirmed the predicted target relationships. Tumor xenograft assay was applied to inspect the effect of TNRC6C-AS1 downregulation on TC development in vivo. TNRC6C-AS1 and UNC5B were overexpressed, while miR-129-5p was underexpressed in TC tissues and cells. TNRC6C-AS1/UNC5B downregulation and miR-129-5p overexpression could suppress proliferation, migration, and invasion of TC cells as well as inhibit tumorigenesis in vivo. MiR-129-5p targeted TNRC6C-AS1 and UNC5B in TC cells; and UNC5B expression was downregulated by knocking down TNRC6C-AS1, which competitively bound with miR-129-5p. Downregulation of TNRC6C-AS1 restrained TC development by knocking down UNC5B through upregulating the expression of miR-129-5p. © 2018 Wiley Periodicals, Inc.

A Digest of UNC System Reports on Freshman Performance: 2006-07. Research Watch. E&R Report No. 10.05

ERIC Educational Resources Information Center

Holdzkom, David

2010-01-01

The University of North Carolina System (UNC) annually reports statistics related to characteristics of freshmen classes from each high school and district in the state. Wake County Public School System (WCPSS) graduates were more successful at gaining admission and making academic progress at the member institutions of the UNC system than was…

NLP-12 engages different UNC-13 proteins to potentiate tonic and evoked release.

PubMed

Hu, Zhitao; Vashlishan-Murray, Amy B; Kaplan, Joshua M

2015-01-21

A neuropeptide (NLP-12) and its receptor (CKR-2) potentiate tonic and evoked ACh release at Caenorhabditis elegans neuromuscular junctions. Increased evoked release is mediated by a presynaptic pathway (egl-30 Gαq and egl-8 PLCβ) that produces DAG, and by DAG binding to short and long UNC-13 proteins. Potentiation of tonic ACh release persists in mutants deficient for egl-30 Gαq and egl-8 PLCβ and requires DAG binding to UNC-13L (but not UNC-13S). Thus, NLP-12 adjusts tonic and evoked release by distinct mechanisms. Copyright © 2015 the authors 0270-6474/15/351038-05$15.00/0.

The forkhead domain gene unc-130 generates chemosensory neuron diversity in C. elegans

PubMed Central

Sarafi-Reinach, Trina R.; Sengupta, Piali

2000-01-01

Caenorhabditis elegans responds to its complex chemical environment using a small number of chemosensory neurons. Each of these neurons exhibits a unique sensory response repertoire. The developmental mechanisms that generate this diversity of function are largely unknown. Many C. elegans chemosensory neurons, including the AWA and ASG neurons, arise as lineal sisters of an asymmetric division. Here we describe the gene unc-130, which plays a role in the generation of the AWA and ASG neurons. In unc-130 mutants, the ASG neurons adopt the fate of the AWA neurons. unc-130 encodes a member of the forkhead domain family of transcription factors, and is expressed in the precursors to AWA and ASG neurons. Misexpression of unc-130 in the AWA neurons is partly sufficient to repress the AWA fate, but not to promote ASG fate. unc-130 also plays a role in the development of additional chemosensory neurons. Our experiments show that the ASG neurons share a developmental default state in common with three types of olfactory neurons. We propose that distinct cell fates and hence diversity of function in the chemosensory neurons of C. elegans are generated in a hierarchical manner, utilizing both lineage-dependent and independent mechanisms. PMID:11018015

Histone Methylation Restrains the Expression of Subtype-Specific Genes during Terminal Neuronal Differentiation in Caenorhabditis elegans

PubMed Central

Chiang, Victor; Chalfie, Martin

2013-01-01

Although epigenetic control of stem cell fate choice is well established, little is known about epigenetic regulation of terminal neuronal differentiation. We found that some differences among the subtypes of Caenorhabditis elegans VC neurons, particularly the expression of the transcription factor gene unc-4, require histone modification, most likely H3K9 methylation. An EGF signal from the vulva alleviated the epigenetic repression of unc-4 in vulval VC neurons but not the more distant nonvulval VC cells, which kept unc-4 silenced. Loss of the H3K9 methyltransferase MET-2 or H3K9me2/3 binding proteins HPL-2 and LIN-61 or a novel chromodomain protein CEC-3 caused ectopic unc-4 expression in all VC neurons. Downstream of the EGF signaling in vulval VC neurons, the transcription factor LIN-11 and histone demethylases removed the suppressive histone marks and derepressed unc-4. Behaviorally, expression of UNC-4 in all the VC neurons caused an imbalance in the egg-laying circuit. Thus, epigenetic mechanisms help establish subtype-specific gene expression, which are needed for optimal activity of a neural circuit. PMID:24348272

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping.

PubMed

Krivega, Ivan; Byrnes, Colleen; de Vasconcellos, Jaira F; Lee, Y Terry; Kaushal, Megha; Dean, Ann; Miller, Jeffery L

2015-07-30

Induction of fetal hemoglobin (HbF) production in adult erythrocytes can reduce the severity of sickle cell disease and β-thalassemia. Transcription of β-globin genes is regulated by the distant locus control region (LCR), which is brought into direct gene contact by the LDB1/GATA-1/TAL1/LMO2-containing complex. Inhibition of G9a H3K9 methyltransferase by the chemical compound UNC0638 activates fetal and represses adult β-globin gene expression in adult human hematopoietic precursor cells, but the underlying mechanisms are unclear. Here we studied UNC0638 effects on β-globin gene expression using ex vivo differentiation of CD34(+) erythroid progenitor cells from peripheral blood of healthy adult donors. UNC0638 inhibition of G9a caused dosed accumulation of HbF up to 30% of total hemoglobin in differentiated cells. Elevation of HbF was associated with significant activation of fetal γ-globin and repression of adult β-globin transcription. Changes in gene expression were associated with widespread loss of H3K9me2 in the locus and gain of LDB1 complex occupancy at the γ-globin promoters as well as de novo formation of LCR/γ-globin contacts. Our findings demonstrate that G9a establishes epigenetic conditions preventing activation of γ-globin genes during differentiation of adult erythroid progenitor cells. In this view, manipulation of G9a represents a promising epigenetic approach for treatment of β-hemoglobinopathies.

Structural analysis of intermolecular interactions in the kinesin adaptor complex fasciculation and elongation protein zeta 1/ short coiled-coil protein (FEZ1/SCOCO).

PubMed

Alborghetti, Marcos Rodrigo; Furlan, Ariane da Silva; da Silva, Júlio César; Sforça, Maurício Luís; Honorato, Rodrigo Vargas; Granato, Daniela Campos; dos Santos Migueleti, Deivid Lucas; Neves, Jorge L; de Oliveira, Paulo Sergio Lopes; Paes-Leme, Adriana Franco; Zeri, Ana Carolina de Mattos; de Torriani, Iris Concepcion Linares; Kobarg, Jörg

2013-01-01

Cytoskeleton and protein trafficking processes, including vesicle transport to synapses, are key processes in neuronal differentiation and axon outgrowth. The human protein FEZ1 (fasciculation and elongation protein zeta 1 / UNC-76, in C. elegans), SCOCO (short coiled-coil protein / UNC-69) and kinesins (e.g. kinesin heavy chain / UNC116) are involved in these processes. Exploiting the feature of FEZ1 protein as a bivalent adapter of transport mediated by kinesins and FEZ1 protein interaction with SCOCO (proteins involved in the same path of axonal growth), we investigated the structural aspects of intermolecular interactions involved in this complex formation by NMR (Nuclear Magnetic Resonance), cross-linking coupled with mass spectrometry (MS), SAXS (Small Angle X-ray Scattering) and molecular modelling. The topology of homodimerization was accessed through NMR (Nuclear Magnetic Resonance) studies of the region involved in this process, corresponding to FEZ1 (92-194). Through studies involving the protein in its monomeric configuration (reduced) and dimeric state, we propose that homodimerization occurs with FEZ1 chains oriented in an anti-parallel topology. We demonstrate that the interaction interface of FEZ1 and SCOCO defined by MS and computational modelling is in accordance with that previously demonstrated for UNC-76 and UNC-69. SAXS and literature data support a heterotetrameric complex model. These data provide details about the interaction interfaces probably involved in the transport machinery assembly and open perspectives to understand and interfere in this assembly and its involvement in neuronal differentiation and axon outgrowth.

Structural Analysis of Intermolecular Interactions in the Kinesin Adaptor Complex Fasciculation and Elongation Protein Zeta 1/ Short Coiled-Coil Protein (FEZ1/SCOCO)

PubMed Central

da Silva, Júlio César; Sforça, Maurício Luís; Honorato, Rodrigo Vargas; Granato, Daniela Campos; dos Santos Migueleti, Deivid Lucas; Neves, Jorge L.; de Oliveira, Paulo Sergio Lopes; Paes-Leme, Adriana Franco; Zeri, Ana Carolina de Mattos; de Torriani, Iris Concepcion Linares; Kobarg, Jörg

2013-01-01

Cytoskeleton and protein trafficking processes, including vesicle transport to synapses, are key processes in neuronal differentiation and axon outgrowth. The human protein FEZ1 (fasciculation and elongation protein zeta 1 / UNC-76, in C. elegans), SCOCO (short coiled-coil protein / UNC-69) and kinesins (e.g. kinesin heavy chain / UNC116) are involved in these processes. Exploiting the feature of FEZ1 protein as a bivalent adapter of transport mediated by kinesins and FEZ1 protein interaction with SCOCO (proteins involved in the same path of axonal growth), we investigated the structural aspects of intermolecular interactions involved in this complex formation by NMR (Nuclear Magnetic Resonance), cross-linking coupled with mass spectrometry (MS), SAXS (Small Angle X-ray Scattering) and molecular modelling. The topology of homodimerization was accessed through NMR (Nuclear Magnetic Resonance) studies of the region involved in this process, corresponding to FEZ1 (92-194). Through studies involving the protein in its monomeric configuration (reduced) and dimeric state, we propose that homodimerization occurs with FEZ1 chains oriented in an anti-parallel topology. We demonstrate that the interaction interface of FEZ1 and SCOCO defined by MS and computational modelling is in accordance with that previously demonstrated for UNC-76 and UNC-69. SAXS and literature data support a heterotetrameric complex model. These data provide details about the interaction interfaces probably involved in the transport machinery assembly and open perspectives to understand and interfere in this assembly and its involvement in neuronal differentiation and axon outgrowth. PMID:24116125

Netrin-1 rescues neuron loss by attenuating secondary apoptosis in ipsilateral thalamic nucleus following focal cerebral infarction in hypertensive rats.

PubMed

Liao, S-J; Gong, Q; Chen, X-R; Ye, L-X; Ding, Q; Zeng, J-S; Yu, J

2013-02-12

Neurological deficit following cerebral infarction correlates with not only primary injury, but also secondary neuronal apoptosis in remote loci connected to the infarction. Netrin-1 is crucial for axonal guidance by interacting with its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H (UNC5H). DCC and UNC5H are also dependence receptors inducing cell apoptosis when unbound by netrin-1. The present study is to investigate the role of netrin-1 and its receptors in ipsilateral ventroposterior thalamic nucleus (VPN) injury secondary to stroke in hypertensive rats. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO). Continuous intracerebroventricular infusion of netrin-1 (600 ng/d for 7 days) or vehicle (IgG/Fc) was given 24h after MCAO. Neurological function was evaluated by postural reflex 8 and 14 days after MCAO. Then, immunoreactivity was determined in the ipsilateral VPN for NeuN, glial fibrillary acidic protein, netrin-1 and its receptors (DCC and UNC5H2), apoptosis was detected with Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling (TUNEL) assay, and the expressions of caspase-3, netrin-1, DCC, and UNC5H2 were quantified by western blot analysis. MCAO resulted in the impaired postural reflex after 8 and 14 days, with decreased NeuN marked neurons and increased TUNEL-positive cells, as well as an up-regulation in the levels of cleaved caspase-3 and UNC5H2 protein in the ipsilateral VPN, without significant change in DCC or netrin-1 expression. By exogenous netrin-1 infusion, the number of neurons was increased in the ipsilateral VPN, and both TUNEL-positive cell number and caspase-3 protein level were reduced, while UNC5H2 expression remained unaffected, simultaneously, the impairment of postural reflex was improved. Taken together, the present study indicates that exogenous netrin-1 could rescue neuron loss by attenuating secondary apoptosis in the ipsilateral VPN after focal cerebral infarction, possibly via its receptor UNC5H2, suggesting that relative insufficiency of endogenous netrin-1 be an underlying mechanism of secondary injury in the VPN post stroke. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

The C. elegans UNC-23 protein, a member of the BCL-2-associated athanogene (BAG) family of chaperone regulators, interacts with HSP-1 to regulate cell attachment and maintain hypodermal integrity.

PubMed

Rahmani, Poupak; Rogalski, Teresa; Moerman, Donald G

2015-01-01

Mutations in the unc-23 gene in the free-living nematode, Caenorhabditis elegans result in detachment and dystrophy of the anterior body wall musculature and a bent-head phenotype when grown on solid substrate. We have determined that the unc-23 gene product is the nematode ortholog of the human BAG-2 protein, a member of the Bcl-2 associated athanogene (BAG) family of molecular chaperone regulators. We show that a functional GFP-tagged UNC-23 protein is expressed throughout development in several tissues of the animal, including body wall muscle and hypodermis, and associates with adhesion complexes and attachment structures within these 2 tissues. In humans, the BAG protein family consists of 6 members that all contain a conserved 45 amino acid BAG domain near their C-termini. These proteins bind to and modulate the activity of the ATPase domain of the heat shock cognate protein 70, Hsc70. We have isolated missense mutations in the ATPase domain of the C. elegans heat shock 70 protein, HSP-1 that suppress the phenotype exhibited by unc-23(e25) mutant hermaphrodites and we show that UNC-23 and HSP-1 interact in a yeast-2-hybrid system. The interaction of UNC-23 with HSP-1 defines a role for HSP-1 function in the maintenance of muscle attachment during development.

The C. elegans UNC-23 protein, a member of the BCL-2-associated athanogene (BAG) family of chaperone regulators, interacts with HSP-1 to regulate cell attachment and maintain hypodermal integrity

PubMed Central

Rahmani, Poupak; Rogalski, Teresa; Moerman, Donald G

2015-01-01

Mutations in the unc-23 gene in the free-living nematode, Caenorhabditis elegans result in detachment and dystrophy of the anterior body wall musculature and a bent-head phenotype when grown on solid substrate. We have determined that the unc-23 gene product is the nematode ortholog of the human BAG-2 protein, a member of the Bcl-2 associated athanogene (BAG) family of molecular chaperone regulators. We show that a functional GFP-tagged UNC-23 protein is expressed throughout development in several tissues of the animal, including body wall muscle and hypodermis, and associates with adhesion complexes and attachment structures within these 2 tissues. In humans, the BAG protein family consists of 6 members that all contain a conserved 45 amino acid BAG domain near their C-termini. These proteins bind to and modulate the activity of the ATPase domain of the heat shock cognate protein 70, Hsc70. We have isolated missense mutations in the ATPase domain of the C. elegans heat shock 70 protein, HSP-1 that suppress the phenotype exhibited by unc-23(e25) mutant hermaphrodites and we show that UNC-23 and HSP-1 interact in a yeast-2-hybrid system. The interaction of UNC-23 with HSP-1 defines a role for HSP-1 function in the maintenance of muscle attachment during development. PMID:26435886

Materiel Solutions for Special Operations Forces

DTIC Science & Technology

2015-03-28

Continually developed a repository of UNC System-wide defense research expertise and infrastructure resources to enable effective identification of UNC...antennas and more. • Mr. Jim Geurts, USSOCOM Acquisition Executive, visited the campuses of UNC Chapel Hill and NCSU in March 2013. He met with...game theory, and political science. The goal of the workshop was to explore cutting edge techniques to measure the effectiveness of special operations

The POU transcription factor UNC-86 controls the timing and ventral guidance of C. elegans axon growth

PubMed Central

Olsson-Carter, Katherine; Slack, Frank J.

2012-01-01

The in vivo mechanisms that coordinate the timing of axon growth and guidance are not well understood. In the C. elegans hermaphrodite specific neurons, the lin-4 microRNA controls the stage of axon initiation independent of the UNC-40 and SAX-3 ventral guidance receptors. lin-4 loss-of-function mutants exhibit marked delays in axon outgrowth, while lin-4 overexpression, leads to precocious growth in the L3. Here we show that loss of the POU transcription factor UNC-86 not only results in penetrant ventral axon growth defects in the HSNs, but also causes processes to extend in the L1, three stages earlier than wild-type. This temporal shift is not dependent on UNC-40 or SAX-3, and does not require the presence of lin-4. We propose that unc-86(lf) HSN axons are misguided due to the temporal decoupling of axon initiation and ventral guidance responses. PMID:21656875

University of Northern Colorado Drug and Alcohol Policy [and] Drug Prevention/Education Program at UNC [and] University of Northern Colorado Alcohol Use Survey.

ERIC Educational Resources Information Center

Merz, Robert; And Others

This document contains a draft of the University of Northern Colorado (UNC) drug and alcohol policy, a description of UNC drug prevention/education programs and an alcohol use survey. After a preamble and university policy statement regarding drugs and alcohol, a section on alcohol details university regulations conforming to City of Greeley and…

UNC Pembroke Laser Scanning Confocal Microscopy Facility

DTIC Science & Technology

2016-04-29

cultures. INVASIVE FIRE ANTS Professor Lisa Kelly of UNC Pembroke has been trained on the new confocal system. Dr. Kelly’s research...interest in the trophic ecology of the invasive fire ant has begun to benefit from the wide field view and long working distances of a confocal imaging...of protein clearance pathways in living brain tissue cultures. INVASIVE FIRE ANTS Professor Lisa Kelly of UNC Pembroke has been trained on

Habenular commissure formation in zebrafish is regulated by the pineal gland-specific gene unc119c.

PubMed

Toyama, Reiko; Kim, Mi Ha; Rebbert, Martha L; Gonzales, John; Burgess, Harold; Dawid, Igor B

2013-09-01

The zebrafish pineal gland (epiphysis) is a site of melatonin production, contains photoreceptor cells, and functions as a circadian clock pacemaker. Since it is located on the surface of the forebrain, it is accessible for manipulation and, therefore, is a useful model system to analyze pineal gland function and development. We previously analyzed the pineal transcriptome during development and showed that many genes exhibit a highly dynamic expression pattern in the pineal gland. Among genes preferentially expressed in the zebrafish pineal gland, we identified a tissue-specific form of the unc119 gene family, unc119c, which is highly preferentially expressed in the pineal gland during day and night at all stages examined from embryo to adult. When expression of unc119c was inhibited, the formation of the habenular commissure (HC) was specifically compromised. The Unc119c interacting factors Arl3l1 and Arl3l2 as well as Wnt4a also proved indispensible for HC formation. We suggest that Unc119c, together with Arl3l1/2, plays an important role in modulating Wnt4a production and secretion during HC formation in the forebrain of the zebrafish embryo. Copyright © 2013 Wiley Periodicals, Inc.

Habenular commissure formation in zebrafish is regulated by the pineal gland specific gene unc119c

PubMed Central

Toyama, Reiko; Kim, Mi Ha; Rebbert, Martha L.; Gonzales, John; Burgess, Harold; Dawid, Igor B.

2013-01-01

Background The zebrafish pineal gland (epiphysis) is a site of melatonin production, contains photoreceptor cells, and functions as a circadian clock pacemaker. Since it is located on the surface of the forebrain, it is accessible for manipulation and therefore is a useful model system to analyze pineal gland function and development. We previously analyzed the pineal transcriptome during development and showed that many genes exhibit a highly dynamic expression pattern in the pineal gland. Results Among genes preferentially expressed in the zebrafish pineal gland, we identified a tissue-specific form of the unc119 gene family, unc119c, which is highly preferentially expressed in the pineal gland during day and night at all stages examined from embryo to adult. When expression of unc119c was inhibited, the formation of the habenular commissure (HC) was specifically compromised. The Unc119c interacting factors Arl3l1 and Arl3l2 as well as Wnt4a also proved indispensible for HC formation. Conclusions We suggest that Unc119c, together with Arl3l1/2, plays an important role in modulating Wnt4a production and secretion during HC formation in the forebrain of the zebrafish embryo. PMID:23749482

Annual Progress Report (17th) and 1992-97 Renewal Proposal Interactive Graphics for Molecular Studies

DTIC Science & Technology

1991-01-24

Molecular Graphics, vol. 6, No. 4 (Dec. 1988), p. 223. Turk, Greg, "Interactive Collision Detection for Molecular Graphics," M.S. thesis , UNC-Chapel Hill...Problem," Master’s thesis , UNC Department of Computer Science Technical Report #TR87-013, May 1987. Pique, ME., "Technical Trends in Molecular Graphics...AD-A236 598 Seventeenth Annual Progress Report and 1992-97 Renewal Proposal Interactive Graphics for Molecular Studies TR91-020 January 24, 1991 red

Self-perceptions of stability and change in personality at midlife: the UNC Alumni Heart Study.

PubMed

Herbst, J H; McCrae, R R; Costa, P T; Feaganes, J R; Siegler, I C

2000-12-01

The finding of personality stability in adulthood may be counterintuitive to people who perceive a great deal of change in their own personality. The purpose of this study is to determine whether self-reported perceived changes in personality are associated with actual changes based on a 6- to 9-year follow-up of 2,242 middle-aged male and female participants of the UNC Alumni Heart Study (UNCAHS). Respondents completed the Revised NEO Personality Inventory on two occasions and were asked to reflect back over a 6-year period and assess changes in their personality. The majority of respondents (n = 1,177; 52.5%) reported they had "stayed the same," while 863 (38.5%) reported they had "changed a little" and 202 (9%) reported they had "changed a good deal." Coefficients of personality profile agreement computed to evaluate global personality change for the three perceived change groups were essentially equivalent. Further, directional analyses of domain-specific changes in personality showed that perceived changes were weak predictors of residual gain scores. In an absolute sense, perceptions of stability or change were discordant in 8 of 15 (53%) comparisons. Self-perceptions of change are not an adequate substitute for objective assessments.

[Clinical characteristics, prognosis and genetic susceptibility of herpes simplex encephalitis in children].

PubMed

Feng, Wenya; Chen, Tianming; Hu, Bing; Wan, Jiabin; Liu, Gang

2015-09-01

To summarize the clinical characteristics and long-term prognosis of herpes simplex virus encephalitis (HSE) in childhood and to analyze genotype of UNC93B1 and TLR3. Data of a total of 30 HSE patients admitted to Beijing Children's Hospital from January 2008 to September 2013 were retrospectively analyzed, the data included clinical manifestations, physical sign, auxiliary examination, therapy and long-term clinical prognosis. The family history obtained during follow-up visit was also analyzed for genetic predisposition. With parents' agreement, the blood specimens of patients were collected in EDTA anticoagulant tubes, the first 2 genetic etiologies UNC93B1 and TLR3 were sequenced, and the genetic susceptibility to HSE in childhood was summarized. (1) All the 30 patients (100%) had fever, 28 (93%) had seizure, 25 (83%) had altered state of consciousness, only 11 (37%) had personality changes, and in 8 (73%) appeared at or after 2 weeks of onset . (2) During the long-term follow up, 2 (7%) patients died after discharge, 23 patients (82%) had neurological sequelae, 13 patients (57%) had moderate, severe disability and vegetative state. (3) After sequencing of UNC93B1, and TLR3, one patient was found homozygous for a single-nucleotide substitution at position C.414C>G in exon 4 of UNC93B1 which affected the expression of UNC93B1, and may block or decrease the production of interferon. (4) Six single nucleotide polymorphisms (SNPs) were found in this study, their genotype frequency and gene frequency of Chinese were respectively searched in Genomes Project in NCBI and defined 1 000 genomes group. The genotype frequency of UNC93B1 rs7149 between 1 000 genomes group and HSE group was significantly different (χ² = 55.37, P<0.05). The frequency of CC type and C type was higher in HSE group, both of them had significant difference (χ² = 93.90, P<0.05, OR=61.563; χ² = 134.40, P<0.05, OR=12.491). HSE lacks specific clinical manifestations, the long-term prognosis is poor. One HSE patient carrying a heterozygous mutation in UNC93B1 which may lead to the susceptibility to HSE and had harmful effect on long-term prognosis. The SNP UNC93B1 rs7149 may also have relationship with susceptibility to HSE and the children carrying CC genotype or C gene in this gene site maybe more susceptible to HSE.

Validation of the UNC TRxANSITION Scale™Version 3 Among Mexican Adolescents With Chronic Kidney Disease.

PubMed

Cantú-Quintanilla, Guillermo; Ferris, María; Otero, Araceli; Gutiérrez-Almaraz, Anabel; Valverde-Rosas, Saúl; Velázquez-Jones, Luis; Luque-Coqui, Mercedes; Cohen, Sarah; Medeiros, Mara

2015-01-01

There is a lack of valid health care transition readiness (HCT) scales in Spanish. To provide initial validation of the UNC TRxANSITION Scale™ among Mexican adolescents and young adults (youth) with chronic kidney disease (CKD). We used the professionally translated/back translated, provider-administered UNC TRxANSITION Scale™ (Ferris et al., 2012). This 33-question scale measures HCT in ten sub-scales including knowledge about diagnosis or treatment, diet, reproductive health, school/work, insurance, ability to self-manage and looking for new health providers. Its maximum score is 10. We enrolled 163 Mexican adolescents (48.5% females) with CKD stage≥3, mean age of 15.1years (±2.1) and whose primary language is Spanish. There were 15 patients on hemodialysis (9.2%) and 30 transplant recipients (18.4%). Results were compared to those reported in adolescents with chronic conditions from the USA. Our cohort's overall median total score was 5.9. Patients≥16years old had a median total score of 6.4, whereas younger patients had median score of 5.6 (p<0.05). Transplant patients had greater scores in the total and the sub-scales of medication knowledge, issues of reproduction, insurance, trade/work and adherence (p<0.05). When comparing the total score (by age), results from our Mexican youth were similar to those reported in youth from the USA. In our Mexican cohort of youth with CKD, health care transition readiness is greater in older patients and in transplant recipients. Our cohort's overall score is low, indicating the need for a health care transition preparation program. The UNC TRxANSITION Scale™ results in Mexican youth with CKD are comparable to findings in youth from the USA. Copyright © 2015 Elsevier Inc. All rights reserved.

MERTK Inhibition Induces Polyploidy and Promotes Cell Death and Cellular Senescence in Glioblastoma Multiforme

PubMed Central

Sufit, Alexandra; Lee-Sherick, Alisa B.; DeRyckere, Deborah; Rupji, Manali; Dwivedi, Bhakti; Varella-Garcia, Marileila; Pierce, Angela M.; Kowalski, Jeanne; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton

2016-01-01

Background MER receptor tyrosine kinase (MERTK) is expressed in a variety of malignancies, including glioblastoma multiforme (GBM). Our previous work demonstrated that inhibition of MERTK using RNA interference induced cell death and chemosensitivity in GBM cells, implicating MERTK as a potential therapeutic target. Here we investigate whether a novel MERTK-selective small molecule tyrosine kinase inhibitor, UNC2025, has similar anti-tumor effects in GBM cell lines. Methods Correlations between expression of GAS6, a MERTK ligand, and prognosis were determined using data from the TCGA database. GBM cell lines (A172, SF188, U251) were treated in vitro with increasing doses of UNC2025 (50-400nM). Cell count and viability were determined by trypan blue exclusion. Cell cycle profiles and induction of apoptosis were assessed by flow cytometric analysis after BrdU or Po-Pro-1/propidium iodide staining, respectively. Polyploidy was detected by propidium iodide staining and metaphase spread. Cellular senescence was determined by β-galactosidase staining and senescence-associated secretory cytokine analysis. Results Decreased overall survival significantly correlated with high levels of GAS6 expression in GBM, highlighting the importance of TAM kinase signaling in GBM tumorigenesis and/or therapy resistance and providing strong rationale for targeting these pathways in the clinic. All three GBM cell lines exhibited dose dependent reductions in cell number and colony formation (>90% at 200nM) after treatment with UNC2025. Cell cycle analysis demonstrated accumulation of cells in the G2/M phase and development of polyploidy. After extended exposure, 60–80% of cells underwent apoptosis. The majority of surviving cells (65–95%) were senescent and did not recover after drug removal. Thus, UNC2025 mediates anti-tumor activity in GBM by multiple mechanisms. Conclusions The findings described here provide further evidence of oncogenic roles for MERTK in GBM, demonstrate the importance of kinase activity for MERTK tumorigenicity and validate UNC2025, a novel MERTK inhibitor, as a potential therapeutic agent for treatment of GBM. PMID:27783662

Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype.

PubMed

Boggio, Elena; Aricò, Maurizio; Melensi, Matteo; Dianzani, Irma; Ramenghi, Ugo; Dianzani, Umberto; Chiocchetti, Annalisa

2013-10-01

This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS, XIAP, and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin (OPN) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab-27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T-cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations.

Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data

PubMed Central

Yu, Lei; Chibnik, Lori B.; Dawe, Robert J.; Yang, Jingyun; Klein, Hans-Ulrich; Honer, William G.; Sperling, Reisa A.; Bennett, David A.; De Jager, Philip L.

2017-01-01

Introduction The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. Methods and findings “Residual cognition” was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10−5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = −0.40, 95% CI −0.69 to −0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10−5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. Conclusions Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy. PMID:28441426

Patient Portals

PubMed Central

Skinner, Asheley; Thornhill, Jonathan; Weinberger, Morris

2016-01-01

Summary Background Patient portals have demonstrated numerous benefits including improved patient-provider communication, patient satisfaction with care, and patient engagement. Recent literature has begun to illustrate how patients use selected portal features and an association between portal usage and improved clinical outcomes. Objectives This study sought to: (1) identify patient characteristics associated with the use of a patient portal; (2) determine the frequency with which common patient portal features are used; and (3) examine whether the level of patient portal use (non-users, light users, active users) is associated with 30-day hospital readmission. Methods My UNC Chart is the patient portal for the UNC Health Care System. We identified adults discharged from three UNC Health Care hospitals with acute myocardial infarction, congestive heart failure, or pneumonia and classified them as active, light, or non-users of My UNC Chart. Multivariable analyses were conducted to compare across user groups; logistic regression was used to predict whether patient portal use was associated with 30-day readmission. Results Of 2,975 eligible patients, 83.4% were non-users; 8.6% were light users; and 8.0% were active users of My UNC Chart. The messaging feature was used most often. For patients who were active users, the odds of being readmitted within 30 days was 66% greater than patients who were non-users (p<0.05). There was no difference in 30-day readmission between non-users and light users. Conclusions The vast majority of patients who were given an access code for My UNC Chart did not use it within 30 days of discharge. Of those who used the portal, active users had a higher odds of being readmitted within 30 days. Health care systems should consider strategies to: (1) increase overall use of patient portals and (2) target patients with the highest comorbidity scores to reduce hospital readmissions. PMID:27437056

Development of Biologically Based Therapies for Basal-Like Tumors

DTIC Science & Technology

2007-04-01

Lynda R. Sawyer5, Xiaping He2,3, Melissa A. Troester6, Carolyn I. Sartor3,7, Thais Rieger-House8, Philip S. Bernard8, Lisa A. Carey5, and Charles M...med.unc.edu Xiaping He: xiaping@med.unc.edu Melissa A.Troester: troester@schoolph.umass.edu Carolyn I. Sartor: carolyn_sartor@med.unc.edu Thais Rieger... Giordano A: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in breast cancer: current status and future development. Front Biosci

Environmental news: coverage of the Earth Summit by Brazilian newspapers.

PubMed

Reis, R

1999-12-01

This article examines how two important Brazilian newspapers (Floha de S. Paulo and O Globo) covered the UN Conference on Environment and Development (UNCED) or Earth Summit. The analysis will also determine the characteristics of the environmental media and its significance when it comes to coverage of environmental issues. This article provides historical background information on the environmental media in the US and in Brazil, contextual information on the Earth Summit, a content analysis of stories about UNCED published by the two Brazilian newspapers. Overall, 649 news items were used to determine the type of sources used, as well as the kind of issues covered. The analysis showed that government officials were the most frequently cited sources, while environmentalists and scientists were all but ignored as news sources. The analysis also indicated that economic issues were surprisingly prominent in the coverage. These results are compatible with the previous studies done in several countries and indicate that environmental media are still extremely reliant on "official" voices. The finding also highlight the fact that the range of issues covered by the environmental media largely reflects the perceived public agenda.

UNC EFRC: Fuels from Sunlight (A "Life at the Frontiers of Energy Research" contest entry from the 2011 Energy Frontier Research Centers (EFRCs) Summit and Forum)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meyer, Thomas J.

"Fuels from Sunlight" was submitted by the University of North Carolina (UNC) EFRC: Center for Solar Fuels, to the "Life at the Frontiers of Energy Research" video contest at the 2011 Science for Our Nation's Energy Future: Energy Frontier Research Centers (EFRCs) Summit and Forum. Twenty-six EFRCs created short videos to highlight their mission and their work. The Center for Solar Fuels (UNC) EFRC directed by Thomas J. Meyer is a partnership of scientists from four institutions: UNC (lead), Brookhaven National Laboratory, Georgia Institute of Technology and University of Texas at San Antonio. The Office of Basic Energy Sciences inmore » the U.S. Department of Energy's Office of Science established the 46 Energy Frontier Research Centers (EFRCs) in 2009. These collaboratively-organized centers conduct fundamental research focused on 'grand challenges' and use-inspired 'basic research needs' recently identified in major strategic planning efforts by the scientific community. The overall purpose is to accelerate scientific progress toward meeting the nation's critical energy challenges. The mission of Center for Solar Fuels (UNC) is 'to combine the best features of academic and translational research to study light/matter interactions and chemical processes for the efficient collection, transfer, and conversion of solar energy into chemical fuels and electricity.' Research topics are: catalysis (CO2, hydrocarbons, water), electrocatalysis, photocatalysis, photoelectrocatalysis, solar photovoltaic, solar fuels, photonic, solar electrodes, photosynthesis, fuel cells, CO2 (convert), greenhosue gas, hydrogen (fuel), interfacial characterization, novel materials synthesis, charge transport, and self-assembly.« less

UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)*

PubMed Central

Kemp, Michael G.; Lindsey-Boltz, Laura A.; Sancar, Aziz

2015-01-01

The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID:25792739

Single-surgeon experience with robot-assisted ureteroneocystostomy for distal ureteral pathologies in adults.

PubMed

Lee, Ziho; Sehgal, Shailen; Llukani, Elton; Reilly, Christopher; Doumanian, Leo; Mydlo, Jack; Lee, David Inkoo; Eun, Daniel Dong-In

2013-08-01

To demonstrate our technical approach for robot-assisted ureteroneocystostomy (R-UNC) for benign and malignant distal ureteral pathologies. Between January 2009 and January 2013, a total of 10 patients underwent R-UNC in the distal ureter by a single surgeon. Indications for R-UNC were as follows: idiopathic (3), fistula (2), iatrogenic (2), malignancy (2), and chronic vesicoureteral reflux (1). Tension-free anastomosis was attained in all 10 R-UNC procedures. A psoas hitch was performed in 6/10 cases (60%). Intravesical and extravesical reimplantations were completed in 5/10 (50%) and 5/10 cases (50%), respectively. A nonrefluxing ureter was constructed in 2/10 cases (20%). The patients' mean age was 52.9±16.6 years, their mean body mass index was 30.8±6.3 kg/m(2), the mean operative time was 211.7±69.3 minutes, mean estimated blood loss was 102.5±110.8 mL, and mean length of stay was 2.8±2.3 days. There were no intraoperative complications. There was one Clavien-Dindo grade I and one Clavien-Dindo grade II postoperative complication. The mean postoperative follow-up duration was 28.5±15.5 months. Two patients had recurrence of ureteral strictures at 3 months postoperatively and were managed successfully with balloon dilation. Our technique for R-UNC demonstrates good perioperative outcomes. However, underlying periureteral inflammation and pelvic adhesions may predispose patients for stricture recurrence after R-UNC.

Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia

PubMed Central

Lee-Sherick, Alisa B.; Zhang, Weihe; Menachof, Kelly K.; Hill, Amanda A.; Rinella, Sean; Kirkpatrick, Gregory; Page, Lauren S.; Stashko, Michael A.; Jordan, Craig T.; Wei, Qi; Liu, Jing; Zhang, Dehui; DeRyckere, Deborah; Wang, Xiaodong; Frye, Stephen; Earp, H. Shelton; Graham, Douglas K.

2015-01-01

Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony formation. In summary, UNC1666 is a novel potent small molecule tyrosine kinase inhibitor that decreases oncogenic signaling and myeloblast survival, thereby validating dual Mer/Flt3 inhibition as an attractive treatment strategy for AML. PMID:25762638

Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development

PubMed Central

Chen, Fei; Zhou, Yu; Qi, Yingchuan B.; Khivansara, Vishal; Li, Hairi; Chun, Sang Young; Kim, John K.; Fu, Xiang-Dong; Jin, Yishi

2015-01-01

Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathway controlling APA in the Caenorhabditis elegans nervous system. Loss of function in ssup-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) C-terminal domain (CTD), dampens transcription termination at a strong intronic polyadenylation site (PAS) in unc-44/ankyrin yet promotes termination at the weak intronic PAS of the MAP kinase dlk-1. A nuclear protein, SYDN-1, which regulates neuronal development, antagonizes the function of SSUP-72 and several nuclear polyadenylation factors. This regulatory pathway allows the production of a neuron-specific isoform of unc-44 and an inhibitory isoform of dlk-1. Dysregulation of the unc-44 and dlk-1 mRNA isoforms in sydn-1 mutants impairs neuronal development. Deleting the intronic PAS of unc-44 results in increased pre-mRNA processing of neuronal ankyrin and suppresses sydn-1 mutants. These results reveal a mechanism by which regulation of CTD phosphorylation controls coding region APA in the nervous system. PMID:26588990

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

PubMed Central

Kim, Yuna; Lee, Hyeong-Min; Xiong, Yan; Sciaky, Noah; Hulbert, Samuel W; Cao, Xinyu; Everitt, Jeffrey I; Jin, Jian; Roth, Bryan L; Jiang, Yong-hui

2017-01-01

Prader–Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11–q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642—two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)—activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS−U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS−U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS. PMID:28024084

Practice Pattern Variation in Pediatric Eosinophilic Esophagitis in the Carolinas EoE Collaborative: A Research Model in Community and Academic Practices.

PubMed

Huang, Kevin Z; Jensen, Elizabeth T; Chen, Hannah X; Landes, Lisa E; McConnell, Kristen A; Almond, M Angie; Johnston, Douglas T; Durban, Raquel; Jobe, Laura; Frost, Carrie; Donnelly, Sarah; Antonio, Brady; Safta, Anca M; Quiros, J Antonio; Markowitz, Jonathan E; Dellon, Evan S

2018-06-01

Differences in the initial management of pediatric eosinophilic esophagitis (EoE) by practice setting have not been well characterized. We aimed to characterize these differences for sites in the Carolinas EoE Collaborative (CEoEC), a multicenter network of academic and community practices. We performed a retrospective cohort study of pediatric EoE patients at five CEoEC sites: University of North Carolina (UNC) Hospital, Charlotte Asthma and Allergy Specialists, Greenville Health Systems, Wake Forest Baptist Medical Center, and the Medical University of South Carolina Hospital. Cases of EoE were defined by consensus guidelines. Data were extracted from electronic medical records. We tested for differences among sites and used a multinomial model (polytomous regression) to assess associations between treatment and site, adjusting on patient factors. We identified 464 children with EoE across the CEoEC sites. The median age was highest at Wake Forest (11.4 years), the median eosinophil count was highest at UNC (69 eos/hpf), and UNC had the most male patients (82%). UNC used topical steroids for initial treatment in 86% of cases, compared with <1% in Greenville ( P < 0.01). Greenville used dietary elimination more frequently than UNC (81% vs 2%, P < 0.01). Differences in treatment approach held after adjusting for potential baseline confounders. There was no significant association between patient factors and initial treatment approach. Significant differences in EoE patient factors and treatment approaches were identified across CEoEC sites and were not explained by patient or practice factors. This suggests that institutional or provider preferences drive initial treatment approaches, and that more data are needed to drive best practice decisions.

Unc-51 controls active zone density and protein composition by downregulating ERK signaling.

PubMed

Wairkar, Yogesh P; Toda, Hirofumi; Mochizuki, Hiroaki; Furukubo-Tokunaga, Katsuo; Tomoda, Toshifumi; Diantonio, Aaron

2009-01-14

Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins. Here we use a genetic analysis in Drosophila to demonstrate that the serine threonine kinase Unc-51 acts in the presynaptic motoneuron to regulate the localization of the active zone protein Bruchpilot opposite to glutamate receptors at each synapse. In the absence of Unc-51, many glutamate receptor clusters are unapposed to Bruchpilot, and ultrastructural analysis demonstrates that fewer active zones contain dense body T-bars. In addition to the presence of these aberrant synapses, there is also a decrease in the density of all synapses. This decrease in synaptic density and abnormal active zone composition is associated with impaired evoked transmitter release. Mechanistically, Unc-51 inhibits the activity of the MAP kinase ERK to promote synaptic development. In the unc-51 mutant, increased ERK activity leads to the decrease in synaptic density and the absence of Bruchpilot from many synapses. Hence, activated ERK negatively regulates synapse formation, resulting in either the absence of active zones or the formation of active zones without their proper complement of proteins. The Unc-51-dependent inhibition of ERK activity provides a potential mechanism for synapse-specific control of active zone protein composition and release probability.

UNC ice vest testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bartley, P.L.

1986-09-04

The Barrir Wear Ice Vest (Barrier Vest) was tested at UNC from June 6, 1986 to June 24, 1986. The test was very successful with 27 of the 29 test responses indicating a safer work environment and a desire to wear the vest again.

Netrins and UNC5 receptors in angiogenesis.

PubMed

Freitas, Catarina; Larrivée, Bruno; Eichmann, Anne

2008-01-01

Both neuronal and vascular development require guidance to establish a precise branching pattern of these systems in the vertebrate body. Several molecules implicated in axon navigation have also been shown to regulate vessel sprouting. Among these guidance cues, Netrins constitute a family of diffusible molecules with a bifuncional role in axon pathfinding. Recent findings implicate Netrins in other developmental processes, including vascular development. We here review recent studies and discuss the possible dual function of Netrins and its receptors during branching of blood vessels in developmental and pathological angiogenesis.

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

PubMed

Lipstein, Noa; Verhoeven-Duif, Nanda M; Michelassi, Francesco E; Calloway, Nathaniel; van Hasselt, Peter M; Pienkowska, Katarzyna; van Haaften, Gijs; van Haelst, Mieke M; van Empelen, Ron; Cuppen, Inge; van Teeseling, Heleen C; Evelein, Annemieke M V; Vorstman, Jacob A; Thoms, Sven; Jahn, Olaf; Duran, Karen J; Monroe, Glen R; Ryan, Timothy A; Taschenberger, Holger; Dittman, Jeremy S; Rhee, Jeong-Seop; Visser, Gepke; Jans, Judith J; Brose, Nils

2017-03-01

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

PubMed Central

Lipstein, Noa; Verhoeven-Duif, Nanda M.; Calloway, Nathaniel; van Hasselt, Peter M.; Pienkowska, Katarzyna; van Haelst, Mieke M.; van Empelen, Ron; Cuppen, Inge; van Teeseling, Heleen C.; Evelein, Annemieke M.V.; Vorstman, Jacob A.; Jahn, Olaf; Duran, Karen J.; Monroe, Glen R.; Ryan, Timothy A.; Taschenberger, Holger; Rhee, Jeong-Seop; Visser, Gepke; Jans, Judith J.

2017-01-01

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies. PMID:28192369

Accuracy of probing attachment levels using a new computerized cemento-enamel junction probe.

PubMed

Deepa, R; Prakash, Shobha

2012-01-01

The assessment of clinical attachment level (CAL) represents the gold standard for diagnosing and monitoring periodontal disease. The aim of the present study was to evaluate the performance of the newly introduced cemento-enamel junction (CEJ) probe in detecting CAL, using CEJ as a fixed reference point, and to compare the CEJ probe with the Florida stent probe (FSP) as well as with a standard manual probe, University of North Carolina-15 (UNC-15). Three examiners recorded the probing attachment level in 384 sites in case group (chronic periodontitis), and in 176 sites, in control group (healthy periodontal status), using the three probes. Subjects included both the sexes and ranged from 35 to 45 years. The experimental design was structured to balance the intra- and inter-examiner consistency at the same site during the two visits. CEJ probe showed higher intra-and inter-examiner consistency over both FSP and UNC-15 in both the case and control groups. Frequency distribution of differences of various magnitudes of repeated measurements ≤1 mm was in the higher range of 86.8% to 87.5% for CEJ probe. The FSP was more reproducible than UNC-15 in detecting relative attachment level (RAL). CEJ automated probe was found to have greatest potential for accuracy and consistency in detecting CAL than FSP and UNC-15. The automated probes appeared to be more reproducible than manual probes.

Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

PubMed Central

Lafaille, Fabien G; Pessach, Itai M.; Zhang, Shen-Ying; Ciancanelli, Michael J.; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A.; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten M.; Daley, George Q.; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, Luigi D.

2012-01-01

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies. PMID:23103873

Genetic and Molecular Characterization of the Caenorhabditis Elegans Spermatogenesis-Defective Gene Spe-17

PubMed Central

L'Hernault, S. W.; Benian, G. M.; Emmons, R. B.

1993-01-01

Two self-sterile mutations that define the spermatogenesis-defective gene spe-17 have been analyzed. These mutations affect unc-22 and fail to complement each other for both Unc-22 and spermatogenesis defects. Both of these mutations are deficiencies (hcDf1 and hDf13) that affect more than one transcription unit. Genomic DNA adjacent to and including the region deleted by the smaller deficiency (hcDf1) has been sequenced and four mRNAs (including unc-22) have been localized to this sequenced region. The three non unc-22 mRNAs are shown to be sex-specific: a 1.2-kb mRNA that can be detected in sperm-free hermaphrodites and 1.2- and 0.56-kb mRNAs found in males. hDf13 deletes at least 55 kb of chromosome IV, including all of unc-22, both male-specific mRNAs and at least part of the female-specific mRNA. hcDf1, which is approximately 15.6 kb, deletes only the 5' end of unc-22 and the gene that encodes the 0.56-kb male-specific mRNA. The common defect that apparently accounts for the defective sperm in hcDf1 and hDf13 homozygotes is deletion of the spe-17 gene, which encodes the 0.56-kb mRNA. Strains carrying two copies of either deletion are self-fertile when they are transgenic for any of four extrachromosomal array that include spe-17. We have sequenced two spe-17 cDNAs, and the deduced 142 amino acid protein sequence is highly charged and rich in serine and threonine, but shows no significant homology to any previously determined protein sequence. PMID:8349108

Commuters and Parking at UNC-G. Preliminary Findings from the Commuting Student Survey.

ERIC Educational Resources Information Center

Reichard, Donald J.; McArver, Patricia P.

Data gleaned from items relating to transportation and parking from the Commuting Student Survey are reported. The survey questionnaire was designed to provide an overview of several aspects of the commuting student's relationship with the university and was sent to a stratified random sample of 2,140 students who were enrolled for the spring 1975…

Creating Realistic Corpora for Security and Forensic Education

DTIC Science & Technology

2011-05-01

School of Information and Library Science University of North Carolina Chapel Hill, NC kamwoods@email.unc.edu Christopher A. Lee School of...Information and Library Science University of North Carolina Chapel Hill, NC callee@ils.unc.edu Simson Garfinkel Graduate School of Operational and

The Bicoid Class Homeodomain Factors ceh-36/OTX and unc-30/PITX Cooperate in C. elegans Embryonic Progenitor Cells to Regulate Robust Development

PubMed Central

Walton, Travis; Preston, Elicia; Nair, Gautham; Zacharias, Amanda L.; Raj, Arjun; Murray, John Isaac

2015-01-01

While many transcriptional regulators of pluripotent and terminally differentiated states have been identified, regulation of intermediate progenitor states is less well understood. Previous high throughput cellular resolution expression studies identified dozens of transcription factors with lineage-specific expression patterns in C. elegans embryos that could regulate progenitor identity. In this study we identified a broad embryonic role for the C. elegans OTX transcription factor ceh-36, which was previously shown to be required for the terminal specification of four neurons. ceh-36 is expressed in progenitors of over 30% of embryonic cells, yet is not required for embryonic viability. Quantitative phenotyping by computational analysis of time-lapse movies of ceh-36 mutant embryos identified cell cycle or cell migration defects in over 100 of these cells, but most defects were low-penetrance, suggesting redundancy. Expression of ceh-36 partially overlaps with that of the PITX transcription factor unc-30. unc-30 single mutants are viable but loss of both ceh-36 and unc-30 causes 100% lethality, and double mutants have significantly higher frequencies of cellular developmental defects in the cells where their expression normally overlaps. These factors are also required for robust expression of the downstream developmental regulator mls-2/HMX. This work provides the first example of genetic redundancy between the related yet evolutionarily distant OTX and PITX families of bicoid class homeodomain factors and demonstrates the power of quantitative developmental phenotyping in C. elegans to identify developmental regulators acting in progenitor cells. PMID:25738873

Family matters: Familial support and science identity formation for African American female STEM majors

NASA Astrophysics Data System (ADS)

Parker, Ashley Dawn

This research seeks to understand the experiences of African American female undergraduates in STEM. It investigates how familial factors and science identity formation characteristics influence persistence in STEM while considering the duality of African American women's status in society. This phenomenological study was designed using critical race feminism as the theoretical framework to answer the following questions: 1) What role does family play in the experiences of African American women undergraduate STEM majors who attended two universities in the UNC system? 2) What factors impact the formation of science identity for African American women undergraduate STEM majors who attended two universities in the UNC system? Purposive sampling was used to select the participants for this study. The researcher conducted in-depth interviews with 10 African American female undergraduate STEM major from a predominantly White and a historically Black institution with the state of North Carolina public university system. Findings suggest that African American families and science identity formation influence the STEM experiences of the African American females interviewed in this study. The following five themes emerged from the findings: (1) independence, (2) support, (3) pressure to succeed, (4) adaptations, and (5) race and gender. This study contributes to the literature on African American female students in STEM higher education. The findings of this study produced knowledge regarding policies and practices that can lead to greater academic success and persistence of African American females in higher education in general, and STEM majors in particular. Colleges and universities may benefit from the findings of this study in a way that allows them to develop and sustain programs and policies that attend to the particular concerns and needs of African American women on their campuses. Finally, this research informs both current and future African American female STEM students so that they might benefit from the knowledge of the experiences of others in STEM-related fields. As a result, other African American female students might be enlightened by these stories and have the confidence to pursue a STEM degree of their own.

The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3.

PubMed

Qian, Yaping; Johnson, Judith A; Connor, Jessica A; Valencia, C Alexander; Barasa, Nathaniel; Schubert, Jeffery; Husami, Ammar; Kissell, Diane; Zhang, Ge; Weirauch, Matthew T; Filipovich, Alexandra H; Zhang, Kejian

2014-06-01

The mutations in UNC13D are responsible for familial hemophagocytic lymphohistiocytosis (FHL) type 3. A 253-kb inversion and two deep intronic mutations, c.118-308C > T and c.118-307G > A, in UNC13D were recently reported in European and Asian FHL3 patients. We sought to determine the prevalence of these three non-coding mutations in North American FHL patients and evaluate the significance of examining these new mutations in genetic testing. We performed DNA sequencing of UNC13D and targeted analysis of these three mutations in 1,709 North American patients with a suspected clinical diagnosis of hemophagocytic lymphohistiocytosis (HLH). The 253-kb inversion, intronic mutations c.118-308C > T and c.118-307G > A were found in 11, 15, and 4 patients, respectively, in which the genetic basis (bi-allelic mutations) explained 25 additional patients. Taken together with previously diagnosed FHL3 patients in our HLH patient registry, these three non-coding mutations were found in 31.6% (25/79) of the FHL3 patients. The 253-kb inversion, c.118-308C > T and c.118-307G > A accounted for 7.0%, 8.9%, and 1.3% of mutant alleles, respectively. Significantly, eight novel mutations in UNC13D are being reported in this study. To further evaluate the expression level of the newly reported intronic mutation c.118-307G > A, reverse transcription PCR and Western blot analysis revealed a significant reduction of both RNA and protein levels suggesting that the c.118-307G > A mutation affects transcription. These specified non-coding mutations were found in a significant number of North American patients and inclusion of them in mutation analysis will improve the molecular diagnosis of FHL3. © 2014 Wiley Periodicals, Inc.

Early Clinical Experiences for Second-Year Student Pharmacists at an Academic Medical Center.

PubMed

McLaughlin, Jacqueline E; Amerine, Lindsey B; Chen, Sheh-Li; Luter, David N; Arnall, Justin; Smith, Shayna; Roth, Mary T; Rodgers, Philip T; Williams, Dennis M; Pinelli, Nicole R

2015-11-25

To examine student outcomes associated with the Student Medication and Reconciliation Team (SMART) program, which was designed to provide second-year student pharmacists at the University of North Carolina (UNC) Eshelman School of Pharmacy direct patient care experience at UNC Medical Center. Twenty-two second-year student pharmacists were randomly selected from volunteers, given program training, and scheduled for three 5-hour evening shifts in 2013-2014. Pre/post surveys and reflection statements were collected from 19 students. Data were analyzed with a mixed methods approach. Survey results revealed an increase in student self-efficacy (p<0.05) and positive perceptions of SMART. Qualitative findings suggest the program provided opportunities for students to develop strategies for practice, promoted an appreciation for the various roles pharmacists play in health care, and fostered an appreciation for the complexity of real-world practice. Early clinical experiences can enhance student learning and development while fostering an appreciation for pharmacy practice.

Effects of Benzo(a)pyrene on Intra-testicular Function in F-344 Rats

PubMed Central

Archibong, Anthony E.; Ramesh, Aramandla; Niaz, Mohammad S.; Brooks, Cynthia M.; Roberson, Shannon I.; Lunstra, Donald D.

2008-01-01

The objective of this study was to evaluate the reproductive risk associated with exposure of adult male Fisher-344 (F-344) rats to inhaled benzo(a)pyrene (BaP), a ubiquitous environmental toxicant present in cigarette smoke, automobile exhaust fumes and industrial emissions. Rats were assigned randomly to a treatment or control group. Treatment consisted of exposure of rats via nose-only inhalation to 75μg BaP/m3, 4 hours daily for 60 days, while control animals were unexposed (UNC). Blood samples were collected immediately on day 60 of exposures (time 0) and subsequently at 24, 48, and 72 hours, to assess the effect of exposures to BaP on plasma testosterone and luteinizing hormone (LH) concentrations. Mean testis weight, total weight of tubules and total tubular length per paired testes were reduced 33% (P< 0.025), 27% (P < 0.01) and 39%, respectively in exposed rats (P < 0.01) compared with UNC rats. The number of homogenization-resistant spermatids was significantly reduced in BaP-exposed versus UNC rats. Plasma testosterone and intra-testicular testosterone (ITT) concentrations were significantly decreased by BaP compared with those of UNC rats. The decreases in circulating plasma testosterone were accompanied by concomitant increases in plasma LH concentrations in BaP-exposed versus control rats (P < 0.05). These data suggest that 60 days exposure to inhaled BaP contribute to reduced testicular endocrine and spermatogenic functions in exposed rats. PMID:18441403

Bridging the gap between research and practice: The development of a digital library of research syntheses.

PubMed

Barroso, Julie; Edlin, April; Sandelowski, Margarete; Lambe, Camille

2006-01-01

This article describes the development of a digital library as a resource for clinicians and researchers working with women with HIV infection. We wanted to find a new way of communicating the findings from the 114 studies that we used as the method case. The development of the SandBar Digital Library (http://sonweb.unc.edu/sandbar), a product of a 5-year project to develop the analytic techniques for qualitative metasynthesis, is described from its inception, including analyses of the potential users and how they might use such a resource. The Digital Library evolved over a 3-year period, with continuous feedback from a group of researchers and clinicians who are also experts in the care of HIV-positive people. It provides a concise and comprehensive compilation of findings in two major areas of concern for the seropositive women who were the participants in the studies: motherhood and stigma.

A Responsive, Integrative Spanish Curriculum at UNC Charlotte

ERIC Educational Resources Information Center

Doyle, Michael S.

2010-01-01

The Spanish program at UNC Charlotte is timely and responsive because it is designed to meet documented societal (job market) needs in today's and tomorrow's global village and economy by providing graduates with strong specialties in English-Spanish translating and in business Spanish. It is integrative in that it does so while maintaining its…

Effects of diesel exhaust on influenza-induced nasal inflammation

EPA Science Inventory

Title: Effects of Diesel Exhaust on Influenza-Induced Nasal Inflammation T L Noah, MD1,2, K Horvath, BS3, C Robinette, RN2, 0 Diaz Sanchez, PhD4 and I Jaspers, PhD1,2. 1UNC Dept. of Pediatrics, United States; 2UNC Center for Environmental Medicine, Asthma and Lung Biology, ...

Providing Quality Laboratories to Long-Distance Educational Programs.

ERIC Educational Resources Information Center

Gammon, Tammy; Sutton, John

2003-01-01

North Carolina State University (UNC) has been on the forefront of long-distance education by offering a Bachelor of Science in Engineering with a Mechatronics Concentration at its remote campus located at UNC Asheville. The program demonstrates that long-distance laboratories are feasible and should not be a stumbling block to offering…

General Education at UNC-Chapel Hill

ERIC Educational Resources Information Center

Schalin, Jay; Robinson, Jenna Ashley

2013-01-01

The general education program at UNC-Chapel Hill has abandoned the concept of a core curriculum. Instead, students choose their "required" classes from lists of thousands of courses that may be as narrow and idiosyncratic as Love, Sex and Marriage in Soviet Culture (RUSS 277) or The Gardens, Shrines and Temples of Japan (ASIA 586).…

SDN-1/syndecan regulates growth factor signaling in distal tip cell migrations in C. elegans.

PubMed

Schwabiuk, Megan; Coudiere, Ludivine; Merz, David C

2009-10-01

Mutations in the sdn-1/syndecan gene act as genetic enhancers of the ventral-to-dorsal distal tip cell (DTC) migration defects caused by a weak allele of the netrin receptor gene unc-5. The sdn-1(ev697) allele was identified in a genetic screen for enhancers of unc-5 DTC migration defects, and carried a nonsense mutation predicted to truncate the SDN-1 protein prior to the transmembrane domain. The enhancement of unc-5 caused by an sdn-1 mutation was rescued by expression of wild-type sdn-1 in the hypodermis or nervous system rather than the DTCs, indicating a cell non-autonomous function of sdn-1. The enhancement was also partially reversed by mutations in the egl-17/FGF or egl-20/Wnt genes, suggesting that sdn-1 affects UNC-5 function through a mis-regulation of signaling in growth factor pathways. egl-20 reporter constructs exhibited increased and mis-localized EGL-20 distribution in sdn-1 mutants compared to wild-type animals. Finally, using loss of function mutations, we show that egl-17/Fgf and egl-20/Wnt are partially redundant in regulating the migration pattern of the posterior DTC, as double mutants exhibit significant frequencies of defects in migration phases along both the anteroposterior and dorsoventral axes. Together these results suggest that SDN-1 affects UNC-5 function by regulating the proper extracellular distribution of growth factors.

"Rekindle and Recapture the Love": Establishing System-Wide Indicators of Progress in Community Engagement and Economic Development

ERIC Educational Resources Information Center

Janke, Emily M.

2014-01-01

In May 2012, University of North Carolina (UNC) President Tom Ross simultaneously commissioned two task forces to develop indicators that all UNC campuses could use to measure "progress in community engagement and economic development." The charge to the Community Engagement Task Force and the Economic Development Task Force was to…

UNC EFRC: Fuels from Sunlight (A "Life at the Frontiers of Energy Research" contest entry from the 2011 Energy Frontier Research Centers (EFRCs) Summit and Forum)

ScienceCinema

Meyer, Thomas J. (Director, UNC EFRC: Solar Fuels and Next Generation Photovoltaics); UNC EFRC Staff

2017-12-09

'Fuels from Sunlight' was submitted by the University of North Carolina (UNC) EFRC: Solar Fuels and Next Generation Photovoltaics to the 'Life at the Frontiers of Energy Research' video contest at the 2011 Science for Our Nation's Energy Future: Energy Frontier Research Centers (EFRCs) Summit and Forum. Twenty-six EFRCs created short videos to highlight their mission and their work. The UNC EFRC directed by Thomas J. Meyer is a partnership of scientists from six institutions: UNC (lead), Duke University, University of Florida, North Caroline Central University, North Carolina State University, and the Research Triangle Institute. The Office of Basic Energy Sciences in the U.S. Department of Energy's Office of Science established the 46 Energy Frontier Research Centers (EFRCs) in 2009. These collaboratively-organized centers conduct fundamental research focused on 'grand challenges' and use-inspired 'basic research needs' recently identified in major strategic planning efforts by the scientific community. The overall purpose is to accelerate scientific progress toward meeting the nation's critical energy challenges. The mission of Solar Fuels and Next Generation Photovoltaics is 'to combine the best features of academic and translational research to study light/matter interactions and chemical processes for the efficient collection, transfer, and conversion of solar energy into chemical fuels and electricity.' Research topics are: catalysis (CO{sub 2}, hydrocarbons, water), electrocatalysis, photocatalysis, photoelectrocatalysis, solar photovoltaic, solar fuels, photonic, solar electrodes, photosynthesis, fuel cells, CO{sub 2} (convert), greenhosue gas, hydrogen (fuel), interfacial characterization, novel materials synthesis, charge transport, and self-assembly.

Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels.

PubMed

Matthewman, Cristina; Miller-Fleming, Tyne W; Miller, David M; Bianchi, Laura

2016-12-01

Hyperactivated DEG/ENaC channels cause neuronal death mediated by intracellular Ca 2+ overload. Mammalian ASIC1a channels and MEC-4(d) neurotoxic channels in Caenorhabditis elegans both conduct Na + and Ca 2+ , raising the possibility that direct Ca 2+ influx through these channels contributes to intracellular Ca 2+ overload. However, we showed that the homologous C. elegans DEG/ENaC channel UNC-8(d) is not Ca 2+ permeable, yet it is neurotoxic, suggesting that Na + influx is sufficient to induce cell death. Interestingly, UNC-8(d) shows small currents due to extracellular Ca 2+ block in the Xenopus oocyte expression system. Thus, MEC-4(d) and UNC-8(d) differ both in current amplitude and Ca 2+ permeability. Given that these two channels show a striking difference in toxicity, we wondered how Na + conductance vs. Ca 2+ permeability contributes to cell death. To address this question, we built an UNC-8/MEC-4 chimeric channel that retains the calcium permeability of MEC-4 and characterized its properties in Xenopus oocytes. Our data support the hypothesis that for Ca 2+ -permeable DEG/ENaC channels, both Ca 2+ permeability and Na + conductance contribute to toxicity. However, for Ca 2+ -impermeable DEG/ENaCs (e.g., UNC-8), our evidence shows that constitutive Na + conductance is sufficient to induce toxicity, and that this effect is enhanced as current amplitude increases. Our work further refines the contribution of different channel properties to cellular toxicity induced by hyperactive DEG/ENaC channels. Copyright © 2016 the American Physiological Society.

Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels

PubMed Central

Matthewman, Cristina; Miller-Fleming, Tyne W.; Miller, David M.

2016-01-01

Hyperactivated DEG/ENaC channels cause neuronal death mediated by intracellular Ca2+ overload. Mammalian ASIC1a channels and MEC-4(d) neurotoxic channels in Caenorhabditis elegans both conduct Na+ and Ca2+, raising the possibility that direct Ca2+ influx through these channels contributes to intracellular Ca2+ overload. However, we showed that the homologous C. elegans DEG/ENaC channel UNC-8(d) is not Ca2+ permeable, yet it is neurotoxic, suggesting that Na+ influx is sufficient to induce cell death. Interestingly, UNC-8(d) shows small currents due to extracellular Ca2+ block in the Xenopus oocyte expression system. Thus, MEC-4(d) and UNC-8(d) differ both in current amplitude and Ca2+ permeability. Given that these two channels show a striking difference in toxicity, we wondered how Na+ conductance vs. Ca2+ permeability contributes to cell death. To address this question, we built an UNC-8/MEC-4 chimeric channel that retains the calcium permeability of MEC-4 and characterized its properties in Xenopus oocytes. Our data support the hypothesis that for Ca2+-permeable DEG/ENaC channels, both Ca2+ permeability and Na+ conductance contribute to toxicity. However, for Ca2+-impermeable DEG/ENaCs (e.g., UNC-8), our evidence shows that constitutive Na+ conductance is sufficient to induce toxicity, and that this effect is enhanced as current amplitude increases. Our work further refines the contribution of different channel properties to cellular toxicity induced by hyperactive DEG/ENaC channels. PMID:27760755

Interactions of UNC-34 Enabled With Rac GTPases and the NIK Kinase MIG-15 in Caenorhabditis elegans Axon Pathfinding and Neuronal Migration

PubMed Central

Shakir, M. Afaq; Gill, Jason S.; Lundquist, Erik A.

2006-01-01

Many genes that affect axon pathfinding and cell migration have been identified. Mechanisms by which these genes and the molecules they encode interact with one another in pathways and networks to control developmental events are unclear. Rac GTPases, the cytoskeletal signaling molecule Enabled, and NIK kinase have all been implicated in regulating axon pathfinding and cell migration. Here we present evidence that, in Caenorhabditis elegans, three Rac GTPases, CED-10, RAC-2, and MIG-2, define three redundant pathways that each control axon pathfinding, and that the NIK kinase MIG-15 acts in each Rac pathway. Furthermore, we show that the Enabled molecule UNC-34 defines a fourth partially redundant pathway that acts in parallel to Rac/MIG-15 signaling in axon pathfinding. Enabled and the three Racs also act redundantly to mediate AQR and PQR neuronal cell migration. The Racs and UNC-34 Ena might all control the formation of actin-based protrusive structures (lamellipodia and filopodia) that mediate growth cone outgrowth and cell migration. MIG-15 does not act with the three Racs in execution of cell migration. Rather, MIG-15 affects direction of PQR neuronal migration, similar to UNC-40 and DPY-19, which control initial Q cell polarity, and Wnt signaling, which acts later to control Q cell-directed migration. MIG-2 Rac, which acts with CED-10 Rac, RAC-2 Rac, and UNC-34 Ena in axon pathfinding and cell migration, also acts with MIG-15 in PQR directional migration. PMID:16204220

Unc-45 Mutations in Caenorhabditis elegans Implicate a CRO1/She4p-like Domain in Myosin Assembly

PubMed Central

Barral, José M.; Bauer, Christopher C.; Ortiz, Irving; Epstein, Henry F.

1998-01-01

The Caenorhabditis elegans unc-45 locus has been proposed to encode a protein machine for myosin assembly. The UNC-45 protein is predicted to contain an NH2-terminal domain with three tetratricopeptide repeat motifs, a unique central region, and a COOH-terminal domain homologous to CRO1 and She4p. CRO1 and She4p are fungal proteins required for the segregation of other molecules in budding, endocytosis, and septation. Three mutations that lead to temperature-sensitive (ts) alleles have been localized to conserved residues within the CRO1/She4p-like domain, and two lethal alleles were found to result from stop codon mutations in the central region that would prevent translation of the COOH-terminal domain. Electron microscopy shows that thick filament accumulation in vivo is decreased by ∼50% in the CB286 ts mutant grown at the restrictive temperature. The thick filaments that assemble have abnormal structure. Immunofluorescence and immunoelectron microscopy show that myosins A and B are scrambled, in contrast to their assembly into distinct regions at the permissive temperature and in wild type. This abnormal structure correlates with the high degree of instability of the filaments in vitro as reflected by their extremely low yields and shortened lengths upon isolation. These results implicate the UNC-45 CRO1/She4p-like region in the assembly of myosin isoforms in C. elegans and suggest a possible common mechanism for the function of this UCS (UNC-45/CRO1/She4p) protein family. PMID:9832550

The University of North Carolina Report on Expanding Access to Higher Education through State-Funded Distance Education Programs

ERIC Educational Resources Information Center

University of North Carolina General Administration, 2012

2012-01-01

Legislation in 1998 provided enrollment funding for UNC distance education. This report documents the growth of UNC distance education programs and their role in meeting the high priority education and economic development needs of the State. As highlighted in the Executive Summary and documented throughout this report, state enrollment funding…

CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16

PubMed Central

Tao, Li; Xie, Qi; Ding, Yue-He; Li, Shang-Tong; Peng, Shengyi; Zhang, Yan-Ping; Tan, Dan; Yuan, Zengqiang; Dong, Meng-Qiu

2013-01-01

The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin (PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6•CNB-1 and UNC-43, the C. elegans Calcineurin and Ca2+/calmodulin-dependent kinase type II (CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC-43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6•CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin. DOI: http://dx.doi.org/10.7554/eLife.00518.001 PMID:23805378

Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions.

PubMed

Weinert, Stefanie; Jabs, Sabrina; Hohensee, Svea; Chan, Wing Lee; Kornak, Uwe; Jentsch, Thomas J

2014-07-01

Loss of the lysosomal ClC-7/Ostm1 2Cl(-)/H(+) exchanger causes lysosomal storage disease and osteopetrosis in humans and additionally changes fur colour in mice. Its conversion into a Cl(-) conductance in Clcn7(unc/unc) mice entails similarly severe lysosomal storage, but less severe osteopetrosis and no change in fur colour. To elucidate the basis for these phenotypical differences, we generated Clcn7(td/td) mice expressing an ion transport-deficient mutant. Their osteopetrosis was as severe as in Clcn7(-/-) mice, suggesting that the electric shunt provided by ClC-7(unc) can partially rescue osteoclast function. The normal coat colour of Clcn7(td/td) mice and their less severe neurodegeneration suggested that the ClC-7 protein, even when lacking measurable ion transport activity, is sufficient for hair pigmentation and that the conductance of ClC-7(unc) is harmful for neurons. Our in vivo structure-function analysis of ClC-7 reveals that both protein-protein interactions and ion transport must be considered in the pathogenesis of ClC-7-related diseases. © 2014 The Authors.

Affective Responsivity to Varying Modes of Police Dress

DTIC Science & Technology

1980-04-16

THIS PAGE (111bef Dot& Entered) Unc as=i f!ed , SECURITrV CLASSIFICATION OF THIS PAGE( te..... .. ...-. ,-in a more postive relationship between the...cause self- reinforcing attitudes of mistrust and cynicism in both citizens and the police. Therefore, it has been hypothesized that the removal of these...involved in some way with the police in the exercise of their law enforcement function. Among the findings, the authors reported that positive contact with

The Nicotinic Acetylcholine Receptors of the Parasitic Nematode Ascaris suum: Formation of Two Distinct Drug Targets by Varying the Relative Expression Levels of Two Subunits

PubMed Central

Williamson, Sally M.; Robertson, Alan P.; Brown, Laurence; Williams, Tracey; Woods, Debra J.; Martin, Richard J.; Sattelle, David B.; Wolstenholme, Adrian J.

2009-01-01

Parasitic nematodes are of medical and veterinary importance, adversely affecting human health and animal welfare. Ascaris suum is a gastrointestinal parasite of pigs; in addition to its veterinary significance it is a good model of the human parasite Ascaris lumbricoides, estimated to infect ∼1.4 billion people globally. Anthelmintic drugs are essential to control nematode parasites, and nicotinic acetylcholine receptors (nAChRs) on nerve and muscle are the targets of cholinergic anthelmintics such as levamisole and pyrantel. Previous genetic analyses of nematode nAChRs have been confined to Caenorhabditis elegans, which is phylogenetically distinct from Ascaris spp. and many other important parasites. Here we report the cloning and expression of two nAChR subunit cDNAs from A. suum. The subunits are very similar in sequence to C. elegans UNC-29 and UNC-38, are expressed on muscle cells and can be expressed robustly in Xenopus oocytes to form acetylcholine-, nicotine-, levamisole- and pyrantel-sensitive channels. We also demonstrate that changing the stoichiometry of the receptor by injecting different ratios of the subunit cRNAs can reproduce two of the three pharmacological subtypes of nAChR present in A. suum muscle cells. When the ratio was 5∶1 (Asu-unc-38∶Asu-unc-29), nicotine was a full agonist and levamisole was a partial agonist, and oocytes responded to oxantel, but not pyrantel. At the reverse ratio (1∶5 Asu-unc-38∶Asu-unc-29), levamisole was a full agonist and nicotine was a partial agonist, and the oocytes responded to pyrantel, but not oxantel. These results represent the first in vitro expression of any parasitic nicotinic receptor and show that their properties are substantially different from those of C. elegans. The results also show that changing the expression level of a single receptor subunit dramatically altered the efficacy of some anthelmintic drugs. In vitro expression of these subunits may permit the development of parasite-specific screens for future anthelmintics. PMID:19609360

Frazzled/DCC facilitates cardiac cell outgrowth and attachment during Drosophila dorsal vessel formation.

PubMed

Macabenta, Frank D; Jensen, Amber G; Cheng, Yi-Shan; Kramer, Joseph J; Kramer, Sunita G

2013-08-15

Drosophila embryonic dorsal vessel (DV) morphogenesis is a highly stereotyped process that involves the migration and morphogenesis of 52 pairs of cardioblasts (CBs) in order to form a linear tube. This process requires spatiotemporally-regulated localization of signaling and adhesive proteins in order to coordinate the formation of a central lumen while maintaining simultaneous adhesion between CBs. Previous studies have shown that the Slit/Roundabout and Netrin/Unc5 repulsive signaling pathways facilitate site-specific loss of adhesion between contralateral CBs in order to form a luminal space. However, the concomitant mechanism by which attraction initiates CB outgrowth and discrete localization of adhesive proteins remains poorly understood. Here we provide genetic evidence that Netrin signals through DCC (Deleted in Colorectal Carcinoma)/UNC-40/Frazzled (Fra) to mediate CB outgrowth and attachment and that this function occurs prior to and independently of Netrin/UNC-5 signaling. fra mRNA is expressed in the CBs prior to and during DV morphogenesis. Loss-of-fra-function results in significant defects in cell shape and alignment between contralateral CB rows. In addition, CB outgrowth and attachment is impaired in both fra loss- and gain-of-function mutants. Deletion of both Netrin genes (NetA and NetB) results in CB attachment phenotypes similar to fra mutants. Similar defects are also seen when both fra and unc5 are deleted. Finally we show that Fra accumulates at dorsal and ventral leading edges of paired CBs, and this localization is dependent upon Netrin. We propose that while repulsive guidance mechanisms contribute to lumen formation by preventing luminal domains from coming together, site-specific Netrin/Frazzled signaling mediates CB attachment. Copyright © 2013 Elsevier Inc. All rights reserved.

Extending Digital Repository Architectures to Support Disk Image Preservation and Access

DTIC Science & Technology

2011-06-01

Extending Digital Repository Architectures to Support Disk Image Preservation and Access Kam Woods School of Information and Library Science University...of North Carolina 216 Lenoir Drive, CB #3360 1-(919)-966-3598 kamwoods@email.unc.edu Christopher A. Lee School of Information and Library ... Science University of North Carolina 216 Lenoir Drive, CB #3360 1-(919)-962-7204 callee@ils.unc.edu Simson Garfinkel Graduate School of

The Institute for Sustained Performance, Energy, and Resilience, University of North Carolina, Final Technical Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, Robert

This is the final report for the UNC component of the SciDAD Institute for Sustained Performance, Energy, and Resilience. In this report, we describe activities on the SUPER project at RENCI at the University of North Carolina at Chapel Hill. While we focus particularly on UNC, we touch on project-wide activities as well as, on interactions with, and impacts on, other projects.

Role of Frontotemporal Fiber Tract Integrity in Task-Switching Performance of Healthy Controls and Patients with Temporal Lobe Epilepsy

PubMed Central

Kucukboyaci, N. Erkut; Girard, H.M.; Hagler, D.J.; Kuperman, J.; Tecoma, E.S.; Iragui, V.J.; Halgren, E.; McDonald, C.R.

2012-01-01

The objective of this study is to investigate the relationships among frontotemporal fiber tract compromise and task-switching performance in healthy controls and patients with temporal lobe epilepsy (TLE). We performed diffusion tensor imaging (DTI) on 30 controls and 32 patients with TLE (15 left TLE). Fractional anisotropy (FA) was calculated for four fiber tracts [uncinate fasciculus (UncF), arcuate fasciculus (ArcF), dorsal cingulum (CING), and inferior fronto-occipital fasciculus (IFOF)]. Participants completed the Trail Making Test-B (TMT-B) and Verbal Fluency Category Switching (VFCS) test. Multivariate analyses of variances (MANOVAs) were performed to investigate group differences in fiber FA and set-shifting performances. Canonical correlations were used to examine the overall patterns of structural-cognitive relationships and were followed by within-group bivariate correlations. We found a significant canonical correlation between fiber FA and task-switching performance. In controls, TMT-B correlated with left IFOF, whereas VFCS correlated with FA of left ArcF and left UncF. These correlations were not significant in patients with TLE. We report significant correlations between frontotemporal fiber tract integrity and set-shifting performance in healthy controls that appear to be absent or attenuated in patients with TLE. These findings suggest a breakdown of typical structure-function relationships in TLE that may reflect aberrant developmental or degenerative processes. PMID:22014246

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion.

PubMed

Hayano, Yasufumi; Sasaki, Kensuke; Ohmura, Nami; Takemoto, Makoto; Maeda, Yurie; Yamashita, Toshihide; Hata, Yoshio; Kitada, Kazuhiro; Yamamoto, Nobuhiko

2014-10-21

Axon branching is remodeled by sensory-evoked and spontaneous neuronal activity. However, the underlying molecular mechanism is largely unknown. Here, we demonstrate that the netrin family member netrin-4 (NTN4) contributes to activity-dependent thalamocortical (TC) axon branching. In the postnatal developmental stages of rodents, ntn4 expression was abundant in and around the TC recipient layers of sensory cortices. Neuronal activity dramatically altered the ntn4 expression level in the cortex in vitro and in vivo. TC axon branching was promoted by exogenous NTN4 and suppressed by depletion of the endogenous protein. Moreover, unc-5 homolog B (Unc5B), which strongly bound to NTN4, was expressed in the sensory thalamus, and knockdown of Unc5B in thalamic cells markedly reduced TC axon branching. These results suggest that NTN4 acts as a positive regulator for TC axon branching through activity-dependent expression.

Fostering intentional interdisciplinary leadership in developmental disabilities: the North Carolina LEND experience.

PubMed

Rosenberg, Angela; Margolis, Lewis H; Umble, Karl; Chewning, Linda

2015-02-01

This study describes the effects of interdisciplinary leadership training on a retrospective cohort (2001-2009) of the University of North Carolina MCH Leadership Education in Neurodevelopmental and Related Disabilities (UNC-CH LEND) program, including LEND graduates who were selected to participate in a focused Interdisciplinary Leadership Development Program (ILDP) in addition to their LEND training. Specifically, the study examined graduates' reports of the relationship between LEND training and their attitudes/beliefs about interdisciplinary practice, as well as their reported use of interdisciplinary skills in their post-fellowship practice settings. Using a post-test design, participants in the LEND and ILDP programs were contacted to complete an on-line survey. Using a Conceptual Model guided by EvaluLEAD, respondents were asked to rate the influence of the UNC-LEND training program on their attitudes/beliefs and skills using a 5-point Likert scale, as well as through open-ended descriptions. The 49 LEND respondents represented a 56% overall response rate from years 2001-2009. ILDP participants reported greater agreement with interdisciplinary attitudes/beliefs and more frequent use of interdisciplinary skills than did the non-participants. Graduates of LEND as well as ILDP reported the influence of training through a range of qualitative responses. Response examples highlight the influence of LEND training to promote outcomes at the individual, organizational and systems level. Findings from this study illustrate that MCHB funded LEND training has a strong influence on the future employment and interdisciplinary practices of graduates for the MCH workforce as well as services for individuals with developmental disabilities, their families and systems of care.

Roadmap for the development of the University of North Carolina at Chapel Hill Genitourinary OncoLogy Database--UNC GOLD.

PubMed

Gallagher, Sarah A; Smith, Angela B; Matthews, Jonathan E; Potter, Clarence W; Woods, Michael E; Raynor, Mathew; Wallen, Eric M; Rathmell, W Kimryn; Whang, Young E; Kim, William Y; Godley, Paul A; Chen, Ronald C; Wang, Andrew; You, Chaochen; Barocas, Daniel A; Pruthi, Raj S; Nielsen, Matthew E; Milowsky, Matthew I

2014-01-01

The management of genitourinary malignancies requires a multidisciplinary care team composed of urologists, medical oncologists, and radiation oncologists. A genitourinary (GU) oncology clinical database is an invaluable resource for patient care and research. Although electronic medical records provide a single web-based record used for clinical care, billing, and scheduling, information is typically stored in a discipline-specific manner and data extraction is often not applicable to a research setting. A GU oncology database may be used for the development of multidisciplinary treatment plans, analysis of disease-specific practice patterns, and identification of patients for research studies. Despite the potential utility, there are many important considerations that must be addressed when developing and implementing a discipline-specific database. The creation of the GU oncology database including prostate, bladder, and kidney cancers with the identification of necessary variables was facilitated by meetings of stakeholders in medical oncology, urology, and radiation oncology at the University of North Carolina (UNC) at Chapel Hill with a template data dictionary provided by the Department of Urologic Surgery at Vanderbilt University Medical Center. Utilizing Research Electronic Data Capture (REDCap, version 4.14.5), the UNC Genitourinary OncoLogy Database (UNC GOLD) was designed and implemented. The process of designing and implementing a discipline-specific clinical database requires many important considerations. The primary consideration is determining the relationship between the database and the Institutional Review Board (IRB) given the potential applications for both clinical and research uses. Several other necessary steps include ensuring information technology security and federal regulation compliance; determination of a core complete dataset; creation of standard operating procedures; standardizing entry of free text fields; use of data exports, queries, and de-identification strategies; inclusion of individual investigators' data; and strategies for prioritizing specific projects and data entry. A discipline-specific database requires a buy-in from all stakeholders, meticulous development, and data entry resources to generate a unique platform for housing information that may be used for clinical care and research with IRB approval. The steps and issues identified in the development of UNC GOLD provide a process map for others interested in developing a GU oncology database. Copyright © 2014 Elsevier Inc. All rights reserved.

Neural Markers and Rehabilitation of Executive Functioning in Veterans with TBI and PTSD

DTIC Science & Technology

2015-10-01

with reduced irritability/impulsivity and improved social/occupational functioning. Functional magnetic resonance imaging ( fMRI ) will be used to...transport Veterans five minutes away to the Dr. Belger’s lab at UNC Hospital where EEG and fMRI will be conducted and then transport Veterans back to... fMRI was arranged through the UNC-Chapel Hill School of Medicine at month 9. Participants may either take a shuttle from the research laboratory to

Scan Directed Load Balancing for Highly-Parallel Mesh-Connected Computers

DTIC Science & Technology

1991-07-01

DTIC ~ ELECTE OCT 2 41991 AD-A242 045 Scan Directed Load Balancing for Highly-Parallel Mesh-Connected Computers’ Edoardo S. Biagioni Jan F. Prins...Department of Computer Science University of North Carolina Chapel Hill, N.C. 27599-3175 USA biagioni @cs.unc.edu prinsOcs.unc.edu Abstract Scan Directed...MasPar Computer Corpora- tion. Bibliography [1] Edoardo S. Biagioni . Scan Directed Load Balancing. PhD thesis., University of North Carolina, Chapel Hill

United Nations Command Armistice Roles on the Korean Peninsula: Is December 2015 the End?

DTIC Science & Technology

2013-06-14

effect, both sides have modified security arrangements to meet changes in the diplomatic, economic, and technological environments. In the north, DPRK...practice, the Korean War remains without a final resolution. The KWAA provided a ceasefire for the two sides to reach a final political arrangement to...entrusted to the U.S. from time the UNC was established. Finally , the UNC became a crucial operational mechanism in the Armistice regime, which

Effectiveness of Mineral Admixtures in Preventing Execessive Expansion of Concrete Due to Alkali-Aggregate Reaction.

DTIC Science & Technology

1958-07-01

81 year 25 1 0.468 0.190 59 2 0.725 0.220 70 15 0.230 0.110 52 F. Uncalcined Diatomite WES, Unc D; NAVCEREL, Johns - Manville Pozzolan 0.018 95 14 25...325 163 225 270 189 -100 + 200 154 135 C Sh N Colton 510 576 405 152 Ce~ D Airoa 390 419 883 772Cal D Airox 545 581 382 270Unc D Johns - Manville POzzolan

Biallelic UNC80 mutations caused infantile hypotonia with psychomotor retardation and characteristic facies 2 in two Chinese patients with variable phenotypes.

PubMed

He, Yunjuan; Ji, Xing; Yan, Hui; Ye, Xiantao; Liu, Yu; Wei, Wei; Xiao, Bing; Sun, Yu

2018-06-20

Biallelic UNC80 mutations cause infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2), which is characterized by hypotonia, developmental delay (DD)/intellectual disability (ID), intrauterine growth retardation, postnatal growth retardation and characteristic facial features. We report two unrelated Chinese patients with compound heterozygous UNC80 mutations inherited from their parents, as identified by whole-exome sequencing (WES). Mutations c.3719G>A (p.W1240*)/c.4926_4937del (p.N1643_L1646del) and c.4963C>T (p.R1655C)/c.8385C>G (p.Y2795*) were identified in patient 1 and patient 2, respectively. Although both patients presented with DD/ID and hypotonia, different manifestations also occurred. Patient 1 presented with infantile hypotonia, epilepsy and hyperactivity without growth retardation, whereas patient 2 presented with persistent hypotonia, growth retardation and self-injury without epilepsy. Furthermore, we herein summarize the genotypes and phenotypes of patients with UNC80 mutations reported in the literature, revealing that IHPRF2 is a phenotypically heterogeneous disease. Common facial dysmorphisms include a thin upper lip, a tented upper lip, a triangular face, strabismus and microcephaly. To some extent, the manifestations of IHPRF2 mimic those of Angelman syndrome (AS)-like syndromes. Copyright © 2018 Elsevier B.V. All rights reserved.

A Combinatorial Platform for the Optimization of Peptidomimetic Methyl-Lysine Reader Antagonists

NASA Astrophysics Data System (ADS)

Barnash, Kimberly D.

Post-translational modification of histone N-terminal tails mediates chromatin compaction and, consequently, DNA replication, transcription, and repair. While numerous post-translational modifications decorate histone tails, lysine methylation is an abundant mark important for both gene activation and repression. Methyl-lysine (Kme) readers function through binding mono-, di-, or trimethyl-lysine. Chemical intervention of Kme readers faces numerous challenges due to the broad surface-groove interactions between readers and their cognate histone peptides; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds for Kme readers are critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains and complexes. The successful discovery of a peptide-derived chemical probe, UNC3866, for the Polycomb repressive complex 1 (PRC1) chromodomain Kme readers has proven the potential for selective peptidomimetic inhibition of reader function. Unfortunately, the systematic modification of peptides-to-peptidomimetics is a costly and inefficient strategy for target-class hit discovery against Kme readers. Through the exploration of biased chemical space via combinatorial on-bead libraries, we have developed two concurrent methodologies for Kme reader chemical probe discovery. We employ biased peptide combinatorial libraries as a hit discovery strategy with subsequent optimization via iterative targeted libraries. Peptide-to-peptidomimetic optimization through targeted library design was applied based on structure-guided library design around the interaction of the endogenous peptide ligand with three target Kme readers. Efforts targeting the WD40 reader EED led to the discovery of the 3-mer peptidomimetic ligand UNC5115 while combinatorial repurposing of UNC3866 for off-target chromodomains resulted in the discovery of UNC4991, a CDYL/2-selective ligand, and UNC4848, a MPP8 and CDYL/2 ligand. Ultimately, our efforts demonstrate the generalizability of a peptidomimetic combinatorial platform for the optimization of Kme reader ligands in a target class manner.

Molecular analysis of two genes between let-653 and let-56 in the unc-22(IV) region of Caenorhabditis elegans.

PubMed

Marra, M A; Prasad, S S; Baillie, D L

1993-01-01

A previous study of genomic organization described the identification of nine potential coding regions in 150 kb of genomic DNA from the unc-22(IV) region of Caenorhabditis elegans. In this study, we focus on the genomic organization of a small interval of 0.1 map unit bordered on the right by unc-22 and on the left by the left-hand breakpoints of the deficiencies sDf9, sDf19 and sDf65. This small interval at present contains a single mutagenically defined locus, the essential gene let-56. The cosmid C11F2 has previously been used to rescue let-56. Therefore, at least some of C11F2 must reside in the interval. In this paper, we report the characterization of two coding elements that reside on C11F2. Analysis of nucleotide sequence data obtained from cDNAs and cosmid subclones revealed that one of the coding elements closely resembles aromatic amino acid decarboxylases from several species. The other of these coding elements was found to closely resemble a human growth factor activatable Na+/H+ antiporter. Paris of oligonucleotide primers, predicted from both coding elements, have been used in PCR experiments to position these coding elements between the left breakpoint of sDf19 and the left breakpoint of sDf65, between the essential genes let-653 and let-56.

Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment.

PubMed

Wang, Zhaoxi; Claus Henn, Birgit; Wang, Chaolong; Wei, Yongyue; Su, Li; Sun, Ryan; Chen, Han; Wagner, Peter J; Lu, Quan; Lin, Xihong; Wright, Robert; Bellinger, David; Kile, Molly; Mazumdar, Maitreyi; Tellez-Rojo, Martha Maria; Schnaas, Lourdes; Christiani, David C

2017-07-28

Neurodevelopment is a complex process involving both genetic and environmental factors. Prenatal exposure to lead (Pb) has been associated with lower performance on neurodevelopmental tests. Adverse neurodevelopmental outcomes are more frequent and/or more severe when toxic exposures interact with genetic susceptibility. To explore possible loci associated with increased susceptibility to prenatal Pb exposure, we performed a genome-wide gene-environment interaction study (GWIS) in young children from Mexico (n = 390) and Bangladesh (n = 497). Prenatal Pb exposure was estimated by cord blood Pb concentration. Neurodevelopment was assessed using the Bayley Scales of Infant Development. We identified a locus on chromosome 8, containing UNC5D, and demonstrated evidence of its genome-wide significance with mental composite scores (rs9642758, p meta  = 4.35 × 10 -6 ). Within this locus, the joint effects of two independent single nucleotide polymorphisms (SNPs, rs9642758 and rs10503970) had a p-value of 4.38 × 10 -9 for mental composite scores. Correlating GWIS results with in vitro transcriptomic profiles identified one common gene, SLC1A5, which is involved in synaptic function, neuronal development, and excitotoxicity. Further analysis revealed interconnected interactions that formed a large network of 52 genes enriched with oxidative stress genes and neurodevelopmental genes. Our findings suggest that certain genetic polymorphisms within/near genes relevant to neurodevelopment might modify the toxic effects of Pb exposure via oxidative stress.

Positive selection of Caenorhabditis elegans mutants with increased stress resistance and longevity.

PubMed Central

Muñoz, Manuel J; Riddle, Donald L

2003-01-01

We developed selective conditions for long-lived mutants of the nematode Caenorhabditis elegans by subjecting the first larval stage (L1) to thermal stress at 30 degrees for 7 days. The surviving larvae developed to fertile adults after the temperature was shifted to 15 degrees. A total of one million F(2) progeny and a half million F(3) progeny of ethyl-methanesulfonate-mutagenized animals were treated in three separate experiments. Among the 81 putative mutants that recovered and matured to the reproductive adult, 63 retested as thermotolerant and 49 (80%) exhibited a >15% increase in mean life span. All the known classes of dauer formation (Daf) mutant that affect longevity were found, including six new alleles of daf-2, and a unique temperature-sensitive, dauer-constitutive allele of age-1. Alleles of dyf-2 and unc-13 were isolated, and mutants of unc-18, a gene that interacts with unc-13, were also found to be long lived. Thirteen additional mutations define at least four new genes. PMID:12586705

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis elegans

PubMed Central

Xu, Yan; Ren, Xing-Cong; Quinn, Christopher C.; Wadsworth, William G.

2011-01-01

Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in culture, and it has been suggested that acetylcholine could act as a guidance cue. However, the role acetylcholine plays in directing axon migrations in vivo is not clear. Here, we show that acetylcholine positively regulates signaling pathways that mediate axon responses to guidance cues in Caenorhabditis elegans. Mutations that disrupt acetylcholine synthesis, transportation, and secretion affect circumferential axon guidance of the AVM neuron and in these mutants exogenously supplied acetylcholine improves AVM circumferential axon guidance. These effects are not observed for the circumferential guidance of the DD and VD motor neuron axons, which are neighbors of the AVM axon. Circumferential guidance is directed by the UNC-6 (netrin) and SLT-1 (slit) extracellular cues, and exogenously supplied acetylcholine can improve AVM axon guidance in mutants when either UNC-6– or SLT-1–induced signaling is disrupted, but not when both signaling pathways are perturbed. Not in any of the mutants does exogenously supplied acetylcholine improve DD and VD axon guidance. The ability of acetylcholine to enhance AVM axon guidance only in the presence of either UNC-6 or SLT-1 indicates that acetylcholine potentiates UNC-6 and SLT-1 guidance activity, rather than acting itself as a guidance cue. Together, our results show that for specific neurons acetylcholine plays an important role in vivo as a modulator of axon responses to guidance cues. PMID:21868605

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency.

PubMed

Soheili, Tayebeh; Durand, Amandine; Sepulveda, Fernando E; Rivière, Julie; Lagresle-Peyrou, Chantal; Sadek, Hanem; de Saint Basile, Geneviève; Martin, Samia; Mavilio, Fulvio; Cavazzana, Marina; André-Schmutz, Isabelle

2017-12-26

Patients with mutations in the UNC13D gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of UNC13D gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from Unc13d -deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)-like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC UNC13D gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8 + T lymphocytes' cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation.

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

PubMed Central

Soheili, Tayebeh; Sepulveda, Fernando E.; Rivière, Julie; de Saint Basile, Geneviève; Martin, Samia; Mavilio, Fulvio

2017-01-01

Patients with mutations in the UNC13D gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of UNC13D gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from Unc13d-deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)–like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC UNC13D gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8+ T lymphocytes’ cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation. PMID:29296930

IDENTIFYING RECRUITMENT AND RETENTION ISSUES FOR THE NATIONAL CHILDREN'S STUDY

EPA Science Inventory

Recruitment and Retention Issues for the National Children's Study
Danelle T Lobdell1, Suzanne Gilboa2, Pauline Mendola1 (1US EPA, NHEERL; 2UNC Chapel Hill)

A better understanding of the most effective recruitment techniques and retention strategies for longitudinal, co...

Mood, stress and longevity: convergence on ANK3.

PubMed

Rangaraju, S; Levey, D F; Nho, K; Jain, N; Andrews, K D; Le-Niculescu, H; Salomon, D R; Saykin, A J; Petrascheck, M; Niculescu, A B

2016-08-01

Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroner's office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with Hutchinson-Gilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a "life switch" actively controlled by mood and stress.

USE OF DISCUSSION GROUPS TO INVESTIGATE RECRUITMENT AND RETENTION ISSUES FOR THE NATIONAL CHILDREN'S STUDY

EPA Science Inventory

Use of Discussion Groups to Investigate Recruitment and Retention Issues for a Longitudinal Study of Children's Environmental Health
DT Lobdell*, S Gutter+, P Mendola* (*US EPA, NHEERL; +UNC Chapel Hill)

Much of what is known about successful recruitment and retention o...

DOP-2 D2-Like Receptor Regulates UNC-7 Innexins to Attenuate Recurrent Sensory Motor Neurons during C. elegans Copulation

PubMed Central

Correa, Paola A.; Gruninger, Todd

2015-01-01

Neuromodulation of self-amplifying circuits directs context-dependent behavioral executions. Although recurrent networks are found throughout the Caenorhabditis elegans connectome, few reports describe the mechanisms that regulate reciprocal neural activity during complex behavior. We used C. elegans male copulation to dissect how a goal-oriented motor behavior is regulated by recurrently wired sensory-motor neurons. As the male tail presses against the hermaphrodite's vulva, cholinergic and glutamatergic reciprocal innervations of post cloaca sensilla (PCS) neurons (PCA, PCB, and PCC), hook neurons (HOA, HOB), and their postsynaptic sex muscles execute rhythmic copulatory spicule thrusts. These repetitive spicule movements continue until the male shifts off the vulva or genital penetration is accomplished. However, the signaling mechanism that temporally and spatially restricts repetitive intromission attempts to vulva cues was unclear. Here, we report that confinement of spicule insertion attempts to the vulva is facilitated by D2-like receptor modulation of gap-junctions between PCB and the hook sensillum. We isolated a missense mutation in the UNC-7(L) gap-junction isoform, which perturbs DOP-2 signaling in the PCB neuron and its electrical partner, HOA. The glutamate-gated chloride channel AVR-14 is expressed in HOA. Our analysis of the unc-7 mutant allele indicates that when DOP-2 promotes UNC-7 electrical communication, AVR-14-mediated inhibitory signals pass from HOA to PCB. As a consequence, PCB is less receptive to be stimulated by its recurrent synaptic partner, PCA. Behavioral observations suggest that dopamine neuromodulation of UNC-7 ensures attenuation of recursive intromission attempts when the male disengages or is dislodged from the hermaphrodite genitalia. SIGNIFICANCE STATEMENT Using C. elegans male copulation as a model, we found that the neurotransmitter dopamine stimulates D2-like receptors in two sensory circuits to terminate futile behavioral loops. The D2-like receptors promote inhibitory electrical junction activity between a chemosensory and a mechanosensory circuit. Therefore, both systems are attenuated and the animal ceases the recursive behavior. PMID:26156999

A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function.

PubMed

Elstak, Edo D; te Loo, Maroeska; Tesselaar, Kiki; van Kerkhof, Peter; Loeffen, Jan; Grivas, Dimitris; Hennekam, Eric; Boelens, Jaap Jan; Hoogerbrugge, Peter M; van der Sluijs, Peter; van Gijn, Marielle E; van de Corput, Lisette

2012-04-01

UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D. Here, we report for the first time a c.2695C>T (p.Arg899X) mutation in exon 28 of UNC13D in three young unrelated Dutch patients. The mutation causes a premature stop codon and encodes munc13-4(1-899), which lacks the C-terminal C2 domain. Genealogical research and haplotyping of the patient families demonstrated that a single ancestral founder introduced the mutation in the Netherlands. We then characterized the mutant protein phenotypically in cell biological and immunological assays. Munc13-4(1-899) was correctly targeted to CD63-positive secretory lysosomes, although its stability was reduced and dynamic turnover on the granule membrane became uncoupled from receptor signaling. In accord, and in contrast to wild-type munc13-4, ectopically expressed mutant failed to rescue degranulation in cells with silenced endogenous munc13-4. The functional and clinical data showed that this novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899). Copyright © 2011 Wiley Periodicals, Inc.

Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling.

PubMed

Tai-Nagara, Ikue; Yoshikawa, Yusuke; Numata, Naoko; Ando, Tomofumi; Okabe, Keisuke; Sugiura, Yuki; Ieda, Masaki; Takakura, Nobuyuki; Nakagawa, Osamu; Zhou, Bin; Okabayashi, Koji; Suematsu, Makoto; Kitagawa, Yuko; Bastmeyer, Martin; Sato, Kohji; Klein, Rüdiger; Navankasattusas, Sutip; Li, Dean Y; Yamagishi, Satoru; Kubota, Yoshiaki

2017-07-01

The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth. Mice lacking FLRT2 in endothelial cells exhibited embryonic lethality at mid-gestation, with systemic congestion and hypoxia. Although they lacked apparent deformities in the embryonic vasculature and heart, the placental labyrinths of these embryos exhibited aberrant alignment of endothelial cells, which disturbed the feto-maternal circulation. Interestingly, this vascular deformity was related to endothelial repulsion through binding to the UNC5B receptor. Our results suggest that the proper organization of the placental labyrinth depends on coordinated inter-endothelial repulsion, which prevents uncontrolled layering of the endothelium. © 2017. Published by The Company of Biologists Ltd.

Genome-wide siRNA screen identifies UNC50 as a regulator of Shiga toxin 2 trafficking

PubMed Central

Iles, Lakesla R.; Bartholomeusz, Geoffrey

2017-01-01

Shiga toxins 1 and 2 (STx1 and STx2) undergo retrograde trafficking to reach the cytosol. Early endosome-to-Golgi transport allows the toxins to evade degradation in lysosomes. Targeting this trafficking step has therapeutic promise, but the mechanism of trafficking for the more potent toxin STx2 is unclear. To identify host factors required for early endosome-to-Golgi trafficking of STx2, we performed a viability-based genome-wide siRNA screen in HeLa cells. 564, 535, and 196 genes were found to be required for toxicity induced by STx1 only, STx2 only, and both toxins, respectively. We focused on validating endosome/Golgi-localized hits specific for STx2 and found that depletion of UNC50 blocked early endosome-to-Golgi trafficking and induced lysosomal degradation of STx2. UNC50 acted by recruiting GBF1, an ADP ribosylation factor–guanine nucleotide exchange factor (ARF-GEF), to the Golgi. These results provide new information about STx2 trafficking mechanisms and may advance efforts to generate therapeutically viable toxin-trafficking inhibitors. PMID:28883040

Genome-wide siRNA screen identifies UNC50 as a regulator of Shiga toxin 2 trafficking.

PubMed

Selyunin, Andrey S; Iles, Lakesla R; Bartholomeusz, Geoffrey; Mukhopadhyay, Somshuvra

2017-10-02

Shiga toxins 1 and 2 (STx1 and STx2) undergo retrograde trafficking to reach the cytosol. Early endosome-to-Golgi transport allows the toxins to evade degradation in lysosomes. Targeting this trafficking step has therapeutic promise, but the mechanism of trafficking for the more potent toxin STx2 is unclear. To identify host factors required for early endosome-to-Golgi trafficking of STx2, we performed a viability-based genome-wide siRNA screen in HeLa cells. 564, 535, and 196 genes were found to be required for toxicity induced by STx1 only, STx2 only, and both toxins, respectively. We focused on validating endosome/Golgi-localized hits specific for STx2 and found that depletion of UNC50 blocked early endosome-to-Golgi trafficking and induced lysosomal degradation of STx2. UNC50 acted by recruiting GBF1, an ADP ribosylation factor-guanine nucleotide exchange factor (ARF-GEF), to the Golgi. These results provide new information about STx2 trafficking mechanisms and may advance efforts to generate therapeutically viable toxin-trafficking inhibitors. © 2017 Selyunin et al.

Implications of the Earth Summit for ocean and coastal governance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cicin-Sain, B.; Knecht, R.W.

1993-10-01

The Earth Summit (United Nations Conference on Environmental and Development (UNCED)), held in Rio de Janeiro in June 1992, was unique in the history of international conferences. Never before had so many heads of state participated in such an international negotiation. UNCED was also unique in both the breadth of environmental and development issues addressed and in the nature of the cross-cutting dimensions that were examined (for example, from poverty, population growth, and the role of indigenous peoples to unsustainable patterns of consumption (in the North), the role of women, and technology transfer). The chapter devoted to oceans and coastsmore » was the longest and, in some ways, the most comprehensive, of the 40 chapters making up the action plan (Agenda 21) that was approved at Rio. This article provides an overview of the events leading up the Earth Summit, describes the principal outputs of the conference and their potential effects on ocean and coastal governance, discusses the main tension seen at UNCED and some of the negotiating processes, and, finally, considers current efforts at implementation of its recommendations. 43 refs., 1 fig.« less

A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis.

PubMed

Castro-Jorge, Luiza A; Pretto, Carla D; Smith, Asa B; Foreman, Oded; Carnahan, Kelly E; Spindler, Katherine R

2017-02-15

Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 -/- mice). Il1r1 -/- mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard -/- mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 -/- mice). Pycard -/- and Unc93b1 -/- mice showed lower survival (similar to Il1r1 -/- mice) than control mice but, unlike Il1r1 -/- mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 -/- mice had a very different inflammatory profile from infected Il1r1 -/- and Pycard -/- mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 -/- mice. A time course of infection of control and Il1r1 -/- mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation. The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis. Copyright © 2017 American Society for Microbiology.

C. elegans dystroglycan coordinates responsiveness of follower axons to dorsal/ventral and anterior/posterior guidance cues

PubMed Central

Johnson, Robert P.; Kramer, James M.

2012-01-01

Neural development in metazoans is characterized by the establishment of initial process tracts by pioneer axons and the subsequent extension of follower axons along these pioneer processes. Mechanisms governing the fidelity of follower extension along pioneered routes are largely unknown. In C. elegans, formation of the right angle-shaped lumbar commissure connecting the lumbar and preanal ganglia is an example of pioneer/follower dynamics. We find that the dystroglycan ortholog DGN-1 mediates the fidelity of follower lumbar commissure axon extension along the pioneer axon route. In dgn-1 mutants, the axon of the pioneer PVQ neuron faithfully establishes the lumbar commissure, but axons of follower lumbar neurons, such as PVC, frequently bypass the lumbar commissure and extend along an oblique trajectory directly toward the preanal ganglion. In contrast, disruption of the UNC-6/netrin guidance pathway principally perturbs PVQ ventral guidance to pioneer the lumbar commissure. Loss of DGN-1 in unc-6 mutants has a quantitatively similar effect on follower axon guidance regardless of PVQ axon route, indicating that DGN-1 does not mediate follower/pioneer adhesion. Instead, DGN-1 appears to block premature responsiveness of follower axons to a preanal ganglion-directed guidance cue which mediates ventral-to-anterior reorientation of lumbar commissure axons. Deletion analysis shows that only the most N-terminal DGN-1 domain is required for these activities. These studies suggest that dystroglycan modulation of growth cone responsiveness to conflicting guidance cues is important for restricting follower axon extension to the tracts laid down by pioneers. PMID:22275151

EFFECTS OF DIESEL EXHAUST PARTICLES ON HUMAN MACROPHAGE RESPONSIVENESS TO LIPOPOLYSACCHARIDE

EPA Science Inventory

EFFECTS OF DIESEL EXHAUST PARTICLES ON HUMAN MACROPHAGE RESPONSIVENESS TO LIPOPOLYSACCHARIDE
S. Mundandhara1 and M.C. Madden2, 1UNC Center for Environmental Medicine, Asthma, and Lung Biology, 2US EPA, NHEERL, Human Studies Division, Chapel Hill, NC, USA

Epidemiologica...

SEM/EDS Characterization of Ambient PM during Agricultural Burns

NASA Astrophysics Data System (ADS)

Wagner, J.; Wall, S.

2010-12-01

Ambient particulate matter (PM) samples were collected with UNC passive samplers during agricultural burns in Imperial Valley, California. Four Bermuda grass field burn events were sampled at 3-8 locations surrounding each burn. Sampling began at the start of each burn (30-60 min) and continued for 24-120 hours. During 3 of the 4 burn events, winds were calm and plumes were observed to travel straight up to the inversion layer. In one event, winds created a ground-level plume that enveloped two UNC samplers mounted on telephone poles very close to the field (0.2-0.3 miles away). Computer-controlled scanning electron microscopy / energy-dispersive x-ray spectroscopy (CCSEM/EDS) was used to measure particle sizes and elemental composition, from which mass concentrations and size distributions were calculated. The median PM2.5 and PM10 levels measured in this study were 3.4 and 20 ug/m3, respectively. To determine quantitative accuracy, UNC sampler PM2.5 results (PM< 2.5 um) were compared to PM2.5 results from four co-located, continuous-reading beta-attenuation monitors (EBAMs). The median agreement (EBAM - UNC) was 3.8 ug/m3. Manual SEM/EDS detected various distinctive species in these samples, including sea salt, spores, plant fragments, and large soot agglomerates. During the ‘plume event’, 24-hour PM2.5 exposures downwind were up to 17 times higher than that measured upwind. Numerous submicron combustion particles with carbon and oxygen only were directly observed by manual SEM/EDS in the two plume-impacted samples, along with larger ash particles enriched in potassium, sulfur, chlorine, calcium, sodium, and phosphorus. CCSEM/EDS data from this event was grouped into 5 particle classes to generate size-fraction-specific pie charts. Burn-related particle types contributed 95% of the PM2.5 in the location directly impacted by the ground-level plume, compared to only 12% in the upwind location. A sample of Imperial County Bermuda grass analyzed in bulk and partially-burned states was found to contain similar inorganic elements as the air samples impacted by the burn plume, as well as mold spores found at trace levels in various air samples.

Facilities Inventory and Utilization Study, Fall of 1994; For the State of North Carolina. Twenty-Eighth Edition.

ERIC Educational Resources Information Center

North Carolina Univ., Chapel Hill. Commission on Higher Education Facilities.

This study presents the results of the 28th annual inventory and utilization study concerning space in North Carolina institutions of higher education during the 1994 fall term. The study provides information on 113 institutions of higher education including the 16 public senior institutions which comprise the University of North Carolina (UNC),…

Facilities Inventory and Utilization Study. Fall of 1995 for the State of North Carolina. Twenty-Ninth Edition.

ERIC Educational Resources Information Center

North Carolina Univ., Chapel Hill. Commission on Higher Education Facilities.

This study presents the results of the 29th annual inventory and utilization study concerning space in North Carolina institutions of higher education during the 1995 fall term. The study provides information on 113 institutions of higher education including the 16 public senior institutions which comprise the University of North Carolina (UNC),…

Food deprivation and nicotine correct akinesia and freezing in Na(+) -leak current channel (NALCN)-deficient strains of Caenorhabditis elegans.

PubMed

Bonnett, K; Zweig, R; Aamodt, E J; Dwyer, D S

2014-09-01

Mutations in various genes adversely affect locomotion in model organisms, and thus provide valuable clues about the complex processes that control movement. In Caenorhabditis elegans, loss-of-function mutations in the Na(+) leak current channel (NALCN) and associated proteins (UNC-79 and UNC-80) cause akinesia and fainting (abrupt freezing of movement during escape from touch). It is not known how defects in the NALCN induce these phenotypes or if they are chronic and irreversible. Here, we report that akinesia and freezing are state-dependent and reversible in NALCN-deficient mutants (nca-1;nca-2, unc-79 and unc-80) when additional cation channels substitute for this protein. Two main measures of locomotion were evaluated: spontaneous movement (traversal of >2 head lengths during a 5 second observation period) and the touch-freeze response (movement greater than three body bends in response to tail touch). Food deprivation for as little as 3 min stimulated spontaneous movement and corrected the touch-freeze response. Conversely, food-deprived animals that moved normally in the absence of bacteria rapidly reverted to uncoordinated movement when re-exposed to food. The effects of food deprivation were mimicked by nicotine, which suggested that acetylcholine mediated the response. Nicotine appeared to act on interneurons or motor neurons rather than directly at the neuromuscular junction because levamisole, which stimulates muscle contraction, did not correct movement. Neural circuits have been proposed to account for the effects of food deprivation and nicotine on spontaneous movement and freezing. The NALCN may play an unrecognized role in human movement disorders characterized by akinesia and freezing gait. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.

PubMed

Torres-Vega, Estefanía; Mancheño, Nuria; Cebrián-Silla, Arantxa; Herranz-Pérez, Vicente; Chumillas, María J; Moris, Germán; Joubert, Bastien; Honnorat, Jérôme; Sevilla, Teresa; Vílchez, Juan J; Dalmau, Josep; Graus, Francesc; García-Verdugo, José Manuel; Bataller, Luis

2017-03-28

To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications. Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers). Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma ( p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome ( p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus. Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis. This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%). © 2017 American Academy of Neurology.

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis

PubMed Central

Torres-Vega, Estefanía; Mancheño, Nuria; Cebrián-Silla, Arantxa; Herranz-Pérez, Vicente; Chumillas, María J.; Moris, Germán; Joubert, Bastien; Honnorat, Jérôme; Sevilla, Teresa; Vílchez, Juan J.; Dalmau, Josep; Graus, Francesc; García-Verdugo, José Manuel

2017-01-01

Objective: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications. Methods: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers). Results: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma (p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome (p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus. Conclusions: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis. Classification of evidence: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%). PMID:28251919

ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN

EPA Science Inventory

Zn2+ Induces COX-2 Expression through Downregulation of Lipid Phosphatase PTEN
Weidong Wu*, James M. Samet, Philip A. Bromberg*?, Young E. Whang?, and Lee M. Graves* ?
*CEMALB, ?Department of Medicine, and ?Department of Pharmacology, UNC-Chapel Hill, NC27599; Human Studie...

COMPARATIVE TOXICITY OF DIFFERENT EMISSION PARTICLES IN MURINE PULMONARY EPITHELIAL CELLS AND MACROPHAGES

EPA Science Inventory

Comparative Toxicity of Different Emission Particles in Murine Pulmonary Epithelial Cells and Macrophages. T Stevens1, M Daniels2, P Singh2, M I Gilmour2. 1 UNC, Chapel Hill 27599 2Experimental Toxicology Division, NHEERL, RTP, NC 27711

Epidemiological studies have shown ...

Transformational Leadership and Organizational Commitment: A Study of UNC System Business School Department Chairs

ERIC Educational Resources Information Center

Luton, Bill

2010-01-01

Ample evidence is available citing a positive relationship between transformational leadership and organizational commitment (Boerner et al., 2007; Bono & Judge, 2003; Bycio, Hackett, & Allen, 1995; Chen, 2004; Emery & Barker, 2007; Walumbwa, Orwa, Wang, & Lawler, 2005). The majority of research on leadership in higher education,…

LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans

PubMed Central

Li, Pengpeng; Collins, Kevin M; Koelle, Michael R; Shen, Kang

2013-01-01

The diverse cell types and the precise synaptic connectivity between them are the cardinal features of the nervous system. Little is known about how cell fate diversification is linked to synaptic target choices. Here we investigate how presynaptic neurons select one type of muscles, vm2, as a synaptic target and form synapses on its dendritic spine-like muscle arms. We found that the Notch-Delta pathway was required to distinguish target from non-target muscles. APX-1/Delta acts in surrounding cells including the non-target vm1 to activate LIN-12/Notch in the target vm2. LIN-12 functions cell-autonomously to up-regulate the expression of UNC-40/DCC and MADD-2 in vm2, which in turn function together to promote muscle arm formation and guidance. Ectopic expression of UNC-40/DCC in non-target vm1 muscle is sufficient to induce muscle arm extension from these cells. Therefore, the LIN-12/Notch signaling specifies target selection by selectively up-regulating guidance molecules and forming muscle arms in target cells. DOI: http://dx.doi.org/10.7554/eLife.00378.001 PMID:23539368

Huntingtin-interacting protein 1 influences worm and mouse presynaptic function and protects Caenorhabditis elegans neurons against mutant polyglutamine toxicity.

PubMed

Parker, J Alex; Metzler, Martina; Georgiou, John; Mage, Marilyne; Roder, John C; Rose, Ann M; Hayden, Michael R; Néri, Christian

2007-10-10

Huntingtin-interacting protein 1 (HIP1) was identified through its interaction with htt (huntingtin), the Huntington's disease (HD) protein. HIP1 is an endocytic protein that influences transport and function of AMPA and NMDA receptors in the brain. However, little is known about its contribution to neuronal dysfunction in HD. We report that the Caenorhabditis elegans HIP1 homolog hipr-1 modulates presynaptic activity and the abundance of synaptobrevin, a protein involved in synaptic vesicle fusion. Presynaptic function was also altered in hippocampal brain slices of HIP1-/- mice demonstrating delayed recovery from synaptic depression and a reduction in paired-pulse facilitation, a form of presynaptic plasticity. Interestingly, neuronal dysfunction in transgenic nematodes expressing mutant N-terminal huntingtin was specifically enhanced by hipr-1 loss of function. A similar effect was observed with several other mutant proteins that are expressed at the synapse and involved in endocytosis, such as unc-11/AP180, unc-26/synaptojanin, and unc-57/endophilin. Thus, HIP1 is involved in presynaptic nerve terminal activity and modulation of mutant polyglutamine-induced neuronal dysfunction. Moreover, synaptic proteins involved in endocytosis may protect neurons against amino acid homopolymer expansion.

Trio’s Rho-specific GEF domain is the missing Gαq effector in C. elegans

PubMed Central

Williams, Stacey L.; Lutz, Susanne; Charlie, Nicole K.; Vettel, Christiane; Ailion, Michael; Coco, Cassandra; Tesmer, John J.G.; Jorgensen, Erik M.; Wieland, Thomas; Miller, Kenneth G.

2007-01-01

The Gαq pathway is essential for animal life and is a central pathway for driving locomotion, egg laying, and growth in Caenorhabditis elegans, where it exerts its effects through EGL-8 (phospholipase Cβ [PLCβ]) and at least one other effector. To find the missing effector, we performed forward genetic screens to suppress the slow growth and hyperactive behaviors of mutants with an overactive Gαq pathway. Four suppressor mutations disrupted the Rho-specific guanine-nucleotide exchange factor (GEF) domain of UNC-73 (Trio). The mutations produce defects in neuronal function, but not neuronal development, that cause sluggish locomotion similar to animals lacking EGL-8 (PLCβ). Strains containing null mutations in both EGL-8 (PLCβ) and UNC-73 (Trio RhoGEF) have strong synthetic phenotypes that phenocopy the arrested growth and near-complete paralysis of Gαq-null mutants. Using cell-based and biochemical assays, we show that activated C. elegans Gαq synergizes with Trio RhoGEF to activate RhoA. Activated Gαq and Trio RhoGEF appear to be part of a signaling complex, because they coimmunoprecipitate when expressed together in cells. Our results show that Trio’s Rho-specific GEF domain is a major Gαq effector that, together with PLCβ, mediates the Gαq signaling that drives the locomotion, egg laying, and growth of the animal. PMID:17942708

Loss of syd-1 from R7 Neurons Disrupts Two Distinct Phases of Presynaptic Development

PubMed Central

Holbrook, Scott; Finley, Jennifer K.; Lyons, Eric L.

2012-01-01

Genetic analyses in both worm and fly have identified the RhoGAP-like protein Syd-1 as a key positive regulator of presynaptic assembly. In worm, loss of syd-1 can be fully rescued by overexpressing wild-type Liprin-α, suggesting that the primary function of Syd-1 in this process is to recruit Liprin-α. We show that loss of syd-1 from Drosophila R7 photoreceptors causes two morphological defects that occur at distinct developmental time points. First, syd-1 mutant R7 axons often fail to form terminal boutons in their normal M6 target layer. Later, those mutant axons that do contact M6 often project thin extensions beyond it. We find that the earlier defect coincides with a failure to localize synaptic vesicles, suggesting that it reflects a failure in presynaptic assembly. We then analyze the relationship between syd-1 and Liprin-α in R7s. We find that loss of Liprin-α causes a stronger early R7 defect and provide a possible explanation for this disparity: we show that Liprin-α promotes Kinesin-3/Unc-104/Imac-mediated axon transport independently of Syd-1 and that Kinesin-3/Unc-104/Imac is required for normal R7 bouton formation. Unlike loss of syd-1, loss of Liprin-α does not cause late R7 extensions. We show that overexpressing Liprin-α partly rescues the early but not the late syd-1 mutant R7 defect. We therefore conclude that the two defects are caused by distinct molecular mechanisms. We find that Trio overexpression rescues both syd-1 defects and that trio and syd-1 have similar loss- and gain-of-function phenotypes, suggesting that the primary function of Syd-1 in R7s may be to promote Trio activity. PMID:23238725

Painful Choices: Emerging Tensions between Universities and Their Publics.

ERIC Educational Resources Information Center

Frost, Susan H.; And Others

This paper investigates the use of enrollment limitations by "flagship" state universities in regard to out-of-state (OOS) students, presenting a case study of the enrollment limitation debate in the University of North Carolina system and its Chapel Hill (UNC-CH) campus over the last decade. The state legislature, in concert with the…

Benefits and challenges to using DNA-based identification methods: An example study of larval fish from nearshore areas of Lake Superior

EPA Science Inventory

DNA-based identification methods could increase the ability of aquatic resource managers to track patterns of invasive species, especially for taxa that are difficult to identify morphologically. Nonetheless, use of DNA-based identification methods in aquatic surveys is still unc...

Kepler's Third Law Without a Calculator

NASA Astrophysics Data System (ADS)

Ruiz, Michael J.

2004-12-01

At the University of North Carolina at Asheville (UNC-A) we have used Kepler's third law in a liberal-arts conceptual astronomy course to help students sharpen their quantitative skills without using a calculator. Doing quantitative physics without a calculator represents one of the many ways we can study the physical world. Furthermore, it is fun.

A History of Soil Science Education in the United States

NASA Astrophysics Data System (ADS)

Brevik, Eric C.

2017-04-01

The formal study of soil science is a fairly recent undertaking in academics. Fields like biology, chemistry, and physics date back hundreds of years, but the scientific study of soils only dates to the late 1800s. Academic programs to train students in soil science are even more recent, with the first such programs only developing in the USA in the early 1900s. Some of the first schools to offer soil science training at the university level included the University of North Carolina (UNC), Earlham College (EC), and Cornell University. The first modern soil science textbook published in the United States was "Soils, Their Properties and Management" by Littleton Lyon, Elmer Fippin and Harry Buckman in 1909. This has evolved over time into the popular modern textbook "The Nature and Properties of Soils", most recently authored by Raymond Weil and Nyle Brady. Over time soil science education moved away from liberal arts schools such as UNC and EC and became associated primarily with land grant universities in their colleges of agriculture. There are currently about 71 colleges and universities in the USA that offer bachelors level soil science degree programs, with 54 of these (76%) being land grant schools. In the 1990s through the early 2000s enrollment in USA soil science programs was on the decline, even as overall enrollment at USA colleges and universities increased. This caused considerable concern in the soil science community. More recently there is evidence that soil science student numbers may be increasing, although additional information on this potential trend is desirable. One challenge soil science faces in the modern USA is finding an academic home, as soils are taught by a wide range of fields and soils classes are taken by students in many fields of study, including soil science, a range of agricultural programs, environmental science, environmental health, engineering, geology, geography, and others.

Role of ANC-1 in tethering nuclei to the actin cytoskeleton.

PubMed

Starr, Daniel A; Han, Min

2002-10-11

Mutations in anc-1 (nuclear anchorage defective) disrupt the positioning of nuclei and mitochondria in Caenorhabditis elegans. ANC-1 is shown to consist of mostly coiled regions with a nuclear envelope localization domain (called the KASH domain) and an actin-binding domain; this structure was conserved with the Drosophila protein Msp-300 and the mammalian Syne proteins. Antibodies against ANC-1 localized cytoplasmically and were enriched at the nuclear periphery in an UNC-84-dependent manner. Overexpression of the KASH domain or the actin-binding domain caused a dominant negative anchorage defect. Thus, ANC-1 may connect nuclei to the cytoskeleton by interacting with UNC-84 at the nuclear envelope and with actin in the cytoplasm.

UNC-Utah NA-MIC framework for DTI fiber tract analysis.

PubMed

Verde, Audrey R; Budin, Francois; Berger, Jean-Baptiste; Gupta, Aditya; Farzinfar, Mahshid; Kaiser, Adrien; Ahn, Mihye; Johnson, Hans; Matsui, Joy; Hazlett, Heather C; Sharma, Anuja; Goodlett, Casey; Shi, Yundi; Gouttard, Sylvain; Vachet, Clement; Piven, Joseph; Zhu, Hongtu; Gerig, Guido; Styner, Martin

2014-01-01

Diffusion tensor imaging has become an important modality in the field of neuroimaging to capture changes in micro-organization and to assess white matter integrity or development. While there exists a number of tractography toolsets, these usually lack tools for preprocessing or to analyze diffusion properties along the fiber tracts. Currently, the field is in critical need of a coherent end-to-end toolset for performing an along-fiber tract analysis, accessible to non-technical neuroimaging researchers. The UNC-Utah NA-MIC DTI framework represents a coherent, open source, end-to-end toolset for atlas fiber tract based DTI analysis encompassing DICOM data conversion, quality control, atlas building, fiber tractography, fiber parameterization, and statistical analysis of diffusion properties. Most steps utilize graphical user interfaces (GUI) to simplify interaction and provide an extensive DTI analysis framework for non-technical researchers/investigators. We illustrate the use of our framework on a small sample, cross sectional neuroimaging study of eight healthy 1-year-old children from the Infant Brain Imaging Study (IBIS) Network. In this limited test study, we illustrate the power of our method by quantifying the diffusion properties at 1 year of age on the genu and splenium fiber tracts.

UNC-Utah NA-MIC framework for DTI fiber tract analysis

PubMed Central

Verde, Audrey R.; Budin, Francois; Berger, Jean-Baptiste; Gupta, Aditya; Farzinfar, Mahshid; Kaiser, Adrien; Ahn, Mihye; Johnson, Hans; Matsui, Joy; Hazlett, Heather C.; Sharma, Anuja; Goodlett, Casey; Shi, Yundi; Gouttard, Sylvain; Vachet, Clement; Piven, Joseph; Zhu, Hongtu; Gerig, Guido; Styner, Martin

2014-01-01

Diffusion tensor imaging has become an important modality in the field of neuroimaging to capture changes in micro-organization and to assess white matter integrity or development. While there exists a number of tractography toolsets, these usually lack tools for preprocessing or to analyze diffusion properties along the fiber tracts. Currently, the field is in critical need of a coherent end-to-end toolset for performing an along-fiber tract analysis, accessible to non-technical neuroimaging researchers. The UNC-Utah NA-MIC DTI framework represents a coherent, open source, end-to-end toolset for atlas fiber tract based DTI analysis encompassing DICOM data conversion, quality control, atlas building, fiber tractography, fiber parameterization, and statistical analysis of diffusion properties. Most steps utilize graphical user interfaces (GUI) to simplify interaction and provide an extensive DTI analysis framework for non-technical researchers/investigators. We illustrate the use of our framework on a small sample, cross sectional neuroimaging study of eight healthy 1-year-old children from the Infant Brain Imaging Study (IBIS) Network. In this limited test study, we illustrate the power of our method by quantifying the diffusion properties at 1 year of age on the genu and splenium fiber tracts. PMID:24409141

Effects of Inner Nuclear Membrane Proteins SUN1/UNC-84A and SUN2/UNC-84B on the Early Steps of HIV-1 Infection.

PubMed

Schaller, Torsten; Bulli, Lorenzo; Pollpeter, Darja; Betancor, Gilberto; Kutzner, Juliane; Apolonia, Luis; Herold, Nikolas; Burk, Robin; Malim, Michael H

2017-10-01

Human immunodeficiency virus type 1 (HIV-1) infection of dividing and nondividing cells involves regulatory interactions with the nuclear pore complex (NPC), followed by translocation to the nucleus and preferential integration into genomic areas in proximity to the inner nuclear membrane (INM). To identify host proteins that may contribute to these processes, we performed an overexpression screen of known membrane-associated NE proteins. We found that the integral transmembrane proteins SUN1/UNC84A and SUN2/UNC84B are potent or modest inhibitors of HIV-1 infection, respectively, and that suppression corresponds to defects in the accumulation of viral cDNA in the nucleus. While laboratory strains (HIV-1 NL4.3 and HIV-1 IIIB ) are sensitive to SUN1-mediated inhibition, the transmitted founder viruses RHPA and ZM247 are largely resistant. Using chimeric viruses, we identified the HIV-1 capsid (CA) protein as a major determinant of sensitivity to SUN1, and in vitro -assembled capsid-nucleocapsid (CANC) nanotubes captured SUN1 and SUN2 from cell lysates. Finally, we generated SUN1 -/- and SUN2 -/- cells by using CRISPR/Cas9 and found that the loss of SUN1 had no effect on HIV-1 infectivity, whereas the loss of SUN2 had a modest suppressive effect. Taken together, these observations suggest that SUN1 and SUN2 may function redundantly to modulate postentry, nuclear-associated steps of HIV-1 infection. IMPORTANCE HIV-1 causes more than 1 million deaths per year. The life cycle of HIV-1 has been studied extensively, yet important steps that occur between viral capsid release into the cytoplasm and the expression of viral genes remain elusive. We propose here that the INM components SUN1 and SUN2, two members of the linker of nucleoskeleton and cytoskeleton (LINC) complex, may interact with incoming HIV-1 replication complexes and affect key steps of infection. While overexpression of these proteins reduces HIV-1 infection, disruption of the individual SUN2 and SUN1 genes leads to a mild reduction or no effect on infectivity, respectively. We speculate that SUN1/SUN2 may function redundantly in early HIV-1 infection steps and therefore influence HIV-1 replication and pathogenesis. Copyright © 2017 Schaller et al.

Loss of unc45a precipitates arteriovenous shunting in the aortic arches

PubMed Central

Anderson, Matthew J.; Pham, Van N.; Vogel, Andreas M.; Weinstein, Brant M.; Roman, Beth L.

2008-01-01

Aortic arch malformations are common congenital disorders that are frequently of unknown etiology. To gain insight into the factors that guide branchial aortic arch development, we examined the process by which these vessels assemble in wild type zebrafish embryos and in kurzschlusstr12 (kus tr12) mutants. In wild type embryos, each branchial aortic arch first appears as an island of angioblasts in the lateral pharyngeal mesoderm, then elaborates by angiogenesis to connect to the lateral dorsal aorta and ventral aorta. In kustr12 mutants, angioblast formation and initial sprouting are normal, but aortic arches 5 and 6 fail to form a lumenized connection to the lateral dorsal aorta. Blood enters these blind-ending vessels from the ventral aorta, distending the arteries and precipitating fusion with an adjacent vein. This arteriovenous malformation (AVM), which shunts nearly all blood directly back to the heart, is not genetically programmed, as its formation correlates with blood flow and aortic arch enlargement. By positional cloning, we have identified a nonsense mutation in unc45a in kustr12 mutants. Our results are the first to ascribe a role for Unc45a, a putative myosin chaperone, in vertebrate development, and identify a novel mechanism by which an AVM can form. PMID:18462713

A powerful and flexible approach to the analysis of RNA sequence count data.

PubMed

Zhou, Yi-Hui; Xia, Kai; Wright, Fred A

2011-10-01

A number of penalization and shrinkage approaches have been proposed for the analysis of microarray gene expression data. Similar techniques are now routinely applied to RNA sequence transcriptional count data, although the value of such shrinkage has not been conclusively established. If penalization is desired, the explicit modeling of mean-variance relationships provides a flexible testing regimen that 'borrows' information across genes, while easily incorporating design effects and additional covariates. We describe BBSeq, which incorporates two approaches: (i) a simple beta-binomial generalized linear model, which has not been extensively tested for RNA-Seq data and (ii) an extension of an expression mean-variance modeling approach to RNA-Seq data, involving modeling of the overdispersion as a function of the mean. Our approaches are flexible, allowing for general handling of discrete experimental factors and continuous covariates. We report comparisons with other alternate methods to handle RNA-Seq data. Although penalized methods have advantages for very small sample sizes, the beta-binomial generalized linear model, combined with simple outlier detection and testing approaches, appears to have favorable characteristics in power and flexibility. An R package containing examples and sample datasets is available at http://www.bios.unc.edu/research/genomic_software/BBSeq yzhou@bios.unc.edu; fwright@bios.unc.edu Supplementary data are available at Bioinformatics online.

Minnesota Innovation Research Program.

DTIC Science & Technology

1986-03-01

Petroleum, Magnetic Controls, Farm Credit Services Corporations, Bush Foundation, and Hospital Corporation of America . .. Unc lassifijed RUNOT...Paper #47 (March, 1986). 7. David Bastien, " Sociolinguistic Studies of Mergers and Acquisitions," to be presented at the Minnesota Conference on...Applied Sociolinguistics , 1986. 8. David Bastien and Andrew Van de Ven, "Managerial and Organizational Dynamics of Mergers and Acquisitions," SNRC

Family Day Care: Some Observations.

ERIC Educational Resources Information Center

Saunders, Minta M.; Keister, Mary Elizabeth

A study comparing family and group day care was conducted. Data were collected over a two-year period on 12 children in a Greensboro, N. C., family day care program and 10 children in the UNC-G Demonstration Center for Infant-Toddler Care, a group day care center. Results, which disproved many assumptions cited as advantages of family day care,…

Malfunction Investigation of the XM935 Point Detonating Fuze

DTIC Science & Technology

1977-04-01

1 PSK* UNCHANGED FUMLY AR! 2 PSM UNCHANGED FULLY ARMED 3 OK PS4 UNCHANGD 4 CK P24 UNC DNGED 5 PSK (more than S.Q. Det Edge Visible FuLLY AP1M other...Continued) F= NO. DRC NO. 1 2 3 4 5 6 7 8 9 10 3 PSK UNCH UNCH UNCE SEE SQ UNCH UNCH UNCH UNCH UN1H 4 PS4 UNCH SKH E SQ UNCH tNCH UNCH UNCH U2 L!CH...EDGE 5 PS UNCH tCH SE SQ UNCH MMH UNCH UNCH UWCH WECH 6 P4M UNCH UNCH Q SEE SQ EDGE 7 PSK UNCH UNCH SEE SO WXC EDGE a P UNCP L4 UNCH SC E SQ 9 PS4 UNCX

Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis type 3

PubMed Central

Sieni, Elena; Cetica, Valentina; Santoro, Alessandra; Beutel, Karin; Mastrodicasa, Elena; Meeths, Marie; Ciambotti, Benedetta; Brugnolo, Francesca; zur Stadt, Udo; Pende, Daniela; Moretta, Lorenzo; Griffiths, Gillian M; Henter, Jan-Inge; Janka, Gritta; Aricò, Maurizio

2014-01-01

Background Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898). Objective To carry out a genotype–phenotype study of patients with FHL3. Methods A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database. Results 84 patients with FHL3 (median age 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=12). Their ethnic origin was Caucasian (n=57), Turkish (n=10), Asian (n=7), Hispanic (n=4), African (n=3) (not reported (n=3)). Thrombocytopenia was present in 94%, splenomegaly in 96%, fever in 89%. The central nervous system (CNS) was involved in 49/81 (60%) patients versus 36% in patients with FHL2 (p=0.001). A combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia was present in 71%. CD107a expression, NK activity and Munc 13-4 protein expression were absent or reduced in all but one of the evaluated patients. 54 different mutations were observed, including 15 new ones: 19 missense, 14 deletions or insertions, 12 nonsense, nine splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p<0.001), but older than comparable patients with FHL2 (p=0.001). Conclusion UNC13D mutations are scattered over the gene. Ethnic-specific mutations were not identified. CNS involvement is more common than in FHL2; in patients with FHL3 and disruptive mutations, age at diagnosis is significantly higher than in FHL2. The combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia appears to be the most easily and frequently recognised clinical pattern and their association with defective granule release assay may herald FHL3. PMID:21248318

[Validation of food security and social support scales in an Afro-Colombian community: application on a prevalence study of nutritional status in children aged 6 to 18 months].

PubMed

Alvarado, Beatriz Eugenia; Zunzunegui, María Victoria; Delisle, Helene

2005-01-01

We conducted a cross-sectional study on 193 mothers of children 6 to 18 months of age in an African-Colombian community, with the objectives: (1) to adapt and validate the Community Childhood Hunger Identification Project scale, the DUKE-UNC-11 social support scale, and the Quebec Longitudinal Study of Child Development (QLSCD) partner support scale, and (2) to identify any existent relationship between nutritional status in infancy and both food insecurity and social support. We determined construct validity using factor analysis and theoretical models-based non-parametric correlations. Length-for-age and weight-for-length Z-results were calculated. Factor analyses reduced the hunger scale to one factor, the DUKE-UNC-11 scale to two factors, and the QLSCD scale to one factor. The Cronbach's alpha test ranged between 0.70 and 0.90. Both food insecurity and social support scales were correlated with mother's social conditions, and social support was positively associated with social networks and mother's self-perceived health status. Food insecurity, emotional-social support, and partner's negative support were associated with lower height-to-age and therefore a higher ratio of chronic malnutrition. The study supports the appropriateness of the instruments to measure the expressed concepts.

Postconstruction report of the United Nuclear Corporation Disposal Site at the Oak Ridge Y-12 Plant, Oak Ridge, Tennessee. Environmental Restoration Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oakley, L.B.; Siberell, J.K.; Voskuil, T.L.

1993-06-01

Remedial actions conducted under the auspices of the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) were completed at the Y-12 United Nuclear Corporation (UNC) Disposal Site in August 1992. The purpose of this Postconstruction Report is to summarize numerous technical reports and provide CERCLA documentation for completion of the remedial actions. Other CERCLA reports, such as the Feasibility Study for the UNC Disposal Site, provide documentation leading up to the remedial action decision. The remedial action chosen, placement of a modified RCRA cap, was completed successfully, and performance standards were either met or exceeded. This remedial action provided solutionsmore » to two environmentally contaminated areas and achieved the goal of minimizing the potential for contamination of the shallow groundwater downgradient of the site, thereby providing protection of human health and the environment. Surveillance and maintenance of the cap will be accomplished to ensure cap integrity, and groundwater monitoring downgradient of the site will continue to confirm the acceptability of the remedial action chosen.« less

A powerful and flexible approach to the analysis of RNA sequence count data

PubMed Central

Zhou, Yi-Hui; Xia, Kai; Wright, Fred A.

2011-01-01

Motivation: A number of penalization and shrinkage approaches have been proposed for the analysis of microarray gene expression data. Similar techniques are now routinely applied to RNA sequence transcriptional count data, although the value of such shrinkage has not been conclusively established. If penalization is desired, the explicit modeling of mean–variance relationships provides a flexible testing regimen that ‘borrows’ information across genes, while easily incorporating design effects and additional covariates. Results: We describe BBSeq, which incorporates two approaches: (i) a simple beta-binomial generalized linear model, which has not been extensively tested for RNA-Seq data and (ii) an extension of an expression mean–variance modeling approach to RNA-Seq data, involving modeling of the overdispersion as a function of the mean. Our approaches are flexible, allowing for general handling of discrete experimental factors and continuous covariates. We report comparisons with other alternate methods to handle RNA-Seq data. Although penalized methods have advantages for very small sample sizes, the beta-binomial generalized linear model, combined with simple outlier detection and testing approaches, appears to have favorable characteristics in power and flexibility. Availability: An R package containing examples and sample datasets is available at http://www.bios.unc.edu/research/genomic_software/BBSeq Contact: yzhou@bios.unc.edu; fwright@bios.unc.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:21810900

Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome.

PubMed

Siegel, Dawn H; Ashton, Gabrielle H S; Penagos, Homero G; Lee, James V; Feiler, Heidi S; Wilhelmsen, Kirk C; South, Andrew P; Smith, Frances J D; Prescott, Alan R; Wessagowit, Vesarat; Oyama, Noritaka; Akiyama, Masashi; Al Aboud, Daifullah; Al Aboud, Khalid; Al Githami, Ahmad; Al Hawsawi, Khalid; Al Ismaily, Abla; Al-Suwaid, Raouf; Atherton, David J; Caputo, Ruggero; Fine, Jo-David; Frieden, Ilona J; Fuchs, Elaine; Haber, Richard M; Harada, Takashi; Kitajima, Yasuo; Mallory, Susan B; Ogawa, Hideoki; Sahin, Sedef; Shimizu, Hiroshi; Suga, Yasushi; Tadini, Gianluca; Tsuchiya, Kikuo; Wiebe, Colin B; Wojnarowska, Fenella; Zaghloul, Adel B; Hamada, Takahiro; Mallipeddi, Rajeev; Eady, Robin A J; McLean, W H Irwin; McGrath, John A; Epstein, Ervin H

2003-07-01

Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed "KIND1" [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

Computer-Mediated Communication: Decisionmaking and Informal Interaction.

DTIC Science & Technology

1985-02-15

the context of a project called the Computer-Administered Panel Study L (CAPS). Respondents in the project were 96 UNC undergraduate students . The...project consisted of the administration of over 100 questionnaires and experimental units to this panel of undergraduates who reported to weekly sessions...humanely (eg., are more likely to ignore or insult) via the more distant media. Audio-only communications are more likely to be depersonalized

Center-Based Child Care in the Pioneer Smart Start Partnerships of North Carolina. UNC Smart Start Evaluation Report.

ERIC Educational Resources Information Center

Maxwell, Kelly; Bryant, Donna; Peisner-Feinberg, Ellen; Buysse, Virginia

Smart Start is North Carolina's partnership between state government and local leaders, service providers, and families to better serve children under 6 years and their families to ensure that all children enter school healthy and prepared to succeed. This study acquired a baseline measure of the quality of child care in the 12 pioneer Smart Start…

Effectiveness of Standardized Nursing Care Plans in Health Outcomes in Patients with Type 2 Diabetes Mellitus: A Two-Year Prospective Follow-Up Study

PubMed Central

Cárdenas-Valladolid, Juan; Salinero-Fort, Miguel A.; Gómez-Campelo, Paloma; de Burgos-Lunar, Carmen; Abánades-Herranz, Juan C.; Arnal-Selfa, Rosa; Andrés, Ana López-

2012-01-01

Background Implementation of a standardized language in Nursing Care Plans (SNCP) allows for increased efficiency in nursing data management. However, the potential relationship with patientś health outcomes remains uncertain. The aim of this study was to evaluate the effectiveness of SNCP implementation, based on North American Nursing Diagnosis Association (NANDA) and Nursing Interventions Classification (NIC), in the improvement of metabolic, weight, and blood pressure control of Type 2 Diabetes Mellitus (T2DM) patients. Methods A two-year prospective follow-up study, in routine clinical practice conditions. 31 primary health care centers (Spain) participated with 24,124 T2DM outpatients. Data was collected from Computerized Clinical Records; SNCP were identified using NANDA and NIC taxonomies. Descriptive and ANCOVA analyses were conducted. Results 18,320 patients were identified in the Usual Nursing Care (UNC) group and 5,168 in the SNCP group. At the two-year follow-up, the SNCP group improved all parameters except LDL cholesterol and diastolic blood pressure. We analyzed data adjustming by the baseline value for these variables and variables with statistically significant differences between groups at baseline visit. Results indicated a lowering of all parameters except HbA1c, but a statistically significant reduction was only observed with diastolic blood pressure results. However, the adjusted reduction of diastolic blood pressure is of little clinical relevance. Greater differences of control values for diastolic blood pressure, HbA1c, LDL-cholesterol and Body Mass Index were found in the SNCP group, but only reached statistical significance for HbA1c. A greater proportion of patients with baseline HbA1c ≥7 decreased to <7% at the two-year follow-up in the SNCP group than in the UNC group (16.9% vs. 15%; respectively; p = 0.01). Conclusions Utilization of SNCP was helpful in achieving glycemic control targets in poorly controlled patients with T2DM (HbA1c ≥7%). Diastolic blood pressure results were slightly improved in the SNCP group compared to the UNC group. Trial Registration ClinicalTrials.gov NCT01482481 PMID:22952794

Effectiveness of standardized Nursing Care Plans in health outcomes in patients with type 2 Diabetes Mellitus: a two-year prospective follow-up study.

PubMed

Cárdenas-Valladolid, Juan; Salinero-Fort, Miguel A; Gómez-Campelo, Paloma; de Burgos-Lunar, Carmen; Abánades-Herranz, Juan C; Arnal-Selfa, Rosa; Andrés, Ana López-

2012-01-01

Implementation of a standardized language in Nursing Care Plans (SNCP) allows for increased efficiency in nursing data management. However, the potential relationship with patientś health outcomes remains uncertain. The aim of this study was to evaluate the effectiveness of SNCP implementation, based on North American Nursing Diagnosis Association (NANDA) and Nursing Interventions Classification (NIC), in the improvement of metabolic, weight, and blood pressure control of Type 2 Diabetes Mellitus (T2DM) patients. A two-year prospective follow-up study, in routine clinical practice conditions. 31 primary health care centers (Spain) participated with 24,124 T2DM outpatients. Data was collected from Computerized Clinical Records; SNCP were identified using NANDA and NIC taxonomies. Descriptive and ANCOVA analyses were conducted. 18,320 patients were identified in the Usual Nursing Care (UNC) group and 5,168 in the SNCP group. At the two-year follow-up, the SNCP group improved all parameters except LDL cholesterol and diastolic blood pressure. We analyzed data adjustming by the baseline value for these variables and variables with statistically significant differences between groups at baseline visit. Results indicated a lowering of all parameters except HbA1c, but a statistically significant reduction was only observed with diastolic blood pressure results. However, the adjusted reduction of diastolic blood pressure is of little clinical relevance. Greater differences of control values for diastolic blood pressure, HbA1c, LDL-cholesterol and Body Mass Index were found in the SNCP group, but only reached statistical significance for HbA1c. A greater proportion of patients with baseline HbA1c ≥7 decreased to <7% at the two-year follow-up in the SNCP group than in the UNC group (16.9% vs. 15%; respectively; p = 0.01). Utilization of SNCP was helpful in achieving glycemic control targets in poorly controlled patients with T2DM (HbA1c ≥7%). Diastolic blood pressure results were slightly improved in the SNCP group compared to the UNC group. ClinicalTrials.gov NCT01482481.

Hospitalist management of vaso-occlusive pain crisis in patients with sickle cell disease using a pathway of care.

PubMed

Allen Liles, Edmund; Kirsch, Jonathan; Gilchrist, Michael; Adem, Mukhtar

2014-04-01

Patients with sickle cell disease (SCD) suffer from intermittent vaso-occlusive pain crises (VOCs). These crises lead to frequent hospitalizations, significant morbidity, and increased mortality risk. Care pathways can enhance efficiency and quality of care. Our study sought to evaluate the development and implementation of a care pathway for patients with SCD experiencing VOCs. The University of North Carolina (UNC) Comprehensive Sickle Cell Program provides all levels of care for a large population of patients with sickle cell anemia. All patients admitted to UNC Hospitals with SCD VOCs from January 2009 through June 2011 were evaluated. During this time period, we also assessed sequential prospective cohorts during progressive phases of developing and implementing a quality improvement and pathway of care program for this patient population in our study. The developed pathway entailed geographic localization for VOC patients, a single group of faculty physicians caring for these patients, and early use of patient-controlled analgesia (PCA) to achieve pain control. Physicians from the UNC Hospital Medicine Program were responsible for the initiatives. Cohorts were compared to a baseline historical control. Outcomes of interest included patient length of stay (LOS) in the hospital, 30-day readmission rate, need for transfusion, incidence of acute chest syndrome, use of naloxone, and use of PCA. Compared with an historical baseline cohort, the development and implementation of a VOC care pathway for patients with SCD led to reduction in average hospital LOS by 1.44 days (P < 0.05) and an increase in use of PCAs (P < 0.05). Patient readmission rates, number of transfusions, incidence of acute chest syndrome, and use of naloxone did not significantly change. Hospitalist-led management of patients with SCD VOCs using a care pathway that emphasizes early, aggressive PCA-based pain control is associated with reduced hospital LOS. The LOS reduction seen in our study is clinically meaningful. Notably, other measures of patient outcomes and quality of care metrics did not change significantly, and some trended towards improvement.

Relationship between brain volumetric changes and interim drinking at six months in alcohol-dependent patients.

PubMed

Segobin, Shailendra H; Chételat, Gaël; Le Berre, Anne-Pascale; Lannuzel, Coralie; Boudehent, Céline; Vabret, François; Eustache, Francis; Beaunieux, Hélène; Pitel, Anne-Lise

2014-03-01

Chronic alcohol consumption results in brain damage potentially reversible with abstinence. It is however difficult to gauge the degree of recovery of brain tissues with abstinence since changes are subtle and a significant portion of patients relapse. State-of-the-art morphometric methods are increasingly used in neuroimaging studies to detect subtle brain changes at a voxel level. Our aim was to use the most refined morphometric methods to observe in alcohol dependence the relationship between volumetric changes and interim drinking over a 6-month follow-up. Overall, 19 patients with alcohol dependence received volumetric T1-weighted magnetic resonance imaging (MRI) after detoxification. A 6-month follow-up study was then conducted, during which 11 of them received a second MRI scan. First, correlations were conducted between gray matter (GM) and white matter (WM) volumes of patients at alcohol treatment entry and the amount of alcohol consumed between treatment entry and follow-up. Second, longitudinal analyses were performed from pairs of MRI scans using tensor-based morphometry in the 11 patients, and correlations were computed between the resultant Jacobian maps of GM and WM and interim drinking. Our preliminary results showed that, among others, alcoholics with smaller thalamus at alcohol treatment entry tended to resume with heavy alcohol consumption (p < 0.005 uncorrected [unc.]). Our longitudinal study revealed an overall inverse relationship between recovery of brain structures like the cerebellum, striatum, and cingulate gyrus, and the amount of alcohol consumed over the 6-month follow-up (p < 0.005 unc.). The recovery could be observed not only with strict abstinence but also in cases of moderate resumption of alcohol consumption, when there had been no drastic relapse into alcohol dependence. Those preliminary findings indicate that the volume of the thalamus at treatment entry may have an influence on subsequent interim drinking. There is recovery of certain brain regions even when patients resume with moderate, but not drastic, alcohol consumption. Copyright © 2014 by the Research Society on Alcoholism.

The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.

PubMed

Zhang, Feifan; Bhattacharya, Abhishek; Nelson, Jessica C; Abe, Namiko; Gordon, Patricia; Lloret-Fernandez, Carla; Maicas, Miren; Flames, Nuria; Mann, Richard S; Colón-Ramos, Daniel A; Hobert, Oliver

2014-01-01

Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

The University of North Carolina Medical Center pharmacy resident leadership certificate program.

PubMed

Lyons, Kayley; Griggs, Danielle; Lebovic, Rachel; Roth, Mary E; South, David A; Hatfield, Chad

2017-03-15

The development and implementation of a certificate program for pharmacy residents are described. University of North Carolina (UNC) Medical Center met the call for increased efforts in the area of pharmacy residency leadership training through the design, implementation, and evaluation of a leadership certificate program. The purpose of the UNC certificate program is to develop leaders who will serve others, improve their communities, and advance the profession. The program is designed to (1) foster self-awareness, social awareness, and altruism, (2) provide transferable and individualized leadership experiences, (3) enrich other residency components through integration of leadership development opportunities, and (4) create role models for departmental leadership. A team of preceptors and residents implemented the certificate program by integrating program components into the existing pharmacy residency infrastructure. The certificate program includes required and flexible components to allow residents to set and achieve their determined leadership development goals. Overall, residents are satisfied with the program and perceive it as worthwhile. During the first 3 years since implementation of the certification initiative, program facilitators improved the feasibility of, participant engagement in, and sustainability of the program. Future directions include an effectiveness evaluation and a "scale-up" to other institutions. The need for a pharmacy residency leadership certificate was met by designing, implementing, and evaluating such a program at UNC. Through its first 3 years, the program was feasible, sustainable, and valued by program participants. Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Synergistic defects of novo FAS and homozygous UNC13D leading to autoimmune lymphoproliferative syndrome-like disease: A 10-year-old Chinese boy case report.

PubMed

Gu, Hao; Ma, Jie; Chen, Zhenping; Wang, Jing; Zhang, Rui; Wu, Runhui

2018-06-01

Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly and lymphadenopathy along with hemocytopenia. This case report describes a 10-year-old boy presenting with signs of autoimmune disease, splenomegaly, hepatomegaly and resistant hemocytopenia. Sirolimus controlled the relapsed thrombocytopenia after splenectomy. Sequencing of the FAS gene identified two spontaneous heterozygous mutations (c.234 T > G, p.D78E) (c.236dupA, p.P80Tfs*26). The boy's homozygous missense variation (c.2588G > A, p.G863D) (rs140184929) in UNC13D gene had been identified as being related to familial hemophagocytic lymphohistiocytosis (FHL). TCRαβ + CD4/CD8 double-negative T cells (markers of ALPS) were not significantly increased from the outset. Elevated cytokines, such as interferon (IFN)-γ, interleukin (IL)-6 and tumor necrosis factor α decreased to normal levels after splenectomy whereas IL-10 remained high. Immunological analysis of the patient revealed a marked depletion of forkhead-box P3 + expressing regulatory T cells (Treg) and Th17 cells. The obtained data demonstrate that mutations to FAS and UNC13D which result in overwhelming T-cell and macrophage activation, one associated with inhibited Treg cell development and a severe ALPS-like symptom. Therefore, we propose that variations of UND13D may be a risk factor of ALPS development. Copyright © 2017. Published by Elsevier B.V.

Renal function and urine drainage after conservative or operative treatment of primary (obstructive) megaureter in infants and children.

PubMed

Tröbs, R-B; Heinecke, K; Elouahidi, T; Nounla, J; Kluge, R

2006-01-01

We examined renal function and urinary drainage of children with primary megaureter (PMU) in dependence on conservative or operative treatment. The retrospective analysis covering the years 1994 to 2000 comprised children at an age of 0-7 years with 35 PMU. Sonography, dynamic MAG3 renography as well as endogenic creatinine clearance (GFR) were used to assess drainage and the renal function. Temporary urinary diversion was established in fourteen patients of both groups. In 14 children with 16 PMU a ureteroneocystostomy (UNC) was performed. The average observation period was 30 months (11-108). The children of the UNC group differed from the non-neoimplanted group in the age at diagnosis (10.5 vs. < 1 months), higher degrees of hydronephrosis on average, a more distinct dilatation of the ureter as well as renographically significant obstruction. Children of the non-UNC group, including four children with a type B drainage curve (O'Reilly), had an unimpaired differential renal function or improved during the observation period (initially 51% vs. 50.5% at the end). In neoimplantation group the differential function improved from 32.5% to 38.5% (p < 0.05) and obstruction resolved with one exception. Given a higher-grade PMU with a reduced function of the kidneys and a significant impaired drainage pattern and/or symptoms, neoimplantation without temporary diversion has proved to be an efficient renoprotective method. Furthermore, data clearly justify a conservative approach without urinary diversion in infants with large asymptomatic PMU.

Bringing the Community into the Process: Issues and Promising Practices for Involving Parents & Business in Local Smart Start Partnerships. UNC Smart Start Evaluation Report.

ERIC Educational Resources Information Center

Cornish, Mary; Noblit, George

Smart Start is North Carolina's partnership between state government and local leaders, service providers, and families to better serve children under age 6 and their families. The aim of the program is ensuring that all children enter school healthy and ready to learn. This study examined parent and business involvement in local Smart Start…

Trends and Characteristics of Pediatric Dentistry Patients Treated under General Anesthesia.

PubMed

Rudie, Maxwell N; Milano, Michael M; Roberts, Michael W; Divaris, Kimon

2018-05-11

The aims of this study were to describe the demographic characteristics of pediatric dentistry patients undergoing dental rehabilitation under general anesthesia (DRGA) at UNC-Chapel Hill during the last 13 years and identify factors associated with multiple (1 versus 2 or more) DRGA visits during that timeframe. Administrative claims data were used to identify children and adolescents (age <18 years) who underwent DRGA between 1/1/2002 and 12/31/2014 at the UNC Hospitals system. Information on children's age, sex and all treatment-associated CDT codes were collected. Descriptive statistics and bivariate tests of association were used for data analyses. There were 4,413 DRGAs among 3,973 children (median age=4 years 8 months, males=55%) during the study period. The annual rate of DRGAs increased over time, peaking (n=447) in 2013. Overall, 9% of children had ≥2 visits with repeat rates up to 18%. There was no association between children's sex and receipt of one versus multiple DRGAs; however, craniofacial cases were more likely (p<0.0005) to have multiple DRGAs compared to non-craniofacial ones. DRGAs are on the increase-with the exception of craniofacial and special health care needs patients, multiple DRGAs may be reflective of sub-optimal adherence to preventive and continuing care recommendations.

Fostering Under-represented Minority Student Success and Interest in the Geosciences: Outcomes of the UNC-Chapel Hill Increasing Diversity and Enhancing Academia (IDEA) Program

NASA Astrophysics Data System (ADS)

Hughes, M. H.; Gray, K.; Drostin, M.

2016-12-01

For under-represented minority (URM) students, opportunities to meaningfully participate in academic communities and develop supportive relationships with faculty and peers influence persistence in STEM majors (Figueroa, Hurtado, & Wilkins, 2015; PCAST, 2012; Tsui, 2007). Creating such opportunities is even more important in the geosciences, where a lower percentage of post-secondary degrees are awarded to URM students than in other STEM fields (NSF, 2015; O'Connell & Holmes, 2011; NSF, 2011). Since 2011, Increasing Diversity and Enhancing Academia (IDEA), a program of the UNC-Chapel Hill Institute for the Environment (UNC-IE), has provided 39 undergraduates (predominantly URM and female students) with career-relevant research experiences and professional development opportunities, including a culminating experience of presenting their research at a campus-wide research symposium. External evaluation data have helped to characterize the effectiveness of the IDEA program. These data included pre- and post-surveys assessing students' interest in geosciences, knowledge of career pathways, and perceptions of their abilities related to a specific set of scientific research skills. Additionally, progress towards degrees and dissemination outcomes were tracked. In this presentation, we will share quantitative and qualitative data that demonstrate that participation in the IDEA program has influenced students' interest and persistence in geosciences research and careers. These data range from self-reported competencies in a variety of scientific skills (such as organizing and interpreting data and reading and interpreting science literature) to documentation of student participation in geoscience study and professions. About 69% of participants continued research begun during their internships beyond the internship; and about 38% pursued graduate degrees and secured jobs in geoscience and other STEM fields. (Nearly half are still in school.) Overall, these evaluation data have shown that the IDEA research experience, combined with program elements focused on professional development, reinforces students' sense of their science abilities, connects them to a network of supportive students and professionals and contributes to their sense of belonging within the geosciences.

Absence of in vitro Procoagulant Activity in Immunoglobulin Preparations due to Activated Coagulation Factors

PubMed Central

Oviedo, Adriana E.; Bernardi, María E.; Guglielmone, Hugo A.; Vitali, María S.

2015-01-01

Summary Background Immunoglobulin (IG) products, including intravenous (IVIG) or subcutaneous (SCIG) immunoglobulins are considered safe and effective for medical therapy; however, a sudden and unexpected increase in thromboembolic events (TE) after administration of certain batches of IVIG products has been attributed to the presence of activated coagulation factors, mainly factor XIa. Our aims were to examine the presence of enduring procoagulant activity during the manufacturing process of IGs, with special focus on monitoring factor XIa, and to evaluate the presence of in vitro procoagulant activity attributed to coagulation factors in different lots of IVIG and SCIG. Methods Samples of different steps of IG purification, 19 lots of IVIG and 9 of SCIG were analyzed and compared with 1 commercial preparation of IVIG and 2 of SCIG, respectively. Factors II, VII, IX, XI and XIa and non-activated partial thromboplastin time (NAPTT) were assayed. Results The levels of factors II, VII, IX, X and XI were non-quantifiable once fraction II had been re-dissolved and in all analyzed lots of IVIG and SCIG. The level of factor XIa at that point was under the detection limits of the assay, and NAPTT yielded values greater than the control during the purification process. In SCIG, we detected higher concentrations of factor XIa in the commercial products, which reached values up to 5 times higher than the average amounts found in the 9 batches produced by UNC-Hemoderivados. Factor XIa in commercial IVIG reached levels slightly higher than those of the 19 batches produced by UNC-Hemoderivados. Conclusion IVIG and SCIG manufactured by UNC-Hemoderivados showed a lack of thrombogenic potential, as demonstrated not only by the laboratory data obtained in this study but also by the absence of any reports of TE registered by the post marketing pharmacovigilance department. PMID:26733772

Perspective: “The Financial Impact of Alternative Water Project Delivery Models” in the Water Sector

EPA Pesticide Factsheets

The Water Finance Center developed this companion perspective document to a UNC EFC report on Alternative Water Project Delivery Models to broaden understanding of this alternative procurement method.

Technology Modernization for DoD Subcontractors: A Study of Market, Business, Financial, and Capital Investment Factors.

DTIC Science & Technology

1983-09-01

contractors requiring the product( s ) offered by the respondent first-tier subcontractor. 3. Knowledge of competition (ordinal)--the amount of market ...Question Interview Schedule Number Factor Question Number( s ) market environment 1, 2, - 4, 5, 7, 8, 9 perceived market environment 6 DOD business 16, 17...ADA T432 ECHNOLO MODERNIZATION FOR DOD SUBCONTRACTORS: A I STUDY 0F MARKET BUSINE..U AIR FORCE INS OF TECH WRIGHT-PATTERS AFB OH SCHOOLOD SS UNC ASS

Cultural Resources, Studies, Eastern North Carolina Above Cape Lookout, Literature Review and Preliminary Research Design.

DTIC Science & Technology

1986-05-01

Survey and Evaluation of the Harrelsville 201 Facilities Site. Ms. on file, Research Laboratories of Anthropology, UNC-Chapel Hill. Stone, Garry ...prepared by Ms. Beth P. Thomas, Ms. Drucilla H. Ycrk, Ms. Bartara W. Howlett, and Ms. Renee Gledhill-Earley, all on the staff of the Archeology and...Outer Banks in the Eastern North Carolina Study Area (after Stick 1952) 4-19 4-7 Distribution of Research Reports on File at the Archeology Branch of

Neural Markers and Rehabilitation of Executive Functioning in Veterans with TBI and PTSD

DTIC Science & Technology

2015-10-01

functioning. Functional magnetic resonance imaging ( fMRI ) will be used to evaluate changes in cortical function in frontostriate and frontoparietal circuits...EEG and fMRI will be conducted and then transport Veterans back to our laboratory. We will assure transportation is running efficiently and without...delays before study commencement.  Transportation to the EEG and fMRI was arranged through the UNC-Chapel Hill School of Medicine at month 9

Building a bioinformatics community of practice through library education programs.

PubMed

Moore, Margaret E; Vaughan, K T L; Hayes, Barrie E

2004-01-01

This paper addresses the following questions:What makes the community of practice concept an intriguing framework for developing library services for bioinformatics? What is the campus context and setting? What has been the Health Sciences Library's role in bioinformatics at the University of North Carolina (UNC) Chapel Hill? What are the Health Sciences Library's goals? What services are currently offered? How will these services be evaluated and developed? How can libraries demonstrate their value? Providing library services for an emerging community such as bioinformatics and computational biology presents special challenges for libraries including understanding needs, defining and communicating the library's role, building relationships within the community, preparing staff, and securing funding. Like many academic health sciences libraries, the University of North Carolina (UNC) at Chapel Hill Health Sciences Library is addressing these challenges in the context of its overall mission and goals.

Radiation effects in nematodes: Results from IML-1 experiments

NASA Technical Reports Server (NTRS)

Nelson, G. A.; Schubert, W. W.; Kazarians, G. A.; Richards, G. F.; Benton, E. V.; Benton, E. R.; Henke, R.

1994-01-01

The nematode Caenorhabditis elegans was exposed to natural space radiation using the ESA biorack facility aboard Spacelab on International Microgravity Laboratory 1, STS-42. For the major experimental objective dormant animals were suspended in buffer or on agar or immobilized next to CR-39 plastic nuclear track detectors to correlate fluence of HZE particles with genetic events. This configuration was used to isolate mutations in a set of 350 essential genes as well as in the unc-22 structural gene. From flight samples 13 mutants in the unc-22 gene were isolated along with 53 lethal mutations from autosomal regions balanced by a translocation eT1(III;V). Preliminary analysis suggests that mutants from worms correlated with specific cosmic ray tracks may have a higher proportion of rearrangements than those isolated from tube cultures on a randomly sampled basis. Flight sample mutation rate was approximately 8-fold higher than ground controls which exhibited laboratory spontaneous frequencies.

The microRNA miR-1 regulates a MEF-2 dependent retrograde signal at neuromuscular junctions

PubMed Central

Simon, David J.; Madison, Jon M.; Conery, Annie L.; Thompson-Peer, Katherine L.; Soskis, Michael; Ruvkun, Gary B.; Kaplan, Joshua M.; Kim, John K.

2008-01-01

Summary We show that miR-1, a conserved muscle specific microRNA, regulates aspects of both pre- and post-synaptic function at C. elegans neuromuscular junctions. miR-1 regulates the expression level of two nicotinic acetylcholine receptor (nAChR) subunits (UNC-29 and UNC-63), thereby altering muscle sensitivity to acetylcholine (ACh). miR-1 also regulates the muscle transcription factor MEF-2, which results in altered pre-synaptic ACh secretion, suggesting that MEF-2 activity in muscles controls a retrograde signal. The effect of the MEF-2-dependent retrograde signal on secretion is mediated by the synaptic vesicle protein RAB-3. Finally, acute activation of levamisole-sensitive nAChRs stimulates MEF-2-dependent transcriptional responses, and induces the MEF-2-dependent retrograde signal. We propose that miR-1 refines synaptic function by coupling changes in muscle activity to changes in pre-synaptic function. PMID:18510933

Molecular Motors and Efficient Motion in a Viscoelastic Environment

NASA Astrophysics Data System (ADS)

Bonin, Keith

2005-11-01

Molecular motors perform many critical functions for cells, including chromosome separation during mitosis, vesicle transport, and muscle contraction. In this talk, we will discuss the ways in which physics concepts and instrumentation are being used to determine the forces and efficiencies of two of these motors, kinesin and dynein, in cells. We will emphasize a) studies at Wake Forest University that focus on the force versus velocity curves (load curves) of kinesin in the neurites of live PC12 cells, and b) work at UNC-Chapel Hill that measures the forces developed by dynein motors within beating cilia on the outer surfaces of live lung cells during mucus transport. We will show how the viscoelastic properties of cytoplasm and mucus can be determined from the Brownian motion of vesicles and beads in these media.. We find that the load on these motors in vivo may exceed that in vitro by a factor of 1000, and that several motors can share the task of moving a single vesicle.

A Standardized Approach for Category II Fetal Heart Rate with Significant Decelerations: Maternal and Neonatal Outcomes.

PubMed

Shields, Laurence E; Wiesner, Suzanne; Klein, Catherine; Pelletreau, Barbara; Hedriana, Herman L

2018-06-12

 To determine if a standardized intervention process for Category II fetal heart rates (FHRs) with significant decels (SigDecels) would improve neonatal outcome and to determine the impact on mode of delivery rates.  Patients with Category II FHRs from six hospitals were prospectively managed using a standardized approach based on the presence of recurrent SigDecels. Maternal and neonatal outcomes were compared between pre- (6 months) and post-(11 months) implementation. Neonatal outcomes were: 5-minute APGAR scores of <7, <5, <3, and severe unexpected newborn complications (UNC). Maternal outcomes included primary cesarean and operative vaginal birth rates of eligible deliveries.  Post implementation there were 8,515 eligible deliveries, 3,799 (44.6%) were screened, and 361 (9.5%) met criteria for recurrent SigDecels. Compliance with the algorithm was 97.8%. The algorithm recommended delivery in 68.0% of cases. Relative to pre-implementation, 5-minute APGAR score of <7 were reduced by 24.6% ( p  < 0.05) and severe UNC by -26.6%, p  = < .05. The rate of primary cesarean decreased (19.8 vs 18.3%, p  < 0.05), while there were nonsignificant increases in vaginal (74.6 vs 75.8%, p  = 0.13) and operative vaginal births (5.7 vs 5.9%, p  = 0.6) CONCLUSION:  Standardized management of recurrent SigDecels reduced the rate of 5-minute APGAR scores of < 7 and severe UNC. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Framework for multi-resolution analyses of advanced traffic management strategies.

DOT National Transportation Integrated Search

2016-11-01

Demand forecasting models and simulation models have been developed, calibrated, and used in isolation of each other. However, the advancement of transportation system technologies and strategies, the increase in the availability of data, and the unc...

Poorer frontolimbic white matter integrity is associated with chronic cannabis use, FAAH genotype, and increased depressive and apathy symptoms in adolescents and young adults.

PubMed

Shollenbarger, Skyler G; Price, Jenessa; Wieser, Jon; Lisdahl, Krista

2015-01-01

The heaviest period of cannabis use coincides with ongoing white matter (WM) maturation. Further, cannabis-related changes may be moderated by FAAH genotype (rs324420). We examined the association between cannabis use and FAAH genotype on frontolimbic WM integrity in adolescents and emerging adults. We then tested whether observed WM abnormalities were linked with depressive or apathy symptoms. Participants included 37 cannabis users and 37 healthy controls (33 female; ages 18-25). Multiple regressions examined the independent and interactive effects of variables on WM integrity. Regular cannabis users demonstrated reduced WM integrity in the bilateral uncinate fasciculus (UNC) (MD, right: p = .009 and left: p = .009; FA, right: p = .04 and left: p = .03) and forceps minor (fMinor) (MD, p = .03) compared to healthy controls. Marginally reduced WM integrity in the cannabis users was found in the left anterior thalamic radiation (ATR) (FA, p = .08). Cannabis group ∗ FAAH genotype interaction predicted WM integrity in bilateral ATR (FA, right: p = .05 and left: p = .001) and fMinor (FA, p = .02). In cannabis users, poorer WM integrity was correlated with increased symptoms of depression and apathy in bilateral ATR and UNC. Consistent with prior findings, cannabis use was associated with reduced frontolimbic WM integrity. WM integrity was also moderated by FAAH genotype, in that cannabis-using FAAH C/C carriers and A carrying controls had reduced WM integrity compared to control C/C carriers. Observed frontolimbic white matter abnormalities were linked with increased depressive and apathy symptoms in the cannabis users.

Poorer frontolimbic white matter integrity is associated with chronic cannabis use, FAAH genotype, and increased depressive and apathy symptoms in adolescents and young adults

PubMed Central

Shollenbarger, Skyler G.; Price, Jenessa; Wieser, Jon; Lisdahl, Krista

2015-01-01

Background The heaviest period of cannabis use coincides with ongoing white matter (WM) maturation. Further, cannabis-related changes may be moderated by FAAH genotype (rs324420). We examined the association between cannabis use and FAAH genotype on frontolimbic WM integrity in adolescents and emerging adults. We then tested whether observed WM abnormalities were linked with depressive or apathy symptoms. Methods Participants included 37 cannabis users and 37 healthy controls (33 female; ages 18–25). Multiple regressions examined the independent and interactive effects of variables on WM integrity. Results Regular cannabis users demonstrated reduced WM integrity in the bilateral uncinate fasciculus (UNC) (MD, right: p = .009 and left: p = .009; FA, right: p = .04 and left: p = .03) and forceps minor (fMinor) (MD, p = .03) compared to healthy controls. Marginally reduced WM integrity in the cannabis users was found in the left anterior thalamic radiation (ATR) (FA, p = .08). Cannabis group ∗ FAAH genotype interaction predicted WM integrity in bilateral ATR (FA, right: p = .05 and left: p = .001) and fMinor (FA, p = .02). In cannabis users, poorer WM integrity was correlated with increased symptoms of depression and apathy in bilateral ATR and UNC. Conclusions Consistent with prior findings, cannabis use was associated with reduced frontolimbic WM integrity. WM integrity was also moderated by FAAH genotype, in that cannabis-using FAAH C/C carriers and A carrying controls had reduced WM integrity compared to control C/C carriers. Observed frontolimbic white matter abnormalities were linked with increased depressive and apathy symptoms in the cannabis users. PMID:26106535

A Study of the Program Management Responsibility Transfer Process for the F-16.

DTIC Science & Technology

1975-09-01

Guidance . . . ... 19 Subjective Criteria. .......... 21 Criteria Based on the Principles of Management ....... ........... ... 27 Planning...26 GSM/SM/75S-8 and then they will be fitted to the management structure of the two commands and IIQ USAF. Criteria Based on the Principles Of Management From...with each of these ýunc- tional areas with emphasis on some of the principles of management that are (in the writer’s opinion) important to the PMRT

An EPA Pilot Study Evaluating Personal, Housing, and ...

EPA Pesticide Factsheets

EPA pilot studyAddresses how young children’s exposures to various indoor pollutants (both chemical and biological agents) change as a result of building renovation-based interventions, potentially affecting their asthma exacerbation and morbidityProvide additional information on chemical exposures and children’s interactions with their environments to enhance ongoing research in the Green Housing Study’s evaluation of green housing and impacts on childhood asthma Invited presentation to the NC Lead and Healthy Homes Task Force Meeting, Wednesday, February 24, 2016, UNC Institute for the Environment, Chapel Hill, NC

Large trucks involved in fatal crashes : the North Carolina data 1993-1997

DOT National Transportation Integrated Search

1999-03-01

An analysis of large, truck-involved crash outcomes in North Carolina for the period 1993-1997 was conducted by the UNC Highway Safety Research Center (HSRC) for the purpose of establishing an empirical basis for subsequent Governor's Highway Safety ...

Pre-Discovery Detection of ASASSN-18fv by Evryscope

NASA Astrophysics Data System (ADS)

Corbett, H.; Law, N.; Goeke, E.; Ratzloff, J.; Howard, W.; Fors, O.; del Ser, D.; Quimby, R. M.

2018-03-01

We have identified pre-discovery imaging of the probable classical nova ASASSN-18fv by Evryscope-South (http://evryscope.astro.unc.edu/), an array of 6-cm telescopes continuously monitoring 8000 square degrees of sky at 2-minute cadence from CTIO, Chile.

A Toxoplasma gondii Class XIV Myosin, Expressed in Sf9 Cells with a Parasite Co-chaperone, Requires Two Light Chains for Fast Motility*

PubMed Central

Bookwalter, Carol S.; Kelsen, Anne; Leung, Jacqueline M.; Ward, Gary E.; Trybus, Kathleen M.

2014-01-01

Many diverse myosin classes can be expressed using the baculovirus/Sf9 insect cell expression system, whereas others have been recalcitrant. We hypothesized that most myosins utilize Sf9 cell chaperones, but others require an organism-specific co-chaperone. TgMyoA, a class XIVa myosin from the parasite Toxoplasma gondii, is required for the parasite to efficiently move and invade host cells. The T. gondii genome contains one UCS family myosin co-chaperone (TgUNC). TgMyoA expressed in Sf9 cells was soluble and functional only if the heavy and light chain(s) were co-expressed with TgUNC. The tetratricopeptide repeat domain of TgUNC was not essential to obtain functional myosin, implying that there are other mechanisms to recruit Hsp90. Purified TgMyoA heavy chain complexed with its regulatory light chain (TgMLC1) moved actin in a motility assay at a speed of ∼1.5 μm/s. When a putative essential light chain (TgELC1) was also bound, TgMyoA moved actin at more than twice that speed (∼3.4 μm/s). This result implies that two light chains bind to and stabilize the lever arm, the domain that amplifies small motions at the active site into the larger motions that propel actin at fast speeds. Our results show that the TgMyoA domain structure is more similar to other myosins than previously appreciated and provide a molecular explanation for how it moves actin at fast speeds. The ability to express milligram quantities of a class XIV myosin in a heterologous system paves the way for detailed structure-function analysis of TgMyoA and identification of small molecule inhibitors. PMID:25231988

Relative to open surgery, minimally-invasive renal and ureteral pediatric surgery offers no improvement in 30-day complications, yet requires longer operative time: Data from the National Surgical Quality Improvement Program Pediatrics.

PubMed

Colaco, Marc; Hester, Austin; Visser, William; Rasper, Alison; Terlecki, Ryan

2018-05-01

Performance of minimally-invasive surgery (MIS) is increasing relative to open surgery. We sought to compare the contemporary rates of short-term complications of open versus laparoscopic renal and ureteral surgery in pediatric patients. A retrospective cross-sectional analysis of the National Surgical Quality Improvement Program Pediatrics database was performed of all cases in 2014 identified using CPT procedure codes for nephrectomy, partial nephrectomy (PN), ureteroneocystostomy (UNC), and pyeloplasty, and reviewed for postoperative complications. Univariate analysis was performed to determine 30-day complications, with comparison between open and MIS approaches. Receiver operator curve (ROC) analysis was performed to determine differences in body surface area (BSA) and age for open versus MIS. Review identified 207 nephrectomies, 72 PN, 920 UNC, and 625 pyeloplasties. MIS was associated with older age and larger BSA except for cases of UNC. Apart from PN, operative durations were longer with MIS. However, only PN was associated with significantly longer length of hospital stay (LOS). There was no difference in incidence of all other 30-day complications. When evaluating BSA via ROC, the area under the curve (AUC) was found to be 0.730 and was significant. Children with a BSA greater than 0.408 m 2 were more likely to have MIS (sensitivity, 66.9%; specificity, 69.3%). Regarding age, the AUC was 0.732. Children older than 637.5 days were more likely to have MIS (sensitivity, 72.8%; specificity, 63.3%). Pediatric MIS is associated with longer operative time for nephrectomy, but shorter LOS following PN. Surgical approach was not associated with difference in short-term complications.

[The significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis].

PubMed

Zhang, J; Wang, Y N; Wang, J S; Wu, L; Wei, N; Fu, L; Gao, Z; Chen, J H; Pei, R J; Wang, Z

2016-07-01

To investigate the significance of pedigree genetic screening and rapid immunological parameters in the diagnosis of primary hemophagocytic lymphohistiocytosis (HLH). Four cases of primary HLH patients with PRF1, UNC13D and SH2D1A gene mutations were conducted pedigree investigation, including family genetic screening and detections of immunological parameters (NK cell activity, CD107a degranulation and expression of HLH related defective protein), to evaluate the significance of these different indicators in the diagnosis of primary HLH and explore their correlations. The DNA mutations of the four families included missense mutation c.T172C (p.S58P) and non- frameshift deletions c.1083_1094del (p.361_365del), missense mutation c.C1349T (p.T450M) and frameshift mutation c.1090_1091delCT (p.T364fsX93) in PRF1 gene, missense mutation c.G2588A (p.G863D) in UNC13D gene and hemizygous mutation c.32T>G (p.I11S) in SH2D1A gene. The patients and their family members presented decreased NK cell activities. Individuals who carried mutations of PRF1 gene and SH2D1A gene showed low expression of perforin (PRF1) and signaling lymphocytic activation molecule associated protein (SAP). And the patient with UNC13D gene mutation and his family member with identical mutation showed significant reducing cytotoxic degranulation function (expression of CD107a). Pedigree genetic screening and rapid detection of immunological parameters might play an important role in the diagnosis of primary HLH, and both of them had good consistency. As an efficient detection means, the rapid immunological detection indicators would provide reliable basis for the early diagnosis of the primary HLH.

Vitamin D and Related Genes, Race, and Prostate Cancer Aggressiveness

DTIC Science & Technology

2014-10-01

Roswell Park Cancer Institute, UCLA, and UNC-CH) and by DoD HSRRB 3. Complete the data acquisition form from the parent PCaP Study a. Data was requested...developed, and the MOP has been assembled. 5. Arrange for shipment of 1,200 serum samples to Roswell Park for vitamin D analyses, 1,200 plasma and 1,200...conducted by Roswell Park Cancer Institute Shared Genomic Resources facility due to their having the appropriate technology and experience for the

Gender, Stress, and Coping in the U.S. Military. Volume 3. Performance.

DTIC Science & Technology

1995-10-01

work force was actually out of work and the production was not getting done. These college students (NTID is basically an undergraduate school for deaf...that can be learned and do not require any kind of mystical involvement in the idea of maleness. For example, 0 one of our Navy ROTC summer students who...an ongoing study at Duke of coronary vascular disease in a group of people who were students at UNC (University of North Carolina) in the early to mid

A Study of United States Air Force Medical Central Processing and Distribution Systems.

DTIC Science & Technology

1981-06-01

5 M t2-8 13. IILL .i 2 5 I C. N SECURITY CLASSIFICATION OF THIS PAGE N,. LC, t,7EPORT DOCUMENTATION P AD-A 195 485 o Is. REPORT SECURITY...CLASSIFICATION lb. RlI𔃺KILIIV MAKKINib Unc lassif led 2a. SECURITY CLASSIFICATION AUTHORITY 3 DISTRIBUTION /AVAILABILITY OF REPORT Approved for public release...8217b, DECLASSIFICATION I DOWNGRADING SCHEDULE Distribution unlimited 4. PERFORMING ORGANIZATION REPORT NUMBER(S) 5. MONITORING ORGANIZATION REPORT NUMBER

Deployable Integral Field Units, Multislits, and Image Slicer for the Goodman Imaging Spectrograph on the SOAR Telescope

NASA Astrophysics Data System (ADS)

Cecil, Gerald N.; Moffett, A. J.; Cui, Y.; Eckert, K. D.; McBride, J.; Kannappan, S.; Keller, K.; Barlow, B. N.; Dunlap, B.; Bland-Hawthorn, J.

2010-01-01

The Goodman Imager-Spectrograph on the 4.1m SOAR telescope has operated on Cerro Pachon, Chile with volume-phase holographic gratings in long-slit mode since its commissioning in 2008. Recently, UNC graduate students played key roles to implement robust upgrades for multi-object spectroscopy that will soon be available to US astronomers through the NOAO time share on SOAR: • Multislits over 3x5 arcmin, generated on PCB solder stencils with exceptional sharpness compared to conventional laser cuts, initially to survey globular clusters for pulsating hot sub-dwarfs • An image slicer to obtain 3 simultaneous parallel spectra 70-arcsec long, 1- or 2-arcsec wide, spanning 320-750 nm to map stellar and gaseous emission and mass over the 1500 galaxies in the RESOLVE survey underway on SOAR • Four integral field units, each composed of 5-arcsec diameter, fused bundles of 0.5-arcsec diameter thin-clad optical fiber, independently deployed over a 10x5 arcmin field targeted by an EMCCD also used for Lucky Imaging. Initially will study aperture effects in single fiber surveys, extragalactic globular clusters, and demonstrate technology prior to deployment on larger telescopes • New wheels supporting a large set of existing narrow-band and Sloan filters • A trombone-style atmospheric dispersion compensator that corrects the full 12-arcmin diameter science field down to 30 deg elevation. Working in UNC's Goodman Laboratory for Astronomical Instrumentation, students employed SolidWorks and ZEMAX to design parts for in-house CAM on CNC machines and a 3D printer. All motors are controlled by LabVIEW as is the SOAR TCS. The deployable IFU axes are controlled by Quicksilver Controls Inc. intelligent servos and $80 model robot (Firgelli Corp.) actuators driven by a PIC-microcontroller and a student designed custom PCB. Upgrades and students were supported by $200K from SOAR Corporation, Research Corporation, NSF, and UNC competitive funds, and NC NASA Space Grant, Sigma Xi, and NASA fellowships.

Açaí (Euterpe oleracea Mart.) Modulates Oxidative Stress Resistance in Caenorhabditis elegans by Direct and Indirect Mechanisms

PubMed Central

Bonomo, Larissa de Freitas; Silva, David Nunes; Boasquivis, Patrícia Ferreira; Paiva, Franciny Aparecida; Guerra, Joyce Ferreira da Costa; Martins, Talita Alves Faria; de Jesus Torres, Álvaro Gustavo; de Paula, Igor Thadeu Borges Raposo; Caneschi, Washington Luiz; Jacolot, Philippe; Grossin, Nicolas; Tessier, Frederic J.; Boulanger, Eric; Silva, Marcelo Eustáquio; Pedrosa, Maria Lúcia; de Paula Oliveira, Riva

2014-01-01

Açaí (Euterpe oleracea Mart.) has recently emerged as a promising source of natural antioxidants. Despite its claimed pharmacological and nutraceutical value, studies regarding the effects of açaí in vivo are limited. In this study, we use the Caenorhabditis elegans model to evaluate the in vivo antioxidant properties of açaí on an organismal level and to examine its mechanism of action. Supplementation with açaí aqueous extract (AAE) increased both oxidative and osmotic stress resistance independently of any effect on reproduction and development. AAE suppressed bacterial growth, but this antimicrobial property did not influence stress resistance. AAE-increased stress resistance was correlated with reduced ROS production, the prevention of sulfhydryl (SH) level reduction and gcs-1 activation under oxidative stress conditions. Our mechanistic studies indicated that AAE promotes oxidative stress resistance by acting through DAF-16 and the osmotic stress response pathway OSR-1/UNC-43/SEK-1. Finally, AAE increased polyglutamine protein aggregation and decreased proteasome activity. Our findings suggest that natural compounds available in AAE can improve the antioxidant status of a whole organism under certain conditions by direct and indirect mechanisms. PMID:24594796

Açaí (Euterpe oleracea Mart.) modulates oxidative stress resistance in Caenorhabditis elegans by direct and indirect mechanisms.

PubMed

Bonomo, Larissa de Freitas; Silva, David Nunes; Boasquivis, Patrícia Ferreira; Paiva, Franciny Aparecida; Guerra, Joyce Ferreira da Costa; Martins, Talita Alves Faria; de Jesus Torres, Álvaro Gustavo; de Paula, Igor Thadeu Borges Raposo; Caneschi, Washington Luiz; Jacolot, Philippe; Grossin, Nicolas; Tessier, Frederic J; Boulanger, Eric; Silva, Marcelo Eustáquio; Pedrosa, Maria Lúcia; Oliveira, Riva de Paula

2014-01-01

Açaí (Euterpe oleracea Mart.) has recently emerged as a promising source of natural antioxidants. Despite its claimed pharmacological and nutraceutical value, studies regarding the effects of açaí in vivo are limited. In this study, we use the Caenorhabditis elegans model to evaluate the in vivo antioxidant properties of açaí on an organismal level and to examine its mechanism of action. Supplementation with açaí aqueous extract (AAE) increased both oxidative and osmotic stress resistance independently of any effect on reproduction and development. AAE suppressed bacterial growth, but this antimicrobial property did not influence stress resistance. AAE-increased stress resistance was correlated with reduced ROS production, the prevention of sulfhydryl (SH) level reduction and gcs-1 activation under oxidative stress conditions. Our mechanistic studies indicated that AAE promotes oxidative stress resistance by acting through DAF-16 and the osmotic stress response pathway OSR-1/UNC-43/SEK-1. Finally, AAE increased polyglutamine protein aggregation and decreased proteasome activity. Our findings suggest that natural compounds available in AAE can improve the antioxidant status of a whole organism under certain conditions by direct and indirect mechanisms.

Genetics Home Reference: UNC80 deficiency

MedlinePlus

... absent, although in some cases individuals have limited communication using body language, gestures, and signs. Seizures, involuntary side-to-side movements of the eyes (nystagmus), eyes that do not point in the same direction (strabismus), and a high-pitched cry can also occur in this disorder. ...

Strongly Interacting Systems at the Nanoscale

DTIC Science & Technology

2006-09-13

Research Topic : cabo@icmf.inf.cu, caboa@yahoo.comPermanent Institute e mail Instituto de Cibernetica, Matematica y Fisica (ICIMAF) Grupo de Fisica Teorica...Research Topic : LFOA@FAMAF.UNC.EDU.AR 28 September 2005Permanent Institute e mail Universidad Nacional de Cordoba Facultad de Matematica , Astronomia y

MYOCARDIAL AND CARDIOVASCULAR EFFECTS FOLLOWING PULMONARY EXPOSURE TO ZINC

EPA Science Inventory

CARDIOVASCULAR INJURY FOLLOWING PULMONARY EXPOSURE TO ZINC
PS Gilmour, A Nyska, MC Schladweiler, AD Ledbetter, CF Moyer, JM Samet, and UP Kodavanti, CEMALB, UNC, Chapel Hill, NC; NIEHS, RTP, NC; US EPA/ORD/NHEERL/HSD, Chapel Hill, NC; Pathology Associates, Inc., Raleigh, NC; ...

Beliefs and Uses of Tagging among Undergraduates

ERIC Educational Resources Information Center

Kramer-Duffield, Jacob

2010-01-01

Context: This dissertation examines beliefs and uses regarding tagging among current undergraduate students, and examines the ecology of communications practice and implications for formation and maintenance of identity within the population. Currently enrolled undergraduate students at UNC-Chapel Hill formed the population for examination. …

Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression.

PubMed

Kerk, Sze Yen; Kratsios, Paschalis; Hart, Michael; Mourao, Romulo; Hobert, Oliver

2017-01-04

A common organizational feature of nervous systems is the existence of groups of neurons that share common traits but can be divided into individual subtypes based on anatomical or molecular features. We elucidate the mechanistic basis of neuronal diversification processes in the context of C.elegans ventral cord motor neurons that share common traits that are directly activated by the terminal selector UNC-3. Diversification of motor neurons into different classes, each characterized by unique patterns of effector gene expression, is controlled by distinct combinations of phylogenetically conserved, class-specific transcriptional repressors. These repressors are continuously required in postmitotic neurons to prevent UNC-3, which is active in all neuron classes, from activating class-specific effector genes in specific motor neuron subsets via discrete cis-regulatory elements. The strategy of antagonizing the activity of broadly acting terminal selectors of neuron identity in a subtype-specific fashion may constitute a general principle of neuron subtype diversification. Copyright © 2017 Elsevier Inc. All rights reserved.

An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons.

PubMed

Kratsios, Paschalis; Kerk, Sze Yen; Catela, Catarina; Liang, Joseph; Vidal, Berta; Bayer, Emily A; Feng, Weidong; De La Cruz, Estanisla Daniel; Croci, Laura; Consalez, G Giacomo; Mizumoto, Kota; Hobert, Oliver

2017-07-05

A core principle of nervous system organization is the diversification of neuron classes into subclasses that share large sets of features but differ in select traits. We describe here a molecular mechanism necessary for motor neurons to acquire subclass-specific traits in the nematode Caenorhabditis elegans . Cholinergic motor neuron classes of the ventral nerve cord can be subdivided into subclasses along the anterior-posterior (A-P) axis based on synaptic connectivity patterns and molecular features. The conserved COE-type terminal selector UNC-3 not only controls the expression of traits shared by all members of a neuron class, but is also required for subclass-specific traits expressed along the A-P axis. UNC-3, which is not regionally restricted, requires region-specific cofactors in the form of Hox proteins to co-activate subclass-specific effector genes in post-mitotic motor neurons. This intersectional gene regulatory principle for neuronal subclass diversification may be conserved from nematodes to mice.

Diverse modes of synaptic signaling, regulation, and plasticity distinguish two classes of C. elegans glutamatergic neurons.

PubMed

Ventimiglia, Donovan; Bargmann, Cornelia I

2017-11-21

Synaptic vesicle release properties vary between neuronal cell types, but in most cases the molecular basis of this heterogeneity is unknown. Here, we compare in vivo synaptic properties of two neuronal classes in the C. elegans central nervous system, using VGLUT-pHluorin to monitor synaptic vesicle exocytosis and retrieval in intact animals. We show that the glutamatergic sensory neurons AWC ON and ASH have distinct synaptic dynamics associated with tonic and phasic synaptic properties, respectively. Exocytosis in ASH and AWC ON is differentially affected by SNARE-complex regulators that are present in both neurons: phasic ASH release is strongly dependent on UNC-13, whereas tonic AWC ON release relies upon UNC-18 and on the protein kinase C homolog PKC-1. Strong stimuli that elicit high calcium levels increase exocytosis and retrieval rates in AWC ON , generating distinct tonic and evoked synaptic modes. These results highlight the differential deployment of shared presynaptic proteins in neuronal cell type-specific functions.

Diverse modes of synaptic signaling, regulation, and plasticity distinguish two classes of C. elegans glutamatergic neurons

PubMed Central

Ventimiglia, Donovan

2017-01-01

Synaptic vesicle release properties vary between neuronal cell types, but in most cases the molecular basis of this heterogeneity is unknown. Here, we compare in vivo synaptic properties of two neuronal classes in the C. elegans central nervous system, using VGLUT-pHluorin to monitor synaptic vesicle exocytosis and retrieval in intact animals. We show that the glutamatergic sensory neurons AWCON and ASH have distinct synaptic dynamics associated with tonic and phasic synaptic properties, respectively. Exocytosis in ASH and AWCON is differentially affected by SNARE-complex regulators that are present in both neurons: phasic ASH release is strongly dependent on UNC-13, whereas tonic AWCON release relies upon UNC-18 and on the protein kinase C homolog PKC-1. Strong stimuli that elicit high calcium levels increase exocytosis and retrieval rates in AWCON, generating distinct tonic and evoked synaptic modes. These results highlight the differential deployment of shared presynaptic proteins in neuronal cell type-specific functions. PMID:29160768

INCREASED APOPTOSIS IN ORGANOGENESIS-STAGED MOUSE EMBRYOS INDUCED BY DISINFECTION BY-PRODUCTS

EPA Science Inventory

Increased apoptosis in organogenesis-staged mouse embryos induced by disinfection by-products. Sid Hunter1,2, Ellen Rogers1 and Keith Ward2, 1 Developmental Biology Branch, Reproductive Toxicology Division, NHEERL, US EPA, RTP, NC; 2 Curriculum in Toxicology, UNC Chapel Hill, Cha...

CYP2E1 MEDIATED EXTRAHEPATIC METABOLISM IN PBPK MODELING OF LIPOPHILIC VOLATILE ORGANIC COMPOUNDS

EPA Science Inventory

Physiologically based pharmacokinetic (PBPK) models increasingly are available for environmental chemicals and applied in risk assessments. Often a simplified representation of a real biological system is used in order to reduce uncertainties in the PBPK predictions caused by unc...

VMAT2-mediated neurotransmission from midbrain leptin receptor neurons in feeding regulation

USDA-ARS?s Scientific Manuscript database

Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unc...

REGIONAL VULNERABILITY ASSESSMENT (REVA): TARGETING RISK MANAGEMENT ACTIONS AND PROVIDING OPTIONS FOR INTEGRATED MANAGEMENT

EPA Science Inventory

EPA's Regional Vulnerability Assessment (ReVA) program is an approach to regional scale, priority-setting assessment being developed by EPA's Office of Research and Development (ORD). ReVA will effectively informs decision-makers as to the magnitude, extent, distribution, and unc...

Using WRF for Regional Climate Modeling: An Emphasis on the Southeast U.S. for Future Air Quality

EPA Science Inventory

This presentation describes preliminary analysis of a five-member regional climate ensemble (developed by AMAD and its contractors, including UNC) to determine if there is any consensus on projected changes to the placement of the North Atlantic Subtropical High (NASH, or Bermuda...

EFFECTS OF DIESEL EXHAUST PARTICLES ON HUMAN ALVEOLAR MACROPHAGE RESPONSIVENESS TO LIPOPOLYSACCHARIDE

EPA Science Inventory

Effects of diesel exhaust particles on human alveolar macrophage responsiveness to lipopolysaccharide
S. Mundandhara1 , S. Becker2 and M. Madden2, 1UNC Center for Environmental Medicine, Asthma, and Lung Biology, 2US EPA, NHEERL, HSD, Chapel Hill, NC, US

Epidemiological...

CYTOKINE PROFILING FOR CHEMICAL RESPIRATORY SENSITIZERS

EPA Science Inventory

CYTOKINE PROFILING FOR CHEMICAL RESPIRATORY SENSITIZERS. LM Plitnick1, SE Loveless2, GS Ladics2, MP Holsapple3, MJ Selgrade4, DM Sailstad4 & RJ Smialowicz4. 1UNC, Chapel Hill, NC; 2DuPont Co., Haskell Laboratory, Newark, DE; 3Dow Chemical, Midland, MI & 4USEPA, NHEERL, RTP, NC.

DEVELOPMENTAL EXPOSURE TO A THYROID DISRUPTING CHEMICAL STIMULATES PHAGOCYTOSIS IN JUVENILE SPRAGUE-DAWLEY RATS

EPA Science Inventory

Developmental Exposure to a Thyroid Disrupting Chemical Stimulates Phagocytosis in Juvenile Sprague-Dawley Rats.
AA Rooney1, R Matulka2, and R Luebke3. 1NCSU/US EPA CVM, Department of Anatomy, Physiological Sciences and Radiology, Raleigh, NC;2UNC Department of Toxicology, Cha...

Evaluation of autophagy as a mechanism involved in air pollutant-induced pulmonary injury

EPA Science Inventory

Evaluation of autophagy as a mechanism involved in air pollutant-induced pulmonary injuryHenriquez, A.1, Snow, S.2, Miller, D1.,Schladweiler, M.2 and Kodavanti, U2.1 Curriculum in Toxicology, UNC, Chapel Hill, NC. 2 EPHD/NHEERL, US EPA, RTP, Durham, NC. ...

NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

EPA Science Inventory

Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

Dose-response estimation is a critical feature of risk assessment. It can be...

Mississippi River, Baton Rouge to the Gulf, Louisiana, Project. Supplement II.

DTIC Science & Technology

1984-04-01

include portions of the west coast of Florida and the northern coast of Yucatan as major feeding areas for green turtles. Hildebrand (1979) has...D. Seneca. 1973. An investigation of propagation and mineral nutrition of Spartina alterniflora. Sea Grant Publication UNC-SG-73-14. North Carolina

CARDIOVASCULAR INJURY FROM ACUTE AND REPEATED EXPOSURE TO PARTICULATE MATTER (PM): POTENTIAL ROLE OF ZINC

EPA Science Inventory

CARDIOVASCULAR INJURY FROM ACUTE AND REPEATED EXPOSURE TO PARTICULATE MATTER (PM): POTENTIAL ROLE OF ZINC. UP Kodavanti, MC Schladweiler, AD Ledbetter, RH Jaskot, PS Gilmour, DC Christiani, WP Watkinson, DL Costa, JK McGee, A Nyska. NHEERL, USEPA, RTP, NC; CEMALB, UNC, Chapel Hil...

RISK FACTORS FOR ENDEMIC GASTROINTESTINAL ILLNESS AMONG A WASHINGTON COHORT

EPA Science Inventory

RISK FACTORS FOR ENDEMIC GASTROINTESTINAL ILLNESS AMONG A WASHINGTON COHORT

*Christina A. Peterson 1,2,3 and Rebecca L. Calderon 2

1 Department of Epidemiology
School of Public Health (SPH)
University of North Carolina at Chapel Hill (UNC-CH), 27516
2 Nat...

PFOA INDUCES DYSMORPHOGENESIS IN MOUSE WHOLE EMBRYO CULTURE

EPA Science Inventory

PFOA Induces Dysmorphogenesis In Mouse Whole Embryo Culture.

MR Blanton1, JM Padowski2, ES Hunter1, JM Rogers1, and C Lau1. 1Reproductive Toxicology Division, NHEERL, ORD, US EPA, RTP, NC, USA. 2Curriculum in Toxicology, UNC, Chapel Hill, NC, USA

Perfluorooctanoa...

HALOACETIC ACIDS AND KINASE INHIBITORS PERTURB MOUSE NEURAL CREST CELLS IN VITRO

EPA Science Inventory

HUNTER, E.S.1, J. SMITH2, J. ANDREWS1. 1 Reproductive Toxicology Division, NHEERL, US EPA, Research Triangle Park and 2 Department of Cell and Developmental Biology, UNC-CH, Chapel Hill, North Carolina. Haloacetic acids and kinase inhibitors perturb mouse neural crest cells in vi...

KINPLOT: An Interactive Pharmacokinetics Graphics Program for Digital Computers.

ERIC Educational Resources Information Center

Wilson, Robert C.; And Others

1982-01-01

Inability to see the relevance of mathematics to understanding the time course of drugs in the body may discourage interest in pharmacokinetics. A UNC-developed computer graphics simulation program helps visualize the nature of pharmacokinetic-patient interactions, generates classroom handouts, and is used in the pharmaceuticals industry to…

PREDICTIVE SIMULATION MODELING FOR ANTIANDROGEN IMPACTS ON RODENT PROSTATE

EPA Science Inventory

Predictive simulation modeling for antiandrogen impacts on rodent prostate
HA Barton1, RW Setzer1, LK Potter1,2
1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Park, NC and 2Curriculum in Toxicology, UNC, Chapel Hill, NC

Changes in rodent prostate weight and functi...

EFFECTS OF INSTILLED AND INHALED PARTICULATE MATTER ON CARDIOPULMONARY PARAMETERS IN RATS

EPA Science Inventory

EFFECTS OF INSTILLED AND INHALED PARTICULATE MATTER ON CARDIOPULMONARY PARAMETERS IN RATS

LB Wichers (UNC - Chapel Hill; Chapel Hill, NC USA), MJ Campen (LRRI; Albuquerque, NM USA), JP Nolan, WH Rowan, AD Ledbetter, DW Winsett, UP Kodavanti, MCJ Schladweiler, DL Costa, and...

Initial Experience With A Prototype Storage System At The University Of North Carolina

NASA Astrophysics Data System (ADS)

Creasy, J. L.; Loendorf, D. D.; Hemminger, B. M.

1986-06-01

A prototype archiving system manufactured by the 3M Corporation has been in place at the University of North Carolina for approximately 12 months. The system was installed as a result of a collaboration between 3M and UNC, with 3M seeking testing of their system, and UNC realizing the need for an archiving system as an essential part of their PACS test-bed facilities. System hardware includes appropriate network and disk interface devices as well as media for both short and long term storage of images and their associated information. The system software includes those procedures necessary to communicate with the network interface elements(NIEs) as well as those procedures necessary to interpret the ACR-NEMA header blocks and to store the images. A subset of the total ACR-NEMA header is parsed and stored in a relational database system. The entire header is stored on disk with the completed study. Interactive programs have been developed that allow radiologists to easily retrieve information about the archived images and to send the full images to a viewing console. Initial experience with the system has consisted primarily of hardware and software debugging. Although the system is ACR-NEMA compatable, further objective and subjective assessments of system performance is awaiting the connection of compatable consoles and acquisition devices to the network.

Exploring virtual worlds with head-mounted displays

NASA Astrophysics Data System (ADS)

Chung, James C.; Harris, Mark R.; Brooks, F. P.; Fuchs, Henry; Kelley, Michael T.

1989-02-01

Research has been conducted in the use of simple head mounted displays in real world applications. Such units provide the user with non-holographic true 3-D information, since the kinetic depth effect, stereoscopy, and other visual cues combine to immerse the user in a virtual world which behaves like the real world in some respects. UNC's head mounted display was built inexpensively from commercially available off-the-shelf components. Tracking of the user's head position and orientation is performed by a Polhemus Navigation Sciences' 3SPACE tracker. The host computer uses the tracking information to generate updated images corresponding to the user's new left eye and right eye views. The images are broadcast to two liquid crystal television screens (220x320 pixels) mounted on a horizontal shelf at the user's forehead. The user views these color screens through half-silvered mirrors, enabling the computer generated image to be superimposed upon the user's real physical environment. The head mounted display was incorporated into existing molecular and architectural applications being developed at UNC. In molecular structure studies, chemists are presented with a room sized molecule with which they can interact in a manner more intuitive than that provided by conventional 2-D displays and dial boxes. Walking around and through the large molecule may provide quicker understanding of its structure, and such problems as drug enzyme docking may be approached with greater insight.

R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family

PubMed Central

Korvatska, Olena; Leverenz, James B.; Jayadev, Suman; McMillan, Pamela; Kurtz, Irina; Guo, Xindi; Rumbaugh, Malia; Matsushita, Mark; Girirajan, Santhosh; Dorschner, Michael O.; Kiianitsa, Kostantin; Yu, Chang-En; Brkanac, Zoran; Garden, Gwenn A.; Raskind, Wendy H.; Bird, Thomas D.

2016-01-01

Importance The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. Objective To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. Design, Setting, and Participants This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. Main Outcomes and Measures We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Results Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; P = .04 and vs 0.033 [0.013] for control individuals; P < .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all patients with AD (AD: 2.5, R47H_AD: 2.7, and control: 1.0; P < .01). Conclusions and Relevance Our results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease. PMID:26076170

Using Comparative Expenditure Data for Institutional Planning. SAIR Conference Paper.

ERIC Educational Resources Information Center

Sanford, Timothy R.; Sadler, James C.

The use of Higher Education General Information Survey (HEGIS) data and a software program to compare public university expenditures is discussed. Financial expenditures at the University of North Carolina, Chapel Hill, (UNC) and other public universities were compared using 1981-1982 and 1982-1983 HEGIS data for public university members of the…

Frasier v. UNC--A Personal Account

ERIC Educational Resources Information Center

Frasier, Ralph K.

2005-01-01

Like the Brown Decision, Frasier was not simply an action challenging the right of three plaintiffs to attend one of the institutions of higher education within the State of North Carolina which historically had limited access to its undergraduate schools to white citizens. Rather, the suit was one of a series seeking to dismantle a system of…

USE OF THE RIBONUCLEASE PROTECTION ASSAY FOR IDENTIFYING CHEMICALS WHICH ELLICIT HYPERSENSITIVITY RESPONSES

EPA Science Inventory

Use of the Ribonuclease Protection Assay (RPA) for Identifying Chemicals that Elicit Hypersensitivity Responses. L.M. Plitnick, 1, D.M. Sailstad, 2, and R.J. Smialowicz, 2 1UNC, Curriculum in Toxicology, Chapel Hill, NC and 2USEPA, NHEERL, RTP, NC.

The incidence of aller...

COMPARISON OF DETOXIFICATION AND BIOACTIVATION PATHWAYS FOR BROMODICHLOROMETHANE IN THE RAT

EPA Science Inventory

Comparison of Detoxification and Bioactivation pathways FOR Bromodichloromethane in the Rat
M.K. Ross1, C.R. Eklund2, and R.A. Pegram2
1Curriculum in Toxicology, UNC-CH, Chapel Hill, NC
2ETD, NHEERL/ORD, USEPA, Research Triangle Park, NC

Bromodichloromethane (BDCM...

A framework for modeling non-steady-state concentrations of semivolatile organic compounds indoors ― II. Interactions with particulate matter

EPA Science Inventory

This paper describes a method for dynamic modeling of the interactions of semivolatile organic compounds (SVOCs) with airborne and settled particulate matter in the indoor environment. This method is fully compatible with the other components within the framework. Despite the unc...

EFFECTS OF SUBCHRONIC EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES IN SPONTANEOUSLY HYPERTENSIVE RATS

EPA Science Inventory

EFFECTS OF SUBCHRONIC EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES IN SPONTANEOUSLY HYPERTENSIVE RATS. WP Watkinson1, LB Wichers2, JP Nolan1, DW Winsett1, UP Kodavanti1, MCJ Schladweiler1, and DL Costa1 1US EPA, ORD/NHEERL/ETD/PTB, RTP, NC; 2UNC SPH and Curriculum in Toxic...

The Leading Edge: Enduring a Campus Crisis

ERIC Educational Resources Information Center

Moeser, James

2003-01-01

On June 2003, the University of North Carolina at Chapel Hill (UNC) faced a frightening crisis when an employee was diagnosed with Severe Acute Respiratory Syndrome (SARS). In this article, the author looks back and identifies four factors that enabled the university to navigate this crisis. These factors were: (1) leadership at every level; (2)…

MORPHOMETRIC ANALYSIS OF RAT HINDLIMB MALFORMATIONS DUE TO GESTATIONAL EXPOSURE TO 5-FU

EPA Science Inventory

SETZER1, R. W., M. D. WILLIAMS2, D. LITTON3, M.G. NAROTSKY4, 1Experimental Toxicology Division and 4Reproductive Toxicology Division, NHEERL, ORD, USEPA, Research Triangle Park, North Carolina; 2UNC School of Medicine, Chapel Hill, North Carolina; and 3Department of Aerospace E...

IN VITRO METABOLISM OF PYRETHROIDS IN RAT LIVER MICROSOMES

EPA Science Inventory

IN VITRO METABOLISM OF PYRETHROIDS IN RAT LIVER MICROSOMES

SJ Godin1, RA Harrison2 MF. Hughes 2, MJ DeVito2; 1Curriculum In Toxicology, UNC-CH, Chapel Hill NC, USA; 2ETD, NHEERL, ORD, US EPA, RTP, NC, 27711, USA.

Pyrethroids are neurotoxic pesticides that bin...

Evaluating Design Enhancements to the Tablet Arm Chair in Language Instruction Classes at UNC Chapel Hill

ERIC Educational Resources Information Center

Henshaw, Robert Griffith; Reubens, Andrea

2014-01-01

Higher education institutions are increasingly interested in cost-effective classroom furniture solutions that support diverse teaching methods by facilitating movement between lecture and interactive instructional methods such as small group work. Several furniture manufacturers are exploring designs based on the traditional tablet arm chair. A…

COMPARISON OF THREE METHODS FOR COUNTING HUMAN SPERMATOZOA

EPA Science Inventory

COMPARISON OF THREE METHODS FOR COUNTING HUMAN SPERMATOZOA SC Jeffay1, LF Strader1, RA Morris1, JE Schmid1, AF Olshan2, LW Lansdell2, SD Perreault1. 1US EPA/ORD, RTP, NC; 2UNC-CH, Chapel Hill, NC.
The IDENT feature of the HTM-IVOS semen analyzer (Hamilton Thorne Research, Bev...

77 FR 36510 - Applications for New Awards: Personnel Development To Improve Services and Results for Children...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-19

... of the institutions of higher education (IHEs) surveyed reported receiving assistance from the... discrete, self-contained units of instruction designed to increase educators' knowledge or skills that can...://community.fpg.unc.edu . User survey results from both of these centers show that college and graduate...

DEVELOPING A PREDICTIVE SIMULATION MODEL FOR ANTIANDROGEN IMPACTS ON RODENT PROSTATE

EPA Science Inventory

Developing a predictive simulation model for antiandrogen impacts on rodent prostate
HA Barton1, RW Setzer1, LK Potter1,2
1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Park, NC and 2Curriculum in Toxicology, UNC, Chapel Hill, NC

Alterations in rodent prostate wei...

WINDOW OF SUSCEPTIBILITY TO PERFLUOROOCTANE SULFONATE (PFOS)-INDUCED NEONATAL MORTALITY IN THE RAT

EPA Science Inventory

GRASTY1, 2, R.C., B.E. GREY1, C.S. LAU1 and J.M. ROGERS1, 2. 1Reproductive Toxicology Division, NHEERL, ORD, US EPA, Research Triangle Park, NC; and 2Curriculum in Toxicology, UNC Chapel Hill, Chapel Hill, NC. Window of susceptibility to perfluorooctane sulfonate (PFOS)-induce...

An examination of data quality on QSAR Modeling in regards to the environmental sciences (UNC-CH talk)

EPA Science Inventory

The development of QSAR models is critically dependent on the quality of available data. As part of our efforts to develop public platforms to provide access to predictive models, we have attempted to discriminate the influence of the quality versus quantity of data available to...

COMPARING ENVIRONMENTALLY RELEVANT PCBS TO TCDD

EPA Science Inventory

COMPARING ENVIRONMENTALLY RELEVANT PCBS TO TCDD. D E Burgin1, J J Diliberto2 and L S Birnbaum3.1UNC, Chapel Hill, NC, USA; 2USEPA/ORD/NHEERL, ETD, RTP, NC, USA

Environmental exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) always occur as part of a complex mixture. ...

Membrane-associated proteomics of chickpea identifies Sad1/UNC-84 protein (CaSUN1), a novel component of dehydration signaling

NASA Astrophysics Data System (ADS)

Jaiswal, Dinesh Kumar; Mishra, Poonam; Subba, Pratigya; Rathi, Divya; Chakraborty, Subhra; Chakraborty, Niranjan

2014-02-01

Dehydration affects almost all the physiological processes including those that result in the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which in turn elicits a highly conserved signaling, the unfolded protein response (UPR). We investigated the dehydration-responsive membrane-associated proteome of a legume, chickpea, by 2-DE coupled with mass spectrometry. A total of 184 protein spots were significantly altered over a dehydration treatment of 120 h. Among the differentially expressed proteins, a non-canonical SUN domain protein, designated CaSUN1 (Cicer arietinum Sad1/UNC-84), was identified. CaSUN1 localized to the nuclear membrane and ER, besides small vacuolar vesicles. The transcripts were downregulated by both abiotic and biotic stresses, but not by abscisic acid treatment. Overexpression of CaSUN1 conferred stress tolerance in transgenic Arabidopsis. Furthermore, functional complementation of the yeast mutant, slp1, could rescue its growth defects. We propose that the function of CaSUN1 in stress response might be regulated via UPR signaling.

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiong, Yan; Li, Fengling; Babault, Nicolas

G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18more » (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.« less

Munc13 homology domain-1 in CAPS/UNC31 mediates SNARE binding required for priming vesicle exocytosis.

PubMed

Khodthong, Chuenchanok; Kabachinski, Greg; James, Declan J; Martin, Thomas F J

2011-08-03

Neuropeptide and peptide hormone secretion from neural and endocrine cells occurs by Ca(2+)-triggered dense-core vesicle exocytosis. The membrane fusion machinery consisting of vesicle and plasma membrane SNARE proteins needs to be assembled for Ca(2+)-triggered vesicle exocytosis. The related Munc13 and CAPS/UNC31 proteins that prime vesicle exocytosis are proposed to promote SNARE complex assembly. CAPS binds SNARE proteins and stimulates SNARE complex formation on liposomes, but the relevance of SNARE binding to CAPS function in cells had not been determined. Here we identify a core SNARE-binding domain in CAPS as corresponding to Munc13 homology domain-1 (MHD1). CAPS lacking a single helix in MHD1 was unable to bind SNARE proteins or to support the Ca(2+)-triggered exocytosis of either docked or newly arrived dense-core vesicles. The results show that MHD1 is a SNARE-binding domain and that SNARE protein binding is essential for CAPS function in dense-core vesicle exocytosis. Copyright © 2011 Elsevier Inc. All rights reserved.

Role of mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) in the recruitment of newcomer insulin granules in both first and second phases of glucose-stimulated insulin secretion in mouse islets.

PubMed

Xie, L; Zhu, D; Gaisano, H Y

2012-10-01

We have previously reported that the haplodeficient Munc13-1(+/-) mouse exhibits impaired biphasic glucose-stimulated insulin secretion (GSIS), causing glucose intolerance mimicking type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can bypass these insulin-secretory defects in type 2 diabetes, but the mechanism of exocytotic events mediated by GLP-1 in rescuing insulin secretion is unclear. The total internal reflection fluorescence microscopy (TIRFM) technique was used to examine single insulin granule fusion events in mouse islet beta cells. There was no difference in the density of docked granules in the resting state between Munc13-1(+/+) and Munc13-1(+/-) mouse islet beta cells. While exocytosis of previously docked granules in Munc13-1(+/-) beta cells is reduced during high-K(+) stimulation as expected, we now find a reduction in additional exocytosis events that account for the major portion of GSIS, namely two types of newcomer granules, one which has a short docking time (short-dock) and another undergoing no docking before exocytosis (no-dock). As mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) is a phorbol ester substrate, phorbol ester could partially rescue biphasic GSIS in Munc13-1-deficient beta cells by enhancing recruitment of short-dock newcomer granules for exocytosis. The more effective rescue of biphasic GSIS by GLP-1 than by phorbol was due to increased recruitment of both short-dock and no-dock newcomer granules. Phorbol ester and GLP-1 potentiation of biphasic GSIS are brought about by recruitment of distinct populations of newcomer granules for exocytosis, which may be mediated by Munc13-1 interaction with syntaxin-SNARE complexes other than that formed by syntaxin-1A.

Agenda 21: biotechnology at the United Nations Conference on Environment and Development.

PubMed

Taylhardat, A R; Zilinskas, R A

1992-04-01

Preparation has yet to be completed for the 1992 Earth Summit, UN Conference on Environment and Development (UNCED), in Rio de Janeiro, Brazil. Nonetheless, it has been planned as a forum in which recommendations will be made to governments and international organizations on how to alleviate environmental damage caused by human activities and how to prevent future damage without retarding development in the Third World. It will declare basic principles for national and individual conduct regarding environmental preservation and sustainable development; adopt international conventions to protect biodiversity and manage climatic change; lay out Agenda 21 activities as specified by UNCED; provide an agenda to help Third World governments manage environmental matters; and provide an agenda for improving the transfer of technology to developing countries. Where biotechnology is concerned, scientists and policy makers in developing countries have shown their interest. Limited resources and capabilities, however, constrain their abilities to engage in serious research and development. International organizations such as the UN Industrial Development Organization (UNIDO) may help UNCED and developing countries with biotechnology. Since 1986, UNIDO has held the International Centre for Genetic Engineering and Biotechnology (ICGEB) as a special project. The ICGEB conducts research and development (R&D) on high priority topics in developing countries; trains scientific and technical personnel from member countries in advanced biotechnology techniques; helps member countries implement and operate ICGEB-affiliated R&D and training centers; and manages an information exchange for internationally affiliated centers. To maximize the potential of biotechnology to help Third World nations clear their environments of pollutants while safely exploiting natural resources, organizations should promote full use of available training resources; promote biosafety and the dissemination of information on risk assessment and risk management; increase funding to support existing information networks; help make equipment and supplies available to developing countries; help bridge the gap between research and applications by encouraging universities and research institutions to market their research; and promote entrepreneurship in developing countries.

High-Throughput All-Optical Analysis of Synaptic Transmission and Synaptic Vesicle Recycling in Caenorhabditis elegans

PubMed Central

Wabnig, Sebastian; Liewald, Jana Fiona; Yu, Szi-chieh; Gottschalk, Alexander

2015-01-01

Synaptic vesicles (SVs) undergo a cycle of biogenesis and membrane fusion to release transmitter, followed by recycling. How exocytosis and endocytosis are coupled is intensively investigated. We describe an all-optical method for identification of neurotransmission genes that can directly distinguish SV recycling factors in C. elegans, by motoneuron photostimulation and muscular RCaMP Ca2+ imaging. We verified our approach on mutants affecting synaptic transmission. Mutation of genes affecting SV recycling (unc-26 synaptojanin, unc-41 stonin, unc-57 endophilin, itsn-1 intersectin, snt-1 synaptotagmin) showed a distinct ‘signature’ of muscle Ca2+ dynamics, induced by cholinergic motoneuron photostimulation, i.e. faster rise, and earlier decrease of the signal, reflecting increased synaptic fatigue during ongoing photostimulation. To facilitate high throughput, we measured (3–5 times) ~1000 nematodes for each gene. We explored if this method enables RNAi screening for SV recycling genes. Previous screens for synaptic function genes, based on behavioral or pharmacological assays, allowed no distinction of the stage of the SV cycle in which a protein might act. We generated a strain enabling RNAi specifically only in cholinergic neurons, thus resulting in healthier animals and avoiding lethal phenotypes resulting from knockdown elsewhere. RNAi of control genes resulted in Ca2+ measurements that were consistent with results obtained in the respective genomic mutants, albeit to a weaker extent in most cases, and could further be confirmed by opto-electrophysiological measurements for mutants of some of the genes, including synaptojanin. We screened 95 genes that were previously implicated in cholinergic transmission, and several controls. We identified genes that clustered together with known SV recycling genes, exhibiting a similar signature of their Ca2+ dynamics. Five of these genes (C27B7.7, erp-1, inx-8, inx-10, spp-10) were further assessed in respective genomic mutants; however, while all showed electrophysiological phenotypes indicative of reduced cholinergic transmission, no obvious SV recycling phenotypes could be uncovered for these genes. PMID:26312752

SLO BK Potassium Channels Couple Gap Junctions to Inhibition of Calcium Signaling in Olfactory Neuron Diversification.

PubMed

Alqadah, Amel; Hsieh, Yi-Wen; Schumacher, Jennifer A; Wang, Xiaohong; Merrill, Sean A; Millington, Grethel; Bayne, Brittany; Jorgensen, Erik M; Chuang, Chiou-Fen

2016-01-01

The C. elegans AWC olfactory neuron pair communicates to specify asymmetric subtypes AWCOFF and AWCON in a stochastic manner. Intercellular communication between AWC and other neurons in a transient NSY-5 gap junction network antagonizes voltage-activated calcium channels, UNC-2 (CaV2) and EGL-19 (CaV1), in the AWCON cell, but how calcium signaling is downregulated by NSY-5 is only partly understood. Here, we show that voltage- and calcium-activated SLO BK potassium channels mediate gap junction signaling to inhibit calcium pathways for asymmetric AWC differentiation. Activation of vertebrate SLO-1 channels causes transient membrane hyperpolarization, which makes it an important negative feedback system for calcium entry through voltage-activated calcium channels. Consistent with the physiological roles of SLO-1, our genetic results suggest that slo-1 BK channels act downstream of NSY-5 gap junctions to inhibit calcium channel-mediated signaling in the specification of AWCON. We also show for the first time that slo-2 BK channels are important for AWC asymmetry and act redundantly with slo-1 to inhibit calcium signaling. In addition, nsy-5-dependent asymmetric expression of slo-1 and slo-2 in the AWCON neuron is necessary and sufficient for AWC asymmetry. SLO-1 and SLO-2 localize close to UNC-2 and EGL-19 in AWC, suggesting a role of possible functional coupling between SLO BK channels and voltage-activated calcium channels in AWC asymmetry. Furthermore, slo-1 and slo-2 regulate the localization of synaptic markers, UNC-2 and RAB-3, in AWC neurons to control AWC asymmetry. We also identify the requirement of bkip-1, which encodes a previously identified auxiliary subunit of SLO-1, for slo-1 and slo-2 function in AWC asymmetry. Together, these results provide an unprecedented molecular link between gap junctions and calcium pathways for terminal differentiation of olfactory neurons.

Exome sequencing for simultaneous mutation screening in children with hemophagocytic lymphohistiocytosis.

PubMed

Mukda, Ekchol; Trachoo, Objoon; Pasomsub, Ekawat; Tiyasirichokchai, Rawiphorn; Iemwimangsa, Nareenart; Sosothikul, Darintr; Chantratita, Wasun; Pakakasama, Samart

2017-08-01

In the present study, we used exome sequencing to analyze PRF1, UNC13D, STX11, and STXBP2, as well as genes associated with primary immunodeficiency disease (RAB27A, LYST, AP3B1, SH2D1A, ITK, CD27, XIAP, and MAGT1) in Thai children with hemophagocytic lymphohistiocytosis (HLH). We performed mutation analysis of HLH-associated genes in 25 Thai children using an exome sequencing method. Genetic variations found within these target genes were compared to exome sequencing data from 133 healthy individuals. Variants identified with minor allele frequencies <5% and novel mutations were confirmed using Sanger sequencing. Exome sequencing data revealed 101 non-synonymous single nucleotide polymorphisms (SNPs) in all subjects. These SNPs were classified as pathogenic (n = 1), likely pathogenic (n = 16), variant of unknown significance (n = 12), or benign variant (n = 72). Homozygous, compound heterozygous, and double-gene heterozygous variants, involving mutations in PRF1 (n = 3), UNC13D (n = 2), STXBP2 (n = 3), LYST (n = 3), XIAP (n = 2), AP3B1 (n = 1), RAB27A (n = 1), and MAGT1 (n = 1), were demonstrated in 12 patients. Novel mutations were found in most patients in this study. In conclusion, exome sequencing demonstrated the ability to identify rare genetic variants in HLH patients. This method is useful in the detection of mutations in multi-gene associated diseases.

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans.

PubMed

Camargo, Gabriela; Elizalde, Alejandro; Trujillo, Xochitl; Montoya-Pérez, Rocío; Mendoza-Magaña, María Luisa; Hernandez-Chavez, Abel; Hernandez, Leonardo

2016-09-01

The mechanisms underlying oxidative stress (OS) resistance are not completely clear. Caenorhabditis elegans (C. elegans) is a good organism model to study OS because it displays stress responses similar to those in mammals. Among these mechanisms, the insulin/IGF-1 signaling (IIS) pathway is thought to affect GABAergic neurotransmission. The aim of this study was to determine the influence of heat shock stress (HS) on GABAergic activity in C. elegans. For this purpose, we tested the effect of exposure to picrotoxin (PTX), gamma-aminobutyric acid (GABA), hydrogen peroxide, and HS on the occurrence of a shrinking response (SR) after nose touch stimulus in N2 (WT) worms. Moreover, the effect of HS on the expression of UNC-49 (GABAA receptor ortholog) in the EG1653 strain and the effect of GABA and PTX exposure on HSP-16.2 expression in the TJ375 strain were analyzed. PTX 1 mM- or H2O2 0.7 mM-exposed worms displayed a SR in about 80 % of trials. GABA exposure did not cause a SR. HS prompted the occurrence of a SR as did PTX 1 mM or H2O2 0.7 mM exposure. In addition, HS increased UNC-49 expression, and PTX augmented HSP-16.2 expression. Thus, the results of the present study suggest that oxidative stress, through either H2O2 exposure or application of heat shock, inactivates the GABAergic system, which subsequently would affect the oxidative stress response, perhaps by enhancing the activity of transcription factors DAF-16 and HSF-1, both regulated by the IIS pathway and related to hsp-16.2 expression.

The UNC/UMN Baby Connectome Project (BCP): An overview of the study design and protocol development.

PubMed

Howell, Brittany R; Styner, Martin A; Gao, Wei; Yap, Pew-Thian; Wang, Li; Baluyot, Kristine; Yacoub, Essa; Chen, Geng; Potts, Taylor; Salzwedel, Andrew; Li, Gang; Gilmore, John H; Piven, Joseph; Smith, J Keith; Shen, Dinggang; Ugurbil, Kamil; Zhu, Hongtu; Lin, Weili; Elison, Jed T

2018-03-22

The human brain undergoes extensive and dynamic growth during the first years of life. The UNC/UMN Baby Connectome Project (BCP), one of the Lifespan Connectome Projects funded by NIH, is an ongoing study jointly conducted by investigators at the University of North Carolina at Chapel Hill and the University of Minnesota. The primary objective of the BCP is to characterize brain and behavioral development in typically developing infants across the first 5 years of life. The ultimate goals are to chart emerging patterns of structural and functional connectivity during this period, map brain-behavior associations, and establish a foundation from which to further explore trajectories of health and disease. To accomplish these goals, we are combining state of the art MRI acquisition and analysis techniques, including high-resolution structural MRI (T1-and T2-weighted images), diffusion imaging (dMRI), and resting state functional connectivity MRI (rfMRI). While the overall design of the BCP largely is built on the protocol developed by the Lifespan Human Connectome Project (HCP), given the unique age range of the BCP cohort, additional optimization of imaging parameters and consideration of an age appropriate battery of behavioral assessments were needed. Here we provide the overall study protocol, including approaches for subject recruitment, strategies for imaging typically developing children 0-5 years of age without sedation, imaging protocol and optimization, a description of the battery of behavioral assessments, and QA/QC procedures. Combining HCP inspired neuroimaging data with well-established behavioral assessments during this time period will yield an invaluable resource for the scientific community. Copyright © 2018 Elsevier Inc. All rights reserved.

DISSCO: direct imputation of summary statistics allowing covariates

PubMed Central

Xu, Zheng; Duan, Qing; Yan, Song; Chen, Wei; Li, Mingyao; Lange, Ethan; Li, Yun

2015-01-01

Background: Imputation of individual level genotypes at untyped markers using an external reference panel of genotyped or sequenced individuals has become standard practice in genetic association studies. Direct imputation of summary statistics can also be valuable, for example in meta-analyses where individual level genotype data are not available. Two methods (DIST and ImpG-Summary/LD), that assume a multivariate Gaussian distribution for the association summary statistics, have been proposed for imputing association summary statistics. However, both methods assume that the correlations between association summary statistics are the same as the correlations between the corresponding genotypes. This assumption can be violated in the presence of confounding covariates. Methods: We analytically show that in the absence of covariates, correlation among association summary statistics is indeed the same as that among the corresponding genotypes, thus serving as a theoretical justification for the recently proposed methods. We continue to prove that in the presence of covariates, correlation among association summary statistics becomes the partial correlation of the corresponding genotypes controlling for covariates. We therefore develop direct imputation of summary statistics allowing covariates (DISSCO). Results: We consider two real-life scenarios where the correlation and partial correlation likely make practical difference: (i) association studies in admixed populations; (ii) association studies in presence of other confounding covariate(s). Application of DISSCO to real datasets under both scenarios shows at least comparable, if not better, performance compared with existing correlation-based methods, particularly for lower frequency variants. For example, DISSCO can reduce the absolute deviation from the truth by 3.9–15.2% for variants with minor allele frequency <5%. Availability and implementation: http://www.unc.edu/∼yunmli/DISSCO. Contact: yunli@med.unc.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25810429

ASSESSING THE ALLERGIC POTENTIAL OF INDOOR AIR FUNGAL CONTAMINANTS

EPA Science Inventory

Assessing the Allergic Potential of Indoor Air Fungal Contaminants
Marsha D W Ward1, Michael E Viana2, Yonjoo Chung3, Najwa Haykal-Coates1, Lisa B Copeland1, Steven H Gavett1, and MaryJane K Selgrade1. 1US EPA, ORD, NHEERL, RTP, NC, USA. 2NCSU, CVM, Raleigh, NC, USA, 3 UNC, S...

THE ALLERGENIC POTENTIAL OF INDOOR AIR FUNGAL CONTAMINANTS

EPA Science Inventory

The Allergenic Potential of Indoor Air Fungal Contaminants
Marsha D W Ward1, Michael E Viana2, Yongjoo Chung3, Najwa Haykal-Coates1, Lisa B Copeland1, Steven H Gavett1, and MaryJane K Selgrade1. 1US EPA, ORD, NHEERL, RTP, NC, USA. 2NCSU, CVM, Raleigh, NC, USA, 3 UNC, SPH,...

ASSESSMENT OF IMMUNE RESPONSES TO PENICILLIUM CHRYSOGENUM AND CHARACTERIZATION OF ITS ALLERGENS

EPA Science Inventory

Assessment of immune responses to Penicillium chrysogenum and characterization of its allergens

Yongjoo Chung1, Michael E Viana2, Lisa B Copeland3, and MaryJane K Selgrade3, Marsha D W Ward3. 1 UNC, SPH, Chapel Hill, NC, 2NCSU, CVM, Raleigh, NC, 3US EPA, ORD, NHEERL, RTP,...

A framework to analyze emissions implications of manufacturing shifts in the industrial sector through integrating bottom-up energy models and economic input-output environmental life cycle assessment models

EPA Science Inventory

Future year emissions depend highly on the evolution of the economy, technology and current and future regulatory drivers. A scenario framework was adopted to analyze various technology development pathways and societal change while considering existing regulations and future unc...

TERATOGENIC RESPONSES OF TGFALPHA KNOCKOUT FETUSES TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)

EPA Science Inventory

ABBOTT1, B.D., A.R. BUCKALEW1, and P.L. BRYANT2. 1Reproductive Toxicology Division, EPA, RAP, NC; 2Dept. Environ. Sciences & Engineering, UNC, Chapel Hill, NC. Teratogenic responses of TGF knockout fetuses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

TCDD induces cl...

List of DOE radioisotope customers with summary of radioisotope shipments FY 1978

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burlison, J.S.; Laidler, R.I.

1979-05-01

The purpose of the document is to list DOE's radioisotopes production and distribution activities by its facilities at Argonne National Laboratory; Pacific Northwest Laboratory; Brookhaven National Laboratory; Hanford Engineering Development Laboratory; Idaho Operations Office; Los Alamos Scientific Laboratory; Mound Facility; Oak Ridge National Laboratory; Savannah River Laboratory; and UNC Nuclear Industries, Inc.

III, ERes, and Ares--A Reserves Comparison

ERIC Educational Resources Information Center

Power, June L.

2011-01-01

Founded in 1887 as the Croatan Normal School, the University of North Carolina at Pembroke (UNCP) is a smaller branch of the UNC System (with an full-time enrollment of about 6,500), yet with awarded diversity and a historical dedication to individualized service. Its dedication to services drives its approach to course reserves, which is to…

How to Incorporate Self-Defense Instruction into Physical Activity Programs

ERIC Educational Resources Information Center

Ousley, Christopher S.; Shuford, Ritchie G.; Roberts, Tom

2013-01-01

Demand for self-defense instruction has found its way to school settings at all levels. Classes are more prevalent on college campuses than ever before because students and administrators acknowledge the value of such instruction. As a point of reference, half of 16 University of North Carolina (UNC) schools and universities offer a course in…

Role of natural gas in meeting an electric sector emissions reduction strategy and effects on greenhouse gas emissions

EPA Science Inventory

With advances in natural gas extraction technologies, there is an increase in availability of domestic natural gas, and natural gas is gaining a larger share of use as a fuel in electricity production. At the power plant, natural gas is a cleaner burning fuel than coal, but unce...

Isolation of "Caenorhabditis elegans" Genomic DNA and Detection of Deletions in the "unc-93" Gene Using PCR

ERIC Educational Resources Information Center

Lissemore, James L.; Lackner, Laura L.; Fedoriw, George D.; De Stasio, Elizabeth A.

2005-01-01

PCR, genomic DNA isolation, and agarose gel electrophoresis are common molecular biology techniques with a wide range of applications. Therefore, we have developed a series of exercises employing these techniques for an intermediate level undergraduate molecular biology laboratory course. In these exercises, students isolate genomic DNA from the…

The Mediation of Literacy Education and Correspondence Composition Courses at UNC-Chapel Hill, 1912-1924

ERIC Educational Resources Information Center

Wooten, Courtney Adams

2013-01-01

Tracing the correspondence composition courses taught at the University of North Carolina-Chapel Hill from 1912 to 1924, this essay argues that examining distance education in the nineteenth and twentieth centuries can reveal possible problems or solutions to issues composition instructors face in twenty-first-century debates about moving…

METABOLISM AND TISSUE DOSIMETRY OF PENTAVALENT AND TRIVALENT MONOMETHYLATED ARSENIC AFTER ORAL

EPA Science Inventory

METABOLISM AND TISSUE DOSIMETRY OF PENTAVALENT AND TRIVALENT MONOMETHYLATED ARSENIC AFTER ORAL ADMINISTRATION IN MICE
M F Hughes1, V Devesa2, B M Adair1, M Styblo2, E M Kenyon1, and D J Thomas1. 1US EPA, ORD, NHEERL, ETD, Research Triangle Park, NC; 2UNC-CH, CEMALB, Chapel Hi...

Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

EPA Science Inventory

Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS

EPA Science Inventory

PERINATAL EXPOSURE TO THE PESTICIDE HEPTACHLOR PRODUCES ALTERATIONS IN IMMUNE FUNCTION PARAMETERS IN SPRAGUE DAWLEY RATS. R A Matulka1, AA Rooney3, W Williams2, CB Copeland2, and R J Smialowicz2. 1Curriculum in Toxicology, UNC, Chapel Hill, NC, USA; 2US EPA, ITB, ETD, NHEERL, RT...

A Model Recycling Program: UNC Takes Action as Landfill Space Shrinks and Costs Rise.

ERIC Educational Resources Information Center

Sherman, Rhonda L.

1991-01-01

The University of North Carolina responded to escalating waste disposal costs and shrinking landfill space with a structured program of recycling, including a mobile recycling drop, student family housing recycling, a newspaper drop-off site, high-volume glass pick-up, high-volume newspaper pick-up, and cardboard recycling. Campus-wide cooperation…

Microcephaly: computational and organotypic modeling of a ...

EPA Pesticide Factsheets

lecture discusses computational and organotypic models of microcephaly in an AOP Framework and ToxCast assays. Lecture slide presentation at UNC Chapel Hill for Advanced Toxicology course lecture on Computational Approaches to Developmental and Reproductive Toxicology with presentation on computational and organotypic modeling of a complex human birth defect microcephaly with is associated with the recent Zika virus outbreak.

INHIBITION OF TOBACCO SMOKE-INDUCED LUNG INFLAMMATION BY A CATALYTIC ANTIOXIDANT

EPA Science Inventory

AMathematical Model for the Kinetics of the Male Reproductive Endocrine System

Laura K. Potter1,2, H.A. Barton2 and R.W. Setzer2
1Curriculum in Toxicology, UNC-Chapel Hill, NC; 2US EPA, ORD, NHEERL, ETD, RTP, NC

In this presentation a model for the hormonal regul...

75 FR 54598 - Schedules for Atlantic Shark Identification Workshops and Protected Species Safe Handling...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-08

... workshop for September 9, 2010, to be held at the same time and location, 9 a.m. to 5 p.m., Comfort Inn (UNC Wilmington), 151 South College Road, Wilmington, NC 28403. DATES: The Atlantic Shark... CONTACT: Richard A. Pearson of the Highly Migratory Species Management Division at (727) 824-5399...

UNC-84: “LINC-ing” chromosome movement and double strand break repair

PubMed Central

Silva, Nicola

2016-01-01

Assaults to our DNA take place at a high frequency and are incompatible with life. In this issue, Lawrence et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201604112) demonstrate that a novel complex links the nucleus with cytoplasmic microtubules for the promotion of DNA repair by homologous recombination. PMID:27974481

Actin-interacting Protein 1 Promotes Disassembly of Actin-depolymerizing Factor/Cofilin-bound Actin Filaments in a pH-dependent Manner.

PubMed

Nomura, Kazumi; Hayakawa, Kimihide; Tatsumi, Hitoshi; Ono, Shoichiro

2016-03-04

Actin-interacting protein 1 (AIP1) is a conserved WD repeat protein that promotes disassembly of actin filaments when actin-depolymerizing factor (ADF)/cofilin is present. Although AIP1 is known to be essential for a number of cellular events involving dynamic rearrangement of the actin cytoskeleton, the regulatory mechanism of the function of AIP1 is unknown. In this study, we report that two AIP1 isoforms from the nematode Caenorhabditis elegans, known as UNC-78 and AIPL-1, are pH-sensitive in enhancement of actin filament disassembly. Both AIP1 isoforms only weakly enhance disassembly of ADF/cofilin-bound actin filaments at an acidic pH but show stronger disassembly activity at neutral and basic pH values. However, a severing-defective mutant of UNC-78 shows pH-insensitive binding to ADF/cofilin-decorated actin filaments, suggesting that the process of filament severing or disassembly, but not filament binding, is pH-dependent. His-60 of AIP1 is located near the predicted binding surface for the ADF/cofilin-actin complex, and an H60K mutation of AIP1 partially impairs its pH sensitivity, suggesting that His-60 is involved in the pH sensor for AIP1. These biochemical results suggest that pH-dependent changes in AIP1 activity might be a novel regulatory mechanism of actin filament dynamics. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Measurement of the Top Quark Mass in the All Hadronic Channel at the Tevatron

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lungu, Gheorghe

2007-01-01

This study presents a measurement of the top quark mass in the all hadronic channel of the top quark pair production mechanism, using 1 fb -1 of pmore » $$\\bar{p}$$ collisions at √s =1.96 TeV collected at the Collider Detector at Fermilab (CDF). Few novel techniques have been used in this measurement. A template technique was used to simultaneously determine the mass of the top quark and the energy scale of the jets. Two sets of distributions have been parameterized as a function of the top quark mass and jet energy scale. One set of distributions is built from the event-by-event reconstructed top masses, determined using the Standard Model matrix element for the t$$\\bar{t}$$ all hadronic process. This set is sensitive to changes in the value of the top quark mass. The other set of distributions is sensitive to changes in the scale of jet energies and is built from the invariant mass of pairs of light flavor jets, providing an in situ calibration of the jet energy scale. The energy scale of the measured jets in the final state is expressed in units of its uncertainty, sigmac. The measured mass of the top quark is 171.1±3.7(stat.unc.)±2.1(syst.unc.) GeV/ c 2 and to the date represents the most precise mass measurement in the all hadronic channel and third best overall.« less

Developing effective interuniversity partnerships and community-based research to address health disparities.

PubMed

Carey, Timothy S; Howard, Daniel L; Goldmon, Moses; Roberson, James T; Godley, Paul A; Ammerman, Alice

2005-11-01

Health disparities are an enormous challenge to American society. Addressing these disparities is a priority for U.S. society and especially for institutions of higher learning, with their threefold mission of education, service, and research. Collaboration across multiple intellectual disciplines will be critical as universities address health disparities. In addition, universities must collaborate with communities, with state partners, and with each other. Development of these collaborations must be sensitive to the history and unique characteristics of each academic institution and population. The authors describe the challenges of all three types of collaboration, but primarily focus on collaboration between research-intensive universities and historically black colleges and universities. The authors describe a four-year collaboration between Shaw University and the University of North Carolina at Chapel Hill (UNC-CH). These universities strategically developed multiple research initiatives to address health disparities, building on modest early success and personal relationships. These activities included participation by Shaw faculty in faculty development activities, multiple collaborative pilot studies, and joint participation in securing grants from the Agency for Health care Research and Quality of the federal Department of Health and Human Services and the National Institutes of Health, including a P-60 Project EXPORT center grant. These multiple activities were sometimes led by UNC-CH, sometimes by Shaw University. Open discussion of problems as they arose, realistic expectations, and mutual recognition of the strengths of each institution and its faculty have been critical in achieving successful collaboration to date.

Developing Effective Interuniversity Partnerships and Community-Based Research to Address Health Disparities

PubMed Central

Carey, Timothy S.; Howard, Daniel L.; Goldmon, Moses; Roberson, James T.; Godley, Paul A.; Ammerman, Alice

2009-01-01

Health disparities are an enormous challenge to American society. Addressing these disparities is a priority for U.S. society and especially for institutions of higher learning, with their threefold mission of education, service, and research. Collaboration across multiple intellectual disciplines will be critical as universities address health disparities. In addition, universities must collaborate with communities, with state partners, and with each other. Development of these collaborations must be sensitive to the history and unique characteristics of each academic institution and population. The authors describe the challenges of all three types of collaboration, but primarily focus on collaboration between research-intensive universities and historically black colleges and universities. The authors describe a four-year collaboration between Shaw University and the University of North Carolina at Chapel Hill (UNC-CH). These universities strategically developed multiple research initiatives to address health disparities, building on modest early success and personal relationships. These activities included participation by Shaw faculty in faculty development activities, multiple collaborative pilot studies, and joint participation in securing grants from the Agency for Health care Research and Quality of the federal Department of Health and Human Services and the National Institutes of Health, including a P-60 Project EXPORT center grant. These multiple activities were sometimes led by UNC-CH, sometimes by Shaw University. Open discussion of problems as they arose, realistic expectations, and mutual recognition of the strengths of each institution and its faculty have been critical in achieving successful collaboration to date. PMID:16249303

The prevalence of premature loss of primary teeth and its impact on malocclusion in the Eastern Province of Saudi Arabia.

PubMed

Al-Shahrani, Nasser; Al-Amri, Abdulaziz; Hegazi, Fahad; Al-Rowis, Khalid; Al-Madani, Abdullah; Hassan, Khalid S

2015-01-01

The present study was designed to determine the prevalence of premature loss of primary teeth and its effect on malocclusion in Eastern Province, Saudi Arabia. This is an observational, cross-sectional study that included 307 male children aged 9-11 years old. Clinical examinations were performed using a disposable sharp explorer, a UNC periodontal probe and a dental mirror. The samples were examined clinically to detect the following traits: Angle's classification of malocclusion, overjet, overbite, anterior open-bite, lateral open-bite, midline shift and cross-bite. Additionally, a dental caries examination was performed using WHO methods. Questionnaires in Arabic were coded and sent to the students' parents. The mean DMFT was 5.61 (SD = 3.01). The d-component was the highest, with a mean of 4 (SD = 2.83). Of the 307 children, it was found that 204 (66.4%) had a high DMFT score, which is defined as a score above 4. It was found that 156/307 (51%) children had premature loss of deciduous teeth. A high prevalence of premature loss of teeth was found in this study. This finding emphasizes the importance of increasing awareness levels about this issue and focuses attention on the need for more preventive efforts to maintain healthy and normal dentitions that would improve the masticatory function and aesthetics of individuals and the whole population. In addition, the findings emphasize the importance of the early detection of premature loss of primary teeth to prevent future malocclusion.

Task 90-17: Decontaminability Study on the U.S. Army Resuscitation Device, Individual, Chemical (RDIC)

DTIC Science & Technology

1991-04-01

RESTRIC-iVE VARK;NGS Unclassified 2a. SECURITY CLASSIF’CAT.ON AuTrHORITr 3 DISTRIBUTION,’AVALA8ILTY OF REPORT Approved for public release; 2b t ... T ;•R7 UTiON, AVAILABILITY OF ABSTRACT 121 A8STRACT SEC:RITY CLASSIFICATION (n UNCý.ASSiFE01IJNL,MITFD C3 SAME AS 7Pr 0 D:)rc usicts Unc la-,qi f it...was used to wipe the RDIC for 3 .i,,. The second, which is impregnated with chloramine B and is wetted with hydroxyethane (45 ± 2 percent), zinc

SESN2 facilitates mitophagy by helping Parkin translocation through ULK1 mediated Beclin1 phosphorylation.

PubMed

Kumar, Ashish; Shaha, Chandrima

2018-01-12

Mitophagy, the selective degradation of mitochondria by autophagy, is crucial for the maintenance of healthy mitochondrial pool in cells. The critical event in mitophagy is the translocation of cytosolic Parkin, a ubiquitin ligase, to the surface of defective mitochondria. This study elucidates a novel role of SESN2/Sestrin2, a stress inducible protein, in mitochondrial translocation of PARK2/Parkin during mitophagy. The data demonstrates that SESN2 downregulation inhibits BECN1/Beclin1 and Parkin interaction, thereby preventing optimum mitochondrial accumulation of Parkin. SESN2 interacts with ULK1 (unc-51 like kinase 1) and assists ULK1 mediated phosphorylation of Beclin1 at serine-14 position required for binding with Parkin prior to mitochondrial translocation. The trigger for SESN2 activation and regulation of Parkin translocation is the generation of mitochondrial superoxide. Scavenging of mitochondrial superoxide lower the levels of SESN2, resulting in retardation of Parkin translocation. Importantly, we observe that SESN2 mediated cytosolic interaction of Parkin and Beclin1 is PINK1 independent but mitochondrial translocation of Parkin is PINK1 dependent. Together, these findings suggest the role of SESN2 as a positive regulator of Parkin mediated mitophagy.

Genetic Control of Vulval Development in Caenorhabditis briggsae

PubMed Central

Sharanya, Devika; Thillainathan, Bavithra; Marri, Sujatha; Bojanala, Nagagireesh; Taylor, Jon; Flibotte, Stephane; Moerman, Donald G.; Waterston, Robert H.; Gupta, Bhagwati P.

2012-01-01

The nematode Caenorhabditis briggsae is an excellent model organism for the comparative analysis of gene function and developmental mechanisms. To study the evolutionary conservation and divergence of genetic pathways mediating vulva formation, we screened for mutations in C. briggsae that cause the egg-laying defective (Egl) phenotype. Here, we report the characterization of 13 genes, including three that are orthologs of Caenorhabditis elegans unc-84 (SUN domain), lin-39 (Dfd/Scr-related homeobox), and lin-11 (LIM homeobox). Based on the morphology and cell fate changes, the mutants were placed into four different categories. Class 1 animals have normal-looking vulva and vulva-uterine connections, indicating defects in other components of the egg-laying system. Class 2 animals frequently lack some or all of the vulval precursor cells (VPCs) due to defects in the migration of P-cell nuclei into the ventral hypodermal region. Class 3 animals show inappropriate fusion of VPCs to the hypodermal syncytium, leading to a reduced number of vulval progeny. Finally, class 4 animals exhibit abnormal vulval invagination and morphology. Interestingly, we did not find mutations that affect VPC induction and fates. Our work is the first study involving the characterization of genes in C. briggsae vulva formation, and it offers a basis for future investigations of these genes in C. elegans. PMID:23275885

Misplaced Priorities and Barrett’s Esophagus | Division of Cancer Prevention

Cancer.gov

Speaker | "Misplaced Priorities and Barrett’s Esophagus" will be presented by Nicholas J. Shaheen, MD, MPH, the Bozymski-Heizer Distinguished Professor of Medicine at the University of North Carolina School of Medicine, and Chief of the Division of Gastroenterology and Hepatology at UNC. Date: April 3, 2018; Time: 11:00 am- 12:00 pm; Location: NCI Shady Grove, Conference Room:

Where Have All the Scientific Data Gone? LIS Perspective on the Data-at-Risk Predicament

ERIC Educational Resources Information Center

Thompson, Cheryl A.; Robertson, W. Davenport; Greenberg, Jane

2014-01-01

Scientists produce vast amounts of data that often are not preserved properly or do not have inventories, placing them at risk. As part of an effort to more fully understand the data-at-risk predicament, researchers who were engaged in the DARI project at UNC's Metadata Research Center surveyed information custodians working in a range of…

Beyond PowerPoint: Visual Presentation Tools for Online Learning

ERIC Educational Resources Information Center

Howerton, Bruce

2005-01-01

In the mid-1990s, the University Of North Carolina (UNC) School of Dentistry entered the digital era by publishing curricula, syllabi, and modules on the Web. The School took this step in part to give students greater access to materials that supplement the lecture-based courses in the program, and in part to help students prepare for examinations…

EFFECTS OF INDUCED RESPIRATORY CHANGES ON CARDIAC, VENTILATORY, AND THERMOREGULATORY PARAMETERS IN HEALTHY SPRAGUE-DAWLEY RATS

EPA Science Inventory

EFFECTS OF INDUCED RESPIRATORY CHANGES ON CARDIAC, VENTILATORY, AND THERMOREGULATORY PARAMETERS IN HEALTHY SPRAGUE-DAWLEY RATS. LB Wichers1, WH Rowan2, DL Costa2, MJ Campen3 and WP Watkinson2 1UNC SPH, Chapel Hill, NC, USA; 2USEPA, ORD/NHEERL/ETD/PTB, RTP, NC, USA; 3LRRI, A...

EFFECTS OF ALLERGIC AIRWAYS DISEASE ON INFLUENZA VIRUS INFECTION IN BROWN NORWAY RATS

EPA Science Inventory

EFFECTS OF ALLERGIC AIRWAYS DISEASE ON INFLUENZA VIRUS INFECTION IN BROWN NORWAY RATS (P. Singhl, D.W. Winsett2, M.J. Daniels2,
C.A.J. Dick', K.B. Adlerl and M.I. Gilmour2, INCSU, Raleigh, N.C., 2NHEERL/ORD/ USEPA, RTP, N.C. and 3UNC, Chapel Hill, N.C.)The interaction between ...

The Extent of Comprehension and Knowledge with Respect to Digital Citizenship among Middle Eastern and US Students at UNC

ERIC Educational Resources Information Center

Alqahtani, Abdullah; Alqahtani, Fatimah; Alqurashi, Mohammed

2017-01-01

Digital technologies have revolutionized the way people acquire information and gain new knowledge. With a click or touch on the screen, anybody who is online can sail in the digital world and accomplish many things. As such, the optimal use of information and communication technology involves user comprehension, knowledge, and awareness of…

VALIDATION TESTING OF NEW MECHANISMS WITH OUTDOOR CHAMBER DATA, VOLUME 3: CALCULATION OF PHOTOCHEMICAL REACTION PHOTOLYSIS RATES IN THE UNC OUTDOOR CHAMBER

EPA Science Inventory

A new model is described for computing in-chamber actinic flux using site specific conditions that include time of day, air pressure, total column ozone, total column water vapor, relative humidity, aerosol type, aerosol optical density at 500 nm, and the spectral albedo of the g...

49 CFR 571.209 - Standard No. 209; Seat belt assemblies.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., plates, or washers, need not have such hardware, but shall have 7/16-20 UNF-2A or 1/2-13 UNC-2A... and other parts from becoming disengaged from the vehicle while in service. Reinforcing plates or... projected area. The distance between any edge of the plate and the edge of the bolt hole shall be at least...

49 CFR 571.209 - Standard No. 209; Seat belt assemblies.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., plates, or washers, need not have such hardware, but shall have 7/16-20 UNF-2A or 1/2-13 UNC-2A... and other parts from becoming disengaged from the vehicle while in service. Reinforcing plates or... projected area. The distance between any edge of the plate and the edge of the bolt hole shall be at least...

49 CFR 571.209 - Standard No. 209; Seat belt assemblies.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., plates, or washers, need not have such hardware, but shall have 7/16-20 UNF-2A or 1/2-13 UNC-2A... and other parts from becoming disengaged from the vehicle while in service. Reinforcing plates or... projected area. The distance between any edge of the plate and the edge of the bolt hole shall be at least...

49 CFR 571.209 - Standard No. 209; Seat belt assemblies.

Code of Federal Regulations, 2011 CFR

2011-10-01

... anchorage nuts, plates, or washers, need not have such hardware, but shall have 7/16-20 UNF-2A or 1/2-13UNC... plates or washers furnished for universal floor, installations shall be of steel, free from burrs and... 2580 mm2 in projected area. The distance between any edge of the plate and the edge of the bolt hole...

Uncertainty and Decision Making

DTIC Science & Technology

1979-09-01

higher productivity and satisfaction than a nonsupportive co-worker and enriched tasks affected attitudes but not performance . The greatest uncertainty...leadership V- 4••,,. • , -9- style, goals, and task HLructure) on psychological uncertainty and the resultant effect on performance and satisfaction . People...turn related to satisfaction and performance . In general, a stric- turing leadership style, specific goals and a structured task result in lower unce

EFFECTS OF INSTILLATION OF RESIDUAL OIL FLY ASH ON INDICES OF CARDIAC, PULMONARY, AND THERMOREGULATORY FUNCTION IN SPONTANEOUSLY HYPERTENSIVE RATS

EPA Science Inventory

EFFECTS OF INSTILLED RESIDUAL OIL FLY ASH (ROFA) ON INDICES OF CARDIAC, PULMONARY, AND THERMOREGULATORY FUNCTION IN SPONTANEOUSLY HYPERTENSIVE (SH) RATS. LB Wichers1, JP Nolan2, UP Kodavanti2, MCJ Schladweiler2, R Hauser3, DW Winsett2, DL Costa2, and WP Watkinson2. 1UNC Sch...

EFFECTS OF INSTILLED EMISSION PARTICULATE MATTER ON ELECTROCARDIOGRAPHIC INDICES AND HEART RATE VARIABILITY (HRV) IN SPONTANEOUSLY HYPERTENSIVE RATS

EPA Science Inventory

EFFECTS OF INSTILLED EMISSION PARTICULATE MATTER (EPM) ON ELECTROCARDIOGRAPHIC INDICES AND HEART RATE VARIABILITY (HRV) IN SPONTANEOUSLY HYPERTENSIVE (SH) RATS. L.B. Wichers1, J.P. Nolan2, W.H. Rowan2, M.J. Campen3, T.P. Jenkins4, D.L. Costa2, and W.P. Watkinson2. 1UNC SPH, Chap...

Human Ozone (O3) Exposure Alters Serum Profile of Lipid Metabolites

EPA Science Inventory

HUMAN OZONE (O3) EXPOSURE ALTERS SERUM PROFILE OF LIPID METABOLITES Miller, D B.1; Kodavanti, U P.2 Karoly, E D.3; Cascio W.E2, Ghio, A J. 21. UNC-Chapel Hill, Chapel Hill, N.C., United States. 2. NHEERL, U.S. EPA, RTP, N.C., United States. 3. METABOLON INC., Durham, N.C., United...

ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING

EPA Science Inventory

ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING

Linskey, C.F.1, Harrison, R.A.2., Zhao, G.3., Barton, H.A., Lipscomb, J.C4., and Evans, M.V2., 1UNC, ESE, Chapel Hill, NC ; 2USEPA, ORD, NHEERL, RTP, NC; 3 UN...

INCREASED IL-8 AND IL-6 EXPRESSION IN HUMAN AIRWAY EPITHELIAL CELLS EXPOSED TO CARBON ULTRAFINE PARTICLES

EPA Science Inventory

INCREASED IL-6 AND IL-8 EXPRESSION IN HUMAN AIRWAY EPITHELIAL CELLS EXPOSED TO CARBON ULTRAFINE PARTICLES.
R Silbajoris1, A G Lenz2, I Jaspers3, J M Samet1. 1NHEERL, USEPA, RTP, NC, USA; 2GSF-Institute for Inhalation Biology, Neuherberg, Germany; 3 CEMLB, UNC-CH, Chapel Hill, ...

EVALUATION OF CHROMOMYCIN A3 ASSAY IN HUMAN SPERM AFTER SIMULATED OVERNIGHT SHIPMENT

EPA Science Inventory

EVALUATION OF CHROMOMYCIN A3ASSAY IN HUMAN SPERM AFTER SIMULATED OVERNIGHT SHIPMENT.
SC Jeffay1, R Morris Buus1, LF Strader1, AF Olshan2, DP Evenson3, SD Perreault1. 1US EPA/ORD, RTP, NC;2UNC-CH, Chapel Hill, NC;3SDSU, Brookings, SD.

Semen collection kits that allow ...

EFFECT OF THREE DIFFERENT SIZED FRACTIONS OF OUTDOOR PM ON INFLAMMATORY AND OXIDATIVE MARKERS IN VIVO

EPA Science Inventory

EFFECT OF THREE DIFFERENT SIZED FRACTIONS OF OUTDOOR PM ON INFLAMMATORY MARKERS IN VIVO
C A J Dick', P Singh2, P. Evansky3, S Becker3 and M I Gilmour3.
'Center For Environmental Medicine and Lung Biology, UNC, Chapel Hill, NC 27599 2NCSU, Raleigh, NC 'Experimental Toxicolog...

CYTOKINE PROFILING FOR CHEMICAL SENSITIZERS: APPLICATION OF THE RIBONUCLEASE PROTECTION ASSAY AND EFFECT OF DOSE

EPA Science Inventory

Cytokine Profiling for Chemical Sensitizers: Application of the Ribonuclease Protection Assay and Effect of Dose. L.M. Plitnick1, S.E. Loveless3, G.S. Ladics3, M.P. Holsapple4, M.J. Selgrade2, D.M. Sailstad2 and R.J. Smialowicz2. 1UNC, Curriculum in Toxicology, Chapel Hill, NC a...

COMPARISON OF PULMONARY RESPONSES TO AUTOMOBILE-GENERATED AND NIST STANDARD REFERENCE MATERIAL DIESEL PARTICULATE EMISSIONS IN MICE

EPA Science Inventory

COMPARISON OF PULMONARY RESPONSES TO AUTOMOBILE-GENERATED AND NIST STANDARD REFERENCE MATERIAL DIESEL PARTICULATE EMISSIONS IN MICE. P. Singh1, C.A.J. Dick2, J. Richards3, M.J. Daniels3, and M.I. Gilmour3. 1NCSU, Raleigh, NC, 2UNC, Chapel Hill, NC and 3 USEPA, ORD, NHEERL, (ETD,...

EXPOSURE PARAMETERS FOR DELAYED PUBERTY AND MAMMARY GLAND DEVELOPMENT IN LONG-EVANS RATS EXPOSED IN UTERO TO ATRAZINE

EPA Science Inventory

Exposure Parameters For Delayed Puberty And Mammary Gland Development In Long-Evans Rats Exposed In Utero To Atrazine

Jennifer L. Rayner1 and Suzanne E. Fenton2

1 UNC-Chapel Hill, DESE, Chapel Hill, NC, and 2 RTD, USEPA, NHEERL/ORD, RTP,NC

Prenatal exposure ...

Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barnash, Kimberly D.; The, Juliana; Norris-Drouin, Jacqueline L.

The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein–protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED’s recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression. By coupling combinatorial chemistry and structure-based design, we optimized a low-affinity methylated jumonji, AT-rich interactive domain 2 (Jarid2) peptide tomore » a smaller, more potent peptidomimetic ligand (K d = 1.14 ± 0.14 μM) of the aromatic cage of EED. Our strategy illustrates the effectiveness of applying combinatorial chemistry to achieve both ligand potency and property optimization. Furthermore, the resulting ligands, UNC5114 and UNC5115, demonstrate that targeted disruption of EED’s reader function can lead to allosteric inhibition of PRC2 catalytic activity.« less

[The study of gene mutations in unknown refractory viral infection and primary hemophagocytic lymphohistiocytosis].

PubMed

Tong, Chun-Rong; Liu, Hong-Xing; Xie, Jian-Jun; Wang, Fang; Cai, Peng; Wang, Hui; Zhu, Juan; Teng, Wen; Zhang, Xian; Yang, Jun-Fang; Zhang, Ya-Li; Fei, Xin-Hong; Zhao, Jie; Yin, Yu-Ming; Wu, Tong; Wang, Jing-Bo; Sun, Yuan; Liu, Rong; Shi, Xiao-Dong; Lu, Dao-Pei

2011-04-01

To study the type and corresponding clinical characteristics of primary hemophagocytic lymphohistiocytosis (HLH) associated immune gene mutations in the refractory virus infection or HLH of unknown causes. From December 2009 to July 2010, the patients with refractory virus infection or HLH of unknown causes were screened for the primary HLH associated immune genes mutations by DNA sequence analysis, including PRF1, UNC13D, STX11, STXBP2, SH2D1A and XIAP. The clinical characteristics and outcomes were followed up. Totally 25 patients with refractory virus infection or HLH of unknown causes were investigated for the 6 genes and 13 cases were found carrying gene mutations, composing of 6 of PRF1 mutation, 3 of UNC13D, and each one of STX11, XIAP, SH2D1A and STXBP2, respectively. Among the 13 cases with gene mutations, 5 suffered from Epstein-Barr virus associated HLH (EBV-HLH), 1 human herpes virus 7 associated HLH (HHV7-HLH), 1 HLH without causes, 4 chronic activated EB virus infection (CAEBV) with 1 progressing to Hodgkin's lymphoma carrying abnormal chromosome of t(15;17) (q22;q25) and hyperdiploid, 2 EBV associated lymphoma. Among the other 12 patients without gene mutation, 4 suffered from EBV-HLH with 1 progressing to peripheral T lymphoma, 8 suffered from CAEBV. Primary HLH associated immune gene mutations are critical causes of refractory virus infection of unknown causes, most patients manifest as HLH, some cases appear in CAEBV and EBV associated lymphoma. DNA sequence analysis is helpful to early diagnosis and correct decision-making for treatment.

Role of Carbohydrate in Glycoprotein Traffic and Secretion

DTIC Science & Technology

1988-01-01

synthesized in normal amounts but accumu- lated intracellularly, with transport to the cell surface being greatly de - layed. Glycoprotein E2 isolated from...UNcLA ,F E 2 Role of Carbohydrate in Glycoprotein Traffic and Secretion JAMES B. PARENT I. Introduction I!. Evidence for Intracellular Transport Signals...Ill. Oligosaccharide Biosynthesis IV. Role of Carbohydrate in Protein Solubility. Structure, and Stability V. Evidence for Carbohydrate Transport

Ensemble kalman filtering to perform data assimilation with soil water content probes and pedotransfer functions in modeling water flow in variably saturated soils

USDA-ARS?s Scientific Manuscript database

Data from modern soil water contents probes can be used for data assimilation in soil water flow modeling, i.e. continual correction of the flow model performance based on observations. The ensemble Kalman filter appears to be an appropriate method for that. The method requires estimates of the unce...

EFFECT OF DOSE ON THE EXCRETION AND METABOLISM OF MONOMETHYLARSONIC ACID IN THE MOUSE

EPA Science Inventory

EFFECT OF DOSE ON THE EXCRETION AND METABOLISM OF MONOMETHYLARSONIC ACID IN THE MOUSE
M F Hughes1, V Devesa2, B C Edwards1, C T Mitchell1, E M Kenyon1, and D J Thomas1. 1US EPA, ORD, NHEERL, ETD, Research Triangle Park, NC; 2UNC-CH, CEMALB, Chapel Hill, NC

Monomethylar...

CONTRIBUTION OF INSPIRATORY FLOW TO ACTIVATION OF EGFR, RAS, MAPK, ATF-2 AND C-JUN DURING LUNG STRETCH

EPA Science Inventory

Contribution of Inspiratory Flow to Activation of EGFR, Ras, MAPK, ATF-2 and c-Jun during Lung Stretch

R. Silbajoris 1, Z. Li 2, J. M. Samet 1 and Y. C. Huang 1. 1 NHEERL, ORD, US EPA, RTP, NC and 2 CEMALB, UNC-CH, Chapel Hill, NC .

Mechanical ventilation with larg...

The Analysis of a Longitudinal Control System for Underwater Vehicles

DTIC Science & Technology

1975-10-01

9 PERFORMING ORGANIZATION NAME AND ADDRESS Naval Coastal Systems Laboratory Panama City, Florida 32401 10. PROGRAM ELEMENT. PROJECT. TASK...TfM.PH) VCNC + 1 ) = 0# U(NC >»QP/UCNC*1 -) V(NC)=0. FORM NEW KFOUCEn COFF »- ICIFVTS Aft 00 A9 T=1#NC 000u6fl<*0 00006660 OOGu6S70 000O68M0

Exploiting Inhibitory Siglecs to Combat Food Allergies

DTIC Science & Technology

2017-10-01

project including mouse handling, liposome preparation, and in vitro assays, such as ELISAs . Shiteng and Kevin Worrell participated in groups...h 2. She also contributed by running some ELISA experiments. Funding Support: N/A Name: Kelly Orgel Project Role: Graduate Student (UNC...flow cytometry, and ELISA . Kelly performed the human CD33 basophil assays as well. Funding Support: N/A Name: Johanna Smeekens, PhD Project

Sub-Saharan Africa Report No. 2843.

DTIC Science & Technology

1983-09-14

Quota System Lifted 33 University Students Boycott Classes 33 Higher University Fees Protested 33 Labor Unions Decline UDF Membership 33 Progress...Friday that Mr Biya might shortly summon a special congress of the country’s only political party, the Cameroon National Union (UNC). Its...understanding of the Soviet Union in its struggle against colonialism, Neocolonialism and apartheid. The OAU secretary general expressed gratitude for the

Engineered Muscle Actuators: Cells and Tissues

DTIC Science & Technology

2007-01-10

tissue culture perfusion bioreactors The UNC group led the development of the final version of the integrated cell culture bioreactor . The system was...construct engineered in vitro from primary mammalian cells (C) The first demonstration of developmental improvements in engineered tendon constitutive...2007 Final Performance Report 1 Nov 2004 - 31 Oct 2006 4. TITLE AND SUBTITLE 5.. CONTRACT NUMBER Engineered Muscle Actuators: Cells and Tissues FA9550

Continued Optical Sensor Operations in a Laser Environment

DTIC Science & Technology

2011-02-16

CANADA G3J 1X5; cMIPS UHA, 61 rue Albert Camus , Mulhouse, FRANCE 68200, http://pubs.drdc.gc.ca/PDFS/unc00/p533547_A1b.pdf (accessed 16 January 2011...Cassagnou, Saint-Louis, FRANCE 68300; bDRDC-Valcartier, 2459 Pie-XI Blvd North, Quebec, QC, CANADA G3J 1X5; cMIPS UHA, 61 rue Albert Camus , Mulhouse

Learning From Errors in Ambulatory Pediatrics

DTIC Science & Technology

2005-01-01

355 Learning from Errors in Ambulatory Pediatrics Julie J. Mohr, Carole M. Lannon, Kathleen A. Thoma, Donna Woods, Eric J. Slora, Richard C...for Healthcare Research and Quality (AHRQ) as part of the University of North Carolina (UNC) Center for Education and Research on Therapeutics...CERTs), in partnership with the American Academy of Pediatrics (AAP) Pediatric Research in Office Settings (PROS) Network. Purpose: Learning from Errors

UNC Cancer Center Director to Lead NCI.

PubMed

2017-08-01

President Donald Trump has selected Norman "Ned" Sharpless, MD, director of the University of North Carolina Lineberger Comprehensive Cancer Center, to lead the NCI. The news was met with widespread approval among cancer researchers, who view Sharpless as a strong communicator who can ably represent the needs of the cancer community in the face of proposed funding cuts. ©2017 American Association for Cancer Research.

Women and Children First: Report of the UNCED/UNICEF/UNFPA Symposium on the Impact of Poverty and Environmental Degradation on Women and Children (Geneva, Switzerland, May 27-30, 1991).

ERIC Educational Resources Information Center

United Nations Conference on Environment and Development, Conches (Switzerland).

The symposium examined the impact of poverty and environmental degradation on women and children and assessed women's real and potential contributions to sustainable development through their knowledge of natural resources. Participants included experts and resource people involved in grassroots activities throughout the world. This report…

Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms

PubMed Central

Abongwa, Melanie; Buxton, Samuel K.; Robertson, Alan P.; Martin, Richard J.

2016-01-01

Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM derquantel alone and in combination with 0.3 μM abamectin. We found that derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics. PMID:26751958

Low-background germanium radioassay for the MAJORANA Collaboration

NASA Astrophysics Data System (ADS)

Trimble, James E., Jr.

The focus of the MAJORANA COLLABORATION is the search for nuclear neutrinoless double beta decay. If discovered, this process would prove that the neutrino is its own anti-particle, or a M AJORANA particle. Being constructed at the Sanford Underground Research Facility, the MAJORANA DEMONSTRATOR aims to show that a background rate of 3 counts per region of interest (ROI) per tonne per year in the 4 keV ROI surrounding the 2039-keV Q-value energy of 76Ge is achievable and to demonstrate the technological feasibility of building a tonne-scale Ge-based experiment. Because of the rare nature of this process, detectors in the system must be isolated from ionizing radiation backgrounds as much as possible. This involved building the system with materials containing very low levels of naturally- occurring and anthropogenic radioactive isotopes at a deep underground site. In order to measure the levels of radioactive contamination in some components, the Majorana Demonstrator uses a low background counting facility managed by the Experimental Nuclear and Astroparticle Physics (ENAP) group at UNC. The UNC low background counting (LBC) facility is located at the Kimballton Underground Research Facility (KURF) located in Ripplemead, VA. The facility was used for a neutron activation analysis of samples of polytetrafluoroethylene (PTFE) and fluorinated ethylene propylene (FEP) tubing intended for use in the Demonstrator. Calculated initial activity limits (90% C.L.) of 238U and 232Th in the 0.002-in PTFE samples were 7.6 ppt and 5.1 ppt, respectively. The same limits in the FEP tubing sample were 150 ppt and 45 ppt, respectively. The UNC LBC was also used to gamma-assay a modified stainless steel flange to be used as a vacuum feedthrough. Trace activities of both 238U and 232Th were found in the sample, but all were orders of magnitude below the acceptable threshold for the Majorana experiment. Also discussed is a proposed next generation ultra-low background system designed to utilize technology designed for the Majorana Demonstrator. Fi- nally, a discussion is presented on the design and construction of an azimuthal scanner used by the Majorana collaboration.

Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species

PubMed Central

Blanchard, Alexandra; Charvet, Claude L.; Sauvé, Christine; Duguet, Thomas; O’Connor, Vincent; Castagnone-Sereno, Philippe; Wolstenholme, Adrian J.; Beech, Robin N.; Holden-Dye, Lindy

2018-01-01

Cholinergic agonists such as levamisole and pyrantel are widely used as anthelmintics to treat parasitic nematode infestations. These drugs elicit spastic paralysis by activating acetylcholine receptors (AChRs) expressed in nematode body wall muscles. In the model nematode Caenorhabditis elegans, genetic screens led to the identification of five genes encoding levamisole-sensitive-AChR (L-AChR) subunits: unc-38, unc-63, unc-29, lev-1 and lev-8. These subunits form a functional L-AChR when heterologously expressed in Xenopus laevis oocytes. Here we show that the majority of parasitic species that are sensitive to levamisole lack a gene orthologous to C. elegans lev-8. This raises important questions concerning the properties of the native receptor that constitutes the target for cholinergic anthelmintics. We demonstrate that the closely related ACR-8 subunit from phylogenetically distant animal and plant parasitic nematode species functionally substitutes for LEV-8 in the C. elegans L-AChR when expressed in Xenopus oocytes. The importance of ACR-8 in parasitic nematode sensitivity to cholinergic anthelmintics is reinforced by a ‘model hopping’ approach in which we demonstrate the ability of ACR-8 from the hematophagous parasitic nematode Haemonchus contortus to fully restore levamisole sensitivity, and to confer high sensitivity to pyrantel, when expressed in the body wall muscle of C. elegans lev-8 null mutants. The critical role of acr-8 to in vivo drug sensitivity is substantiated by the successful demonstration of RNAi gene silencing for Hco-acr-8 which reduced the sensitivity of H. contortus larvae to levamisole. Intriguingly, the pyrantel sensitivity remained unchanged thus providing new evidence for distinct modes of action of these important anthelmintics in parasitic species versus C. elegans. More broadly, this highlights the limits of C. elegans as a predictive model to decipher cholinergic agonist targets from parasitic nematode species and provides key molecular insight to inform the discovery of next generation anthelmintic compounds. PMID:29719008

UbSRD: The Ubiquitin Structural Relational Database.

PubMed

Harrison, Joseph S; Jacobs, Tim M; Houlihan, Kevin; Van Doorslaer, Koenraad; Kuhlman, Brian

2016-02-22

The structurally defined ubiquitin-like homology fold (UBL) can engage in several unique protein-protein interactions and many of these complexes have been characterized with high-resolution techniques. Using Rosetta's structural classification tools, we have created the Ubiquitin Structural Relational Database (UbSRD), an SQL database of features for all 509 UBL-containing structures in the PDB, allowing users to browse these structures by protein-protein interaction and providing a platform for quantitative analysis of structural features. We used UbSRD to define the recognition features of ubiquitin (UBQ) and SUMO observed in the PDB and the orientation of the UBQ tail while interacting with certain types of proteins. While some of the interaction surfaces on UBQ and SUMO overlap, each molecule has distinct features that aid in molecular discrimination. Additionally, we find that the UBQ tail is malleable and can adopt a variety of conformations upon binding. UbSRD is accessible as an online resource at rosettadesign.med.unc.edu/ubsrd. Copyright © 2015 Elsevier Ltd. All rights reserved.

Excitatory motor neurons are local oscillators for backward locomotion

PubMed Central

Guan, Sihui Asuka; Fouad, Anthony D; Meng, Jun; Kawano, Taizo; Huang, Yung-Chi; Li, Yi; Alcaire, Salvador; Hung, Wesley; Lu, Yangning; Qi, Yingchuan Billy; Jin, Yishi; Alkema, Mark; Fang-Yen, Christopher

2018-01-01

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron’s oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron’s intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network. PMID:29360035

Excitatory motor neurons are local oscillators for backward locomotion.

PubMed

Gao, Shangbang; Guan, Sihui Asuka; Fouad, Anthony D; Meng, Jun; Kawano, Taizo; Huang, Yung-Chi; Li, Yi; Alcaire, Salvador; Hung, Wesley; Lu, Yangning; Qi, Yingchuan Billy; Jin, Yishi; Alkema, Mark; Fang-Yen, Christopher; Zhen, Mei

2018-01-23

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron's oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron's intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network. © 2017, Gao et al.

3-Decylcatechol induces autophagy-mediated cell death through the IRE1α/JNK/p62 in hepatocellular carcinoma cells

PubMed Central

Kim, Jin-A; Jo, In-Hwa; Han, Yeon Soo; Jo, Yong Hun; Kim, Kwang-Youn; Seo, Young-Kyo; Moon, Jae-Hak; Jung, Chang Hwa; Jeon, Tae-Il

2017-01-01

The natural, phenolic lipid urushiol exhibits both antioxidant and anticancer activities; however, its biological activity on hepatocellular carcinoma (HCC) has not been previously investigated. Here, we demonstrate that an urushiol derivative, 3-decylcatechol (DC), induces human HCC Huh7 cell death by induction of autophagy. DC initiates the autophagic process by activation of the mammalian target of rapamycin signaling pathway via Unc-51-like autophagy activating kinase 1, leading to autophagosome formation. The autophagy inhibitor, chloroquine, suppressed autolysosome formation and cell death induction by DC, indicating an autophagic cell death. Interestingly, DC also activated the endoplasmic reticulum (ER) stress response that promotes autophagy via p62 transcriptional activation involving the inositol-requiring enzyme 1α/c-Jun N-terminal kinase/c-jun pathway. We also show that cytosolic calcium mobilization is necessary for the ER stress response and autophagy induction by DC. These findings reveal a novel mechanism by which this urushiol derivative induces autophagic cell death in HCC. PMID:28938597

Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.

PubMed

Li, Ran; Yuan, Fengjie; Fu, Wan; Zhang, Luyao; Zhang, Nan; Wang, Yanan; Ma, Ke; Li, Xue; Wang, Lina; Zhu, Wei-Guo; Zhao, Ying

2017-02-17

The serine/threonine kinase Unc-51-like kinase-1 (Ulk1) is thought to be essential for induction of autophagy, an intracellular bulk degradation process that is activated by various stresses. Although several proteins have been suggested as Ulk1 substrates during autophagic process, it still remains largely unknown about Ulk1's physiological substrates. Here, by performing in vitro and in vivo phosphorylation assay, we report that the co-chaperone cell division cycle protein 37 (Cdc37) is a Ulk1 substrate. Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90. Because the recruitment of protein kinase clients to the Hsp90 complex is essential for their stability and functions, Ser-339 phosphorylation of Cdc37 disrupts its ability as a co-chaperone to coordinate Hsp90. Hsp90 inhibitors are cancer chemotherapeutic agents by inducing depletion of clients, many of which are oncogenes. Upon treatment with an Hsp90 inhibitor in cancer cells, Ulk1 promoted the degradation of Hsp90-Cdc37 client kinases, resulting in increased cellular sensitivity to Hsp90 inhibitors. Thus, our study provides evidence for an anti-proliferative role of Ulk1 in response to Hsp90 inhibition in cancer cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Mental hoop diaries: Emotional memories of a college basketball game in rival fans

PubMed Central

Botzung, Anne; Rubin, David C.; Miles, Amanda; Cabeza, Roberto; LaBar, Kevin S.

2012-01-01

The rivalry between the men’s basketball teams of Duke University and the University of North Carolina-Chapel Hill (UNC) is one of the most storied traditions in college sports. A subculture of students at each university form social bonds with fellow fans, develop expertise in college basketball rules, team statistics, and individual players, and self-identify as a member of a fan group. The present study capitalized on the high personal investment of these fans and the strong affective tenor of a Duke-UNC basketball game to examine the neural correlates of emotional memory retrieval for a complex sporting event. Male fans watched a competitive, archived game in a social setting. During a subsequent functional magnetic resonance imaging session, participants viewed video clips depicting individual plays of the game that ended with the ball being released towards the basket. For each play, participants recalled whether or not the shot went into the basket. Hemodynamic signal changes time-locked to correct memory decisions were analyzed as a function of emotional intensity and valence, according to the fan’s perspective. Results showed intensity-modulated retrieval activity in midline cortical structures, sensorimotor cortex, the striatum, and the medial temporal lobe, including the amygdala. Positively-valent memories specifically recruited processing in dorsal frontoparietal regions, and additional activity in the insula and medial temporal lobe for positively-valent shots recalled with high confidence. This novel paradigm reveals how brain regions implicated in emotion, memory retrieval, visuomotor imagery, and social cognition contribute to the recollection of specific plays in the mind of a sports fan. PMID:20147540

Enhancement of anesthesiology in-training exam performance with institution of an academic improvement policy.

PubMed

Joseph, Julie A; Terry, Chris M; Waller, Eva J; Bortsov, Andrey V; Zvara, David A; Mayer, David C; Martinelli, Susan M

2014-01-01

Anesthesiology resident physicians across the United States complete an annual in-training examination (ITE). The ITE evaluates resident knowledge and provides personalized feedback to guide future study in low scoring sections(1). Performance on the ITE correlates with outcomes on the American Board of Anesthesiology (ABA) written board examination(2). Over the last several years, declining ITE scores were observed at the University of North Carolina (UNC). In response to this decline, our department reprioritized the ITE by instituting an academic improvement policy (AIP). The AIP employed both reward for satisfactory achievement and consequence for under-performance to elevate the ITE as a "high stakes" examination. Our hypothesis was that implementation of this AIP would improve ITE scores. ITE scores were compiled from 150 residents in the Department of Anesthesiology at UNC for graduating classes from 2004-2015. Data is presented as the number of residents scoring below the 20th percentile when compared to the national distribution before and after the AIP. In addition, average USMLE Step 1 three-digit scores for each graduating class were compared to average ITE percentile scores of the corresponding graduating class (USMLE does not provide percentile scores). Between 2009 and 2013, the number of residents who scored below the 20th percentile on the ITE increased steadily to a peak of 10 in 2011. After implementation of the AIP in July 2011, there was an 80% decrease in those scoring below the 20th percentile, from 10 to 2 residents (p<0.05). Anesthesiology resident ITE scores improved after implementation of an academic improvement policy.

A Pre- and Co-Knockdown of RNAseT Enzyme, Eri-1, Enhances the Efficiency of RNAi Induced Gene Silencing in Caenorhabditis elegans

PubMed Central

Jadiya, Pooja; Nazir, Aamir

2014-01-01

Background The approach of RNAi mediated gene knockdown, employing exogenous dsRNA, is being beneficially exploited in various fields of functional genomics. The immense utility of the approach came to fore from studies with model system C. elegans, but quickly became applicable with varied research models ranging from in vitro to various in vivo systems. Previously, there have been reports on the refractoriness of the neuronal cells to RNAi mediated gene silencing following which several modulators like eri-1 and lin-15 were described in C. elegans which, when present, would negatively impact the gene knockdown. Methodology/Principal Findings Taking a clue from these findings, we went on to screen hypothesis-driven- methodologies towards exploring the efficiency in the process of RNAi under various experimental conditions, wherein these genes would be knocked down preceding to, or concurrently with, the knocking down of a gene of interest. For determining the efficiency of gene knockdown, we chose to study visually stark phenotypes of uncoordinated movement, dumpy body morphology and blistered cuticle obtained by knocking down of genes unc-73, dpy-9 and bli-3 respectively, employing the RNAi-by-feeding protocol in model system C. elegans. Conclusions/Significance Our studies led to a very interesting outcome as the results reveal that amongst various methods tested, pre-incubation with eri-1 dsRNA synthesizing bacteria followed by co-incubation with eri-1 and gene-of-interest dsRNA synthesizing bacteria leads to the most efficient gene silencing as observed by the analysis of marker phenotypes. This provides an approach for effectively employing RNAi induced gene silencing while working with different genetic backgrounds including transgenic and mutant strains. PMID:24475317

Analysis of host microRNA function uncovers a role for miR-29b-2-5p in Shigella capture by filopodia

PubMed Central

Silva, Ricardo Jorge; Cruz, Ana Rita; Mano, Miguel

2017-01-01

MicroRNAs play an important role in the interplay between bacterial pathogens and host cells, participating as host defense mechanisms, as well as exploited by bacteria to subvert host cellular functions. Here, we show that microRNAs modulate infection by Shigella flexneri, a major causative agent of bacillary dysentery in humans. Specifically, we characterize the dual regulatory role of miR-29b-2-5p during infection, showing that this microRNA strongly favors Shigella infection by promoting both bacterial binding to host cells and intracellular replication. Using a combination of transcriptome analysis and targeted high-content RNAi screening, we identify UNC5C as a direct target of miR-29b-2-5p and show its pivotal role in the modulation of Shigella binding to host cells. MiR-29b-2-5p, through repression of UNC5C, strongly enhances filopodia formation thus increasing Shigella capture and promoting bacterial invasion. The increase of filopodia formation mediated by miR-29b-2-5p is dependent on RhoF and Cdc42 Rho-GTPases. Interestingly, the levels of miR-29b-2-5p, but not of other mature microRNAs from the same precursor, are decreased upon Shigella replication at late times post-infection, through degradation of the mature microRNA by the exonuclease PNPT1. While the relatively high basal levels of miR-29b-2-5p at the start of infection ensure efficient Shigella capture by host cell filopodia, dampening of miR-29b-2-5p levels later during infection may constitute a bacterial strategy to favor a balanced intracellular replication to avoid premature cell death and favor dissemination to neighboring cells, or alternatively, part of the host response to counteract Shigella infection. Overall, these findings reveal a previously unappreciated role of microRNAs, and in particular miR-29b-2-5p, in the interaction of Shigella with host cells. PMID:28394930

Analysis of host microRNA function uncovers a role for miR-29b-2-5p in Shigella capture by filopodia.

PubMed

Sunkavalli, Ushasree; Aguilar, Carmen; Silva, Ricardo Jorge; Sharan, Malvika; Cruz, Ana Rita; Tawk, Caroline; Maudet, Claire; Mano, Miguel; Eulalio, Ana

2017-04-01

MicroRNAs play an important role in the interplay between bacterial pathogens and host cells, participating as host defense mechanisms, as well as exploited by bacteria to subvert host cellular functions. Here, we show that microRNAs modulate infection by Shigella flexneri, a major causative agent of bacillary dysentery in humans. Specifically, we characterize the dual regulatory role of miR-29b-2-5p during infection, showing that this microRNA strongly favors Shigella infection by promoting both bacterial binding to host cells and intracellular replication. Using a combination of transcriptome analysis and targeted high-content RNAi screening, we identify UNC5C as a direct target of miR-29b-2-5p and show its pivotal role in the modulation of Shigella binding to host cells. MiR-29b-2-5p, through repression of UNC5C, strongly enhances filopodia formation thus increasing Shigella capture and promoting bacterial invasion. The increase of filopodia formation mediated by miR-29b-2-5p is dependent on RhoF and Cdc42 Rho-GTPases. Interestingly, the levels of miR-29b-2-5p, but not of other mature microRNAs from the same precursor, are decreased upon Shigella replication at late times post-infection, through degradation of the mature microRNA by the exonuclease PNPT1. While the relatively high basal levels of miR-29b-2-5p at the start of infection ensure efficient Shigella capture by host cell filopodia, dampening of miR-29b-2-5p levels later during infection may constitute a bacterial strategy to favor a balanced intracellular replication to avoid premature cell death and favor dissemination to neighboring cells, or alternatively, part of the host response to counteract Shigella infection. Overall, these findings reveal a previously unappreciated role of microRNAs, and in particular miR-29b-2-5p, in the interaction of Shigella with host cells.

Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations.

PubMed

Xue, Jing; Schoenrock, Sarah A; Valdar, William; Tarantino, Lisa M; Ideraabdullah, Folami Y

2016-01-01

Environmental perturbation of epigenetic mechanisms is linked to a growing number of diseases. Characterizing the role environmental factors play in modifying the epigenome is important for disease etiology. Vitamin D is an essential nutrient affecting brain, bone, heart, immune and reproductive health. Vitamin D insufficiency is a global issue, and the role in maternal and child health remains under investigation. We used Collaborative Cross (CC) inbred mice to characterize the effect of maternal vitamin D depletion on offspring phenotypic and epigenetic outcomes at imprinted domains ( H19/Igf2 , Snrpn , Dlk1/Gtl2 , and Grb10 ) in the soma (liver) and germline (sperm). We assessed outcomes in two generations of offspring to determine heritability. We used reciprocal crosses between lines CC001/Unc and CC011/Unc to investigate parent of origin effects. Maternal vitamin D deficiency led to altered body weight and DNA methylation in two generations of offspring. Loci assayed in adult liver and sperm were mostly hypomethylated, but changes were few and small in effect size (<7 % difference on average). There was no change in total expression of genes adjacent to methylation changes in neonatal liver. Methylation changes were cell type specific such that changes at IG-DMR were present in sperm but not in liver. Some methylation changes were distinct between generations such that methylation changes at the H19ICR in second-generation liver were not present in first-generation sperm or liver. Interestingly, some diet-dependent changes in body weight and methylation were seemingly influenced by parent of origin such that reciprocal crosses exhibited inverse effects. These findings demonstrate that maternal vitamin D status plays a role in determining DNA methylation state in the germline and soma. Detection of methylation changes in the unexposed second-generation demonstrates that maternal vitamin D depletion can have long-term effects on the epigenome of subsequent generations. Differences in vitamin D-dependent epigenetic state between cell types and generations indicate perturbation of the epigenetic landscape rather than a targeted, locus-specific effect. While the biological importance of these subtle changes remains unclear, they warrant an investigation of epigenome-wide effects of maternal vitamin D depletion.

4 Birds 1 Stone to Inhibit 5androstane-3alpha,17beta-diol Conversion to DHT

DTIC Science & Technology

2016-09-01

GFP and ARE-luciferase were tested by our laboratory and the Roswell Park Cancer Institute Small Molecule Screening Facility (SMSF). PC-3 cells that...outside UNC-Lineberger Comprehensive Cancer and Roswell Park Cancer Institute. Administration Core A will have direct responsibility for organization...Supporting Agency: Roswell Park Alliance Foundation Name and address of the Funding Agency’s Procuring Contracting/Grants Officer: Judith Epstein

Aircraft Mishap Fire Pattern Investigations

DTIC Science & Technology

1985-08-01

AD-AI61 094 AIRC1Arr WSWEA FlREg PATMEN INVESTIGATIONS . Joseph M. Kuchta Mining and industrial Cadre15143 Green latetrutiovalp 𔃻nco 54 Sewickley...ORGANIZATION REPORT NUMSER(S) AFWAL-TR-85-2057 6. NAME OF PERFORMING ORGANIZATION kb. OFFICE SYMBOL 7a. NAME OF MONITORING ORGANIZATION Mining and Industrial...IS OBSOLETE. Unc .assi fied SECURITY CLASSIFICATION OF THIS PAGE ( / FOREWARD This report was prepared by the Mining and Industrial Cadre of Green

Impact of diet on ozone-induced pulmonary and systemic effects in female Brown Norway (BN) rats

EPA Science Inventory

Impact of diet on ozone-induced pulmonary and systemic effects in female Brown Norway (BN) ratsV.L. Bass1, M.C. Schladweiler2, S. Snow5, C.J. Gordon4, K.A. Jarema4, P. Phillips4, A.D. Ledbetter2, D.B. Miller3, J.E. Richards2, U.P. Kodavanti2. 1. SPH, UNC, Chapel Hill2. EPHD, NHE...

UNC Collaboratory Project: Overview

DTIC Science & Technology

1990-11-01

technical, and other expository documents. Crucial to our success has been the selection of driving problems whose solutions have been of significance not...systems, and with the growing necessity for "team science", we believe the time is right to select a new driving problem -- support for multiple...the WE computer system. The WE system includes sensors imbedded within it that record each users’ action These records include each menu selection

Psychophysics, reliability, and norm values for temporal contrast sensitivity implemented on the two alternative forced choice C-Quant device.

PubMed

van den Berg, Thomas J T P; Franssen, Luuk; Kruijt, Bastiaan; Coppens, Joris E

2011-08-01

The current paper describes the design and population testing of a flicker sensitivity assessment technique corresponding to the psychophysical approach for straylight measurement. The purpose is twofold: to check the subjects' capability to perform the straylight test and as a test for retinal integrity for other purposes. The test was implemented in the Oculus C-Quant straylight meter, using homemade software (MATLAB). The geometry of the visual field lay-out was identical, as was the subjects' 2AFC task. A comparable reliability criterion ("unc") was developed. Outcome measure was logTCS (temporal contrast sensitivity). The population test was performed in science fair settings on about 400 subjects. Moreover, 2 subjects underwent extensive tests to check whether optical defects, mimicked with trial lenses and scatter filters, affected the TCS outcome. Repeated measures standard deviation was 0.11 log units for the reference population. Normal values for logTCS were around 2 (threshold 1%) with some dependence on age (range 6 to 85 years). The test outcome did not change upon a tenfold (optical) deterioration in visual acuity or straylight. The test has adequate precision for checking a subject's capability to perform straylight assessment. The unc reliability criterion ensures sufficient precision, also for assessment of retinal sensitivity loss.

Phylum-Level Conservation of Regulatory Information in Nematodes despite Extensive Non-coding Sequence Divergence

PubMed Central

Gordon, Kacy L.; Arthur, Robert K.; Ruvinsky, Ilya

2015-01-01

Gene regulatory information guides development and shapes the course of evolution. To test conservation of gene regulation within the phylum Nematoda, we compared the functions of putative cis-regulatory sequences of four sets of orthologs (unc-47, unc-25, mec-3 and elt-2) from distantly-related nematode species. These species, Caenorhabditis elegans, its congeneric C. briggsae, and three parasitic species Meloidogyne hapla, Brugia malayi, and Trichinella spiralis, represent four of the five major clades in the phylum Nematoda. Despite the great phylogenetic distances sampled and the extensive sequence divergence of nematode genomes, all but one of the regulatory elements we tested are able to drive at least a subset of the expected gene expression patterns. We show that functionally conserved cis-regulatory elements have no more extended sequence similarity to their C. elegans orthologs than would be expected by chance, but they do harbor motifs that are important for proper expression of the C. elegans genes. These motifs are too short to be distinguished from the background level of sequence similarity, and while identical in sequence they are not conserved in orientation or position. Functional tests reveal that some of these motifs contribute to proper expression. Our results suggest that conserved regulatory circuitry can persist despite considerable turnover within cis elements. PMID:26020930

New paleontological and geological data on the Ordovician and Silurian of Bolivia

NASA Astrophysics Data System (ADS)

Gagnier, P. Y.; Blieck, A.; Emig, C. C.; Sempere, T.; Vachard, D.; Vanguestaine, M.

1996-11-01

The oldest vertebrates of South America are from the thick Anzaldo (=Cuchupunata) Formation in central Bolivia. At the scale of the basin, the Anzaldo is overlain by the San Benito, Tokochi, Cancañiri, Llallagua and Kirusillas/Uncía formations. The Anzaldo was classically dated Caradoc (early Late Ordovician), but recent paleontological data have suggested a Llanvirn age (early Middle Ordovician). The only significant fossil invertebrates recently collected in the Anzaldo, viz., lingulid brachiopods, give an age not older than Late Ordovician. Fossils from the Tokochi suggest a Caradoc age. The microfossils (acritarchs and foraminifers mainly) collected in the Cancañiri and Kirusillas/Uncía formations indicate an Ashgill to Wenlock age (late Late Ordovician to late Early Silurian) for these formations. A Caradoc (or perhaps older) age thus seems more correct for the Anzaldo Formation. These new paleontological data have major implications on our knowledge of the Ordovician-Silurian basins of Bolivia: 1) transition from a Middle Ordovician marine foreland basin to a Late Ordovician-Llandovery glacial-marine to turbidite trough in the Altiplano occurred in the (late?) Caradoc; 2) a major sea-level rise developed around the Llandovery-Wenlock boundary; 3) a fossiliferous limestone member of shallow origin and early Wenlock age is present approximately between Cochabamba and Santa Cruz.

Morphogenesis of the C. elegans Intestine Involves Axon Guidance Genes

PubMed Central

Asan, Alparsan; Raiders, Stephan A.; Priess, James R.

2016-01-01

Genetic and molecular studies have provided considerable insight into how various tissue progenitors are specified in early embryogenesis, but much less is known about how those progenitors create three-dimensional tissues and organs. The C. elegans intestine provides a simple system for studying how a single progenitor, the E blastomere, builds an epithelial tube of 20 cells. As the E descendants divide, they form a primordium that transitions between different shapes over time. We used cell contours, traced from confocal optical z-stacks, to build a 3D graphic reconstruction of intestine development. The reconstruction revealed several new aspects of morphogenesis that extend and clarify previous observations. The first 8 E descendants form a plane of four right cells and four left cells; the plane arises through oriented cell divisions and VANG-1/Van Gogh-dependent repositioning of any non-planar cells. LIN-12/Notch signaling affects the left cells in the E8 primordium, and initiates later asymmetry in cell packing. The next few stages involve cell repositioning and intercalation events that shuttle cells to their final positions, like shifting blocks in a Rubik’s cube. Repositioning involves breaking and replacing specific adhesive contacts, and some of these events involve EFN-4/Ephrin, MAB-20/semaphorin-2a, and SAX-3/Robo. Once cells in the primordium align along a common axis and in the correct order, cells at the anterior end rotate clockwise around the axis of the intestine. The anterior rotation appears to align segments of the developing lumen into a continuous structure, and requires the secreted ligand UNC-6/netrin, the receptor UNC-40/DCC, and an interacting protein called MADD-2. Previous studies showed that rotation requires a second round of LIN-12/Notch signaling in cells on the right side of the primordium, and we show that MADD-2-GFP appears to be downregulated in those cells. PMID:27035721

The predicted impact of VOCs from Marijuana cultivation operations on ozone concentrations in great Denver, CO.

NASA Astrophysics Data System (ADS)

Wang, C. T.; Vizuete, W.; Wiedinmyer, C.; Ashworth, K.

2016-12-01

Colorado is the first the marijuana legal states in the United States since 2014. As a result, thousands of legal Marijuana cultivation operations are at great Denver area now. Those Marijuana cultivation operations could be the potential to release a lot of biogenic VOCs, such as monoterpene(C10H16), alpha-pinene, and D-limonene. Those alkene species could rapidly increase the peroxy radicals and chemical reactions in the atmosphere, especially in the urban area which belong to VOC-limited ozone regime. These emissions will increase the ozone in Denver city, where is ozone non-attainment area. Some previous research explained the marijuana smoke and indoor air quality (Martyny, Serrano, Schaeffer, & Van Dyke, 2013) and the smell of marijuana chemical compounds(Rice & Koziel, 2015). However, there have been no studies discuss on identifying and assessing emission rate from marijuana and how those species impact on atmospheric chemistry and ozone concentration, and the marijuana emissions have been not considered in the national emission inventory, either. This research will use air quality model to identify the possibility of ozone impact by marijuana cultivation emission. The Comprehensive Air Quality Model with Extensions, CAMx, are applied for this research to identify the impact of ozone concentration. This model is government regulatory model based on the Three-State Air Quality Modeling Study (3SAQS), which developed by UNC-Chapel Hill and ENVIRON in 2012. This model is used for evaluation and regulate the ozone impact in ozone non-attainment area, Denver city. The details of the 3SAQS model setup and protocol can be found in the 3SAQS report(UNC-IE, 2013). For the marijuana emission study scenarios, we assumed the monoterpene (C10H16) is the only emission species in air quality model and identify the ozone change in the model by the different quantity of emission rate from marijuana cultivation operations.

Cigarette Smoking Predicts Differential Benefit from Naltrexone for Alcohol Dependence

PubMed Central

Fucito, Lisa M.; Park, Aesoon; Gulliver, Suzy Bird; Mattson, Margaret E.; Gueorguieva, Ralitza V.; O’Malley, Stephanie S.

2012-01-01

Background Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. Methods We examined the association between cigarette smoking and drinking outcomes in the COMBINE study, a randomized, double-blind placebo-controlled 16-week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management (MM), combined behavioral therapy (CBI)) in 1383 alcohol dependent individuals. Results Smokers (i.e., more than half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received CBI or MM and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. Conclusions These results suggest that naltrexone may be particularly beneficial for improving alcohol use outcomes in alcohol dependent smokers. Trial Registration The COMBINE Study, NCT000626, http://www.cscc.unc.edu/combine/. PMID:22541040

Behavioral deficits and neural damage of Caenorhabditis elegans induced by three rare earth elements.

PubMed

Xu, Tiantian; Zhang, Manke; Hu, Jiani; Li, Zihan; Wu, Taipu; Bao, Jianing; Wu, Siyu; Lei, Lili; He, Defu

2017-08-01

Rare earth elements (REEs) are widely used in industry, agriculture, medicine and daily life in recent years. However, environmental and health risks of REEs are still poorly understood. In this study, neurotoxicity of trichloride neodymium, praseodymium and scandium were evaluated using nematode Caenorhabditis elegans as the assay system. Median lethal concentrations (48 h) were 99.9, 157.2 and 106.4 mg/L for NdCl 3 , PrCl 3 and ScCl 3 , respectively. Sublethal dose (10-30 mg/L) of these trichloride salts significantly inhibited body length of nematodes. Three REEs resulted in significant declines in locomotor frequency of body bending, head thrashing and pharyngeal pumping. In addition, mean speed and wavelength of crawling movement were significantly reduced after chronic exposure. Using transgenic nematodes, we found NdCl 3 , PrCl 3 and ScCl 3 resulted in loss of dendrite and soma of neurons, and induced down-expression of dat-1::GFP and unc-47::GFP. It indicates that REEs can lead to damage of dopaminergic and GABAergic neurons. Our data suggest that exposure to REEs may cause neurotoxicity of inducing behavioral deficits and neural damage. These findings provide useful information for understanding health risk of REE materials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Incorporating Temporal Information in Microblog Retrieval

DTIC Science & Technology

2012-11-01

Urbana-Champaign Urbana-Champaign, IL, USA willis8@illinois.edu Richard Medlin School of Information & Library Science University of North Carolina at...Chapel Hill Chapel Hill, NC, USA rich_medlin@med.unc.edu Jaime Arguello † School of Information & Library Science University of North Carolina at...published prior to time tQ. The School of Information and Library Science at the Uni- versity of Carolina at Chapel Hill submitted four runs to the Microblog

UNC Center for Dynamic Combinatorial Chemistry

DTIC Science & Technology

2014-04-09

Thioester Exchange, Organic Letters (04 2010) Chung, Schiltz, Lee, and Gagne. The Effect of Gas-Phase Reactions on the Quantitation of Cyclic...Figure 6.1c) These monomers have L-tryptophan, L-leucine, L- phenylalanine , and the sequential L-proline and D-proline functions. These functions...are known as the parts of three hydrophobic side chains in the tumor suppressor protein p53 and make direct contacts deep in the MDM2 cleft (Figure

Single Stage Rocket Technology (SSRT) DC-X Test Program Environmental Assessment

DTIC Science & Technology

1992-06-01

23). 2.2.1.5 Cultural Resources Section 106 of the National Historic Preservation Act (NHPA) requires Federal agencies to consider the affects of...were coordinated with the New Mexico State Historic Preservation Office. June 1992 UncLassified 2-7 EaWronmemW~ AWsnevssln SSRT Habitat lor White... Preservation (ACHP), and the New Mexico State Historic Preservation Office. Compliance with Section 106 of the National Historic Preservation Act for the

Pumping Performance and Turbidity Generation of Model 600/100 PNEUMA Pump. Main Text and Appendixes A and B.

DTIC Science & Technology

1982-04-01

E. Hite, Jr. Richard A. Shafer James D. Ethridge, Jr. 9 . PERFORMING ORGANIZATION NAME AND ADDRESS i0. PROGRAM ELEMENT. PROJECT. TASK AREA A WORK UNIT...Appendix C (bound separately) contains tables of measured dat a and cal-LnIuated parameters interpolated at 9 -sec intervals for each test run. Unc lassi...Test Program . . . . . . . . . . . . . . . . . . . . . . . . 9 PART III: TEST RESULTS....................... Data Reduction and Presentation

2,3,7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)-MEDIATED OXIDATIVE STRESS IN FEMALE CYP1A-2 KNOCKOUT (CYP1A2-/-) MICE

EPA Science Inventory

2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD)-Mediated Oxidative Stress in Female CYP1A2 Knockout (CYP1A2-/-) Mice

Deborah Burgin1, Janet Diliberto2, Linda Birnbaum2
1UNC Toxicology; 2USEPA/ORD/NHEERL, RTP, NC

Most of the effects due to TCDD exposure are mediated via...

Molecular analysis of neocortical layer structure in the ferret

PubMed Central

Rowell, Joanna J.; Mallik, Atul K.; Dugas-Ford, Jennifer; Ragsdale, Clifton W.

2010-01-01

Molecular markers that distinguish specific layers of rodent neocortex are increasingly employed to study cortical development and the physiology of cortical circuits. The extent to which these markers represent general features of neocortical cell type identity across mammals is, however, unknown. To assess the conservation of layer markers more broadly, we isolated orthologs for fifteen layer-enriched genes in the ferret, a carnivore with a large, gyrencephalic brain, and analyzed their patterns of neocortical gene expression. Our major findings are: (1) Many but not all layer markers tested show similar patterns of layer-specific gene expression between mouse and ferret cortex, supporting the view that layer-specific cell type identity is conserved at a molecular level across mammalian superorders; (2) Our panel of deep layer markers (ER81/ETV1, SULF2, PCP4, FEZF2/ZNF312, CACNA1H, KCNN2/SK2, SYT6, FOXP2, CTGF) provides molecular evidence that the specific stratifications of layer 5 and 6 into 5a, 5b, 6a and 6b are also conserved between rodents and carnivores. (3) Variations in layer-specific gene expression are more pronounced across areas of ferret cortex than between homologous areas of mouse and ferret cortex; (4) This variation of area gene expression was clearest with the superficial layer markers studied (SERPINE2, MDGA1, CUX1, UNC5D, RORB/NR1F2, EAG2/KCNH5). Most dramatically, the layer 4 markers RORB and EAG2 disclosed a molecular sublamination to ferret visual cortex and demonstrated a molecular dissociation among the so-called agranular areas of the neocortex. Our findings establish molecular markers as a powerful complement to cytoarchitecture for neocortical layer and cell-type comparisons across mammals. PMID:20575059

Molecular analysis of neocortical layer structure in the ferret.

PubMed

Rowell, Joanna J; Mallik, Atul K; Dugas-Ford, Jennifer; Ragsdale, Clifton W

2010-08-15

Molecular markers that distinguish specific layers of rodent neocortex are increasingly employed to study cortical development and the physiology of cortical circuits. The extent to which these markers represent general features of neocortical cell type identity across mammals, however, is unknown. To assess the conservation of layer markers more broadly, we isolated orthologs for 15 layer-enriched genes in the ferret, a carnivore with a large, gyrencephalic brain, and analyzed their patterns of neocortical gene expression. Our major findings are: 1) Many but not all layer markers tested show similar patterns of layer-specific gene expression between mouse and ferret cortex, supporting the view that layer-specific cell type identity is conserved at a molecular level across mammalian superorders; 2) Our panel of deep layer markers (ER81/ETV1, SULF2, PCP4, FEZF2/ZNF312, CACNA1H, KCNN2/SK2, SYT6, FOXP2, CTGF) provides molecular evidence that the specific stratifications of layers 5 and 6 into 5a, 5b, 6a, and 6b are also conserved between rodents and carnivores; 3) Variations in layer-specific gene expression are more pronounced across areas of ferret cortex than between homologous areas of mouse and ferret cortex; 4) This variation of area gene expression was clearest with the superficial layer markers studied (SERPINE2, MDGA1, CUX1, UNC5D, RORB/NR1F2, EAG2/KCNH5). Most dramatically, the layer 4 markers RORB and EAG2 disclosed a molecular sublamination to ferret visual cortex and demonstrated a molecular dissociation among the so-called agranular areas of the neocortex. Our findings establish molecular markers as a powerful complement to cytoarchitecture for neocortical layer and cell-type comparisons across mammals. (c) 2010 Wiley-Liss, Inc.

Mucus secretion by single tracheal submucosal glands from normal and cystic fibrosis transmembrane conductance regulator knockout mice

PubMed Central

Ianowski, Juan P; Choi, Jae Young; Wine, Jeffrey J; Hanrahan, John W

2007-01-01

Submucosal glands line the cartilaginous airways and produce most of the antimicrobial mucus that keeps the airways sterile. The glands are defective in cystic fibrosis (CF), but how this impacts airway health remains uncertain. Although most CF mouse strains exhibit mild airway defects, those with the C57Bl/6 genetic background have increased airway pathology and susceptibility to Pseudomonas. Thus, they offer the possibility of studying whether, and if so how, abnormal submucosal gland function contributes to CF airway disease. We used optical methods to study fluid secretion by individual glands in tracheas from normal, wild-type (WT) mice and from cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice (Cftrm1UNC/Cftrm1UNC; CF mice). Glands from WT mice qualitatively resembled those in humans by responding to carbachol and vasoactive intestinal peptide (VIP), although the relative rates of VIP- and forskolin-stimulated secretion were much lower in mice than in large mammals. The pharmacology of mouse gland secretion was also similar to that in humans; adding bumetanide or replacement of HCO3− by Hepes reduced the carbachol response by ∼50%, and this inhibition increased to 80% when both manoeuvres were performed simultaneously. It is important to note that glands from CFTR knockout mice responded to carbachol but did not secrete when exposed to VIP or forskolin, as has been shown previously for glands from CF patients. Tracheal glands from WT and CF mice both had robust secretory responses to electrical field stimulation that were blocked by tetrodotoxin. It is interesting that local irritation of the mucosa using chili pepper oil elicited secretion from WT glands but did not stimulate glands from CF mice. These results clarify the mechanisms of murine submucosal gland secretion and reveal a novel defect in local regulation of glands lacking CFTR which may also compromise airway defence in CF patients. PMID:17204498

COMPARISON OF OVERALL METABOLISM OF 1,2,3,7,8-PENTACHLORODIBENZO-P-DIOXIN (PECDD) IN CYP1A2(-L-)KNOCKOUT (KO) AND C57BL/6N PARENTAL STRAINS OF MICE

EPA Science Inventory

Assessment of immune responses to Penicillium chrysogenum and characterization of its allergens

Yongjoo Chung1, Michael E Viana2, Lisa B Copeland3, and MaryJane K Selgrade3, Marsha D W Ward3. 1 UNC, SPH, Chapel Hill, NC, 2NCSU, CVM, Raleigh, NC, 3US EPA, ORD, NHEERL, RTP,...

Analysis of Central Design Agency Alternatives for Navy Industrial Fund Accounting Systems: A Proposed Methodology.

DTIC Science & Technology

1980-03-01

creation of a "buyer- seller" relationship between the producer of the good or ser- vice and the customer activity. The notion of "free" supplies and...riors in the customers ’ chains of command from whom they receive their funding) [2;28-30]. C. NAVY INDUSTRIAL FUND ORGANIZATIONAL RELATIONSHIPS The...project budget levels unchanged 2. standardization efforts hindered 3. current customer relationships 3. inefficient ptilization of unc hanged

Monolithic GaAs Dual-Gate FET Phase Shifter.

DTIC Science & Technology

1981-01-01

r ADAO 6 8 CA LABS PRINCETON NJ F/6 9/5 MNOLC4ITHIC SAAS DUAL-GATE FET PHASE SHIFTER.(U) UNC AN 81 M KUMAR, R HENNA, S N SUBBARAO NOOOI’-79-C-0568...PHASNT NUMBERls) M./Kumar S. N./ Subbarao G. T./Taylor -N 4 C 8 R./Menna H./Huang . 9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT...PROGRESS ........................................................... 1 A. Development of Discrete 3600 Phase Shifter ....................... 2 B . Development

A COMPARISON OF THE METABOLISM OF METHOXYRESORUFIN, ACETANILIDE AND CAFFIENE IN RAT AND HUMAN CYP1A2 SUPERSOMES AND THEIR INHIBITION BY 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)

EPA Science Inventory

A COMPARISON OF THE METABOLISM OF METHOXYRESORUFIN, ACETANILIDE AND CAFFIENE IN RAT AND HUMAN CYP1A2 SUPERSOMES AND THEIR INHIBITION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD). DF Staskal1, DG Ross2, LS Birnbaum2 and MJ DeVito2 1Curriculum In Toxicology, UNC-CH, Chapel Hill ...

INFLUENCE OF TYPE II DIABETES, OBESITY, AND EXPOSURE TO 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) EXPOSURE ON THE EXPRESSION OF HEPATIC CYP1A2 IN A MURIN MODEL OF TYPE II DIABETES

EPA Science Inventory

Influence of type II diabetes, obesity and exposure 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on the expression of hepatic CYPIA2 in a murine model of type II diabetes. SJ Godin', VM Richardson2, JJ Diliberto2, LS Birnbaum', MJ DeVito2; 'Curriculum In Toxicology, UNC-CH...

Creating a new rural pharmacy workforce: Development and implementation of the Rural Pharmacy Health Initiative.

PubMed

Scott, Mollie Ashe; Kiser, Stephanie; Park, Irene; Grandy, Rebecca; Joyner, Pamela U

2017-12-01

An innovative certificate program aimed at expanding the rural pharmacy workforce, increasing the number of pharmacists with expertise in rural practice, and improving healthcare outcomes in rural North Carolina is described. Predicted shortages of primary care physicians and closures of critical access hospitals are expected to worsen existing health disparities. Experiential education in schools and colleges of pharmacy primarily takes place in academic medical centers and, unlike experiential education in medical schools, rarely emphasizes the provision of patient care in rural U.S. communities, where chronic diseases are prevalent and many residents struggle with poverty and poor access to healthcare. To help address these issues, UNC Eshelman School of Pharmacy developed the 3-year Rural Pharmacy Health Certificate program. The program curriculum includes 4 seminar courses, interprofessional education and interaction with medical students, embedding of each pharmacy student into a specific rural community for the duration of training, longitudinal ambulatory care practice experiences, community engagement initiatives, leadership training, development and implementation of a population health project, and 5 pharmacy practice experiences in rural settings. The Rural Pharmacy Health Certificate program at UNC Eshelman School of Pharmacy seeks to transform rural pharmacy practice by creating a pipeline of rural pharmacy leaders and teaching a unique skillset that will be beneficial to healthcare systems, communities, and patients. Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion.

PubMed

Kolter, Julia; Feuerstein, Reinhild; Spoeri, Evelyne; Gharun, Kourosh; Elling, Roland; Trieu-Cuot, Patrick; Goldmann, Tobias; Waskow, Claudia; Chen, Zhijian J; Kirschning, Carsten J; Deshmukh, Sachin D; Henneke, Philipp

2016-03-15

Streptococci are common human colonizers with a species-specific mucocutaneous distribution. At the same time, they are among the most important and most virulent invasive bacterial pathogens. Thus, site-specific cellular innate immunity, which is predominantly executed by resident and invading myeloid cells, has to be adapted with respect to streptococcal sensing, handling, and response. In this article, we show that TLR13 is the critical mouse macrophage (MΦ) receptor in the response to group B Streptococcus, both in bone marrow-derived MΦs and in mature tissue MΦs, such as those residing in the lamina propria of the colon and the dermis, as well as in microglia. In contrast, TLR13 and its chaperone UNC-93B are dispensable for a potent cytokine response of blood monocytes to group B Streptococcus, although monocytes serve as the key progenitors of intestinal and dermal MΦs. Furthermore, a specific role for TLR13 with respect to MΦ function is supported by the response to staphylococci, where TLR13 and UNC-93B limit the cytokine response in bone marrow-derived MΦs and microglia, but not in dermal MΦs. In summary, TLR13 is a critical and site-specific receptor in the single MΦ response to β-hemolytic streptococci. Copyright © 2016 by The American Association of Immunologists, Inc.

The Caenorhabditis elegans Iodotyrosine Deiodinase Ortholog SUP-18 Functions through a Conserved Channel SC-Box to Regulate the Muscle Two-Pore Domain Potassium Channel SUP-9

PubMed Central

de la Cruz, Ignacio Perez; Ma, Long; Horvitz, H. Robert

2014-01-01

Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K+ channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian iodotyrosine deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP-18, which appears to require catalytic activity to function. Genetic analyses suggest that SUP-10 can function with SUP-18 to activate SUP-9 through a pathway that is independent of the presumptive SUP-9 regulatory subunit UNC-93. We identified a novel evolutionarily conserved serine-cysteine-rich region in the C-terminal cytoplasmic domain of SUP-9 required for its specific activation by SUP-10 and SUP-18 but not by UNC-93. Since two-pore domain K+ channels regulate the resting membrane potentials of numerous cell types, we suggest that the SUP-18 IYD regulates the activity of the SUP-9 channel using NADH as a coenzyme and thus couples the metabolic state of muscle cells to muscle membrane excitability. PMID:24586202

Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment

PubMed Central

Seoane, Samuel; Arias, Efigenia; Sigueiro, Rita; Sendon-Lago, Juan; Martinez-Ordoñez, Anxo; Castelao, Esteban; Eiró, Noemí; Garcia-Caballero, Tomás; Macia, Manuel; Lopez-Lopez, Rafael; Maestro, Miguel; Vizoso, Francisco; Mouriño, Antonio; Perez-Fernandez, Roman

2015-01-01

The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown. We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents. Administration of 1α, 25-dihydroxy-3-epi-vitamin D3 (3-Epi, an endogenous low calcemic vitamin D metabolite) reduced Pit-1 expression, and synergized with cisplatin, thus, decreasing cell proliferation and apoptosis in vitro, and reducing tumor growth in vivo. In addition, fifteen primary cultures of human breast tumors showed significantly decreased proliferation when treated with 3-Epi+cisplatin, compared to cisplatin alone. This response positively correlated with Pit-1 levels. Our findings demonstrate that high levels of Pit-1 and reduced BRCA1 levels increase breast cancer cell susceptibility to 3-Epi+cisplatin therapy. PMID:25992773

A small-molecule activator induces ULK1-modulating autophagy-associated cell death in triple negative breast cancer.

PubMed

Ouyang, Liang; Zhang, Lan; Fu, Leilei; Liu, Bo

2017-04-03

ULK1 (unc-51 like autophagy activating kinase 1) is well known to be required to initiate the macroautophagy/autophagy process, and thus activation of ULK1-modulating autophagy/autophagy-associated cell death (ACD) may be a possible therapeutic strategy in triple negative breast cancer (TNBC). Here, our integrated The Cancer Genome Atlas (TCGA) data set, tissue microarray-based analyses and multiple biologic evaluations together demonstrate a new small-molecule activator of ULK1 for better understanding of how ULK1, the mammalian homolog of yeast Atg1, as a potential drug target can regulate ACD by the ULK complex (ULK1-ATG13-RB1CC1/FIP200-ATG101), as well as other possible ULK1 interactors, including ATF3, RAD21 and CASP3/caspase3 in TNBC. Moreover, such new inspiring findings may help us discover that this activator of ULK1 (LYN-1604) with its anti-tumor activity and ACD-modulating mechanisms can be further exploited as a small-molecule candidate drug for future TNBC therapy.

Nuclear migration events throughout development

PubMed Central

Bone, Courtney R.

2016-01-01

ABSTRACT Moving the nucleus to a specific position within the cell is an important event during many cell and developmental processes. Several different molecular mechanisms exist to position nuclei in various cell types. In this Commentary, we review the recent progress made in elucidating mechanisms of nuclear migration in a variety of important developmental models. Genetic approaches to identify mutations that disrupt nuclear migration in yeast, filamentous fungi, Caenorhabditis elegans, Drosophila melanogaster and plants led to the identification of microtubule motors, as well as Sad1p, UNC-84 (SUN) domain and Klarsicht, ANC-1, Syne homology (KASH) domain proteins (LINC complex) that function to connect nuclei to the cytoskeleton. We focus on how these proteins and various mechanisms move nuclei during vertebrate development, including processes related to wound healing of fibroblasts, fertilization, developing myotubes and the developing central nervous system. We also describe how nuclear migration is involved in cells that migrate through constricted spaces. On the basis of these findings, it is becoming increasingly clear that defects in nuclear positioning are associated with human diseases, syndromes and disorders. PMID:27182060

Chemical Durability Improvement and Static Fatigue of Glasses.

DTIC Science & Technology

1982-08-01

Afl-Alla 837 RENSSELAER POLYIECmfJ!C INST TRtOY NY DEPT OF MATERIAL--ETC F/6 ii/ CHEMICAL DURABILITY IMPROVEMENT AND STATIC FATIGUE OF GLASSESW AUC2...82 M TOMOZAWA NOGGIN 7A-C-0315 UNC LASS IF IED N ENEEEEEE FINAL TECHNICAL REPORT For the period April 1, 1978 "u March 31, 198200 CHEMICAL DURABILITY...REPORT A PERIOD COVERED Chemical Durability Improvement and Static Final Technical Report Fatiue o GlasesApril 1, 1978"’,March 31, 1982 S. PERFORMING ORG

Soviet Reinforcement in Europe

DTIC Science & Technology

1987-04-01

0C t. 7-’S Form Approved ; REPORT DOCUMENTATION PAGE OMB No. 0704-0188 -la REPORt SEC.RiTY C-ASS.ý CATiON lb RESTRICTIVE MARKINGS Unc la ssi f ied 2a...SECUR1TY CLASSIFICATON AUTHORITY 3 DISTRIBUTION /AVAILABILITY OF REPORT 20. DECLASS,,CAT ION / DOANCRADiNUG SCHEDULE .. " r7OA., t4’ i , M -r ) 4...REPORT (Year, Month, Day) 15. PAGE COUNT Final FROM TO ____ I /2- 16. SUPPLEMENTARY NOTATION 17. COSATI CODES 18. SUBJECT TERMS (Continue on reverse if

DoD Electronic Data Interchange (EDI) Convention: ASC X12 Transaction Set 856 Ship Notice/Manifest (Version 003030)

DTIC Science & Technology

1993-01-01

from the Department of Defense Ecutive Agent for Elctronic Com••rce/Electronic Data interrrhange/Ped~on of Logisti Unc.iaassfed/fen-une Systers...Convention: Electronic Commerce ; ANSI X12, X12; 62 electronic standards, electronic business standards; computer-to-computer exchange of data...Ship Notice Manifest Information From Invoicng Party to DFAS Using ASC X12 856A 10.1) Reserved 10. E Reserved CV QUAMY Tr7 4 10O.F Reserved__

DOE Office of Scientific and Technical Information (OSTI.GOV)

Catterall, Simon; Veernala, Aarti

We construct a lattice theory with one exact supersymmetry which consists of fields transforming in both the adjoint and fundamental representations of a U(Nc) gauge group. In addition to gluons and gluinos, the theory contains Nf flavors of fermion in the fundamental representation along with their scalar partners and is invariant under a global U(Nf) flavor symmetry. The lattice action contains an additional Fayet-Iliopoulos term which can be used to generate a scalar potential. We perform numerical simulations that corroborate the theoretical expectation that supersymmetry is spontaneously broken for Nf

P53 Mutation Analysis to Predict Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer

DTIC Science & Technology

2006-10-01

then sequenced (for GeneChip- positiv SSCP (for GeneChip-negative). We have received a total of 43 core breast biopsy DNA samples from the UNC... quantitative luciferase reporter. Both reporters exploit a “rheostatable” promoter for p53 expression and utilize the “delitto perfetto” in vivo... quantitative luciferase-based assay is also being used to characterize the altered function sistent an tion T mutants in greater detail. Preliminary

Design Guidelines for User Transactions with Battlefield Automated Systems: Prototype for a Handbook

DTIC Science & Technology

1984-05-01

83-86. Codd , E. F ., Seven Steps to Rendezvous with the Casual User (Technical Report RJ-1333). San Jose, California: IBM Research Laboratory, January...SCIENCES A Field Operating Agency under the Jurisdiction of the - Deputy Chief of Staff for Personnel L. NEALE COSBY EDGAR M. JOHNSON Colonel, IN...automated systems. The work here demonstrates that the concept can be productively extended to the behavioral domain. .I: UNC!•ASSI! F I TD SeCURITY CL

Cost Effectiveness Analysis, A DTIC Bibliography.

DTIC Science & Technology

1980-07-01

CoSt.Nonstetionary Case. - AD-AO46 808 AD-AO0O 505 -PERSONAL AUTHOR -IKDEX-49 UNCLASSIFIED ZOW)? SAV-C"U F UNC LASS IF! ED *SCHUMACHER. WILLIAM J. OSEABERO. ERNEST ...Laboratory. Wright- Patterson AFB. envirOnmelnks wnder risk. Historically- VERT hs Ohio 45433. This work was ai calibration and been used crirnCiPally to...WRIGHT- PATTERSON AFB OH SCHOOL OF ALEXANDRIA VA SYSTEMS A𔃾D LOGISTICS A Methodology and Analysis for Cost-EffzCtive An Investigation of Changes in

Attenuation Effects of Thermal Radiation on Internal Blast Overpressure.

DTIC Science & Technology

1979-12-01

SECURITY CLASSIFICATION OF THIS ZaGt ("OR. 08e. Enered) REPORT DOCUMENTATION PAGE READ MTRU,-TIORS REPORT MU01 Ia.VT ACCEMIOl Mo. MY r CATALOG UMrERt...014-6o 0 SECURITY CLASSIFICATION OFr..Is , . o. l I UNCLASSIFIED Secum". CLUIUCYIOW O s margWn o fee e. pressure was computed. Reports of the results...were calculated and thermodynamic equilibrium was demonstrated through statistical considerations. \\AccessiMf nor NTIS .I DDC TA UG ann o unc e

The Boundary Element Method Applied to the Two Dimensional Stefan Moving Boundary Problem

DTIC Science & Technology

1991-03-15

Unc), - ( UGt )t - (UG,,),,] - (UG), If we integrate this equation with respect to r from 0 to t - c and with respect to and ij on the region 11(r...and others. "Moving Boundary Problems in Phase Change Mod- els," SIGNUM Newsletter, 20: 8-12 (1985). 21. Stefan, J. "Ober einige Probleme der Theorie ...ier Wirmelcitung," S.-B. \\Vein. Akad. Mat. Natur., 98: 173-484 (1889). 22.-. "flber (lie Theorie der Eisbildung insbesondere fiber die lisbildung im

Local intra-articular injection of resveratrol delays cartilage degeneration in C57BL/6 mice by inducing autophagy via AMPK/mTOR pathway.

PubMed

Qin, Na; Wei, Liwei; Li, Wuyin; Yang, Wei; Cai, Litao; Qian, Zhuang; Wu, Shufang

2017-07-01

Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA) cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM) in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51-like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1α, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2α, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1α and HIF-2α expressions and thereby regulating AMPK/mTOR signaling pathway. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Survey of Emergency Department staff on disaster preparedness and training for Ebola virus disease.

PubMed

Siddle, Jennica; Tolleson-Rinehart, Sue; Brice, Jane

2016-01-01

In the domestic response to the outbreak of Ebola virus disease from 2013 to 2015, many US hospitals developed and implemented specialized training programs to care for patients with Ebola. This research reports on the effects of targeted training on Emergency Department (ED) staff's Ebola-related perceptions and attitudes. One hundred fifty-nine members of the UNC Health Care System ED staff participated in a voluntary cross-sectional, anonymous Web survey administered using a one-time "post then pre" design. Participants responded to questions about risk, roles, willingness to provide care, preparedness, and the contributions of media, training, or time to opinion change using a Likert agree-disagree scale. The authors conducted t test comparisons of Likert responses to pretraining and post-training attitudes about Ebola preparedness. The authors conducted multinomial logistic regression analyses of index scores of change and positivity of responses, controlling for the effects of independent variables. ED staff's opinions supported training; 73 percent felt all workers should receive Ebola education, 60 percent agreed all hospitals should prepare for Ebola, 66 percent felt UNC was better prepared, and 66 percent felt it had done enough to be ready for an Ebola case. Most staff (79 percent) said they had gotten more training for Ebola than for other disease outbreaks; 58 percent had experienced prior epidemics. After training, workers' attitudes were more positive about Ebola preparation including perceived risk of transmission, readiness and ability to manage a patient case, understanding team roles, and trust in both personal protective equipment and the hospital system's preparations (13 measures, p < 0.0001 to p < 0.001). Overall, total opinion indices also changed significantly over the training period (Mean Difference [MD] = 17.45, SD = 9.89) and in the intended positive direction (MD = 15.80, SD = 0.91, p < 0.0001). Positive change and overall change from pre to post were significantly associated with more hours of training (p = 0.003). Despite different occupations, mean scores were similar. Staff rated training most important and media least important, as the sources of change in their attitudes (p < 0.0001). These findings suggest that diseasespecific training for novel pathogens such as Ebola may result in positive staff perceptions of self-efficacy and occupational efficacy to treat potentially infected patients in the ED setting. Training, in this case, outweighed media content in changing staff perceptions of Ebola management.

Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.

PubMed

Lorés-Motta, Laura; Riaz, Moeen; Grunin, Michelle; Corominas, Jordi; van Asten, Freekje; Pauper, Marc; Leenders, Mathieu; Richardson, Andrea J; Muether, Philipp; Cree, Angela J; Griffiths, Helen L; Pham, Connie; Belanger, Marie-Claude; Meester-Smoor, Magda A; Ali, Manir; Heid, Iris M; Fritsche, Lars G; Chakravarthy, Usha; Gale, Richard; McKibbin, Martin; Inglehearn, Chris F; Schlingemann, Reinier O; Omar, Amer; Chen, John; Koenekoop, Robert K; Fauser, Sascha; Guymer, Robyn H; Hoyng, Carel B; de Jong, Eiko K; Lotery, Andrew J; Mitchell, Paul; den Hollander, Anneke I; Baird, Paul N; Chowers, Itay

2018-05-31

Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

Atmospheric Seeing and Transparency Robotic Observatory

NASA Astrophysics Data System (ADS)

Cline, J. D.; Castelaz, M. W.

2002-12-01

A robotic 12.7 cm telescope and camera (together called OVIEW) have been designed to do photometry of 50 of the brightest stars in the local sky 24 hours a day. Each star is imaged through a broadband 500 nm filter. Software automatically analyzes the brightness of the star and the stellar seeing disk. The results are published in real-time on a web page. Comparison of stellar brightness with known apparent magnitude is a measure of transparency with instrument resolution of one arcsecond. We will describe the observatory, software, and website. We will also describe other telescopes on the Optical Ridge at the Pisgah Astronomical Research Institute (PARI). On the same pier as OVIEW is a second robotic 12.7 cm telescope and camera that image the sun and moon. The solar and lunar images are published live on the Internet. Also on the Optical Ridge is a robotic 20 cm telescope. This telescope is operated by UNC-Chapel Hill and has been operating on the Optical Ridge for more than 2 years surveying the plane of the Milky Way for binary low mass stars. UNC-Chapel Hill also operates a 25 cm telescope with an IR camera for photometry of gamma ray burst optical afterglows. An additional 25 cm telescope with a new 3.2 megapixel CCD is used for undergraduate research and W UMa binary star photometry. We acknowledge the AAS Small Grant Program for partial support of the solar/lunar telescope.

Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice.

PubMed

Gralinski, Lisa E; Menachery, Vineet D; Morgan, Andrew P; Totura, Allison L; Beall, Anne; Kocher, Jacob; Plante, Jessica; Harrison-Shostak, D Corinne; Schäfer, Alexandra; Pardo-Manuel de Villena, Fernando; Ferris, Martin T; Baric, Ralph S

2017-06-07

Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2 , an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam2 -/- mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses. Copyright © 2017 Gralinski et al.

Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice

PubMed Central

Gralinski, Lisa E.; Menachery, Vineet D.; Morgan, Andrew P.; Totura, Allison L.; Beall, Anne; Kocher, Jacob; Plante, Jessica; Harrison-Shostak, D. Corinne; Schäfer, Alexandra; Pardo-Manuel de Villena, Fernando; Ferris, Martin T.; Baric, Ralph S.

2017-01-01

Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1–58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam2−/− mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses. PMID:28592648

The UNC-CH MCH Leadership Training Consortium: building the capacity to develop interdisciplinary MCH leaders.

PubMed

Dodds, Janice; Vann, William; Lee, Jessica; Rosenberg, Angela; Rounds, Kathleen; Roth, Marcia; Wells, Marlyn; Evens, Emily; Margolis, Lewis H

2010-07-01

This article describes the UNC-CH MCH Leadership Consortium, a collaboration among five MCHB-funded training programs, and delineates the evolution of the leadership curriculum developed by the Consortium to cultivate interdisciplinary MCH leaders. In response to a suggestion by the MCHB, five MCHB-funded training programs--nutrition, pediatric dentistry, social work, LEND, and public health--created a consortium with four goals shared by these diverse MCH disciplines: (1) train MCH professionals for field leadership; (2) address the special health and social needs of women, infants, children and adolescents, with emphasis on a public health population-based approach; (3) foster interdisciplinary practice; and (4) assure competencies, such as family-centered and culturally competent practice, needed to serve effectively the MCH population. The consortium meets monthly. Its primary task to date has been to create a leadership curriculum for 20-30 master's, doctoral, and post-doctoral trainees to understand how to leverage personal leadership styles to make groups more effective, develop conflict/facilitation skills, and identify and enhance family-centered and culturally competent organizations. What began as an effort merely to understand shared interests around leadership development has evolved into an elaborate curriculum to address many MCH leadership competencies. The collaboration has also stimulated creative interdisciplinary research and practice opportunities for MCH trainees and faculty. MCHB-funded training programs should make a commitment to collaborate around developing leadership competencies that are shared across disciplines in order to enhance interdisciplinary leadership.

Urocortin1-induced anorexia is regulated by activation of the serotonin 2C receptor in the brain.

PubMed

Harada, Yumi; Takayama, Kiyoshige; Ro, Shoki; Ochiai, Mitsuko; Noguchi, Masamichi; Iizuka, Seiichi; Hattori, Tomohisa; Yakabi, Koji

2014-01-01

This study was conducted to determine the mechanisms by which serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in the suppression of food intake in a rat stress model and to observe the degree of activation in the areas of the brain involved in feeding. In the stress model, male Sprague-Dawley rats (8 weeks old) were given intracerebroventricular injections of urocortin (UCN) 1. To determine the role of the 5-HT2c receptor (5-HT2cR) in the decreased food intake in UCN1-treated rats, specific 5-HT2cR or 5-HT2b receptor (5-HT2bR) antagonists were administered. Food intake was markedly reduced in UCN1-injected rats compared with phosphate buffered saline treated control rats. Intraperitoneal administration of a 5-HT2cR antagonist, but not a 5-HT2bR antagonist, significantly inhibited the decreased food intake. To assess the involvement of neural activation, we tracked the expression of c-fos mRNA as a neuronal activation marker. Expression of the c-fos mRNA in the arcuate nucleus, ventromedial hypothalamic nucleus (VMH) and rostral ventrolateral medulla (RVLM) in UNC1-injected rats showed significantly higher expression than in the PBS-injected rats. Increased c-fos mRNA was also observed in the paraventricular nucleus (PVN), the nucleus of the solitary tract (NTS), and the amygdala (AMG) after injection of UCN1. Increased 5-HT2cR protein expression was also observed in several areas. However, increased coexpression of 5-HT2cR and c-fos was observed in the PVN, VMH, NTS, RVLM and AMG. Whereas, pro-opiomelanocortin mRNA expression was not changed. In an UNC1-induced stress model, 5-HT2cR expression and activation was found in brain areas involved in feeding control. Copyright © 2013 Elsevier Inc. All rights reserved.

Assessing student understanding of measurement and uncertainty

NASA Astrophysics Data System (ADS)

Abbott, David Scot

A test to assess student understanding of measurement and uncertainty has been developed and administered to more than 500 students at two large research universities. The aim is two-fold: (1) to assess what students learn in the first semester of introductory physics labs and (2) to uncover patterns in student reasoning and practice. The forty minute, eleven item test focuses on direct measurement and student attitudes toward multiple measurements. After one revision cycle using think-aloud interviews, the test was administered to students to three groups: students enrolled in traditional laboratory lab sections of first semester physics at North Carolina State University (NCSU), students in an experimental (SCALE-UP) section of first semester physics at NCSU, and students in first semester physics at the University of North Carolina at Chapel Hill. The results were analyzed using a mixture of qualitative and quantitative methods. In the traditional NCSU labs, where students receive no instruction in uncertainty and measurement, students show no improvement on any of the areas examined by the test. In SCALE-UP and at UNC, students show statistically significant gains in most areas of the test. Gains on specific test items in SCALE-UP and at UNC correspond to areas of instructional emphasis. Test items were grouped into four main aspects of performance: "point/set" reasoning, meaning of spread, ruler reading and "stacking." Student performance on the pretest was examined to identify links between these aspects. Items within each aspect are correlated to one another, sometimes quite strongly, but items from different aspects rarely show statistically significant correlation. Taken together, these results suggest that student difficulties may not be linked to a single underlying cause. The study shows that current instruction techniques improve student understanding, but that many students exit the introductory physics lab course without appreciation or coherent understanding for the concept of measurement uncertainty.

Mojave Toxin: A Selective Ca(++) Channel Antagonist

DTIC Science & Technology

1988-07-01

other editions are obsolete. UNC LASSF 1 % I ’ UNCLbASS I FIELD 0._. ,ECUm Y ’LAS$tFICATI N W TIS PAGE S , a.Q 0 ,5 UNCLASI I D % 2 TIN OFTHIS AGE0 ’ " I...has been approved for release to the public. Acknowledgments The authors thank Dr. Eppie D . Rael (Univerity of Texas at El Paso, El Paso, TX) for...to their surroundings for at least 1 week prior to the experiments. 2.2 Toxin. MoTX was provided by Dr. Eppie D . Rael (University of Texas at El Paso

Technology Transfer - A Look at the Federal Sector.

DTIC Science & Technology

1978-03-01

with need s at the other by means of a complex “br okerage process. ” At the technology end , ther e is a body of knowledge which resul t s fr om...sive right to their respective writing s and discoveries . ” [Ref. 40 , p. 3] The first patent law was enacted in 1790. Through the years the patent laws...Advisor: 3. W. Creig htor i Approved for public release; distribution unlimited / Unc la s si.fied SECURITY CLA ISIPICAYIOW OP THIS PAGE (U~uIn 0.1

Geomagnetic Pulsations-Production/Interpretation.

DTIC Science & Technology

1982-09-01

7 AD-A131 448 GEOMAGNETIC PuLSATIONS-PRODLJCTON/INTERPINETATON(U) /EMMANUEL COL BOSTON MA E MAPLE SEP 82 AFOSR-TR-83-0832 AFOSR-77-3467 UNC ASS I F E...thou,7n’ this tech-nicu,-e ha-s teen u,.-.d Ini ra ny paners that have been rub- lished In thje TC,! and else-ohere ,,I-hout evoking:- any great con...froim each of the two ad,’acent reoonce bands. 26 rjne total Lim~e durationi of the wavetrains observed in eac-, n~ ass - band wa: rxt753: c." the duaLnof

Proceedings of a Workshop on Calibration and Application of Hydrologic Models Held in Gulf Shores, Alabama on October 18-20, 1988

DTIC Science & Technology

1988-12-01

of a frequency analysis, some form of hydraulic model should be used to verify the conveyance capacity of the floodway. Negative skewness of the...minimum of 40 years of record was used to compute the 100-year to 2-year ratios which were subsequently used to develop the isopluvial maps. A partial ...applying the 100-year TP-40 precipitation adjusted to reproduce the expected probability and partial duration aajustments to the HEC-1 model. unce the

Torquing preload in a lubricated bolt

NASA Technical Reports Server (NTRS)

Seegmiller, H. L.

1978-01-01

The tension preload obtained by torquing a 7/8 in. diam UNC high strength bolt was determined for lubricated and dry conditions. Consistent preload with a variation of + or - 3% was obtained when the bolt head area was lubricated prior to each torque application. Preload tensions nearly 70% greater than the value predicted with the commonly used formula occurred with the lubricated bolt. A reduction to 39% of the initial preload was observed during 50 torque applications without relubrication. Little evidence of wear was noted after 203 cycles of tightening.

Genetic variation in Toll-like receptors and disease susceptibility.

PubMed

Netea, Mihai G; Wijmenga, Cisca; O'Neill, Luke A J

2012-05-18

Toll-like receptors (TLRs) are key initiators of the innate immune response and promote adaptive immunity. Much has been learned about the role of TLRs in human immunity from studies linking TLR genetic variation with disease. First, monogenic disorders associated with complete deficiency in certain TLR pathways, such as MyD88-IRAK4 or TLR3-Unc93b-TRIF-TRAF3, have demonstrated the specific roles of these pathways in host defense against pyogenic bacteria and herpesviruses, respectively. Second, common polymorphisms in genes encoding several TLRs and associated genes have been associated with both infectious and autoimmune diseases. The study of genetic variation in TLRs in various populations combined with information on infection has demonstrated complex interaction between genetic variation in TLRs and environmental factors. This interaction explains the differences in the effect of TLR polymorphisms on susceptibility to infection and autoimmune disease in various populations.

The Response to High CO2 Levels Requires the Neuropeptide Secretion Component HID-1 to Promote Pumping Inhibition

PubMed Central

Sharabi, Kfir; Charar, Chayki; Friedman, Nurit; Mizrahi, Inbar; Zaslaver, Alon; Sznajder, Jacob I.; Gruenbaum, Yosef

2014-01-01

Carbon dioxide (CO2) is a key molecule in many biological processes; however, mechanisms by which organisms sense and respond to high CO2 levels remain largely unknown. Here we report that acute CO2 exposure leads to a rapid cessation in the contraction of the pharynx muscles in Caenorhabditis elegans. To uncover the molecular mechanisms underlying this response, we performed a forward genetic screen and found that hid-1, a key component in neuropeptide signaling, regulates this inhibition in muscle contraction. Surprisingly, we found that this hid-1-mediated pathway is independent of any previously known pathways controlling CO2 avoidance and oxygen sensing. In addition, animals with mutations in unc-31 and egl-21 (neuropeptide secretion and maturation components) show impaired inhibition of muscle contraction following acute exposure to high CO2 levels, in further support of our findings. Interestingly, the observed response in the pharynx muscle requires the BAG neurons, which also mediate CO2 avoidance. This novel hid-1-mediated pathway sheds new light on the physiological effects of high CO2 levels on animals at the organism-wide level. PMID:25101962

Enhancing Next-Generation Sequencing-Guided Cancer Care Through Cognitive Computing.

PubMed

Patel, Nirali M; Michelini, Vanessa V; Snell, Jeff M; Balu, Saianand; Hoyle, Alan P; Parker, Joel S; Hayward, Michele C; Eberhard, David A; Salazar, Ashley H; McNeillie, Patrick; Xu, Jia; Huettner, Claudia S; Koyama, Takahiko; Utro, Filippo; Rhrissorrakrai, Kahn; Norel, Raquel; Bilal, Erhan; Royyuru, Ajay; Parida, Laxmi; Earp, H Shelton; Grilley-Olson, Juneko E; Hayes, D Neil; Harvey, Stephen J; Sharpless, Norman E; Kim, William Y

2018-02-01

Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB. One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis. Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case. These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials. The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data. © AlphaMed Press 2017.

Radiology workstation for mammography: preliminary observations, eyetracker studies, and design

NASA Astrophysics Data System (ADS)

Beard, David V.; Johnston, Richard E.; Pisano, Etta D.; Hemminger, Bradley M.; Pizer, Stephen M.

1991-07-01

For the last four years, the UNC FilmPlane project has focused on constructing a radiology workstation facilitating CT interpretations equivalent to those with film and viewbox. Interpretation of multiple CT studies was originally chosen because handling such large numbers of images was considered to be one of the most difficult tasks that could be performed with a workstation. The authors extend the FilmPlane design to address mammography. The high resolution and contrast demands coupled with the number of images often cross- compared make mammography a difficult challenge for the workstation designer. This paper presents the results of preliminary work with workstation interpretation of mammography. Background material is presented to justify why the authors believe electronic mammographic workstations could improve health care delivery. The results of several observation sessions and a preliminary eyetracker study of multiple-study mammography interpretations are described. Finally, tentative conclusions of what a mammographic workstation might look like and how it would meet clinical demand to be effective are presented.

Community Structure in Online Collegiate Social Networks

NASA Astrophysics Data System (ADS)

Traud, Amanda; Kelsic, Eric; Mucha, Peter; Porter, Mason

2009-03-01

Online social networking sites have become increasingly popular with college students. The networks we studied are defined through ``friendships'' indicated by Facebook users from UNC, Oklahoma, Caltech, Georgetown, and Princeton. We apply the tools of network science to study the Facebook networks from these five different universities at a single point in time. We investigate each single-institution network's community structure, which we obtain through partitioning the graph using an eigenvector method. We use both graphical and quantitative tools, including pair-counting methods, which we interpret through statistical analysis and permutation tests to measure the correlations between the network communities and a set of characteristics given by each user (residence, class year, major, and high school). We also analyze the single gender subsets of these networks, and the impact of missing demographical data. Our study allows us to compare the online social networks for the five schools as well as infer differences in offline social interactions. At the schools studied, we were able to define which characteristics of the Facebook users correlate best with friendships.

Clinical efficacy of utilizing Ultrapulse CO2 combined with fractional CO2 laser for the treatment of hypertrophic scars in Asians-A prospective clinical evaluation.

PubMed

Lei, Ying; Li, Shi Feng; Yu, Yi Ling; Tan, Jun; Gold, Michael H

2017-06-01

Hypertrophic scarring is seen regularly. Tissue penetration of laser energy into hypertrophic scars using computer defaults from some lasers may be insufficient and penetration not enough. We have developed a treatment with an interrupted laser "drilling" by the Ultrapulse CO 2 (Manual Fractional Technology, MFT) and, a second pass, with fractional CO 2 . The MFT with fractional CO 2 lasers to treat hypertrophic scars is evaluated. A total of 158 patients with hypertrophic scars had three sessions of MFT with fractional CO 2 laser at 3-month intervals. Evaluations made before and 6 months after the 3rd treatment: (1) the Vancouver Scar Scale (VSS), (2) the University of North Carolina (UNC) Scar Scale, and (3) a survey of patient satisfaction. All data were analyzed using a t-test before and after treatment. The VSS score decreased from 9.35 to 3.12 (P<.0001), and the UNC Scar Scale score decreased from 8.03 to 1.62 (P<.0001). The overall satisfaction rate was 92%. No long-term complications occurred in the clinical trial. The interrupted laser drilling by MFT and a fractional CO2 laser had profound effects on the hypertrophic scars treated. It works by increasing the penetration depth of the CO 2 laser in the scar tissue, exerting more precise effects on the hypertrophic scars. MFT combined with fractional CO 2 laser has the potential to be a major advance in the treatment of hypertrophic scars. © 2017 Wiley Periodicals, Inc.

A variant Tc4 transposable element in the nematode C. elegans could encode a novel protein.

PubMed Central

Li, W; Shaw, J E

1993-01-01

A variant C. elegans Tc4 transposable element, Tc4-rh1030, has been sequenced and is 3483 bp long. The Tc4 element that had been analyzed previously is 1605 bp long, consists of two 774-bp nearly perfect inverted terminal repeats connected by a 57-bp loop, and lacks significant open reading frames. In Tc4-rh1030, by comparison, a 2343-bp novel sequence is present in place of a 477-bp segment in one of the inverted repeats. The novel sequence of Tc4-rh1030 is present about five times per haploid genome and is invariably associated with Tc4 elements; we have used the designation Tc4v to denote this variant subfamily of Tc4 elements. Sequence analysis of three cDNA clones suggests that a Tc4v element contains at least five exons that could encode a novel basic protein of 537 amino acid residues. On northern blots, a 1.6-kb Tc4v-specific transcript was detected in the mutator strain TR679 but not in the wild-type strain N2; Tc4 elements are known to transpose in TR679 but appear to be quiescent in N2. We have analyzed transcripts produced by an unc-33 gene that has the Tc4-rh1030 insertional mutation in its transcribed region; all or almost all of the Tc4v sequence is frequently spliced out of the mutant unc-33 transcripts, sometimes by means of non-consensus splice acceptor sites. Images PMID:8382791

Development of an Easy-to-Use Spanish Health Literacy Test

PubMed Central

Lee, Shoou-Yih D; Bender, Deborah E; Ruiz, Rafael E; Cho, Young Ik

2006-01-01

Objective The study was intended to develop and validate a health literacy test, termed the Short Assessment of Health Literacy for Spanish-speaking Adults (SAHLSA), for the Spanish-speaking population. Study Design The design of SAHLSA was based on the Rapid Estimate of Adult Literacy in Medicine (REALM), known as the most easily administered tool for assessing health literacy in English. In addition to the word recognition test in REALM, SAHLSA incorporates a comprehension test using multiple-choice questions designed by an expert panel. Data Collection Validation of SAHLSA involved testing and comparing the tool with other health literacy instruments in a sample of 201 Spanish-speaking and 202 English-speaking subjects recruited from the Ambulatory Care Center at UNC Health Care. Principal Findings With only the word recognition test, REALM could not differentiate the level of health literacy in Spanish. The SAHLSA significantly improved the differentiation. Item response theory analysis was performed to calibrate the SAHLSA and reduce the instrument to 50 items. The resulting instrument, SAHLSA-50, was correlated with the Test of Functional Health Literacy in Adults, another health literacy instrument, at r = 0.65. The SAHLSA-50 score was significantly and positively associated with the physical health status of Spanish-speaking subjects (p < .05), holding constant age and years of education. The instrument displayed good internal reliability (Cronbach's α = 0.92) and test–retest reliability (Pearson's r = 0.86). Conclusions The new instrument, SAHLSA-50, has good reliability and validity. It could be used in the clinical or community setting to screen for low health literacy among Spanish speakers. PMID:16899014

Social Relationships, Inflammation, and Cancer Survival.

PubMed

Boen, Courtney E; Barrow, David A; Bensen, Jeannette T; Farnan, Laura; Gerstel, Adrian; Hendrix, Laura H; Yang, Yang Claire

2018-05-01

Background: Social stressors, such as social relationship deficits, have been increasingly linked to chronic disease outcomes, including cancer. However, critical gaps exist in our understanding of the nature and strength of such links, as well as the underlying biological mechanisms relating social relationships to cancer progression and survival. Methods: Utilizing novel questionnaire and biomarker data from the UNC Health Registry/Cancer Survivorship Cohort, this study examines the associations between diverse measures of social support and mortality risk among individuals with cancer ( N = 1,004). We further assess the role of multiple serum markers of inflammation, including high-sensitivity C-reactive protein (CRP), IL6, TNFα, and VEGF, as potential mediators in the social relationship-cancer link. Results: The findings revealed that one's appraisal of their social support was associated with cancer mortality, such that individuals reporting higher levels of social support satisfaction had lower mortality risk than individuals reporting lower levels of satisfaction. The amount of support received, on the other hand, was not predictive of cancer survival. We further found evidence that inflammatory processes may undergird the link between social support satisfaction and mortality among individuals with cancer, with individuals reporting higher levels of social support satisfaction having lower levels of CRP, IL6, and TNFα. Conclusions: These results provide new knowledge of the biosocial processes producing population disparities in cancer outcomes. Impact: Our study offers new insights for intervention efforts aimed at promoting social connectedness as a means for improving cancer survival. Cancer Epidemiol Biomarkers Prev; 27(5); 541-9. ©2018 AACR . ©2018 American Association for Cancer Research.

Preoperative preparation. Value, perspective, and practice in patient care.

PubMed

Kopp, V J

2000-09-01

Preanesthesia preparation will continue to stimulate creativity and debate. Strategies for process improvement will take various shapes and require tools previously unfamiliar to many medical managers. At UNC Health System, anesthesiologists currently are committed to the centralized preanesthesia clinic approach used in PreCare. To date, their strategies have been validated by their institutional measures of success: a 0.7% first-case AM work-up rate, a 5% no PreCare visit rate, a 5% consent problem rate, and a 0% rejected specimen rate, with a 43% blood-draw rate for all patients. As their health system expands, however, other strategies and preparation modalities may become necessary. Telemedicine and Internet-dependent processes are appealing in the highly educated and technologically sophisticated marketplace. As the region becomes increasingly urbanized, local employment patterns prevent easy access to services, and functional compromises, such as bypassing PreCare or reliance on telephone or on-line interviews for preparation, may become necessary. The need to expand PreCare in the near future is already evident. As was found during initial planning, process improvement and space planning are enhanced by computer modeling. UNC Health System employed a proprietary animated simulation modeling (ASM) tool, MedModel, (ProModel, Orem, UT), although other techniques exist for the same purpose. Use of ASM as a strategy management tool allowed generation of ideal space-time-personnel scenarios that could expose potential problems before resources and physical restructuring occurred. ASM also can be used to compare data obtained from real-time observations to any reference scenario, including any that looks at economic measures of process, to help refine strategic visions before instituting tactical solutions. Used in this manner, ASM can reveal physical, temporal, personnel, and policy-related factors not otherwise seen as exerting effects on overall preprocedural preparation processes. Coupled with other classic planning techniques, such as time-motion studies, modified Delphi techniques, customer satisfaction surveys, benchmarking studies, and financial analysis and growth projections, ASM has helped enhance total quality management efforts in PreCare and other planning projects at UNC Health System. Other researchers have used other simulation techniques to assess clinic functions. Operational challenges that exist in preanesthesia preparation clinics place these clinics on the same level as other kinds of medical service clinics. The lessons learned in most clinic settings may be applied in a cross-wise manner to the preanesthesia clinic. Dexter contends that efficient delivery of care that respects patients' time and needs does more than assist the procedural preparation process; it also supports the physician's ethical obligation to the patient to give the best possible care. Documenting patient medical information, education efforts, and maintaining the medical-legal integrity of the preanesthesia preparation materials is another area of increasing concern and research. When hand-held computers capable of linking by way of infrared technologies or that use rented downloadable software to run specific applications become commonly used, the complexity of ensuring privacy will grow. The complexity, however, will not be insurmountable. Privacy problems exist in any information management system, whether paper-based (i.e., reducing redundant forms, eliminating indiscriminant photocopying of records), electronic-based (i.e., encryption, server access, system failure), or both. Electronic conveyance of medical information faces more legal and economic than technical hurdles. The penetration in US households of Internet services presently is less than 40%, whereas the penetration of personal computers is just over 50%. These figures are compared with penetration of corded telephones, televisions, and radios at levels greater tha

Association between perceived social support and induced abortion: A study in maternal health centers in Lima, Peru

PubMed Central

Rodríguez-Medina, Angélica; Piscoya, Alejandro; Bernabe-Ortiz, Antonio

2018-01-01

Objectives This study aimed to assess the association between perceived social support and induced abortion among young women in Lima, Peru. In addition, prevalence and incidence of induced abortion was estimated. Methods/Principal findings A cross-sectional study enrolling women aged 18–25 years from maternal health centers in Southern Lima, Peru, was conducted. Induced abortion was defined as the difference between the total number of pregnancies ended in abortion and the number of spontaneous abortions; whereas perceived social support was assessed using the DUKE-UNC scale. Prevalence and incidence of induced abortion (per 100 person-years risk) was estimated, and the association of interest was evaluated using Poisson regression models with robust variance. A total of 298 women were enrolled, mean age 21.7 (± 2.2) years. Low levels of social support were found in 43.6% (95%CI 38.0%–49.3%), and 17.4% (95%CI: 13.1%– 21.8%) women reported at least one induced abortion. The incidence of induced abortion was 2.37 (95%CI: 1.81–3.11) per 100 person-years risk. The multivariable model showed evidence of the association between low perceived social support and induced abortion (RR = 1.94; 95%CI: 1.14–3.30) after controlling for confounders. Conclusions There was evidence of an association between low perceived social support and induced abortion among women aged 18 to 25 years. Incidence of induced abortion was similar or even greater than rates of countries where abortion is legal. Strategies to increase social support and reduce induced abortion rates are needed. PMID:29649229

The 1986 ARI (Army Research Institute) Survey of U.S. Army Recruits: Media Habits

DTIC Science & Technology

1988-04-01

EDGAR M. JOHNSONCOI Technical Director Cmadn Technical review by Accesion For Curtis L. Gilroy NTAS CRA&:AI Laurel N. Oliver DI A UnC ABm~jc NOTICES...NBC SOURCE T681 X240 SOLID GOLD X241 SOUL TRAIN X242 AMERICAN BANDSTAND X243 DANCE FEVER U" X244 MOVIES ON NETWORK TV X755 MUSIC VIDEOS (NOT...BLACKE’S MAGIC Y080 MOONLIGHTING Y081 MACGIVER Y082 STINGRAY Y083 AIRWOLF Y084 THE A-TEAM Y085 HUNTER Y086 MIAMI VICE Y087 HARDCASTLE AND MCCORMICK Y088

Opportunities in Air Force Research and Development: Three Regional Workshop

DTIC Science & Technology

1982-08-01

BAFB DC 20332-6448 F49620-81-C-0049 J1. SUPPLEMENTARY NOTES 12a. DISTRUITION/iAVAILABLUTY STATEMENT t2A. OISTWILUTION CODE d ~ztr:L . oeasgJ 13. A1STUACT...Mewmwflm 200 waV* J ) conduct, on a regional basis, a series of three one day workshops, convening 300- 400 minority scientists from 19 states, 77...OF ABSTRACT OF REPORT OF THIS PAGE j OF ABSTRACT unc lass ified I unclass ified __ NSN 7540-01-2SSOO Stanaro Form 2" (890104 Draft) ft5VW " A" VidMS89

CDK-5 regulates the polarized trafficking of neuropeptide-containing dense-core vesicles in C. elegans motor neurons

PubMed Central

Goodwin, Patricia R.; Sasaki, Jennifer M.; Juo, Peter

2012-01-01

The polarized trafficking of axonal and dendritic proteins is essential for the structure and function of neurons. Cyclin-dependent kinase-5 (CDK-5) and its activator CDKA-1/p35 regulate diverse aspects of nervous system development and function. Here, we show that CDK-5 and CDKA-1/p35 are required for the polarized distribution of neuropeptide-containing dense-core vesicles (DCVs) in C. elegans cholinergic motor neurons. In cdk-5 or cdka-1/p35 mutants, the predominantly axonal localization of DCVs containing INS-22 neuropeptides was disrupted and DCVs accumulated in dendrites. Time-lapse microscopy in DB class motor neurons revealed decreased trafficking of DCVs in axons and increased trafficking and accumulation of DCVs in cdk-5 mutant dendrites. The polarized distribution of several axonal and dendritic markers, including synaptic vesicles, was unaltered in cdk-5 mutant DB neurons. We found that microtubule polarity is plus-end out in axons and predominantly minus-end out in dendrites of DB neurons. Surprisingly, cdk-5 mutants had increased amounts of plus-end-out microtubules in dendrites, suggesting that CDK-5 regulates microtubule orientation. However, these changes in microtubule polarity are not responsible for the increased trafficking of DCVs into dendrites. Genetic analysis of cdk-5 and the plus-end-directed axonal DCV motor unc-104/KIF1A suggest that increased trafficking of UNC-104 into dendrites cannot explain the dendritic DCV accumulation. Instead, we found that mutations in the minus-end-directed motor cytoplasmic dynein, completely block the increased DCVs observed in cdk-5 mutant dendrites without affecting microtubule polarity. We propose a model where CDK-5 regulates DCV polarity by both promoting DCV trafficking in axons and preventing dynein-dependent DCV trafficking into dendrites. PMID:22699897

Information systems for engineering sustainable development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leonard, R.S.

1992-02-27

The ability of a country to follow sustainable development paths is determined to a large extent by the capacity or capabilities of its people and its institutions. Specifically, capacity-building in the UNCED terminology encompasses the country's human, scientific, technological, organizational, institutional, and resource capabilities. A fundamental goal of capacity-building is to enhance the ability to pose, evaluate and address crucial questions related to policy choices and methods of implementation among development options. As a result the United Nations Conference on Environment and Development (UNCED) Agenda 21 planning process has identified the need for better methods by which information can bemore » transferred between industrialized nations and developing nations. The reasons for better methods of information transfer include facilitating decisions related to sustainable development and building the capacity of developing nations to better plan their future in both an economical and environmentally sound manner. This paper is a discussion on mechanisms for providing information and technologies available for presenting the information to a variety of cultures and levels of technical literacy. Consideration is given to access to information technology as well as to the cost to the user. One concept discussed includes an Engineering Partnership'' which brings together the talents and resources of private consulting engineers, corporations, non-profit professional organizations, government agencies and funding institution which work in partnership with each other and associates in developing countries. Concepts which are related to information technologies include a hypertext based, user configurable cultural translator and information navigator and the use of multi-media technologies to educate engineers about the concepts of sustainability, and the adaptation of the concept of metabolism to creating industrial systems.« less

Information systems for engineering sustainable development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leonard, R.S.

1992-02-27

The ability of a country to follow sustainable development paths is determined to a large extent by the capacity or capabilities of its people and its institutions. Specifically, capacity-building in the UNCED terminology encompasses the country`s human, scientific, technological, organizational, institutional, and resource capabilities. A fundamental goal of capacity-building is to enhance the ability to pose, evaluate and address crucial questions related to policy choices and methods of implementation among development options. As a result the United Nations Conference on Environment and Development (UNCED) Agenda 21 planning process has identified the need for better methods by which information can bemore » transferred between industrialized nations and developing nations. The reasons for better methods of information transfer include facilitating decisions related to sustainable development and building the capacity of developing nations to better plan their future in both an economical and environmentally sound manner. This paper is a discussion on mechanisms for providing information and technologies available for presenting the information to a variety of cultures and levels of technical literacy. Consideration is given to access to information technology as well as to the cost to the user. One concept discussed includes an ``Engineering Partnership`` which brings together the talents and resources of private consulting engineers, corporations, non-profit professional organizations, government agencies and funding institution which work in partnership with each other and associates in developing countries. Concepts which are related to information technologies include a hypertext based, user configurable cultural translator and information navigator and the use of multi-media technologies to educate engineers about the concepts of sustainability, and the adaptation of the concept of metabolism to creating industrial systems.« less

Loss of zebrafish Smyd1a interferes with myofibrillar integrity without triggering the misfolded myosin response.

PubMed

Paone, Christoph; Rudeck, Steven; Etard, Christelle; Strähle, Uwe; Rottbauer, Wolfgang; Just, Steffen

2018-02-05

Sarcomeric protein turnover needs to be tightly balanced to assure proper assembly and renewal of sarcomeric units within muscle tissues. The mechanisms regulating these fundamental processes are only poorly understood, but of great clinical importance since many cardiac and skeletal muscle diseases are associated with defective sarcomeric organization. The SET- and MYND domain containing protein 1b (Smyd1b) is known to play a crucial role in myofibrillogenesis by functionally interacting with the myosin chaperones Unc45b and Hsp90α1. In zebrafish, Smyd1b, Unc45b and Hsp90α1 are part of the misfolded myosin response (MMR), a regulatory transcriptional response that is activated by disturbed myosin homeostasis. Genome duplication in zebrafish led to a second smyd1 gene, termed smyd1a. Morpholino- and CRISPR/Cas9-mediated knockdown of smyd1a led to significant perturbations in sarcomere structure resulting in decreased cardiac as well as skeletal muscle function. Similar to Smyd1b, we found Smyd1a to localize to the sarcomeric M-band in skeletal and cardiac muscles. Overexpression of smyd1a efficiently compensated for the loss of Smyd1b in flatline (fla) mutant zebrafish embryos, rescued the myopathic phenotype and suppressed the MMR in Smyd1b-deficient embryos, suggesting overlapping functions of both Smyd1 paralogs. Interestingly, Smyd1a is not transcriptionally activated in Smyd1b-deficient fla mutants, demonstrating lack of genetic compensation despite the functional redundancy of both zebrafish Smyd1 paralogs. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans.

PubMed

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans

PubMed Central

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma. PMID:24149939

Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking

PubMed Central

Bird, Jonathan E.; Takagi, Yasuharu; Billington, Neil; Strub, Marie-Paule; Sellers, James R.; Friedman, Thomas B.

2014-01-01

Unconventional myosin 15 is a molecular motor expressed in inner ear hair cells that transports protein cargos within developing mechanosensory stereocilia. Mutations of myosin 15 cause profound hearing loss in humans and mice; however, the properties of this motor and its regulation within the stereocilia organelle are unknown. To address these questions, we expressed a subfragment 1-like (S1) truncation of mouse myosin 15, comprising the predicted motor domain plus three light-chain binding sites. Following unsuccessful attempts to express functional myosin 15-S1 using the Spodoptera frugiperda (Sf9)-baculovirus system, we discovered that coexpression of the muscle-myosin–specific chaperone UNC45B, in addition to the chaperone heat-shock protein 90 (HSP90) significantly increased the yield of functional protein. Surprisingly, myosin 15-S1 did not bind calmodulin with high affinity. Instead, the IQ domains bound essential and regulatory light chains that are normally associated with class II myosins. We show that myosin 15-S1 is a barbed-end–directed motor that moves actin filaments in a gliding assay (∼430 nm·s−1 at 30 °C), using a power stroke of 7.9 nm. The maximum ATPase rate (kcat ∼6 s−1) was similar to the actin-detachment rate (kdet = 6.2 s−1) determined in single molecule optical trapping experiments, indicating that myosin 15-S1 was rate limited by transit through strongly actin-bound states, similar to other processive myosin motors. Our data further indicate that in addition to folding muscle myosin, UNC45B facilitates maturation of an unconventional myosin. We speculate that chaperone coexpression may be a simple method to optimize the purification of other myosin motors from Sf9 insect cells. PMID:25114250

UNC-45/CRO1/She4p (UCS) Protein Forms Elongated Dimer and Joins Two Myosin Heads Near Their Actin Binding Region

DOE Office of Scientific and Technical Information (OSTI.GOV)

H Shi; G Blobel

2011-12-31

UNC-45/CRO1/She4p (UCS) proteins have variously been proposed to affect the folding, stability, and ATPase activity of myosins. They are the only proteins known to interact directly with the motor domain. To gain more insight into UCS function, we determined the atomic structure of the yeast UCS protein, She4p, at 2.9 {angstrom} resolution. We found that 16 helical repeats are organized into an L-shaped superhelix with an amphipathic N-terminal helix dangling off the short arm of the L-shaped molecule. In the crystal, She4p forms a 193-{angstrom}-long, zigzag-shaped dimer through three distinct and evolutionary conserved interfaces. We have identified She4p's C-terminal regionmore » as a ligand for a 27-residue-long epitope on the myosin motor domain. Remarkably, this region consists of two adjacent, but distinct, binding epitopes localized at the nucleotide-responsive cleft between the nucleotide- and actin-filament-binding sites. One epitope is situated inside the cleft, the other outside the cleft. After ATP hydrolysis and Pi ejection, the cleft narrows at its base from 20 to 12 {angstrom} thereby occluding the inside the cleft epitope, while leaving the adjacent, outside the cleft binding epitope accessible to UCS binding. Hence, one cycle of higher and lower binding affinity would accompany one ATP hydrolysis cycle and a single step in the walk on an actin filament rope. We propose that a UCS dimer links two myosins at their motor domains and thereby functions as one of the determinants for step size of myosin on actin filaments.« less

Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity.

PubMed

Gursoy-Yuzugullu, Ozge; Carman, Chelsea; Serafim, Rodolfo Bortolozo; Myronakis, Marios; Valente, Valeria; Price, Brendan D

2017-04-11

Radiation therapy is widely used to treat human malignancies, but many tumor types, including gliomas, exhibit significant radioresistance. Radiation therapy creates DNA double-strand breaks (DSBs), and DSB repair is linked to rapid changes in epigenetic modifications, including increased histone methylation. This increased histone methylation recruits DNA repair proteins which can then alter the local chromatin structure and promote repair. Consequently, combining inhibitors of specific histone methyltransferases with radiation therapy may increase tumor radiosensitivity, particularly in tumors with significant therapeutic resistance. Here, we demonstrate that inhibitors of the H4K20 methyltransferase SETD8 (UNC-0379) and the H3K9 methyltransferase G9a (BIX-01294) are effective radiosensitizers of human glioma cells. UNC-0379 blocked H4K20 methylation and reduced recruitment of the 53BP1 protein to DSBs, although this loss of 53BP1 caused only limited changes in radiosensitivity. In contrast, loss of H3K9 methylation through G9a inhibition with BIX-01294 increased radiosensitivity of a panel of glioma cells (SER2Gy range: 1.5 - 2.9). Further, loss of H3K9 methylation reduced DSB signaling dependent on H3K9, including reduced activation of the Tip60 acetyltransferase, loss of ATM signaling and reduced phosphorylation of the KAP-1 repressor. In addition, BIX-0194 inhibited DSB repair through both the homologous recombination and nonhomologous end-joining pathways. Inhibition of G9a and loss of H3K9 methylation is therefore an effective approach for increasing radiosensitivity of glioma cells. These results suggest that combining inhibitors of histone methyltransferases which are critical for DSB repair with radiation therapy may provide a new therapeutic route for sensitizing gliomas and other tumors to radiation therapy.

Nematode radiobiology and development in space. Results from IML-1

NASA Technical Reports Server (NTRS)

Nelson, Gregory A.; Schubert, W. W.; Kazarians, G. A.; Richards, G. F.; Benton, E. V.; Benton, E. R.; Henke, R.

1994-01-01

The Radiat experiment was one of 17 investigations which used the ESA Biorack on IML-1 (International Microgravity Laboratory) and it had two objectives. The first objective was to isolate and characterize mutations induced by cosmic rays; the second was to assess the fidelity of development in 0-gravity over two consecutive generations. Two strategies were used to isolate mutations in a set of essential genes or a specific gene and to correlate the genetic events with the passage of charged particles. The results were isolation of 60 lethal mutations whose phenotypes are related to the local pattern of energy deposition. 12 mutations in the unc-22 gene include large deletions as characterized by DNA hybridization studies. Development of nematodes proceeded through two consecutive generations with no obvious defects. Cytoplasmic determinants in embryos, nuclear location and symmetry of cellular anatomy were normal as were Mendelian segregation and recombination of genetic markers.

Tract specific analysis in patients with sickle cell disease

NASA Astrophysics Data System (ADS)

Chai, Yaqiong; Coloigner, Julie; Qu, Xiaoping; Choi, Soyoung; Bush, Adam; Borzage, Matt; Vu, Chau; Lepore, Natasha; Wood, John

2015-12-01

Sickle cell disease (SCD) is a hereditary blood disorder in which the oxygen-carrying hemoglobin molecule in red blood cells is abnormal. It affects numerous people in the world and leads to a shorter life span, pain, anemia, serious infections and neurocognitive decline. Tract-Specific Analysis (TSA) is a statistical method to evaluate white matter alterations due to neurocognitive diseases, using diffusion tensor magnetic resonance images. Here, for the first time, TSA is used to compare 11 major brain white matter (WM) tracts between SCD patients and age-matched healthy subjects. Alterations are found in the corpus callosum (CC), the cortico-spinal tract (CST), inferior fronto-occipital fasciculus (IFO), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and uncinated fasciculus (UNC). Based on previous studies on the neurocognitive functions of these tracts, the significant areas found in this paper might be related to several cognitive impairments and depression, both of which are observed in SCD patients.

ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins

DOE PAGES

Caballe, Anna; Wenzel, Dawn M.; Agromayor, Monica; ...

2015-05-26

The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1,more » an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations.« less

Essential role for SUN5 in anchoring sperm head to the tail

PubMed Central

Wang, Lina; Ouyang, Ying-Chun; Dong, Ming-Zhe; Liu, Chao; Zhao, Haichao; Cui, Xiuhong; Ma, Dongyuan; Zhang, Zhiguo; Yang, Xiaoyu; Guo, Yueshuai; Liu, Feng; Yuan, Li

2017-01-01

SUN (Sad1 and UNC84 domain containing)-domain proteins are reported to reside on the nuclear membrane playing distinct roles in nuclear dynamics. SUN5 is a new member of the SUN family, with little knowledge regarding its function. Here, we generated Sun5−/− mice and found that male mice were infertile. Most Sun5-null spermatozoa displayed a globozoospermia-like phenotype but they were actually acephalic spermatozoa. Additional studies revealed that SUN5 was located in the neck of the spermatozoa, anchoring sperm head to the tail, and without functional SUN5 the sperm head to tail coupling apparatus was detached from nucleus during spermatid elongation. Finally, we found that healthy heterozygous offspring could be obtained via intracytoplasmic injection of Sun5-mutated sperm heads for both male mice and patients. Our studies reveal the essential role of SUN5 in anchoring sperm head to the tail and provide a promising way to treat this kind of acephalic spermatozoa-associated male infertility. PMID:28945193

[Development and reliability evaluation of an instrument to measure health-related quality of life in independent elderly].

PubMed

Lima, Maria José Barbosa de; Portela, Margareth Crisóstomo

2010-08-01

This study presents an instrument, the health-related quality of life (HRQOL) profile for independent elderly, to measure the health-related quality of life of the functionally independent elderly assisted in the outpatient setting, based on the adaptation of four validated scales: Short-Form Health Survey (SF-36), Duke-UNC Health Profile (DUHP), Sickness Impact Profile (SIP), and Nottingham Health Profile (NHP). The study also evaluates the instrument's reliability based on its use by two different observers with a 15-day interval. The instrument includes five dimensions (health perception, symptoms, physical function, psychological function, and social function) and 45 items. Reliability evaluation of the QUASI instrument was based on interviews with 142 elderly outpatients in the city of Rio de Janeiro, Brazil. Prevalence-adjusted kappa statistic was used to assess all 45 items. Correlation was also calculated between overall scores and scores on individual dimensions. In the reliability evaluation, 39 of the 45 items showed prevalence-adjusted kappa greater than 0.60.

ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caballe, Anna; Wenzel, Dawn M.; Agromayor, Monica

The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1,more » an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations.« less

ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins

PubMed Central

Caballe, Anna; Wenzel, Dawn M; Agromayor, Monica; Alam, Steven L; Skalicky, Jack J; Kloc, Magdalena; Carlton, Jeremy G; Labrador, Leticia; Sundquist, Wesley I; Martin-Serrano, Juan

2015-01-01

The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations. DOI: http://dx.doi.org/10.7554/eLife.06547.001 PMID:26011858

Chemotext: A Publicly Available Web Server for Mining Drug-Target-Disease Relationships in PubMed.

PubMed

Capuzzi, Stephen J; Thornton, Thomas E; Liu, Kammy; Baker, Nancy; Lam, Wai In; O'Banion, Colin P; Muratov, Eugene N; Pozefsky, Diane; Tropsha, Alexander

2018-02-26

Elucidation of the mechanistic relationships between drugs, their targets, and diseases is at the core of modern drug discovery research. Thousands of studies relevant to the drug-target-disease (DTD) triangle have been published and annotated in the Medline/PubMed database. Mining this database affords rapid identification of all published studies that confirm connections between vertices of this triangle or enable new inferences of such connections. To this end, we describe the development of Chemotext, a publicly available Web server that mines the entire compendium of published literature in PubMed annotated by Medline Subject Heading (MeSH) terms. The goal of Chemotext is to identify all known DTD relationships and infer missing links between vertices of the DTD triangle. As a proof-of-concept, we show that Chemotext could be instrumental in generating new drug repurposing hypotheses or annotating clinical outcomes pathways for known drugs. The Chemotext Web server is freely available at http://chemotext.mml.unc.edu .

Encouraging self-development. Profile: Louise Lassonde.

PubMed

Rowley, J

1992-01-01

A profile of Louise Lassonde, population advisor to the UN Conference on Environment and Development (UNCED) portrays her ethnic and educational background, her interests, and achievements. She was born a French Canadian near Montreal and earned a degree in anthropology with an emphasis on the ancient cultures of Peru. A second degree was earned in sociology and a Ph.D. in demography. In her investigations, it was discovered that there were few remnants of the old Indian culture remaining in the Andean highlands; Quechua and Spanish languages were learned in the process. Her professional responsibilities have included university teaching in development and demography in Montreal, development assistance work in Burundi, Rwanda, and eastern Zaire as regional director for a Canadian nongovernmental organization, and consultancy activities for UNICEF and UNFPA. As a consultant, she was engaged in studying women and their ways of generating income and improving the quality of their lives. In 1989, her position was as country director to Togo and Benin within the UN Population Fund followed by a position in the UNCED secretariat in Geneva. Her field experience has contributed to a view that time is precious and that there is accountability for action or inaction. A little bit of effort can go a long way, i.e., improved management and information and good will. The assumption is that people have the will and desire to improve their own and their families as long as there is hope and freedom from a discouraging atmosphere. Lack of understanding can create tremendous barriers. The example is given of a man presenting with malaria at an African health center and not being treated because of his tribal affiliation; he died when medicine was within reach. Support must be provided in terms of health and education so that people can set the targets for themselves and develop creative solutions compatible with their own cultures. Her positive approach is visible in her insistence that population issues be included in preparatory documents. She helped prepare a chapter in Agenda 21, the draft action plan for the Earth Summit in Rio de Janeiro which established the principle of stabilization of world population.

FIJI Macro 3D ART VeSElecT: 3D Automated Reconstruction Tool for Vesicle Structures of Electron Tomograms

PubMed Central

Kaltdorf, Kristin Verena; Schulze, Katja; Helmprobst, Frederik; Kollmannsberger, Philip; Stigloher, Christian

2017-01-01

Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation. Both automatic and semi-automatic modes are explained including a tutorial. PMID:28056033

Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a†

PubMed Central

Liu, Feng; Chen, Xin; Allali-Hassani, Abdellah; Quinn, Amy M.; Wasney, Gregory A.; Dong, Aiping; Barsyte, Dalia; Kozieradzki, Ivona; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Kireev, Dmitri B.; Jadhav, Ajit; Herold, J. Martin; Frye, Stephen V.; Arrowsmith, Cheryl H.; Brown, Peter J.; Simeonov, Anton; Vedadi, Masoud; Jin, Jian

2010-01-01

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. The co-crystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling. PMID:19891491

Nuclear astrophysics in the laboratory and in the universe

DOE Office of Scientific and Technical Information (OSTI.GOV)

Champagne, A. E., E-mail: artc@physics.unc.edu; Iliadis, C.; Longland, R.

Nuclear processes drive stellar evolution and so nuclear physics, stellar models and observations together allow us to describe the inner workings of stars and their life stories. This Information on nuclear reaction rates and nuclear properties are critical ingredients in addressing most questions in astrophysics and often the nuclear database is incomplete or lacking the needed precision. Direct measurements of astrophysically-interesting reactions are necessary and the experimental focus is on improving both sensitivity and precision. In the following, we review recent results and approaches taken at the Laboratory for Experimental Nuclear Astrophysics (LENA, http://research.physics.unc.edu/project/nuclearastro/Welcome.html )

CAPS and Munc13: CATCHRs that SNARE Vesicles.

PubMed

James, Declan J; Martin, Thomas F J

2013-12-04

CAPS (Calcium-dependent Activator Protein for Secretion, aka CADPS) and Munc13 (Mammalian Unc-13) proteins function to prime vesicles for Ca(2+)-triggered exocytosis in neurons and neuroendocrine cells. CAPS and Munc13 proteins contain conserved C-terminal domains that promote the assembly of SNARE complexes for vesicle priming. Similarities of the C-terminal domains of CAPS/Munc13 proteins with Complex Associated with Tethering Containing Helical Rods domains in multi-subunit tethering complexes (MTCs) have been reported. MTCs coordinate multiple interactions for SNARE complex assembly at constitutive membrane fusion steps. We review aspects of these diverse tethering and priming factors to identify common operating principles.

A role for autophagy in long-term spatial memory formation in male rodents.

PubMed

Hylin, Michael J; Zhao, Jing; Tangavelou, Karthikeyan; Rozas, Natalia S; Hood, Kimberly N; MacGowan, Jacalyn S; Moore, Anthony N; Dash, Pramod K

2018-03-01

A hallmark of long-term memory formation is the requirement for protein synthesis. Administration of protein synthesis inhibitors impairs long-term memory formation without influencing short-term memory. Rapamycin is a specific inhibitor of target of rapamycin complex 1 (TORC1) that has been shown to block protein synthesis and impair long-term memory. In addition to regulating protein synthesis, TORC1 also phosphorylates Unc-51-like autophagy activating kinase-1 (Ulk-1) to suppress autophagy. As autophagy can be activated by rapamycin (and rapamycin inhibits long-term memory), our aim was to test the hypothesis that autophagy inhibitors would enhance long-term memory. To examine if learning alters autophagosome number, we used male reporter mice carrying the GFP-LC3 transgene. Using these mice, we observed that training in the Morris water maze task increases the number of autophagosomes, a finding contrary to our expectations. For learning and memory studies, male Long Evans rats were used due to their relatively larger size (compared to mice), making it easier to perform intrahippocampal infusions in awake, moving animals. When the autophagy inhibitors 3-methyladenine (3-MA) or Spautin-1 were administered bilaterally into the hippocampii prior to training in the Morris water maze task, the drugs did not alter learning. In contrast, when memory was tested 24 hours later by a probe trial, significant impairments were observed. In addition, intrahippocampal infusion of an autophagy activator peptide (TAT-Beclin-1) improved long-term memory. These results indicate that autophagy is not necessary for learning, but is required for long-term memory formation. © 2017 Wiley Periodicals, Inc.

A study of the periodontal state of a late Medieval United Kingdom population.

PubMed

Gonçalves, Pedro César Gaspar; Griffiths, Gareth; Rawlinson, Andrew

2015-12-01

To study the severity of bone loss in a Medieval UK population, and compare this with other ancient UK populations from different time periods. Skulls from a burial site in York (XI-XV century) were investigated. Skulls with a minimum of 17 teeth were included and were divided from childhood into five age groups. Direct measurements from the cement enamel junction (CEJ) to the alveolar crest (AC) were undertaken at six points around each tooth with a UNC 15 probe. The mean bone loss was calculated for each tooth type. Seventy five skulls were included in the study (12-60 years of age). Bone loss was found to increase with age, but stabilized in older individuals (>45 years). The mean CEJ-AC distance varied from 2.1mm in the youngest group to a maximum of 4.1mm in 36-45 year olds. Results were compared with a Roman-British population (Whittaker et al., 1982) where comparable values for mean bone loss were 2.2mm and 5.4mm respectively, and a population of XVIII century Londoners (Whittaker et al., 1998) where bone loss of 1.1mm and 4.0mm was reported for the youngest and oldest age groups respectively. Measuring the CEJ-AC distance in dried skulls from ancient populations may be used as a proxy for the levels of periodontal disease irrespective of tooth wear. The findings from the current study suggest that the severity of periodontitis as determined by measurements of alveolar bone loss on dried skulls from this ancient population, seems to have declined in the United Kingdom from the III-V century to XVIII century. This may be due to changes in environmental factors including living conditions and diet, together with individual characteristics including systemic illness and genetic make up. Copyright © 2015. Published by Elsevier Ltd.

Solid State Clipper Diodes for High Power Modulators.

DTIC Science & Technology

1978-11-01

modeled at low powers and later confirmed in actua l P W pulsar operation. 0~ \\ ~~~~~~~~~ . ~~~~~ .. . .— - - I. ~~~~~ 3 J~ItV~ . \\ W \\_ UNC l ASSIFIE...and CG is the di ide api-i tance to 1avg — Ip ~ j- ground . In our design the worst case diode leakage (I 2( lO ~C) was 15 milliamperes (mA) at I kV...without it. I2rms 1p 2 ~~ ( 4) the diode junction capacitance and stray l’nns — 5 x lO ~ A 2 capacitance affect the voltage division whenever the

Realities of sustainable development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Annan, R.H.

1997-12-01

The author gives a brief overview of rural electrification projects which have been developed worldwide based on different forms of renewable energy sources. Rural electrification provides hope to the 1.3 billion people who are still unserved by the power grid, and as a consequence are severely disadvantaged in todays economy in most facits of daily life and health. He recommends a more concerted effort to consolidate the experiences gained from present programs in order to present a more organized program by the time of the 2002 UNCED conference. His recommendation is that the National Renewable Energy Laboratory serve as amore » secretariat, to gather and formalize the information which has been learned to this point in time.« less

No Evidence for Multiple Stellar Populations in the Low-mass Galactic Globular Cluster E 3

NASA Astrophysics Data System (ADS)

Salinas, Ricardo; Strader, Jay

2015-08-01

Multiple stellar populations are a widespread phenomenon among Galactic globular clusters. Even though the origin of the enriched material from which new generations of stars are produced remains unclear, it is likely that self-enrichment will be feasible only in clusters massive enough to retain this enriched material. We searched for multiple populations in the low mass (M˜ 1.4× {10}4 {M}⊙ ) globular cluster E3, analyzing SOAR/Goodman multi-object spectroscopy centered on the blue cyanogen (CN) absorption features of 23 red giant branch stars. We find that the CN abundance does not present the typical bimodal behavior seen in clusters hosting multistellar populations, but rather a unimodal distribution that indicates the presence of a genuine single stellar population, or a level of enrichment much lower than in clusters that show evidence for two populations from high-resolution spectroscopy. E3 would be the first bona fide Galactic old globular cluster where no sign of self-enrichment is found. Based on observations obtained at the Southern Astrophysical Research (SOAR) Telescope, which is a joint project of the Ministério da Ciência, Tecnologia, e Inovação (MCTI) da República Federativa do Brasil, the US National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU).

TLR9-Dependent and Independent Pathways Drive Activation of the Immune System by Propionibacterium Acnes

PubMed Central

Tchaptchet, Sandrine; Gumenscheimer, Marina; Kalis, Christoph; Freudenberg, Nikolaus; Hölscher, Christoph; Kirschning, Carsten J.; Lamers, Marinus; Galanos, Chris; Freudenberg, Marina A.

2012-01-01

Propionibacterium acnes is usually a relatively harmless commensal. However, under certain, poorly understood conditions it is implicated in the etiology of specific inflammatory diseases. In mice, P. acnes exhibits strong immunomodulatory activity leading to splenomegaly, intrahepatic granuloma formation, hypersensitivity to TLR ligands and endogenous cytokines, and enhanced resistance to infection. All these activities reach a maximum one week after P. acnes priming and require IFN-γ and TLR9. We report here the existence of a markedly delayed (1–2 weeks), but phenotypically similar TLR9-independent immunomodulatory response to P. acnes. This alternative immunomodulation is also IFN-γ dependent and requires functional MyD88. From our experiments, a role for MyD88 in the IFN-γ-mediated P. acnes effects seems unlikely and the participation of the known MyD88-dependent receptors, including TLR5, Unc93B-dependent TLRs, IL-1R and IL-18R in the development of the alternative response has been excluded. However, the crucial role of MyD88 can partly be attributed to TLR2 and TLR4 involvement. Either of these two TLRs, activated by bacteria and/or endogenously generated ligands, can fulfill the required function. Our findings hint at an innate immune sensitizing mechanism, which is potentially operative in both infectious and sterile inflammatory disorders. PMID:22745710

Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons

PubMed Central

Poliak, Sebastian; Morales, Daniel; Croteau, Louis-Philippe; Krawchuk, Dayana; Palmesino, Elena; Morton, Susan; Cloutier, Jean-François; Charron, Frederic; Dalva, Matthew B; Ackerman, Susan L; Kao, Tzu-Jen; Kania, Artur

2015-01-01

During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing trajectory selection of spinal motor axons entering the limb. We first demonstrate that Netrin-1 attracts and repels distinct motor axon populations, according to their expression of Netrin receptors. Quantitative in vitro assays demonstrate that motor axons synergistically integrate both attractive or repulsive Netrin-1 signals together with repulsive ephrin signals. Our investigations of the mechanism of ephrin-B2 and Netrin-1 integration demonstrate that the Netrin receptor Unc5c and the ephrin receptor EphB2 can form a complex in a ligand-dependent manner and that Netrin–ephrin synergistic growth cones responses involve the potentiation of Src family kinase signaling, a common effector of both pathways. DOI: http://dx.doi.org/10.7554/eLife.10841.001 PMID:26633881

A Novel Nondevelopmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in Caenorhabditis elegans

PubMed Central

Opperman, Karla; Moseley-Alldredge, Melinda; Yochem, John; Bell, Leslie; Kanayinkal, Tony; Chen, Lihsia

2015-01-01

The L1CAM family of cell adhesion molecules is a conserved set of single-pass transmembrane proteins that play diverse roles required for proper nervous system development and function. Mutations in L1CAMs can cause the neurological L1 syndrome and are associated with autism and neuropsychiatric disorders. L1CAM expression in the mature nervous system suggests additional functions besides the well-characterized developmental roles. In this study, we demonstrate that the gene encoding the Caenorhabditis elegans L1CAM, sax-7, genetically interacts with gtl-2, as well as with unc-13 and rab-3, genes that function in neurotransmission. These sax-7 genetic interactions result in synthetic phenotypes that are consistent with abnormal synaptic function. Using an inducible sax-7 expression system and pharmacological reagents that interfere with cholinergic transmission, we uncovered a previously uncharacterized nondevelopmental role for sax-7 that impinges on synaptic function. PMID:25488979

Body Dissatisfaction in Women Across the Lifespan: Results of the UNC-SELF and Gender and Body Image (GABI) Studies

PubMed Central

Runfola, Cristin D.; Von Holle, Ann; Trace, Sara E.; Brownley, Kimberly A.; Hofmeier, Sara M.; Gagne, Danielle A.; Bulik, Cynthia M.

2013-01-01

To explore age differences in current and preferred silhouette and body dissatisfaction (current -preferred silhouette discrepancy) in women aged 25-89 years using figural stimuli (range: 1-very small to 9-very large). Data were abstracted from two online convenience samples (N = 5,868). t-tests with permutation-adjusted p-values examined linear associations between mean silhouette scores (current, preferred, discrepancy score) and age with/without stratification by body mass index (BMI). Modal current silhouette was 5; modal preferred silhouette was 4; mean discrepancy score was 1.8. There was no significant association between current silhouette and age, but a positive linear association between preferred silhouette and age remained after stratification by BMI. A significant inverse linear association of silhouette discrepancy score and age was found only prior to stratification by BMI. Body dissatisfaction exists in women across the adult life span and is influenced by BMI. PMID:22949165

The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation.

PubMed

Pack, Thomas F; Orlen, Margo I; Ray, Caroline; Peterson, Sean M; Caron, Marc G

2018-04-20

The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways. Therefore, βarr recruitment appears to be intimately tied to G protein activation via GRKs. Here we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on βarr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or βarrs as well as a βarr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the βarr-preferring D2R achieves βarr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the βarr-preferring D2R and also contributes to βarr recruitment at the WT D2R. Additionally, we found an additive interaction between the βarr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving βarr-biased signaling. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Political non-speak. Gadfly: Norman Myers.

PubMed

Myers, N

1992-01-01

Election years in Britain, the USA, France, and Italy have not granted the environment a high place on the political agenda even in the year of the UN Conference on Environment and Development (UNCED). The erosion of the natural resources base is not included as natural resource accounting in the computation of gross national product (GNP). In countries such as Germany, Australia, Indonesia, and Costa Rica, 50% of GNP growth annually is cancelled out by soil erosion, pollution, excessive logging, and other environmental degradation. The economic health of the country including recovery from recessions is related to environmental protection. The economic practices involve ecological deficit accounting. It has been suggested by Lester Brown of the Worldwatch Institute that an economical deflator is needed to gage economic progress. The ecological illiteracy of politicians prevents the American people from realizing the actual cost of ignoring the problems. Politicians fight against raising taxes on gasoline and ignore the cost of carbon dioxide emissions and destabilization of climate. Americans pay a 1/4 the price Europeans pay for gasoline. Energy conservation must be expanded from current levels. Improvements have been made since the first OPEC price hike in 1973; the economy saved $100 billion a year and improved efficiency and production. American conservation in line with European conservation would save $200 billion a year; matching Japanese conservation would generate a savings of $300 billion. This sum exceeds the Federal deficit or the Pentagon budget. It is enough to save 8 million children who die from preventable causes or provide $4.5 billion/year annually to the year 2000 for foreign aid for UN family planning programs. The savings compares favorable with the UNCED estimates of $125 billion/year for environmental protection in the South. The question is whether politicians really would be committing political suicide by listening less to oil and car lobbyists and listening more to those promoting long term interests and security.

A uniquely adaptable pore is consistent with NALCN being an ion sensor

PubMed Central

Senatore, Adriano; Spafford, J. David

2013-01-01

NALCN is an intriguing, orphan ion channel among the 4x6TM family of related voltage-gated cation channels, sharing a common architecture of four homologous domains consisting of six transmembrane helices, separated by three cytoplasmic linkers and delimited by N and C-terminal ends. NALCN is one of the shortest 4x6TM family members, lacking much of the variation that provides the diverse palate of gating features, and tissue specific adaptations of sodium and calcium channels. NALCN’s most distinctive feature is that that it possesses a highly adaptable pore with a calcium-like EEEE selectivity filter in radially symmetrical animals and a more sodium-like EEKE or EKEE selectivity filter in bilaterally symmetrical animals including vertebrates. Two lineages of animals evolved alternative calcium-like EEEE and sodium-like EEKE / EKEE pores, spliced to regulate NALCN functions in differing cellular environments, such as muscle (heart and skeletal) and secretory tissue (brain and glands), respectively. A highly adaptable pore in an otherwise conserved ion channel in the 4x6TM channel family is not consistent with a role for NALCN in directly gating a significant ion conductance that can be either sodium ions or calcium ions. NALCN was proposed to be an expressible Gd3+-sensitive, NMDG+-impermeant, non-selective and ohmic leak conductance in HEK-293T cells, but we were unable to distinguish these reported currents from leaky patch currents (ILP) in control HEK-293T cells. We suggest that NALCN functions as a sensor for the much larger UNC80/UNC79 complex, in a manner consistent with the coupling mechanism known for other weakly or non-conducting 4x6TM channel sensor proteins such as Nax or Cav1.1. We propose that NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels. PMID:23442378

A uniquely adaptable pore is consistent with NALCN being an ion sensor.

PubMed

Senatore, Adriano; Spafford, J David

2013-01-01

NALCN is an intriguing, orphan ion channel among the 4x6TM family of related voltage-gated cation channels, sharing a common architecture of four homologous domains consisting of six transmembrane helices, separated by three cytoplasmic linkers and delimited by N and C-terminal ends. NALCN is one of the shortest 4x6TM family members, lacking much of the variation that provides the diverse palate of gating features, and tissue specific adaptations of sodium and calcium channels. NALCN's most distinctive feature is that that it possesses a highly adaptable pore with a calcium-like EEEE selectivity filter in radially symmetrical animals and a more sodium-like EEKE or EKEE selectivity filter in bilaterally symmetrical animals including vertebrates. Two lineages of animals evolved alternative calcium-like EEEE and sodium-like EEKE / EKEE pores, spliced to regulate NALCN functions in differing cellular environments, such as muscle (heart and skeletal) and secretory tissue (brain and glands), respectively. A highly adaptable pore in an otherwise conserved ion channel in the 4x6TM channel family is not consistent with a role for NALCN in directly gating a significant ion conductance that can be either sodium ions or calcium ions. NALCN was proposed to be an expressible Gd ( 3+) -sensitive, NMDG (+) -impermeant, non-selective and ohmic leak conductance in HEK-293T cells, but we were unable to distinguish these reported currents from leaky patch currents (ILP) in control HEK-293T cells. We suggest that NALCN functions as a sensor for the much larger UNC80/UNC79 complex, in a manner consistent with the coupling mechanism known for other weakly or non-conducting 4x6TM channel sensor proteins such as Nax or Cav 1.1. We propose that NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels.

Chronic exposure to graphene-based nanomaterials induces behavioral deficits and neural damage in Caenorhabditis elegans.

PubMed

Li, Ping; Xu, Tiantian; Wu, Siyu; Lei, Lili; He, Defu

2017-10-01

Nanomaterials of graphene and its derivatives have been widely applied in recent years, but whose impacts on the environment and health are still not well understood. In the present study, the potential adverse effects of graphite (G), graphite oxide nanoplatelets (GO) and graphene quantum dots (GQDs) on the motor nervous system were investigated using nematode Caenorhabditis elegans as the assay system. After being characterized using TEM, SEM, XPS and PLE, three nanomaterials were chronically exposed to C. elegans for 6 days. In total, 50-100 mg l -1 GO caused a significant reduction in the survival rate, but G and GDDs showed low lethality on nematodes. After chronic exposure of sub-lethal dosages, three nanomaterials were observed to distribute primarily in the pharynx and intestine; but GQDs were widespread in nematode body. Three graphene-based nanomaterials resulted in significant declines in locomotor frequency of body bending, head thrashing and pharynx pumping. In addition, mean speed, bending angle-frequency and wavelength of the crawling movement were significantly reduced after exposure. Using transgenic nematodes, we found high concentrations of graphene-based nanomaterials induced down-expression of dat-1::GFP and eat-4::GFP, but no significant changes in unc-47::GFP. This indicates that graphene-based nanomaterials can lead to damages in the dopaminergic and glutamatergic neurons. The present data suggest that chronic exposure of graphene-based nanomaterials may cause neurotoxicity risks of inducing behavioral deficits and neural damage. These findings provide useful information to understand the toxicity and safe application of graphene-based nanomaterials. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

An empirical comparison of several recent epistatic interaction detection methods.

PubMed

Wang, Yue; Liu, Guimei; Feng, Mengling; Wong, Limsoon

2011-11-01

Many new methods have recently been proposed for detecting epistatic interactions in GWAS data. There is, however, no in-depth independent comparison of these methods yet. Five recent methods-TEAM, BOOST, SNPHarvester, SNPRuler and Screen and Clean (SC)-are evaluated here in terms of power, type-1 error rate, scalability and completeness. In terms of power, TEAM performs best on data with main effect and BOOST performs best on data without main effect. In terms of type-1 error rate, TEAM and BOOST have higher type-1 error rates than SNPRuler and SNPHarvester. SC does not control type-1 error rate well. In terms of scalability, we tested the five methods using a dataset with 100 000 SNPs on a 64 bit Ubuntu system, with Intel (R) Xeon(R) CPU 2.66 GHz, 16 GB memory. TEAM takes ~36 days to finish and SNPRuler reports heap allocation problems. BOOST scales up to 100 000 SNPs and the cost is much lower than that of TEAM. SC and SNPHarvester are the most scalable. In terms of completeness, we study how frequently the pruning techniques employed by these methods incorrectly prune away the most significant epistatic interactions. We find that, on average, 20% of datasets without main effect and 60% of datasets with main effect are pruned incorrectly by BOOST, SNPRuler and SNPHarvester. The software for the five methods tested are available from the URLs below. TEAM: http://csbio.unc.edu/epistasis/download.php BOOST: http://ihome.ust.hk/~eeyang/papers.html. SNPHarvester: http://bioinformatics.ust.hk/SNPHarvester.html. SNPRuler: http://bioinformatics.ust.hk/SNPRuler.zip. Screen and Clean: http://wpicr.wpic.pitt.edu/WPICCompGen/. wangyue@nus.edu.sg.

In Vivo Visualizing the IFN-β Response Required for Tumor Growth Control in a Therapeutic Model of Polyadenylic-Polyuridylic Acid Administration.

PubMed

Nocera, David Andrés; Roselli, Emiliano; Araya, Paula; Nuñez, Nicolás Gonzalo; Lienenklaus, Stefan; Jablonska, Jadwiga; Weiss, Siegfried; Gatti, Gerardo; Brinkmann, Melanie M; Kröger, Andrea; Morón, Gabriel; Maccioni, Mariana

2016-03-15

The crucial role that endogenously produced IFN-β plays in eliciting an immune response against cancer has recently started to be elucidated. Endogenous IFN-β has an important role in immune surveillance and control of tumor development. Accordingly, the role of TLR agonists as cancer therapeutic agents is being revisited via the strategy of intra/peritumoral injection with the idea of stimulating the production of endogenous type I IFN inside the tumor. Polyadenylic-polyuridylic acid (poly A:U) is a dsRNA mimetic explored empirically in cancer immunotherapy a long time ago with little knowledge regarding its mechanisms of action. In this work, we have in vivo visualized the IFN-β required for the antitumor immune response elicited in a therapeutic model of poly A:U administration. In this study, we have identified the role of host type I IFNs, cell populations that are sources of IFN-β in the tumor microenvironment, and other host requirements for tumor control in this model. One single peritumoral dose of poly A:U was sufficient to induce IFN-β, readily visualized in vivo. IFN-β production relied mainly on the activation of the transcription factor IFN regulatory factor 3 and the molecule UNC93B1, indicating that TLR3 is required for recognizing poly A:U. CD11c(+) cells were an important, but not the only source of IFN-β. Host type I IFN signaling was absolutely required for the reduced tumor growth, prolonged mice survival, and the strong antitumor-specific immune response elicited upon poly A:U administration. These findings add new perspectives to the use of IFN-β-inducing compounds in tumor therapy. Copyright © 2016 by The American Association of Immunologists, Inc.

PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3.

PubMed

Noh, Hae Sook; Hah, Young-Sool; Zada, Sahib; Ha, Ji Hye; Sim, Gyujin; Hwang, Jin Seok; Lai, Trang Huyen; Nguyen, Huynh Quoc; Park, Jae-Yong; Kim, Hyun Joon; Byun, June-Ho; Hahm, Jong Ryeal; Kang, Kee Ryeon; Kim, Deok Ryong

2016-11-01

Autophagy plays a critical role in maintaining cell homeostasis in response to various stressors through protein conjugation and activation of lysosome-dependent degradation. MAP1LC3B/LC3B (microtubule- associated protein 1 light chain 3 β) is conjugated with phosphatidylethanolamine (PE) in the membranes and regulates initiation of autophagy through interaction with many autophagy-related proteins possessing an LC3-interacting region (LIR) motif, which is composed of 2 hydrophobic amino acids (tryptophan and leucine) separated by 2 non-conserved amino acids (WXXL). In this study, we identified a new putative LIR motif in PEBP1/RKIP (phosphatidylethanolamine binding protein 1) that was originally isolated as a PE-binding protein and also a cellular inhibitor of MAPK/ERK signaling. PEBP1 was specifically bound to PE-unconjugated LC3 in cells, and mutation (WXXL mutated to AXXA) of this LIR motif disrupted its interaction with LC3 proteins. Interestingly, overexpression of PEBP1 significantly inhibited starvation-induced autophagy by activating the AKT and MTORC1 (mechanistic target of rapamycin [serine/threonine kinase] complex 1) signaling pathway and consequently suppressing the ULK1 (unc-51 like autophagy activating kinase 1) activity. In contrast, ablation of PEBP1 expression dramatically promoted the autophagic process under starvation conditions. Furthermore, PEBP1 lacking the LIR motif highly stimulated starvation-induced autophagy through the AKT-MTORC1-dependent pathway. PEBP1 phosphorylation at Ser153 caused dissociation of LC3 from the PEBP1-LC3 complex for autophagy induction. PEBP1-dependent suppression of autophagy was not associated with the MAPK pathway. These findings suggest that PEBP1 can act as a negative mediator in autophagy through stimulation of the AKT-MTORC1 pathway and direct interaction with LC3.

Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes.

PubMed

Jin, Yingli; Liu, Shuping; Ma, Qingshan; Xiao, Dong; Chen, Li

2017-01-05

High glucose concentration can induce injury of podocytes and berberine has a potent activity against diabetic nephropathy. However, whether and how berberine can inhibit high glucose-mediated injury of podocytes have not been clarified. This study tested the effect of berberine on high glucose-mediated apoptosis and the AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) activation and autophagy in podocytes. The results indicated that berberine significantly mitigated high glucose-decreased cell viability, and nephrin and podocin expression as well as apoptosis in mouse podocytes. Berberine significantly increased the AMPK activation and mitigated high glucose and/or the AMPK inhibitor, compound C-mediated mTOR activation and apoptosis in podocytes. Berberine significantly enhanced the AMPK activation and protected from high glucose-induced apoptosis in the AMPK-silencing podocytes. Furthermore, berberine significantly increased the high glucose-elevated Unc-51-like autophagy-activating kinase 1 (ULK1) S317/S555 phosphorylation, Beclin-1 expression, the ratios of LC3II to LC3I expression and the numbers of autophagosomes, but reduced ULK1 S757 phosphorylation in podocytes. In addition, berberine significantly attenuated compound C-mediated inhibition of autophagy in podocytes. The protective effect of berberine on high glucose-induced podocyte apoptosis was significantly mitigated by pre-treatment with 3-methyladenine or bafilomycin A1. Collectively, berberine enhanced autophagy and protected from high glucose-induced injury in podocytes by promoting the AMPK activation. Our findings may provide new insights into the molecular mechanisms underlying the anti-diabetic nephropathy effect of berberine and may aid in design of new therapies for intervention of diabetic nephropathy. Copyright © 2016 Elsevier B.V. All rights reserved.

Mitophagy is required for acute cardioprotection by simvastatin.

PubMed

Andres, Allen M; Hernandez, Genaro; Lee, Pamela; Huang, Chengqun; Ratliff, Eric P; Sin, Jon; Thornton, Christine A; Damasco, Marichris V; Gottlieb, Roberta A

2014-11-10

We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy.

Metal-poor Stars Observed with the Magellan Telescope. II. Discovery of Four Stars with [Fe/H] <= -3.5

NASA Astrophysics Data System (ADS)

Placco, Vinicius M.; Frebel, Anna; Beers, Timothy C.; Christlieb, Norbert; Lee, Young Sun; Kennedy, Catherine R.; Rossi, Silvia; Santucci, Rafael M.

2014-01-01

We report on the discovery of seven low-metallicity stars selected from the Hamburg/ESO Survey, six of which are extremely metal-poor (EMP, [Fe/H] <= -3.0), with four having [Fe/H] <= -3.5. Chemical abundances or upper limits are derived for these stars based on high-resolution (R ~ 35,000) Magellan/MIKE spectroscopy, and are in general agreement with those of other very and extremely metal-poor stars reported in the literature. Accurate metallicities and abundance patterns for stars in this metallicity range are of particular importance for studies of the shape of the metallicity distribution function of the Milky Way's halo system, in particular for probing the nature of its low-metallicity tail. In addition, taking into account suggested evolutionary mixing effects, we find that six of the program stars (with [Fe/H] <= -3.35) possess atmospheres that were likely originally enriched in carbon, relative to iron, during their main-sequence phases. These stars do not exhibit overabundances of their s-process elements, and hence may be, within the error bars, additional examples of the so-called CEMP-no class of objects. Based on observations gathered with: The 6.5 m Magellan Telescopes located at Las Campanas Observatory, Chile; the Southern Astrophysical Research (SOAR) telescope (SO2011B-002), which is a joint project of the Ministério da Ciência, Tecnologia, e Inovação (MCTI) da República Federativa do Brasil, the U.S. National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU); and the New Technology Telescope (NTT) of the European Southern Observatory (088.D-0344A), La Silla, Chile.

The Secret Life of Quarks, Final Report for the University of North Carolina at Chapel Hill

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, Robert J.

This final report summarizes activities and results at the University of North Carolina as part of the the SciDAC-2 Project The Secret Life of Quarks: National Computational Infrastructure for Lattice Quantum Chromodynamics. The overall objective of the project is to construct the software needed to study quantum chromo- dynamics (QCD), the theory of the strong interactions of subatomic physics, and similar strongly coupled gauge theories anticipated to be of importance in the LHC era. It built upon the successful efforts of the SciDAC-1 project National Computational Infrastructure for Lattice Gauge Theory, in which a QCD Applications Programming Interface (QCD API)more » was developed that enables lat- tice gauge theorists to make effective use of a wide variety of massively parallel computers. In the SciDAC-2 project, optimized versions of the QCD API were being created for the IBM Blue- Gene/L (BG/L) and BlueGene/P (BG/P), the Cray XT3/XT4 and its successors, and clusters based on multi-core processors and Infiniband communications networks. The QCD API is being used to enhance the performance of the major QCD community codes and to create new applications. Software libraries of physics tools have been expanded to contain sharable building blocks for inclusion in application codes, performance analysis and visualization tools, and software for au- tomation of physics work flow. New software tools were designed for managing the large data sets generated in lattice QCD simulations, and for sharing them through the International Lattice Data Grid consortium. As part of the overall project, researchers at UNC were funded through ASCR to work in three general areas. The main thrust has been performance instrumentation and analysis in support of the SciDAC QCD code base as it evolved and as it moved to new computation platforms. In support of the performance activities, performance data was to be collected in a database for the purpose of broader analysis. Third, the UNC work was done at RENCI (Renaissance Computing Institute), which has extensive expertise and facilities for scientific data visualization, so we acted in an ongoing consulting and support role in that area.« less

Advanced Motor-Controller Development.

DTIC Science & Technology

1983-06-22

OUTPUTS: 16 BIT PROE:UCT IN ACCA , FiCC:B Oi:t2 -* 0011: 0172 B:7 .04E SIFY STA A MCAN:,* SF,-’E MULTIPLICAND 001t4 0175 iF CLF: A INIT RESUI_I_T AOll5...OL-:t41) 04: ELSE ACCA IS UNC:HANGED 0-142 01SF ::,A 0CI CLAMP 0’Fi A #0 TEST SIGN OF A C0It 0l91 E’E: fBM I C.LIPI EBRFNCH IF NEG 01t4 4 : : 001,15 19...ELSE S.:ET ACCA =-ACCB:1B TQJ5. 01 .’ NEG B .ESTOPE ACCE: 01155 C. l1’-9 E -9 PTI RETUR’N Al? I .9~~ _________ . .... ... | |- - - - . . rjOt :E

8(th) Symposium on Hemostasis: Translational and Basic Science Discoveries.

PubMed

Margaritis, Paris; Key, Nigel S

2016-05-01

It has been 14 years since the first symposium on hemostasis at UNC Chapel Hill that focused primarily on the tissue factor (TF) and Factor VIIa (FVIIa) biology, biochemistry and translational work for the treatment of bleeding. Concepts, mechanistic data and therapeutic agents have since emerged that permeate not only aspects of the TF and FVIIa functions, but also broader processes in hemostasis and thrombosis. These processes involve circulating proteins, receptors, cells and cellular components that interact within the coagulation system as well as with additional systems that are dysregulated in disorders seemingly unrelated to bleeding/thrombosis. The reviews in this symposium provide the research background to understand such interactions and integrations. Copyright © 2016 Elsevier Ltd. All rights reserved.