The Caenorhabditis Elegans Unc-31 Gene Affects Multiple Nervous System-Controlled Functions

PubMed Central

Avery, L.; Bargmann, C. I.; Horvitz, H. R.

1993-01-01

We have devised a method for selecting Caenorhabditis elegans mutants that execute feeding motions in the absence of food. One mutation isolated in this way is an allele of the gene unc-31, first discovered by S. Brenner in 1974, because of its effects on locomotion. We find that strong unc-31 mutations cause defects in four functions controlled by the nervous system. Mutant worms are lethargic, feed constitutively, are defective in egg-laying and produce dauer larvae that fail to recover. We discuss two extreme models to explain this pleiotropy: either unc-31 affects one or a few neurons that coordinately control several different functions, or it affects many neurons that independently control different functions. PMID:8325482

SDN-1/Syndecan Acts in Parallel to the Transmembrane Molecule MIG-13 to Promote Anterior Neuroblast Migration.

PubMed

Sundararajan, Lakshmi; Norris, Megan L; Lundquist, Erik A

2015-05-28

The Q neuroblasts in Caenorhabditis elegans display left-right asymmetry in their migration, with QR and descendants on the right migrating anteriorly, and QL and descendants on the left migrating posteriorly. Initial QR and QL migration is controlled by the transmembrane receptors UNC-40/DCC, PTP-3/LAR, and the Fat-like cadherin CDH-4. After initial migration, QL responds to an EGL-20/Wnt signal that drives continued posterior migration by activating MAB-5/Hox activity in QL but not QR. QR expresses the transmembrane protein MIG-13, which is repressed by MAB-5 in QL and which drives anterior migration of QR descendants. A screen for new Q descendant AQR and PQR migration mutations identified mig-13 as well as hse-5, the gene encoding the glucuronyl C5-epimerase enzyme, which catalyzes epimerization of glucuronic acid to iduronic acid in the heparan sulfate side chains of heparan sulfate proteoglycans (HSPGs). Of five C. elegans HSPGs, we found that only SDN-1/Syndecan affected Q migrations. sdn-1 mutants showed QR descendant AQR anterior migration defects, and weaker QL descendant PQR migration defects. hse-5 affected initial Q migration, whereas sdn-1 did not. sdn-1 and hse-5 acted redundantly in AQR and PQR migration, but not initial Q migration, suggesting the involvement of other HSPGs in Q migration. Cell-specific expression studies indicated that SDN-1 can act in QR to promote anterior migration. Genetic interactions between sdn-1, mig-13, and mab-5 suggest that MIG-13 and SDN-1 act in parallel to promote anterior AQR migration and that SDN-1 also controls posterior migration. Together, our results indicate previously unappreciated complexity in the role of multiple signaling pathways and inherent left-right asymmetry in the control of Q neuroblast descendant migration. Copyright © 2015 Sundararajan et al.

SDN-1/Syndecan Acts in Parallel to the Transmembrane Molecule MIG-13 to Promote Anterior Neuroblast Migration

PubMed Central

Sundararajan, Lakshmi; Norris, Megan L.; Lundquist, Erik A.

2015-01-01

The Q neuroblasts in Caenorhabditis elegans display left-right asymmetry in their migration, with QR and descendants on the right migrating anteriorly, and QL and descendants on the left migrating posteriorly. Initial QR and QL migration is controlled by the transmembrane receptors UNC-40/DCC, PTP-3/LAR, and the Fat-like cadherin CDH-4. After initial migration, QL responds to an EGL-20/Wnt signal that drives continued posterior migration by activating MAB-5/Hox activity in QL but not QR. QR expresses the transmembrane protein MIG-13, which is repressed by MAB-5 in QL and which drives anterior migration of QR descendants. A screen for new Q descendant AQR and PQR migration mutations identified mig-13 as well as hse-5, the gene encoding the glucuronyl C5-epimerase enzyme, which catalyzes epimerization of glucuronic acid to iduronic acid in the heparan sulfate side chains of heparan sulfate proteoglycans (HSPGs). Of five C. elegans HSPGs, we found that only SDN-1/Syndecan affected Q migrations. sdn-1 mutants showed QR descendant AQR anterior migration defects, and weaker QL descendant PQR migration defects. hse-5 affected initial Q migration, whereas sdn-1 did not. sdn-1 and hse-5 acted redundantly in AQR and PQR migration, but not initial Q migration, suggesting the involvement of other HSPGs in Q migration. Cell-specific expression studies indicated that SDN-1 can act in QR to promote anterior migration. Genetic interactions between sdn-1, mig-13, and mab-5 suggest that MIG-13 and SDN-1 act in parallel to promote anterior AQR migration and that SDN-1 also controls posterior migration. Together, our results indicate previously unappreciated complexity in the role of multiple signaling pathways and inherent left-right asymmetry in the control of Q neuroblast descendant migration. PMID:26022293

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.

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.

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

Commercial Slit-Lamp Anterior Segment Photography versus Digital Compact Camera Mounted on a Standard Slit-Lamp with an Adapter.

PubMed

Oliphant, Huw; Kennedy, Alasdair; Comyn, Oliver; Spalton, David J; Nanavaty, Mayank A

2018-06-16

To compare slit lamp mounted cameras (SLC) versus digital compact camera (DCC) with slit-lamp adaptor when used by an inexperienced technician. In this cross sectional study, where posterior capsule opacification (PCO) was used as a comparator, patients were consented for one photograph with SLC and two with DCC (DCC1 and DCC2), with a slit-lamp adaptor. An inexperienced clinic technician, who took all the photographs and masked the images, recruited one eye of each patient. Images were graded for PCO using ECPO2000 software by two independent masked graders. Repeatability between DCC1 & DCC2 and limits-of-agreement between SLC and DCC1 mounted on slit-lamp with an adaptor were assessed. Coefficient-of-repeatability and Bland-Altmann plots were analyzed. Seventy-two patients (eyes) were recruited in the study. First 9 patients (eyes) were excluded due to unsatisfactory image quality from both the systems. Mean EPCO score for SLC was 2.28 (95% CI: 2.09 -2.45), for DCC1 was 2.28 (95% CI: 2.11-2.45), and for the DCC2 was 2.11 (95% CI: 2.11-2.45). There was no significant difference in EPCO scores between SLC Vs. DCC1 (p = 0.98) and between DCC1 and DCC 2 (p = 0.97). Coefficient of repeatability between DCC images was 0.42, and the coefficient of repeatability between DCC and SLC was 0.58. DCC on slit-lamp with an adaptor is comparable to a SLC. There is an initial learning curve, which is similar for both for an inexperienced person. This opens up the possibility for low cost anterior segment imaging in the clinical, research and teaching settings.

MUC1 and colorectal cancer pathophysiology considerations.

PubMed

Niv, Yaron

2008-04-14

Several lines of evidence point towards a biological role of mucin and particularly MUC1 in colorectal cancer. A positive correlation was described between mucin secretion, proliferation, invasiveness, metastasis and bad prognosis. But, the role of MUC1 in cancer progression is still controversial and somewhat confusing. While Mukherjee and colleagues developed MUC1-specific immune therapy in a CRC model, Lillehoj and co-investigators showed recently that MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. In carcinoma cells the polarization of MUC1 is lost and the protein is over expressed at high levels over the entire cell surface. A competitive interaction between MUC1 and E-cadherin, through beta-catenin binding, disrupts E-cadherin-mediated cell-cell interactions at sites of MUC1 expression. In addition, the complex of MUC1-beta-catenin enters the nucleus and activates T-cell factor/leukocyte enhancing factor 1 transcription factors and activates gene expression. This mechanism may be similar to that just described for DCC and UNC5H, which induced apoptosis when not engaged with their ligand netrin, but mediate signals for proliferation, differentiation or migration when ligand bound.

Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes

PubMed Central

Reuten, Raphael; Patel, Trushar R.; McDougall, Matthew; Rama, Nicolas; Nikodemus, Denise; Gibert, Benjamin; Delcros, Jean-Guy; Prein, Carina; Meier, Markus; Metzger, Stéphanie; Zhou, Zhigang; Kaltenberg, Jennifer; McKee, Karen K.; Bald, Tobias; Tüting, Thomas; Zigrino, Paola; Djonov, Valentin; Bloch, Wilhelm; Clausen-Schaumann, Hauke; Poschl, Ernst; Yurchenco, Peter D.; Ehrbar, Martin; Mehlen, Patrick; Stetefeld, Jörg; Koch, Manuel

2016-01-01

Netrins, a family of laminin-related molecules, have been proposed to act as guidance cues either during nervous system development or the establishment of the vascular system. This was clearly demonstrated for netrin-1 via its interaction with the receptors DCC and UNC5s. However, mainly based on shared homologies with netrin-1, netrin-4 was also proposed to play a role in neuronal outgrowth and developmental/pathological angiogenesis via interactions with netrin-1 receptors. Here, we present the high-resolution structure of netrin-4, which shows unique features in comparison with netrin-1, and show that it does not bind directly to any of the known netrin-1 receptors. We show that netrin-4 disrupts laminin networks and basement membranes (BMs) through high-affinity binding to the laminin γ1 chain. We hypothesize that this laminin-related function is essential for the previously described effects on axon growth promotion and angiogenesis. Our study unveils netrin-4 as a non-enzymatic extracellular matrix protein actively disrupting pre-existing BMs. PMID:27901020

Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers.

PubMed

Vosberg, Daniel E; Zhang, Yu; Menegaux, Aurore; Chalupa, Amanda; Manitt, Colleen; Zehntner, Simone; Eng, Conrad; DeDuck, Kristina; Allard, Dominique; Durand, France; Dagher, Alain; Benkelfat, Chawki; Srour, Myriam; Joober, Ridha; Lepore, Franco; Rouleau, Guy; Théoret, Hugo; Bedell, Barry J; Flores, Cecilia; Leyton, Marco

2018-05-16

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc -haploinsufficient mice. The human volunteers were 20 DCC +/- mutation carriers, 16 DCC +/+ relatives, and 20 DCC +/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc +/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC +/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [ DCC +/+ : p = 0.0005, r ( effect size ) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex ( DCC +/+ : p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores ( DCC +/+ : p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume ( DCC +/+ : p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc +/- mice, and these were seen during adolescence ( p = 0.0058, d = 1.09) and adulthood ( p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders. SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC , enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC -haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders. Copyright © 2018 the authors 0270-6474/18/384655-11$15.00/0.

Validation of the UNC OCT Index for the Diagnosis of Early Glaucoma

PubMed Central

Lee, Gary; Budenz, Donald L.; Warren, Joshua L.; Wall, Michael; Artes, Paul H.; Callan, Thomas M.; Flanagan, John G.

2018-01-01

Purpose To independently validate the performance of the University of North Carolina Optical Coherence Tomography (UNC OCT) Index in diagnosing and predicting early glaucoma. Methods Data of 118 normal subjects (118 eyes) and 96 subjects (96 eyes) with early glaucoma defined as visual field mean deviation (MD) greater than −4 decibels (dB), aged 40 to 80 years, and who were enrolled in the Full-Threshold Testing Size III, V, VI comparison study were used in this study. CIRRUS OCT average and quadrants' retinal nerve fiber layer (RNFL); optic disc vertical cup-to-disc ratio (VCDR), cup-to-disc area ratio, and rim area; and average, minimum, and six sectoral ganglion cell-inner plexiform layer (GCIPL) measurements were run through the UNC OCT Index algorithm. Area under the receiver operating characteristic curve (AUC) and sensitivities at 95% and 99% specificity were calculated and compared between single parameters and the UNC OCT Index. Results Mean age was 60.1 ± 11.0 years for normal subjects and 66.5 ± 8.1 years for glaucoma patients (P < 0.001). MD was 0.29 ± 1.04 dB and −1.30 ± 1.35 dB in normal and glaucomatous eyes (P < 0.001), respectively. The AUC of the UNC OCT Index was 0.96. The best single metrics when compared to the UNC OCT Index were VCDR (0.93, P = 0.054), average RNFL (0.92, P = 0.014), and minimum GCIPL (0.91, P = 0.009). The sensitivities at 95% and 99% specificity were 85.4% and 76.0% (UNC OCT Index), 71.9% and 62.5% (VCDR, all P < 0.001), 64.6% and 53.1% (average RNFL, all P < 0.001), and 66.7% and 58.3% (minimum GCIPL, all P < 0.001), respectively. Conclusions The findings confirm that the UNC OCT Index may provide improved diagnostic perforce over that of single OCT parameters and may be a good tool for detection of early glaucoma. Translational Relevance The UNC OCT Index algorithm may be incorporated easily into routine clinical practice and be useful for detecting early glaucoma. PMID:29629238

Validation of the UNC OCT Index for the Diagnosis of Early Glaucoma.

PubMed

Mwanza, Jean-Claude; Lee, Gary; Budenz, Donald L; Warren, Joshua L; Wall, Michael; Artes, Paul H; Callan, Thomas M; Flanagan, John G

2018-04-01

To independently validate the performance of the University of North Carolina Optical Coherence Tomography (UNC OCT) Index in diagnosing and predicting early glaucoma. Data of 118 normal subjects (118 eyes) and 96 subjects (96 eyes) with early glaucoma defined as visual field mean deviation (MD) greater than -4 decibels (dB), aged 40 to 80 years, and who were enrolled in the Full-Threshold Testing Size III, V, VI comparison study were used in this study. CIRRUS OCT average and quadrants' retinal nerve fiber layer (RNFL); optic disc vertical cup-to-disc ratio (VCDR), cup-to-disc area ratio, and rim area; and average, minimum, and six sectoral ganglion cell-inner plexiform layer (GCIPL) measurements were run through the UNC OCT Index algorithm. Area under the receiver operating characteristic curve (AUC) and sensitivities at 95% and 99% specificity were calculated and compared between single parameters and the UNC OCT Index. Mean age was 60.1 ± 11.0 years for normal subjects and 66.5 ± 8.1 years for glaucoma patients ( P < 0.001). MD was 0.29 ± 1.04 dB and -1.30 ± 1.35 dB in normal and glaucomatous eyes ( P < 0.001), respectively. The AUC of the UNC OCT Index was 0.96. The best single metrics when compared to the UNC OCT Index were VCDR (0.93, P = 0.054), average RNFL (0.92, P = 0.014), and minimum GCIPL (0.91, P = 0.009). The sensitivities at 95% and 99% specificity were 85.4% and 76.0% (UNC OCT Index), 71.9% and 62.5% (VCDR, all P < 0.001), 64.6% and 53.1% (average RNFL, all P < 0.001), and 66.7% and 58.3% (minimum GCIPL, all P < 0.001), respectively. The findings confirm that the UNC OCT Index may provide improved diagnostic perforce over that of single OCT parameters and may be a good tool for detection of early glaucoma. The UNC OCT Index algorithm may be incorporated easily into routine clinical practice and be useful for detecting early glaucoma.

UNC-1 regulates gap junctions important to locomotion in C. elegans.

PubMed

Chen, Bojun; Liu, Qiang; Ge, Qian; Xie, Jia; Wang, Zhao-Wen

2007-08-07

In C. elegans, loss-of-function (lf) mutations of the stomatin-like protein (SLP) UNC-1 and the innexin UNC-9 inhibit locomotion [1, 2] and modulate sensitivity to volatile anesthetics [3, 4]. It was unknown why unc-1(lf) and unc-9(lf) mutants have similar phenotypes. We tested the hypothesis that UNC-1 is a regulator of gap junctions formed by UNC-9. Analyses of junctional currents between body-wall muscle cells showed that electrical coupling was inhibited to a similar degree in unc-1(lf), unc-9(lf), and unc-1(lf);unc-9(lf) double mutants, suggesting that UNC-1 and UNC-9 function together. Expression of Punc-1::DsRED2 and Punc-9::GFP transcriptional fusions suggests that unc-1 and unc-9 are coexpressed in neurons and body-wall muscle cells. Immunohistochemistry showed that UNC-1 and UNC-9 colocalized at intercellular junctions and that unc-1(lf) did not alter UNC-9 expression or subcellular localization. Bimolecular fluorescence complementation (BiFC) assays suggest that UNC-1 and UNC-9 are physically very close at intercellular junctions. Targeted rescue experiments suggest that UNC-9 and UNC-1 function predominantly in neurons to control locomotion. Thus, in addition to the recently reported function of regulating mechanosensitive ion channels [5, 6], SLPs might have a novel function of regulating gap junctions.

Estimating effective particle size of tropical deep convective clouds with a look-up table method using satellite measurements of brightness temperature differences

NASA Astrophysics Data System (ADS)

Hong, Gang; Minnis, Patrick; Doelling, David; Ayers, J. Kirk; Sun-Mack, Szedung

2012-03-01

A method for estimating effective ice particle radius Re at the tops of tropical deep convective clouds (DCC) is developed on the basis of precomputed look-up tables (LUTs) of brightness temperature differences (BTDs) between the 3.7 and 11.0 μm bands. A combination of discrete ordinates radiative transfer and correlated k distribution programs, which account for the multiple scattering and monochromatic molecular absorption in the atmosphere, is utilized to compute the LUTs as functions of solar zenith angle, satellite zenith angle, relative azimuth angle, Re, cloud top temperature (CTT), and cloud visible optical thickness τ. The LUT-estimated DCC Re agrees well with the cloud retrievals of the Moderate Resolution Imaging Spectroradiometer (MODIS) for the NASA Clouds and Earth's Radiant Energy System with a correlation coefficient of 0.988 and differences of less than 10%. The LUTs are applied to 1 year of measurements taken from MODIS aboard Aqua in 2007 to estimate DCC Re and are compared to a similar quantity from CloudSat over the region bounded by 140°E, 180°E, 0°N, and 20°N in the Western Pacific Warm Pool. The estimated DCC Re values are mainly concentrated in the range of 25-45 μm and decrease with CTT. Matching the LUT-estimated Re with ice cloud Re retrieved by CloudSat, it is found that the ice cloud τ values from DCC top to the vertical location where LUT-estimated Re is located at the CloudSat-retrieved Re profile are mostly less than 2.5 with a mean value of about 1.3. Changes in the DCC τ can result in differences of less than 10% for Re estimated from LUTs. The LUTs of 0.65 μm bidirectional reflectance distribution function (BRDF) are built as functions of viewing geometry and column amount of ozone above upper troposphere. The 0.65 μm BRDF can eliminate some noncore portions of the DCCs detected using only 11 μm brightness temperature thresholds, which result in a mean difference of only 0.6 μm for DCC Re estimated from BTD LUTs.

MUC1 and colorectal cancer pathophysiology considerations

PubMed Central

Niv, Yaron

2008-01-01

Several lines of evidence point towards a biological role of mucin and particularly MUC1 in colorectal cancer. A positive correlation was described between mucin secretion, proliferation, invasiveness, metastasis and bad prognosis. But, the role of MUC1 in cancer progression is still controversial and somewhat confusing. While Mukherjee and colleagues developed MUC1-specific immune therapy in a CRC model, Lillehoj and co-investigators showed recently that MUC1 inhibits cell proliferation by a β-catenin-dependent mechanism. In carcinoma cells the polarization of MUC1 is lost and the protein is over expressed at high levels over the entire cell surface. A competitive interaction between MUC1 and E-cadherin, through β-catenin binding, disrupts E-cadherin-mediated cell-cell interactions at sites of MUC1 expression. In addition, the complex of MUC1-β-catenin enters the nucleus and activates T-cell factor/leukocyte enhancing factor 1 transcription factors and activates gene expression. This mechanism may be similar to that just described for DCC and UNC5H, which induced apoptosis when not engaged with their ligand netrin, but mediate signals for proliferation, differentiation or migration when ligand bound. PMID:18407586

A novel DCC mutation and genetic heterogeneity in congenital mirror movements.

PubMed

Depienne, C; Cincotta, M; Billot, S; Bouteiller, D; Groppa, S; Brochard, V; Flamand, C; Hubsch, C; Meunier, S; Giovannelli, F; Klebe, S; Corvol, J C; Vidailhet, M; Brice, A; Roze, E

2011-01-18

DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the body's midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity.

The Role of the UNC-82 Protein Kinase in Organizing Myosin Filaments in Striated Muscle of Caenorhabditis elegans

PubMed Central

Schiller, NaTasha R.; Duchesneau, Christopher D.; Lane, Latrisha S.; Reedy, April R.; Manzon, Emily R.; Hoppe, Pamela E.

2017-01-01

We study the mechanisms that guide the formation and maintenance of the highly ordered actin-myosin cytoskeleton in striated muscle. The UNC-82 kinase of Caenorhabditis elegans is orthologous to mammalian kinases ARK5/NUAK1 and SNARK/NUAK2. UNC-82 localizes to the M-line, and is required for proper organization of thick filaments, but its substrate and mechanism of action are unknown. Antibody staining of three mutants with missense mutations in the UNC-82 catalytic domain revealed muscle structure that is less disorganized than in the null unc-82(0), but contained distinctive ectopic accumulations not found in unc-82(0). These accumulations contain paramyosin and myosin B, but lack myosin A and myosin A-associated proteins, as well as proteins of the integrin-associated complex. Fluorescently tagged missense mutant protein UNC-82 E424K localized normally in wild type; however, in unc-82(0), the tagged protein was found in the ectopic accumulations, which we also show to label with recently synthesized paramyosin. Recruitment of wild-type UNC-82::GFP to aggregates of differing protein composition in five muscle-affecting mutants revealed that colocalization of UNC-82 and paramyosin does not require UNC-96, UNC-98/ZnF, UNC-89/obscurin, CSN-5, myosin A, or myosin B individually. Dosage effects in paramyosin mutants suggest that UNC-82 acts as part of a complex, in which its stoichiometric relationship with paramyosin is critical. UNC-82 dosage affects muscle organization in the absence of paramyosin, perhaps through myosin B. We present evidence that the interaction of UNC-98/ZnF with myosin A is independent of UNC-82, and that UNC-82 acts upstream of UNC-98/ZnF in a pathway that organizes paramyosin during thick filament assembly. PMID:28040740

The Role of the UNC-82 Protein Kinase in Organizing Myosin Filaments in Striated Muscle of Caenorhabditis elegans.

PubMed

Schiller, NaTasha R; Duchesneau, Christopher D; Lane, Latrisha S; Reedy, April R; Manzon, Emily R; Hoppe, Pamela E

2017-03-01

We study the mechanisms that guide the formation and maintenance of the highly ordered actin-myosin cytoskeleton in striated muscle. The UNC-82 kinase of Caenorhabditis elegans is orthologous to mammalian kinases ARK5/NUAK1 and SNARK/NUAK2. UNC-82 localizes to the M-line, and is required for proper organization of thick filaments, but its substrate and mechanism of action are unknown. Antibody staining of three mutants with missense mutations in the UNC-82 catalytic domain revealed muscle structure that is less disorganized than in the null unc-82(0) , but contained distinctive ectopic accumulations not found in unc-82(0) These accumulations contain paramyosin and myosin B, but lack myosin A and myosin A-associated proteins, as well as proteins of the integrin-associated complex. Fluorescently tagged missense mutant protein UNC-82 E424K localized normally in wild type; however, in unc-82(0) , the tagged protein was found in the ectopic accumulations, which we also show to label with recently synthesized paramyosin. Recruitment of wild-type UNC-82::GFP to aggregates of differing protein composition in five muscle-affecting mutants revealed that colocalization of UNC-82 and paramyosin does not require UNC-96, UNC-98/ZnF, UNC-89/obscurin, CSN-5, myosin A, or myosin B individually. Dosage effects in paramyosin mutants suggest that UNC-82 acts as part of a complex, in which its stoichiometric relationship with paramyosin is critical. UNC-82 dosage affects muscle organization in the absence of paramyosin, perhaps through myosin B. We present evidence that the interaction of UNC-98/ZnF with myosin A is independent of UNC-82, and that UNC-82 acts upstream of UNC-98/ZnF in a pathway that organizes paramyosin during thick filament assembly. Copyright © 2017 by the Genetics Society of America.

[The risk of direct current countershock].

PubMed

Gajek, J; Zyśko, D

2001-07-01

Direct current cardioversion (DCC) is a procedure commonly used to restore the sinus rhythm in patients with supraventricular and ventricular arrhythmias. Its safety, regarding the use of electric current, is still a matter of controversy and debate. The patients with atrial fibrillation/flutter, supraventricular or ventricular tachycardia represent a broad spectrum of clinical conditions and it is difficult to draw the conclusions. The high success rate of DCC in restoring the sinus rhythm, may be partly responsible for enhancing and revealing proarrhythmic properties of antiarrhythmic drugs. The deaths described as a complications of DCC were mainly due to the proarrhythmia and less common to the progression of the pathologic process. The embolic, arrhythmic and anesthetic complications of DCC can be prevented if the known recommendations of performing the DCC are followed. The authors review critically the literature data about the complications of the procedure and come to the conclusion of safety of DCC.

Anchoring of protein kinase A by ERM (ezrin-radixin-moesin) proteins is required for proper netrin signaling through DCC (deleted in colorectal cancer).

PubMed

Deming, Paula B; Campbell, Shirley L; Stone, Jamie B; Rivard, Robert L; Mercier, Alison L; Howe, Alan K

2015-02-27

Netrin-1, acting through its principal receptor DCC (deleted in colorectal cancer), serves as an axon guidance cue during neural development and also contributes to vascular morphogenesis, epithelial migration, and the pathogenesis of some tumors. Several lines of evidence suggest that netrin-DCC signaling can regulate and be regulated by the cAMP-dependent protein kinase, PKA, although the molecular details of this relationship are poorly understood. Specificity in PKA signaling is often achieved through differential subcellular localization of the enzyme by interaction with protein kinase A anchoring proteins (AKAPs). Here, we show that AKAP function is required for DCC-mediated activation of PKA and phosphorylation of cytoskeletal regulatory proteins of the Mena/VASP (vasodilator-stimulated phosphoprotein) family. Moreover, we show that DCC and PKA physically interact and that this association is mediated by the ezrin-radixin-moesin (ERM) family of plasma membrane-actin cytoskeleton cross-linking proteins. Silencing of ERM protein expression inhibits DCC-PKA interaction, DCC-mediated PKA activation, and phosphorylation of Mena/VASP proteins as well as growth cone morphology and neurite outgrowth. Finally, although expression of wild-type radixin partially rescued growth cone morphology and tropism toward netrin in ERM-knockdown cells, expression of an AKAP-deficient mutant of radixin did not fully rescue growth cone morphology and switched netrin tropism from attraction to repulsion. These data support a model in which ERM-mediated anchoring of PKA activity to DCC is required for proper netrin/DCC-mediated signaling. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Principles of metadata organization at the ENCODE data coordination center

PubMed Central

Hong, Eurie L.; Sloan, Cricket A.; Chan, Esther T.; Davidson, Jean M.; Malladi, Venkat S.; Strattan, J. Seth; Hitz, Benjamin C.; Gabdank, Idan; Narayanan, Aditi K.; Ho, Marcus; Lee, Brian T.; Rowe, Laurence D.; Dreszer, Timothy R.; Roe, Greg R.; Podduturi, Nikhil R.; Tanaka, Forrest; Hilton, Jason A.; Cherry, J. Michael

2016-01-01

The Encyclopedia of DNA Elements (ENCODE) Data Coordinating Center (DCC) is responsible for organizing, describing and providing access to the diverse data generated by the ENCODE project. The description of these data, known as metadata, includes the biological sample used as input, the protocols and assays performed on these samples, the data files generated from the results and the computational methods used to analyze the data. Here, we outline the principles and philosophy used to define the ENCODE metadata in order to create a metadata standard that can be applied to diverse assays and multiple genomic projects. In addition, we present how the data are validated and used by the ENCODE DCC in creating the ENCODE Portal (https://www.encodeproject.org/). Database URL: www.encodeproject.org PMID:26980513

Condensin-driven remodelling of X chromosome topology during dosage compensation

NASA Astrophysics Data System (ADS)

Crane, Emily; Bian, Qian; McCord, Rachel Patton; Lajoie, Bryan R.; Wheeler, Bayly S.; Ralston, Edward J.; Uzawa, Satoru; Dekker, Job; Meyer, Barbara J.

2015-07-01

The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (~1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.

Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation

PubMed Central

Crane, Emily; Bian, Qian; McCord, Rachel Patton; Lajoie, Bryan R.; Wheeler, Bayly S.; Ralston, Edward J.; Uzawa, Satoru; Dekker, Job; Meyer, Barbara J.

2015-01-01

The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure1,2. Here we perform genome-wide chromosome conformation capture analysis, FISH, and RNA-seq to obtain comprehensive 3D maps of the Caenorhabditis elegans genome and to dissect X-chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half3–7. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes5,6. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (~1 Mb) resembling mammalian Topologically Associating Domains (TADs)8,9. TADs on X have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X while regulating gene expression chromosome wide. PMID:26030525

Dermatology discharge continuity clinic enhances resident autonomy and insight into transitions-of-care competencies: a cross-sectional survey study.

PubMed

Rana, Jasmine; Mostaghimi, Arash

2017-05-15

Dermatology residents perform consults on hospitalized patients, but are often limited in their ability to follow-up with these patients after discharge, leading to inadequate follow-up and understanding of post-discharge transitions of care. In 2013, a discharge continuity clinic (DCC) staffed by the inpatient consult dermatology resident and attending dermatologist was established at one of the four adult hospital sites residents rotate through in the Harvard Combined Dermatology Residency Program. Resident perceptions about the DCC and their educational experience on inpatient consult rotations with a DCC and without a DCC were obtained using a cross-sectional survey instrument in June 2016. Self-reported data from a multi-year cohort of dermatology residents (n = 14 of 20, 70% response rate) reveals that the DCC enabled resident autonomy and resident satisfaction in care of their patients,insight into the disease-related challenges and the broader social context during transitions of care from inpatient to outpatient settings, and more enriching learning experiences than inpatient consult rotations without a DCC. Dermatology residents self-report participation in an inpatient consult rotation with aDCC supports their autonomy and achievement of post-discharge transitions-of-care competencies.

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.

Microsphere-based scaffolds encapsulating chondroitin sulfate or decellularized cartilage

PubMed Central

Gupta, Vineet; Tenny, Kevin M; Barragan, Marilyn; Berkland, Cory J; Detamore, Michael S

2016-01-01

Extracellular matrix materials such as decellularized cartilage (DCC) and chondroitin sulfate (CS) may be attractive chondrogenic materials for cartilage regeneration. The goal of the current study was to investigate the effects of encapsulation of DCC and CS in homogeneous microsphere-based scaffolds, and to test the hypothesis that encapsulation of these extracellular matrix materials would induce chondrogenesis of rat bone marrow stromal cells. Four different types of homogeneous scaffolds were fabricated from microspheres of poly(D,L-lactic-co-glycolic acid): Blank (poly(D,L-lactic-co-glycolic acid) only; negative control), transforming growth factor-β3 encapsulated (positive control), DCC encapsulated, and CS encapsulated. These scaffolds were then seeded with rat bone marrow stromal cells and cultured for 6 weeks. The DCC and CS encapsulation altered the morphological features of the microspheres, resulting in higher porosities in these groups. Moreover, the mechanical properties of the scaffolds were impacted due to differences in the degree of sintering, with the CS group exhibiting the highest compressive modulus. Biochemical evidence suggested a mitogenic effect of DCC and CS encapsulation on rat bone marrow stromal cells with the matrix synthesis boosted primarily by the inherently present extracellular matrix components. An important finding was that the cell seeded CS and DCC groups at week 6 had up to an order of magnitude higher glycosaminoglycan contents than their acellular counterparts. Gene expression results indicated a suppressive effect of DCC and CS encapsulation on rat bone marrow stromal cell chondrogenesis with differences in gene expression patterns existing between the DCC and CS groups. Overall, DCC and CS were easily included in microsphere-based scaffolds; however, there is a requirement to further refine their concentrations to achieve the differentiation profiles we seek in vitro. PMID:27358376

UNC-18 Promotes Both the Anterograde Trafficking and Synaptic Function of Syntaxin

PubMed Central

McEwen, Jason M.

2008-01-01

The SM protein UNC-18 has been proposed to regulate several aspects of secretion, including synaptic vesicle docking, priming, and fusion. Here, we show that UNC-18 has a chaperone function in neurons, promoting anterograde transport of the plasma membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein Syntaxin-1. In unc-18 mutants, UNC-64 (Caenorhabditis elegans Syntaxin-1) accumulates in neuronal cell bodies. Colocalization studies and analysis of carbohydrate modifications both suggest that this accumulation occurs in the endoplasmic reticulum. This trafficking defect is specific for UNC-64 Syntaxin-1, because 14 other SNARE proteins and two active zone markers were unaffected. UNC-18 binds to Syntaxin through at least two mechanisms: binding to closed Syntaxin, or to the N terminus of Syntaxin. It is unclear which of these binding modes mediates UNC-18 function in neurons. The chaperone function of UNC-18 was eliminated in double mutants predicted to disrupt both modes of Syntaxin binding, but it was unaffected in single mutants. By contrast, mutations predicted to disrupt UNC-18 binding to the N terminus of Syntaxin caused significant defects in locomotion behavior and responsiveness to cholinesterase inhibitors. Collectively, these results demonstrate the UNC-18 acts as a molecular chaperone for Syntaxin transport in neurons and that the two modes of UNC-18 binding to Syntaxin are involved in different aspects of UNC-18 function. PMID:18596236

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.

dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.

PubMed

Manitt, C; Eng, C; Pokinko, M; Ryan, R T; Torres-Berrío, A; Lopez, J P; Yogendran, S V; Daubaras, M J J; Grant, A; Schmidt, E R E; Tronche, F; Krimpenfort, P; Cooper, H M; Pasterkamp, R J; Kolb, B; Turecki, G; Wong, T P; Nestler, E J; Giros, B; Flores, C

2013-12-17

Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.

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

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.

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

UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 in Caenorhabditis elegans

PubMed Central

Park, Seungmee; Bin, Na-Ryum; Wong, Raymond; Sitarska, Ewa; Sugita, Kyoko; Ma, Ke; Algouneh, Arash; Turlova, Ekaterina; Wang, Siyan; Siriya, Pranay; Kalia, Lorraine; Feng, Zhong-Ping; Monnier, Philippe P.; Zhen, Mei; Gao, Shangbang

2017-01-01

Munc18-1/UNC-18 is believed to prime SNARE-mediated membrane fusion, yet the underlying mechanisms remain enigmatic. Here, we examine how potential gain-of-function mutations of Munc18-1/UNC-18 affect locomotory behavior and synaptic transmission, and how Munc18-1-mediated priming is related to Munc13-1/UNC-13 and Tomosyn/TOM-1, positive and negative SNARE regulators, respectively. We show that a Munc18-1(P335A)/UNC-18(P334A) mutation leads to significantly increased locomotory activity and acetylcholine release in Caenorhabditis elegans, as well as enhanced synaptic neurotransmission in cultured mammalian neurons. Importantly, similar to tom-1 null mutants, unc-18(P334A) mutants partially bypass the requirement of UNC-13. Moreover, unc-18(P334A) and tom-1 null mutations confer a strong synergy in suppressing the phenotypes of unc-13 mutants. Through biochemical experiments, we demonstrate that Munc18-1(P335A) exhibits enhanced activity in SNARE complex formation as well as in binding to the preformed SNARE complex, and partially bypasses the Munc13-1 requirement in liposome fusion assays. Our results indicate that Munc18-1/UNC-18 primes vesicle fusion downstream of Munc13-1/UNC-13 by templating SNARE complex assembly and acts antagonistically with Tomosyn/TOM-1. SIGNIFICANCE STATEMENT At presynaptic sites, SNARE-mediated membrane fusion is tightly regulated by several key proteins including Munc18/UNC-18, Munc13/UNC-13, and Tomosyn/TOM-1. However, how these proteins interact with each other to achieve the precise regulation of neurotransmitter release remains largely unclear. Using Caenorhabditis elegans as an in vivo model, we found that a gain-of-function mutant of UNC-18 increases locomotory activity and synaptic acetylcholine release, that it partially bypasses the requirement of UNC-13 for release, and that this bypass is synergistically augmented by the lack of TOM-1. We also elucidated the biochemical basis for the gain-of-function caused by this mutation. Thus, our study provides novel mechanistic insights into how Munc18/UNC-18 primes synaptic vesicle release and how this protein interacts functionally with Munc13/UNC-13 and Tomosyn/TOM-1. PMID:28821673

Principles of metadata organization at the ENCODE data coordination center.

PubMed

Hong, Eurie L; Sloan, Cricket A; Chan, Esther T; Davidson, Jean M; Malladi, Venkat S; Strattan, J Seth; Hitz, Benjamin C; Gabdank, Idan; Narayanan, Aditi K; Ho, Marcus; Lee, Brian T; Rowe, Laurence D; Dreszer, Timothy R; Roe, Greg R; Podduturi, Nikhil R; Tanaka, Forrest; Hilton, Jason A; Cherry, J Michael

2016-01-01

The Encyclopedia of DNA Elements (ENCODE) Data Coordinating Center (DCC) is responsible for organizing, describing and providing access to the diverse data generated by the ENCODE project. The description of these data, known as metadata, includes the biological sample used as input, the protocols and assays performed on these samples, the data files generated from the results and the computational methods used to analyze the data. Here, we outline the principles and philosophy used to define the ENCODE metadata in order to create a metadata standard that can be applied to diverse assays and multiple genomic projects. In addition, we present how the data are validated and used by the ENCODE DCC in creating the ENCODE Portal (https://www.encodeproject.org/). Database URL: www.encodeproject.org. © The Author(s) 2016. Published by Oxford University Press.

Radiative Effects of the Diurnal Cycle of Clouds and their Response to Climate Change

NASA Astrophysics Data System (ADS)

Yin, J.; Porporato, A. M.

2017-12-01

Clouds effectively control the Earth's energy budget by reflecting solar radiation and restricting the terrestrial one. While these dynamics have been regarded as one of vexing problem in understanding the climate system and have thus attracted much attention in the literature, less research has been devoted to the diurnal cycle of clouds (DCC). Here we first quantify the mean, amplitude, and phase of the cloud cycles in current climate models and compare them with satellite observations and reanalysis data. We show that the mean values appear to be reliable but the amplitude and phase of the DCC are less consistent. These inconsistencies are interpreted using a minimalist radiative balance model to demonstrate their impacts on surface temperature. The DCC radiative impacts are then analyzed in terms of phase shift and amplitude modulation of DCC and their so-called cloud radiative effects are estimated directly from climate model outputs. This allows us to show that DCC variations may account for up to 10-20% of the total cloud radiative impacts, calling for increased attention to the temporal evolution of the DCC in climate models.

Absorber modeling for NGCC carbon capture with aqueous piperazine.

PubMed

Zhang, Yue; Freeman, Brice; Hao, Pingjiao; Rochelle, Gary T

2016-10-20

A hybrid system combining amine scrubbing with membrane technology for carbon capture from natural gas combined cycle (NGCC) power plants is proposed in this paper. In this process, the CO 2 in the flue gas can be enriched from 4% to 18% by the membrane, and the amine scrubbing system will have lower capture costs. Aqueous piperazine (PZ) is chosen as the solvent. Different direct contact cooler (DCC) options, multiple absorber operating conditions, optimal intercooling designs, and different cooling options have been evaluated across a wide range of inlet CO 2 . Amine scrubbing without DCC is a superior design for NGCC carbon capture. Pump-around cooling at the bottom of the absorber can effectively manage the temperature of the hot flue gas, and still be effective for CO 2 absorption. The absorber gas inlet must be designed to avoid excessive localized temperature and solvent evaporation. When the inlet CO 2 increases from 4% to 18%, total absorber CAPEX decreases by 60%; another 10% of the total absorber CAPEX can be saved by eliminating the DCC. In-and-out intercooling works well for high CO 2 , while pump-around intercooling is more effective for low CO 2 . Dry cooling requires more packing and energy but appears to be technically and economically feasible if cooling water availability is limited.

[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.

High blood lead levels are associated with lead concentrations in households and day care centers attended by Brazilian preschool children.

PubMed

da Rocha Silva, Júlia Prestes; Salles, Fernanda Junqueira; Leroux, Isabelle Nogueira; da Silva Ferreira, Ana Paula Sacone; da Silva, Agnes Soares; Assunção, Nilson Antonio; Nardocci, Adelaide Cassia; Sayuri Sato, Ana Paula; Barbosa, Fernando; Cardoso, Maria Regina Alves; Olympio, Kelly Polido Kaneshiro

2018-08-01

A previous study observed high blood lead levels (BLL) in preschool children attending 50 day care centers (DCC) in São Paulo, Brazil. To identify whether lead levels found in both homes and DCC environments are associated with high blood lead levels. Children attending 4 DCCs, quoted here as NR, VA, PS and PF, were divided into two groups according to BLL: high exposure (HE: ≥13.9 μg/dL; 97.5 percentile of the 2013 year sample) and low exposure (LE: <5 μg/dL). For in situ lead measurements (lead paint mode: mg/cm 2 and ROHS mode: μg/g) in the children's households and in the DCC environments, a field portable X-ray-fluorescence analyzer was used. Multiple logistic regressions were performed to control for confounding factors. Odds ratios were adjusted for age, sex, day care center's measured lead, and tobacco. In an NR DCC building, 33.8% of the measurements had lead levels >600 μg/g, whereas such levels were observed in 77.1% of NR playground measurements. In VA DCC, 22% and 23% of the measurements in the building and in the playgrounds had levels higher than 600 μg/g, respectively. The percentage of high lead levels in the children's houses of the LE group was 5.9% (95% CI: 4.3-7.6%) and 13.2 (95% CI: 8.3-18.0%) in the HE group. Moreover, a significant association was found between high BLLs and lead levels found both in households and DCCs (p < 0.001). Most of the high lead measurements were found in tiles and playground equipment. Lead exposure estimated from the DCCs, where children spend about 10 h/day, can be as relevant as their household exposure. Therefore, public authorities should render efforts to provide a rigorous surveillance for lead-free painting supplies and for all objects offered to children. Copyright © 2018 Elsevier Ltd. All rights reserved.

Shelf-Life of Chlorine Solutions Recommended in Ebola Virus Disease Response.

PubMed

Iqbal, Qais; Lubeck-Schricker, Maya; Wells, Emma; Wolfe, Marlene K; Lantagne, Daniele

2016-01-01

In Ebola Virus Disease (EVD) outbreaks, it is widely recommended to wash living things (handwashing) with 0.05% (500 mg/L) chlorine solution and non-living things (surfaces, personal protective equipment, dead bodies) with 0.5% (5,000 mg/L) chlorine solution. Chlorine solutions used in EVD response are primarily made from powdered calcium hypochlorite (HTH), granular sodium dichloroisocyanurate (NaDCC), and liquid sodium hypochlorite (NaOCl), and have a pH range of 5-11. Chlorine solutions degrade following a reaction highly dependent on, and unusually sensitive to, pH, temperature, and concentration. We determined the shelf-life of 0.05% and 0.5% chlorine solutions used in EVD response, including HTH, NaDCC, stabilized NaOCl, generated NaOCl, and neutralized NaOCl solutions. Solutions were stored for 30 days at 25, 30, and 35°C, and tested daily for chlorine concentration and pH. Maximum shelf-life was defined as days until initial concentration fell to <90% of initial concentration in ideal laboratory conditions. At 25-35°C, neutralized-NaOCl solutions (pH = 7) had a maximum shelf-life of a few hours, NaDCC solutions (pH = 6) 2 days, generated NaOCl solutions (pH = 9) 6 days, and HTH and stabilized NaOCl solutions (pH 9-11) >30 days. Models were developed for solutions with maximum shelf-lives between 1-30 days. Extrapolating to 40°C, the maximum predicted shelf-life for 0.05% and 0.5% NaDCC solutions were 0.38 and 0.82 hours, respectively; predicted shelf-life for 0.05% and 0.5% generated NaOCl solutions were >30 and 5.4 days, respectively. Each chlorine solution type offers advantages and disadvantages to responders, as: NaDCC is an easy-to-import high-concentration effervescent powder; HTH is similar, but forms a precipitate that may clog pipes; and, NaOCl solutions can be made locally, but are difficult to transport. We recommend responders chose the most appropriate source chlorine compound for their use, and ensure solutions are stored at appropriate temperatures and used or replaced before expiring.

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

The Characterization of Deep Convective Clouds as an Invariant Calibration Target and as a Visible Calibration Technique

NASA Technical Reports Server (NTRS)

Doelling, David R.; Morstad, Daniel; Scarino, Benjamin R.; Bhatt, Rajendra; Gopalan, Arun

2012-01-01

Deep convective clouds (DCCs) are ideal visible calibration targets because they are bright nearly isotropic solar reflectors located over the tropics and they can be easily identified using a simple infrared threshold. Because all satellites view DCCs, DCCs provide the opportunity to uniformly monitor the stability of all operational sensors, both historical and present. A collective DCC anisotropically corrected radiance calibration approach is used to construct monthly probability distribution functions (PDFs) to monitor sensor stability. The DCC calibration targets were stable to within 0.5% and 0.3% per decade when the selection criteria were optimized based on Aqua MODerate Resolution Imaging Spectroradiometer 0.65-micrometer-band radiances. The Tropical Western Pacific (TWP), African, and South American regions were identified as the dominant DCC domains. For the 0.65-micrometer band, the PDF mode statistic is preferable, providing 0.3%regional consistency and 1%temporal uncertainty over land regions. It was found that the DCC within the TWP had the lowest radiometric response and DCC over land did not necessarily have the highest radiometric response. For wavelengths greater than 1 micrometer, the mean statistic is preferred, and land regions provided a regional variability of 0.7%with a temporal uncertainty of 1.1% where the DCC land response was higher than the response over ocean. Unlike stratus and cirrus clouds, the DCC spectra were not affected by water vapor absorption.

Comparative evaluation of effectiveness of sodium dichloroisocyanurate and calcium hydroxide against Candida albicans.

PubMed

Kurian, Jacob; Bolla, Nagesh; Damaraju, Bhargavi

2012-09-01

Candida albicans is the most commonly isolated fungi from the oral cavity. It is the most infective to various intracanal medicaments and is considered as invasive yeast. Sodium dichloroisocyanurate (NaDCC) which is used as a disinfectant and as a biocide in treating potable water has similar action to that of sodium hypochlorite against microbes. The aim of the present study is to compare the effectiveness of calcium hydroxide and NaDCC against Candida albicans. After obtaining the stock cultures of Candida, the isolates were divided into six groups which were exposed to different concentrations of NaDCC and calcium hydroxide Ca(OH)₂. Group 1 consisted of the isolates which were subdivided into three groups, subjected to three different concentrations of NaDCC. Group 2 also consisted of three subgroups exposed to three different concentrations of Ca(OH)₂. Group three consisted of three subgroups which were exposed to three different concentrations of combinations of both NaDCC and Ca(OH)₂. The results of the present study show that calcium hydroxide was totally ineffective at all concentrations and NaDCC was effective and also the combination of both was shown to be effective. NaDCC alone was effective at all concentrations and the combination with Ca(OH)₂ was found to be less effective. Ca(OH)₂ was totally ineffective.

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

Functional characterisation of a TLR accessory protein, UNC93B1, in Atlantic salmon (Salmo salar).

PubMed

Lee, P T; Zou, J; Holland, J W; Martin, S A M; Scott, C J W; Kanellos, T; Secombes, C J

2015-05-01

Toll-like receptors (TLRs) are indispensable components of the innate immune system, which recognise conserved pathogen associated molecular patterns (PAMPs) and induce a series of defensive immune responses to protect the host. Biosynthesis, localisation and activation of TLRs are dependent on TLR accessory proteins. In this study, we identified the accessory protein, UNC93B1, from Atlantic salmon (Salmo salar) whole-genome shotgun (WGS) contigs aided by the conserved gene synteny of genes flanking UNC93B1 in fish, birds and mammals. Phylogenetic analysis showed that salmon UNC93B1 grouped with other vertebrate UNC93B1 molecules, and had highest amino acid identity and similarity to zebrafish UNC93B1. The salmon UNC93B1 gene organisation was also similar in structure to mammalian UNC93B1. Our gene expression studies revealed that salmon UNC93B1 was more highly expressed in spleen, liver and gill tissues but was expressed at a lower level in head kidney tissue in post-smolts relative to parr. Moreover, salmon UNC93B1 mRNA transcripts were up-regulated in vivo in spleen tissue from polyI:C treated salmon and in vitro in polyI:C or IFNγ stimulated Salmon Head Kidney-1 (SHK-1) cells. Initial studies into the functional role of salmon UNC93B1 in fish TLR signalling found that both wild type salmon UNC93B1 and a molecule with a site-directed mutation (H424R) co-immunoprecipitated with salmon TLR19, TLR20a and TLR20d. Overall, these data illustrate the potential importance of UNC93B1 as an accessory protein in fish TLR signalling. Copyright © 2014 Elsevier Ltd. All rights reserved.

Placental transfusion in preterm neonates of 30-33 weeks' gestation: a randomized controlled trial.

PubMed

Das, Bikramjit; Sundaram, Venkataseshan; Tarnow-Mordi, William; Ghadge, Alpana; Dhaliwal, Lakhbir Kaur; Kumar, Praveen

2018-02-06

To compare effect of placental transfusion by delayed cord clamping (DCC) or cord milking (CM) with early cord clamping (ECC) on a composite of mortality or abnormal neurological status at 40 weeks' post-menstrual age (PMA) and 24-30 months' chronological age in neonates of 30-33 weeks' gestation. Randomized, controlled trial. A composite of mortality or abnormal neurological status at 40 weeks PMA and survival free of neurodevelopmental abnormalities at 24-30 months' chronological age. A total of 461 neonates were randomized to placental transfusion (n = 233) or to ECC (n = 228). Among those assigned to placental transfusion group, 173 underwent DCC while in the remaining 60, CM was done. Incidence of mortality or abnormal neurological status at 40 weeks PMA (43 (18%) vs 35 (15%), RR (95% CI) 1.2 (0.8, 1.8), p = 0.4) and survival free of neurodevelopmental impairment at 24-30 months of chronological age (99 (47%) vs. 100 (50%); RR (95% CI): 0.9 (0.8, 1.2); P = 0.9) was similar between the study groups. The placental transfusion group showed a trend towards lower incidence of necrotizing enterocolitis. In 30-33 weeks' gestation preterm neonates, placental transfusion as compared to early cord clamping resulted in similar mortality or abnormal neurological status at 40 weeks PMA and at 24-30 months of chronological age.

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

Quality of life assessment in advanced cancer patients treated at home, an inpatient unit, and a day care center

PubMed Central

Leppert, Wojciech; Majkowicz, Mikolaj; Forycka, Maria; Mess, Eleonora; Zdun-Ryzewska, Agata

2014-01-01

Aim of the study To assess quality of life (QoL) in cancer patients treated at home, at an in-patient palliative care unit (PCU), and at a day care center (DCC). Patients and methods QoL was assessed in advanced cancer patients at baseline and after 7 days of symptomatic treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative Care (EORTC QLQ-C15-PAL), the Edmonton Symptom Assessment System (ESAS), and the Karnofsky Performance Status (KPS) scale. Results A total of 129 patients completed the study, with 51 patients treated at home, 51 patients treated at the PCU, and 27 patients at DCC. In the EORTC QLQ-C15-PAL, improvement in functional and symptom scales was observed except in physical functioning and fatigue levels; patients at DCC had a better physical functioning, global QoL, appetite, and fatigue levels. In the ESAS, improvement in all items was found except for drowsiness levels, which was stable in patients treated at DCC and deteriorated in home and PCU patients. Higher activity, better appetite and well-being, and less drowsiness were observed in patients treated at DCC. KPS was better in DCC patients compared to those treated at home and at the PCU; the latter group deteriorated. Conclusions QoL improved in all patient groups, with better results in DCC patients and similar scores in those staying at home and at the PCU. Along with clinical assessment, baseline age, KPS, physical and emotional functioning may be considered when assigning patients to care at a DCC, PCU, or at home. PMID:24855379

Diel activity patterns of juvenile late fall-run Chinook salmon with implications for operation of a gated water diversion in the Sacramento–San Joaquin River Delta

USGS Publications Warehouse

Plumb, John M.; Adams, Noah S.; Perry, Russell W.; Holbrook, Christopher; Romine, Jason G.; Blake, Aaron R.; Burau, Jon R.

2016-01-01

In the Sacramento-San Joaquin River Delta, California, tidal forces that reverse river flows increase the proportion of water and juvenile late fall-run Chinook salmon diverted into a network of channels that were constructed to support agriculture and human consumption. This area is known as the interior delta, and it has been associated with poor fish survival. Under the rationale that the fish will be diverted in proportion to the amount of water that is diverted, the Delta Cross Channel (DCC) has been prescriptively closed during the winter out-migration to reduce fish entrainment and mortality into the interior delta. The fish are thought to migrate mostly at night, and so daytime operation of the DCC may allow for water diversion that minimizes fish entrainment and mortality. To assess this, the DCC gate was experimentally opened and closed while we released 2983 of the fish with acoustic transmitters upstream of the DCC to monitor their arrival and entrainment into the DCC. We used logistic regression to model night-time arrival and entrainment probabilities with covariates that included the proportion of each diel period with upstream flow, flow, rate of change in flow and water temperature. The proportion of time with upstream flow was the most important driver of night-time arrival probability, yet river flow had the largest effect on fish entrainment into the DCC. Modelling results suggest opening the DCC during daytime while keeping the DCC closed during night-time may allow for water diversion that minimizes fish entrainment into the interior delta.

Unexpected role for dosage compensation in the control of dauer arrest, insulin-like signaling, and FoxO transcription factor activity in Caenorhabditis elegans.

PubMed

Dumas, Kathleen J; Delaney, Colin E; Flibotte, Stephane; Moerman, Donald G; Csankovszki, Gyorgyi; Hu, Patrick J

2013-07-01

During embryogenesis, an essential process known as dosage compensation is initiated to equalize gene expression from sex chromosomes. Although much is known about how dosage compensation is established, the consequences of modulating the stability of dosage compensation postembryonically are not known. Here we define a role for the Caenorhabditis elegans dosage compensation complex (DCC) in the regulation of DAF-2 insulin-like signaling. In a screen for dauer regulatory genes that control the activity of the FoxO transcription factor DAF-16, we isolated three mutant alleles of dpy-21, which encodes a conserved DCC component. Knockdown of multiple DCC components in hermaphrodite and male animals indicates that the dauer suppression phenotype of dpy-21 mutants is due to a defect in dosage compensation per se. In dpy-21 mutants, expression of several X-linked genes that promote dauer bypass is elevated, including four genes encoding components of the DAF-2 insulin-like pathway that antagonize DAF-16/FoxO activity. Accordingly, dpy-21 mutation reduced the expression of DAF-16/FoxO target genes by promoting the exclusion of DAF-16/FoxO from nuclei. Thus, dosage compensation enhances dauer arrest by repressing X-linked genes that promote reproductive development through the inhibition of DAF-16/FoxO nuclear translocation. This work is the first to establish a specific postembryonic function for dosage compensation in any organism. The influence of dosage compensation on dauer arrest, a larval developmental fate governed by the integration of multiple environmental inputs and signaling outputs, suggests that the dosage compensation machinery may respond to external cues by modulating signaling pathways through chromosome-wide regulation of gene expression.

Sodium dichloroisocyanurate (NaDCC) tablets as an alternative to sodium hypochlorite for the routine treatment of drinking water at the household level.

PubMed

Clasen, Thomas; Edmondson, Paul

2006-03-01

Household water treatment using sodium hypochlorite (NaOCl) has been recognized as a cost-effective means of reducing the heavy burden of diarrhea and other waterborne diseases, especially among populations without access to improved water supplies. Sodium dichloroisocyanurate (NaDCC), which is widely used in emergencies, is an alternative source of chlorine that may present certain advantages over NaOCl for household-based interventions in development settings. We summarize the basic chemistry and possible benefits of NaDCC, and review the available literature concerning its safety and regulatory treatment and microbiological effectiveness. We review the evidence concerning NaDCC in field studies, including microbiological performance and health outcomes. Finally, we examine studies and data to compare NaDCC with NaOCl in terms of compliance, acceptability, affordability and sustainability, and suggest areas for further research.

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

Respiratory infection with Francisella novicida induces rapid dystrophic cardiac calcinosis (DCC).

PubMed

Roth, Kimberly M; Oghumu, Steve; Satoskar, Anjali A; Gunn, John S; van Rooijen, Nico; Satoskar, Abhay R

2008-06-01

Francisella tularensis causes pulmonary tularemia and death in humans when left untreated. Here, using a novel aerosol infection model, we show that acute pulmonary Francisella novicida infection not only causes pneumonia and liver damage, but also induces dystrophic cardiac calcinosis (DCC) in BALB/c mice. C57BL/6 mice also develop pneumonia and hepatic damage, but fail to develop DCC. Development of DCC in BALB/c mice is associated with significant induction of RANKL but not osteopontin in their organs. Depletion of lung macrophages prior to infection markedly reduces pericarditis and calcification in BALB/c mice but does not increase their susceptibility to infection.

Frequency of Tropical Ocean Deep Convection and Global Warming

NASA Astrophysics Data System (ADS)

Aumann, H. H.; Behrangi, A.; Ruzmaikin, A.

2017-12-01

The average of 36 CMIP5 models predicts about 3K of warming and a 4.7% increase in precipitation for the tropical oceans with a doubling of the CO2 by the end of this century. For this scenario we evaluate the increase in the frequency of Deep Convective Clouds (DCC) in the tropical oceans. We select only DCC which reach or penetrate the tropopause in the 15 km AIRS footprint. The evaluation is based on Probability Distribution Functions (PDFs) of the current temperatures of the tropical oceans, those predicted by the mean of the CMIP5 models and the PDF of the DCC process. The PDF of the DCC process is derived from the Atmospheric Infrared Sounder (AIRS) between the years 2003 and 2016. During this time the variability due Enso years provided a 1 K p-p change in the mean tropical SST. The key parameter is the SST associated with the onset of the DCC process. This parameter shifts only 0.5 K for each K of warming of the oceans. As a result the frequency of DCC is expected to increases by the end of this century by about 50% above the current frequency.

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

Disinfection efficacy of sodium dichloroisocyanurate (NADCC) against common food-borne intestinal protozoa.

PubMed

El Zawawy, Lobna A; El-Said, Doaa; Ali, Safia M; Fathy, Fouad M

2010-04-01

The present study was conducted to investigate the efficacy of sodium dichloroisocyanurate (NaDCC) on the infective stages of common food-borne intestinal protozoa; Entamoeba histolytica (E. histolytica), Giardia lamblia (G. lamblia), Cryptosporidium, Cyclospora and Microsporidia; beside its effect on raw green vegetables and fruits. Parasites, isolated from stool of patients with diarrhea or dysentery, were exposed to NaDCC solution (1g/l) for one and two hours. Disinfection effect of NaDCC was assessed by in-vitro viability, using trypan blue stain, and infectivity bioassay in laboratory animals as indicated by fecal and intestinal parasitic counts. Raw vegetables and fruits were dipped in NaDCC solution in the same concentration and exposure time as used for treatment of the parasites. Results revealed statistically significant reductions in viability and infectivity of all examined parasites indicating their susceptibility to NaDCC. Relative variations in susceptibility were revealed; E. histolytica and G. lamblia were most susceptible (100% reduction) followed by Microsporidia then Cryptospridium and Cyclospora. NaDCC did not affect the consistency, color, taste or flavor of raw green vegetables and fruits. The proved efficacy of NaDCC, in cheap and convenient dry tablet form, makes it a promising tool in decontaminating raw vegetables and fruits from food-borne protozoan parasites at household and restaurant levels as well as in catering and fresh produce industry. It is also recommended for disinfection of food preparation surfaces and equipment.

Timing of umbilical cord clamping among infants born at 22 through 27 weeks' gestation.

PubMed

Backes, C H; Huang, H; Iams, J D; Bauer, J A; Giannone, P J

2016-01-01

To investigate the safety, feasibility and efficacy of delayed cord clamping (DCC) compared with immediate cord clamping (ICC) at delivery among infants born at 22 to 27 weeks' gestation. This was a pilot, randomized, controlled trial in which women in labor with singleton pregnancies at 22 to 27 weeks' gestation were randomly assigned to ICC (cord clamped at 5 to 10 s) or DCC (30 to 45 s). Forty mother-infant pairs were randomized. Infants in the ICC and DCC groups had mean gestational ages (GA) of 24.6 and 24.4 weeks, respectively. No differences were observed between the groups across all available safety measures, although infants in the DCC group had higher admission temperatures than infants in the ICC group (97.4 vs. 96.2 °F, P=0.04). During the first 24 h of life, blood pressures were lower in the ICC group than in the DCC group (P<0.05), despite a threefold greater incidence of treatment for hypotension (45% vs. 12%, P<0.01). Infants in the ICC group had increased numbers of red blood transfusions (in first 28 days of life) than infants in DCC group (4.1±3.9 vs. 2.8±2.2, P=0.04). Among infants born at an average GA of 24 weeks', DCC appears safe, logistically feasible, and offers hematological and circulatory advantages compared with ICC. A more comprehensive appraisal of this practice is needed.

Digital intelligent booster for DCC miniature train networks

NASA Astrophysics Data System (ADS)

Ursu, M. P.; Condruz, D. A.

2017-08-01

Modern miniature trains are now driven by means of the DCC (Digital Command and Control) system, which allows the human operator or a personal computer to launch commands to each individual train or even to control different features of the same train. The digital command station encodes these commands and sends them to the trains by means of electrical pulses via the rails of the railway network. Due to the development of the miniature railway network, it may happen that the power requirement of the increasing number of digital locomotives, carriages and accessories exceeds the nominal output power of the digital command station. This digital intelligent booster relieves the digital command station from powering the entire railway network all by itself, and it automatically handles the multiple powered sections of the network. This electronic device is also able to detect and process short-circuits and overload conditions, without the intervention of the digital command station.

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

Cooperation between a hierarchical set of recruitment sites targets the X chromosome for dosage compensation

PubMed Central

Albritton, Sarah Elizabeth; Kranz, Anna-Lena; Winterkorn, Lara Heermans; Street, Lena Annika; Ercan, Sevinc

2017-01-01

In many organisms, it remains unclear how X chromosomes are specified for dosage compensation, since DNA sequence motifs shown to be important for dosage compensation complex (DCC) recruitment are themselves not X-specific. Here, we addressed this problem in C. elegans. We found that the DCC recruiter, SDC-2, is required to maintain open chromatin at a small number of primary DCC recruitment sites, whose sequence and genomic context are X-specific. Along the X, primary recruitment sites are interspersed with secondary sites, whose function is X-dependent. A secondary site can ectopically recruit the DCC when additional recruitment sites are inserted either in tandem or at a distance (>30 kb). Deletion of a recruitment site on the X results in reduced DCC binding across several megabases surrounded by topologically associating domain (TAD) boundaries. Our work elucidates that hierarchy and long-distance cooperativity between gene-regulatory elements target a single chromosome for regulation. DOI: http://dx.doi.org/10.7554/eLife.23645.001 PMID:28562241

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

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

Molecular Effects of Polymorphism in the 3’UTR of Unc-5 homolog C Associated with Conception Rate in Holsteins

PubMed Central

Sugimoto, Mayumi; Gotoh, Yusaku; Kawahara, Takayoshi; Sugimoto, Yoshikazu

2015-01-01

Conception rates among dairy cows in Japan have declined in recent decades. To enhance our understanding of the genes involved in conception rates, we conducted a genome-wide association study (GWAS) using 822 Holsteins and identified a single-nucleotide polymorphism (SNP) associated with conception rate: A+169G in the 3’ untranslated region (UTR) of unc-5 homolog C (UNC5C). Cows with higher conception rates carried the A polymorphism in the UNC5C 3’UTR. Luciferase assays and quantitative analysis of allele ratios revealed that UNC5C transcripts with the A polymorphism were expressed at higher levels than those carrying the G polymorphism. UNC5C transmits either pro- or anti-apoptotic signals depending on the availability of its ligand, Netrin-1. UNC5C expression is negatively regulated by reproductive homeobox X-linked 5 (Rhox5), and the Rhox5 locus is methylated by G9a methyltransferase. G9a-knockout mice have previously been demonstrated to be subfertile, and we found that UNC5C, G9a, and Netrin-1 expression levels increased from the 4-cell stage to the blastocyst stage in fertilized murine embryos, whereas Rhox5 expression decreased. Repression of UNC5C, G9a, or Netrin-1 or forced expression of Rhox5 in the anterior nucleus stage inhibited development to the blastocyst stage, suggesting that cows carrying the G polymorphism in UNC5C might have lower conception rates because of the poor development of preimplantation embryos. This study provides novel insights into the role of UNC5C during embryonic development. PMID:26147436

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.

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

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.

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

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.

Examining the impact of case management in Vancouver's downtown community court: a quasi-experimental design.

PubMed

Somers, Julian M; Moniruzzaman, Akm; Rezansoff, Stefanie N; Patterson, Michelle

2014-01-01

Problem solving courts (PSC) have been implemented internationally, with a common objective to prevent reoffending by addressing criminogenic needs and strengthening social determinants of health. There has been no empirical research on the effectiveness of community courts, which are a form of PSC designed to harness community resources and inter-disciplinary expertise to reduce recidivism in a geographic catchment area. We used the propensity score matching method to examine the effectiveness of Vancouver's Downtown Community Court (DCC). We focused on the subset of DCC participants who were identified as having the highest criminogenic risk and were assigned to a case management team (CMT). A comparison group was derived using one-to-one matching on a large array variables including static and dynamic criminogenic factors, geography, and time. Reductions in offences (one year pre minus one year post) were compared between CMT and comparison groups. Compared to other DCC offenders, those triaged to CMT (9.5% of the DCC population) had significantly higher levels of healthcare, social service use, and justice system involvement over the ten years prior to the index offence. Compared to matched offenders who received traditional court outcomes, those assigned to CMT (n=249) exhibited significantly greater reductions in overall offending (p<0.001), primarily comprised of significant reductions in property offences (p<0.001). Our findings indicate that CMT achieved significantly greater reductions in recidivism than traditional court among offenders with complex needs and high numbers of previous offences. Limitations of this research include a non-experimental design and one year follow up. Strengths include a robust matching process and extensive client level data spanning multiple sectors. Further research is needed to replicate the observed outcomes, to investigate the extension of community courts to settings with divergent offender needs and local resources, and to estimate potential cost avoidance attributable to this intervention.

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 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

Role of the DIP Molecules in DCC Signaling

DTIC Science & Technology

2001-03-01

DIP13 interacts with AKT , a key molecule for cell survival. Our results suggest that the DCC apoptotic signal is mediated by DIP13 that interferes with... AKT cell survival pathway, resulting in cell death. Finally, we have cloned DIP13 beta, suggesting that DIP13 represents a family of molecules with at...interacts with DCC through its PTB domain (Fig. 4). Interestingly, Mitsuuchi et al. (1999) identified a gene dubbed APPL that interacts with AKT , a key

ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

PubMed Central

Konopacki, Filip A.; Dwivedy, Asha; Bellon, Anaïs; Blower, Michael D.

2016-01-01

Endocytosis and local protein synthesis (LPS) act coordinately to mediate the chemotropic responses of axons, but the link between these two processes is poorly understood. The endosomal sorting complex required for transport (ESCRT) is a key regulator of cargo sorting in the endocytic pathway, and here we have investigated the role of ESCRT-II, a critical ESCRT component, in Xenopus retinal ganglion cell (RGC) axons. We show that ESCRT-II is present in RGC axonal growth cones (GCs) where it co-localizes with endocytic vesicle GTPases and, unexpectedly, with the Netrin-1 receptor, deleted in colorectal cancer (DCC). ESCRT-II knockdown (KD) decreases endocytosis and, strikingly, reduces DCC in GCs and leads to axon growth and guidance defects. ESCRT-II-depleted axons fail to turn in response to a Netrin-1 gradient in vitro and many axons fail to exit the eye in vivo. These defects, similar to Netrin-1/DCC loss-of-function phenotypes, can be rescued in whole (in vitro) or in part (in vivo) by expressing DCC. In addition, ESCRT-II KD impairs LPS in GCs and live imaging reveals that ESCRT-II transports mRNAs in axons. Collectively, our results show that the ESCRT-II-mediated endocytic pathway regulates both DCC and LPS in the axonal compartment and suggest that ESCRT-II aids gradient sensing in GCs by coupling endocytosis to LPS. PMID:27248654

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

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.

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

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.

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.

A novel approach of dynamic cross correlation analysis on molecular dynamics simulations and its application to Ets1 dimer-DNA complex.

PubMed

Kasahara, Kota; Fukuda, Ikuo; Nakamura, Haruki

2014-01-01

The dynamic cross correlation (DCC) analysis is a popular method for analyzing the trajectories of molecular dynamics (MD) simulations. However, it is difficult to detect correlative motions that appear transiently in only a part of the trajectory, such as atomic contacts between the side-chains of amino acids, which may rapidly flip. In order to capture these multi-modal behaviors of atoms, which often play essential roles, particularly at the interfaces of macromolecules, we have developed the "multi-modal DCC (mDCC)" analysis. The mDCC is an extension of the DCC and it takes advantage of a Bayesian-based pattern recognition technique. We performed MD simulations for molecular systems modeled from the (Ets1)2-DNA complex and analyzed their results with the mDCC method. Ets1 is an essential transcription factor for a variety of physiological processes, such as immunity and cancer development. Although many structural and biochemical studies have so far been performed, its DNA binding properties are still not well characterized. In particular, it is not straightforward to understand the molecular mechanisms how the cooperative binding of two Ets1 molecules facilitates their recognition of Stromelysin-1 gene regulatory elements. A correlation network was constructed among the essential atomic contacts, and the two major pathways by which the two Ets1 molecules communicate were identified. One is a pathway via direct protein-protein interactions and the other is that via the bound DNA intervening two recognition helices. These two pathways intersected at the particular cytosine bases (C110/C11), interacting with the H1, H2, and H3 helices. Furthermore, the mDCC analysis showed that both pathways included the transient interactions at their intermolecular interfaces of Tyr396-C11 and Ala327-Asn380 in multi-modal motions of the amino acid side chains and the nucleotide backbone. Thus, the current mDCC approach is a powerful tool to reveal these complicated behaviors and scrutinize intermolecular communications in a molecular system.

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

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

Anchoring of Heterochromatin to the Nuclear Lamina Reinforces Dosage Compensation-Mediated Gene Repression.

PubMed

Snyder, Martha J; Lau, Alyssa C; Brouhard, Elizabeth A; Davis, Michael B; Jiang, Jianhao; Sifuentes, Margarita H; Csankovszki, Györgyi

2016-09-01

Higher order chromosome structure and nuclear architecture can have profound effects on gene regulation. We analyzed how compartmentalizing the genome by tethering heterochromatic regions to the nuclear lamina affects dosage compensation in the nematode C. elegans. In this organism, the dosage compensation complex (DCC) binds both X chromosomes of hermaphrodites to repress transcription two-fold, thus balancing gene expression between XX hermaphrodites and XO males. X chromosome structure is disrupted by mutations in DCC subunits. Using X chromosome paint fluorescence microscopy, we found that X chromosome structure and subnuclear localization are also disrupted when the mechanisms that anchor heterochromatin to the nuclear lamina are defective. Strikingly, the heterochromatic left end of the X chromosome is less affected than the gene-rich middle region, which lacks heterochromatic anchors. These changes in X chromosome structure and subnuclear localization are accompanied by small, but significant levels of derepression of X-linked genes as measured by RNA-seq, without any observable defects in DCC localization and DCC-mediated changes in histone modifications. We propose a model in which heterochromatic tethers on the left arm of the X cooperate with the DCC to compact and peripherally relocate the X chromosomes, contributing to gene repression.

Anchoring of Heterochromatin to the Nuclear Lamina Reinforces Dosage Compensation-Mediated Gene Repression

PubMed Central

Brouhard, Elizabeth A.; Jiang, Jianhao; Sifuentes, Margarita H.

2016-01-01

Higher order chromosome structure and nuclear architecture can have profound effects on gene regulation. We analyzed how compartmentalizing the genome by tethering heterochromatic regions to the nuclear lamina affects dosage compensation in the nematode C. elegans. In this organism, the dosage compensation complex (DCC) binds both X chromosomes of hermaphrodites to repress transcription two-fold, thus balancing gene expression between XX hermaphrodites and XO males. X chromosome structure is disrupted by mutations in DCC subunits. Using X chromosome paint fluorescence microscopy, we found that X chromosome structure and subnuclear localization are also disrupted when the mechanisms that anchor heterochromatin to the nuclear lamina are defective. Strikingly, the heterochromatic left end of the X chromosome is less affected than the gene-rich middle region, which lacks heterochromatic anchors. These changes in X chromosome structure and subnuclear localization are accompanied by small, but significant levels of derepression of X-linked genes as measured by RNA-seq, without any observable defects in DCC localization and DCC-mediated changes in histone modifications. We propose a model in which heterochromatic tethers on the left arm of the X cooperate with the DCC to compact and peripherally relocate the X chromosomes, contributing to gene repression. PMID:27690361

Automatic control of clock duty cycle

NASA Technical Reports Server (NTRS)

Feng, Xiaoxin (Inventor); Roper, Weston (Inventor); Seefeldt, James D. (Inventor)

2010-01-01

In general, this disclosure is directed to a duty cycle correction (DCC) circuit that adjusts a falling edge of a clock signal to achieve a desired duty cycle. In some examples, the DCC circuit may generate a pulse in response to a falling edge of an input clock signal, delay the pulse based on a control voltage, adjust the falling edge of the input clock signal based on the delayed pulse to produce an output clock signal, and adjust the control voltage based on the difference between a duty cycle of the output clock signal and a desired duty cycle. Since the DCC circuit adjusts the falling edge of the clock cycle to achieve a desired duty cycle, the DCC may be incorporated into existing PLL control loops that adjust the rising edge of a clock signal without interfering with the operation of such PLL control loops.

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

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.

The Arabidopsis AtUNC-93 Acts as a Positive Regulator of Abiotic Stress Tolerance and Plant Growth via Modulation of ABA Signaling and K+ Homeostasis.

PubMed

Xiang, Jianhua; Zhou, Xiaoyun; Zhang, Xianwen; Liu, Ailing; Xiang, Yanci; Yan, Mingli; Peng, Yan; Chen, Xinbo

2018-01-01

Potassium (K + ) is one of the essential macronutrients required for plant growth and development, and the maintenance of cellular K + homeostasis is important for plants to adapt to abiotic stresses and growth. However, the mechanism involved has not been understood clearly. In this study, we demonstrated that AtUNC-93 plays a crucial role in this process under the control of abscisic acid (ABA). AtUNC-93 was localized to the plasma membrane and mainly expressed in the vascular tissues in Arabidopsis thaliana . The atunc-93 mutants showed typical K + -deficient symptoms under low-K + conditions. The K + contents of atunc-93 mutants were significantly reduced in shoots but not in roots under either low-K + or normal conditions compared with wild type plants, whereas the AtUNC-93 -overexpressing lines still maintained relatively higher K + contents in shoots under low-K + conditions, suggesting that AtUNC-93 positively regulates K + translocation from roots to shoots. The atunc-93 plants exhibited dwarf phenotypes due to reduced cell expansion, while AtUNC-93 -overexpressing plants had larger bodies because of increased cell expansion. After abiotic stress and ABA treatments, the atunc-93 mutants was more sensitive to salt, drought, osmotic, heat stress and ABA than wild type plants, while the AtUNC-93 -overexpressing lines showed enhanced tolerance to these stresses and insensitive phenotype to ABA. Furthermore, alterations in the AtUNC-93 expression changed expression of many ABA-responsive and stress-related genes. Our findings reveal that AtUNC-93 functions as a positive regulator of abiotic stress tolerance and plant growth by maintaining K + homeostasis through ABA signaling pathway in Arabidopsis.

Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B.

PubMed

Koch, Alexander W; Mathivet, Thomas; Larrivée, Bruno; Tong, Raymond K; Kowalski, Joe; Pibouin-Fragner, Laurence; Bouvrée, Karine; Stawicki, Scott; Nicholes, Katrina; Rathore, Nisha; Scales, Suzie J; Luis, Elizabeth; del Toro, Raquel; Freitas, Catarina; Bréant, Christiane; Michaud, Annie; Corvol, Pierre; Thomas, Jean-Léon; Wu, Yan; Peale, Franklin; Watts, Ryan J; Tessier-Lavigne, Marc; Bagri, Anil; Eichmann, Anne

2011-01-18

Robo4 is an endothelial cell-specific member of the Roundabout axon guidance receptor family. To identify Robo4 binding partners, we performed a protein-protein interaction screen with the Robo4 extracellular domain. We find that Robo4 specifically binds to UNC5B, a vascular Netrin receptor, revealing unexpected interactions between two endothelial guidance receptors. We show that Robo4 maintains vessel integrity by activating UNC5B, which inhibits signaling downstream of vascular endothelial growth factor (VEGF). Function-blocking monoclonal antibodies against Robo4 and UNC5B increase angiogenesis and disrupt vessel integrity. Soluble Robo4 protein inhibits VEGF-induced vessel permeability and rescues barrier defects in Robo4(-/-) mice, but not in mice treated with anti-UNC5B. Thus, Robo4-UNC5B signaling maintains vascular integrity by counteracting VEGF signaling in endothelial cells, identifying a novel function of guidance receptor interactions in the vasculature. Copyright © 2011 Elsevier Inc. All rights reserved.

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

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.

Frequency of Deep Convective Clouds and Global Warming

NASA Technical Reports Server (NTRS)

Aumann, Hartmut H.; Teixeira, Joao

2008-01-01

This slide presentation reviews the effect of global warming on the formation of Deep Convective Clouds (DCC). It concludes that nature responds to global warming with an increase in strong convective activity. The frequency of DCC increases with global warming at the rate of 6%/decade. The increased frequency of DCC with global warming alone increases precipitation by 1.7%/decade. It compares the state of the art climate models' response to global warming, and concludes that the parametrization of climate models need to be tuned to more closely emulate the way nature responds to global warming.

Numerical investigations on unstable direct contact condensation of cryogenic fluids

NASA Astrophysics Data System (ADS)

Jayachandran, K. N.; Arnab, Roy; Parthasarathi, Ghosh

2017-02-01

A typical problem of Direct Contact Condensation (DCC) occurs at the liquid oxygen (LOX) booster turbopump exit of oxidiser rich staged combustion cycle based semi-cryogenic rocket engines, where the hot gas mixture (predominantly oxygen and small amounts of combustion products) that runs the turbine mixes with LOX from the pump exit. This complex multiphase phenomena leads to the formation of solid CO2 & H2O, which is undesirable for the functioning of the main LOX turbopump. As a starting point for solving this complex problem, in this study, the hot gas mixture is taken as pure oxygen and hence, DCC of pure oxygen vapour jets in subcooled liquid oxygen is simulated using the commercial CFD package ANSYS CFX®. A two fluid model along with the thermal phase change model is employed for capturing the heat and mass transfer effects. The study mainly focuses on the subsonic DCC bubbling regime, which is reported as unstable with bubble formation, elongation, necking and collapsing effects. The heat transfer coefficients over a period of time have been computed and the various stages of bubbling have been analysed with the help of vapour volume fraction and pressure profiles. The results obtained for DCC of oxygen vapour-liquid mixtures is in qualitative agreement with the experimental results on DCC of steam-water mixtures.

Progress on thermobrachytherapy surface applicator for superficial tissue disease

NASA Astrophysics Data System (ADS)

Arunachalam, Kavitha; Craciunescu, Oana I.; Maccarini, Paolo F.; Schlorff, Jaime L.; Markowitz, Edward; Stauffer, Paul R.

2009-02-01

This work reports the ongoing development of a combination applicator for simultaneous heating of superficial tissue disease using a 915 MHz DCC (dual concentric conductor) array and High Dose Rate (HDR) brachytherapy delivered via an integrated conformal catheter array. The progress includes engineering design changes in the waterbolus, DCC configurations and fabrication techniques of the conformal multilayer applicator. The dosimetric impact of the thin copper DCC array is also assessed. Steady state fluid dynamics of the new waterbolus bag indicates nearly uniform flow with less than 1°C variation across a large (19×32cm) bolus. Thermometry data of the torso phantom acquired with computer controlled movement of fiberoptic temperature probes inside thermal mapping catheters indicate feasibility of real time feedback control for the DCC array. MR (magnetic resonance) scans of a torso phantom indicate that the waterbolus thickness across the treatment area is controlled by the pressure applied by the surrounding inflatable airbladder and applicator securing straps. The attenuation coefficient of the DCC array was measured as 3+/- 0.001% and 2.95+/-0.03 % using an ion chamber and OneDose dosimeters respectively. The performance of the combination applicator on patient phantoms provides valuable feedback to optimize the applicator prior use in the patient clinic.

Netrin1/DCC signaling promotes neuronal migration in the dorsal spinal cord.

PubMed

Junge, Harald J; Yung, Andrea R; Goodrich, Lisa V; Chen, Zhe

2016-10-26

Newborn neurons often migrate before undergoing final differentiation, extending neurites, and forming synaptic connections. Therefore, neuronal migration is crucial for establishing neural circuitry during development. In the developing spinal cord, neuroprogenitors first undergo radial migration within the ventricular zone. Differentiated neurons continue to migrate tangentially before reaching the final positions. The molecular pathways that regulate these migration processes remain largely unknown. Our previous study suggests that the DCC receptor is important for the migration of the dorsal spinal cord progenitors and interneurons. In this study, we determined the involvement of the Netrin1 ligand and the ROBO3 coreceptor in the migration. By pulse labeling neuroprogenitors with electroporation, we examined their radial migration in Netrin1 (Ntn1), Dcc, and Robo3 knockout mice. We found that all three mutants exhibit delayed migration. Furthermore, using immunohistochemistry of the BARHL2 interneuron marker, we found that the mediolateral and dorsoventral migration of differentiated dorsal interneurons is also delayed. Together, our results suggest that Netrin1/DCC signaling induce neuronal migration in the dorsal spinal cord. Netrin1, DCC, and ROBO3 have been extensively studied for their functions in regulating axon guidance in the spinal commissural interneurons. We reveal that during earlier development of dorsal interneurons including commissural neurons, these molecules play an important role in promoting cell migration.

Overcorrection during treatment of pectus deformities with DCC orthoses: experience in 17 cases

PubMed Central

Haje, D. P.

2006-01-01

Treatment of pectus carinatum and pectus excavatum with dynamic chest compressor (DCC) orthoses have been reported by Haje and others. The goal of this study was to demonstrate that overcorrection during orthotic treatment of children and adolescents with pectus deformities can occur and requires medical attention. Of 3,028 children and adolescents with pectus deformities, observed between 1977 and October 2005, 1,824 were prescribed treatment with DCC orthoses and, after a few months of treatment, some overcorrection was noted in 30 patients. Of the patients who received orthoses, 738 had a minimum follow-up of 1 year and 17 of these, 2 with pectus excavatum and 15 with pectus carinatum, presented overcorrection and were studied. The dynamic remodeling method (DCC orthoses + exercises) was applied. The procedures, adopted according to each patient’s needs, were: decreasing the time of orthosis wear and/or the tightening of the screws, introducing a second orthosis, and improving the prescribed exercises and/or encouraging the patient to perform them more intensively. The therapy was successful in all patients, and the result was maintained in one case of pectus excavatum followed up until adulthood. It was concluded that overcorrection during DCC orthosis wear can occur and that careful medical follow-up is necessary if this complication is to be successfully reversed. PMID:16474937

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

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.

The use of deep convective clouds to uniformly calibrate the next generation of geostationary reflective solar imagers

NASA Astrophysics Data System (ADS)

Doelling, David R.; Bhatt, Rajendra; Haney, Conor O.; Gopalan, Arun; Scarino, Benjamin R.

2017-09-01

The new 3rd generation geostationary (GEO) imagers will have many of the same NPP-VIIRS imager spectral bands, thereby offering the opportunity to apply the VIIRS cloud, aerosol, and land use retrieval algorithms on the new GEO imager measurements. Climate quality retrievals require multi-channel calibrated radiances that are stable over time. The deep convective cloud calibration technique (DCCT) is a large ensemble statistical technique that assumes that the DCC reflectance is stable over time. Because DCC are found in sufficient numbers across all GEO domains, they provide a uniform calibration stability evaluation across the GEO constellation. The baseline DCCT has been successful in calibrating visible and near-infrared channels. However, for shortwave infrared (SWIR) channels the DCCT is not as effective to monitor radiometric stability. The DCCT was optimized as a function wavelength in this paper. For SWIR bands, the greatest reduction of the DCC response trend standard error was achieved through deseasonalization. This is effective because the DCC reflectance exhibits small regional seasonal cycles that can be characterized on a monthly basis. On the other hand, the inter-annually variability in DCC response was found to be extremely small. The Met-9 0.65-μm channel DCC response was found to have a 3% seasonal cycle. Deseasonalization reduced the trend standard error from 1% to 0.4%. For the NPP-VIIRS SWIR bands, deseasonalization reduced the trend standard error by more than half. All VIIRS SWIR band trend standard errors were less than 1%. The DCCT should be able to monitor the stability of all GEO imager solar reflective bands across the tropical domain with the same uniform accuracy.

FACTORS ASSOCIATED WITH THE UPTAKE OF SODIUM DICHLOROISOCYANURATE (NADCC) TABLETS AS HOUSEHOLD WATER-TREATMENT PRODUCT AMONG CAREGIVERS OF CHILDREN UNDER FIVE IN BENIN, WEST AFRICA.

PubMed

Inungu, Joseph N; Zinsou, Cyprien E; Mustafa, Younis; Singbo, Narcisse

2016-01-01

Improving access to safe drinking water is a critical step in mitigating diarrheal diseases that affect millions of children under 5 years throughout the developing world each year. While the delivery of safe water is out of the reach of many countries, the utilization of Sodium dichloroisocyanurate (NaDCC) is a proven cost-effective alternative to prevent diarrhea caused by waterborne pathogens. However, its uptake remains low in many developing countries, such as the Republic of Benin. This study examines the trends and the determinants of NaDCC uptake in Benin. Population Services International and its affiliate conducted two multistage household surveys among caregivers of children under five in Benin to examine the practices towards diarrheal disease in children under five and identify the factors associated with the use of NaDCC in this population. 2912 respondents/caregivers of children under five were interviewed in 2009 versus 3196 in 2011. The proportion of caregivers who reported ever treating water with NaDCC increased from 5.8% in 2009 to 11.5% in 2011, p < 0.001. The logistic regression model showed that caregivers who knew places that sell NaDCC in the community; those who felt capable of utilizing NADCC correctly to treat drinking water as well as caregivers who reported to be Muslim were more likely than their counterparts to use NaDCC as water treatment product. In order to increase the use of NADCC among caregivers, the Government of Benin and its development partners should focus not only on making NADCC available in the community and informing the community members about the different points of sale, but also in building up the capacity and confidence of caregivers in utilizing it.

Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11, and 15 for age-related cardiac fibrosis.

PubMed

Li, Qiaoli; Berndt, Annerose; Sundberg, Beth A; Silva, Kathleen A; Kennedy, Victoria E; Cario, Clinton L; Richardson, Matthew A; Chase, Thomas H; Schofield, Paul N; Uitto, Jouni; Sundberg, John P

2016-06-01

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.

Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11 and 15 for age-related cardiac fibrosis

PubMed Central

Li, Qiaoli; Berndt, Annerose; Sundberg, Beth A.; Silva, Kathleen A.; Kennedy, Victoria E.; Cario, Clinton L; Richardson, Matthew A.; Chase, Thomas H.; Schofield, Paul N.; Uitto, Jouni; Sundberg, John P.

2017-01-01

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscal loci 1 through 4. Here we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10−13) and Chr 4 at 122 Mb (P < 10−11) and 134 Mb (P < 10−7). At the Chr 15 locus Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximate 6 Mb away from the Dyscal 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits. PMID:27126641

Association of gingivitis with dental calculus thickness or dental calculus coverage and subgingival bacteria in feline leukemia virus- and feline immunodeficiency virus-negative cats.

PubMed

Thengchaisri, Naris; Steiner, Jörg M; Suchodolski, Jan S; Sattasathuchana, Panpicha

2017-01-01

Periodontal disease is the most common oral disease in cats. The objectives of this study were to determine the relationships between gingivitis and dental calculus thickness (DCT), or dental calculus coverage (DCC); determine the association of gingivitis scores and types of oral bacteria; and to evaluate bacterial co-infection in cats with periodontal disease. Twelve cats that were not infected with feline leukemia or feline immunodeficiency viruses were enrolled in the study. Gingivitis, DCT, and DCC were scored and recorded. A Kruskal-Wallis test was used to compare scores among canine, 2nd premolar, 3rd premolar, 4th premolar, and 1st molar teeth. The relationship between gingivitis and DCT or DCC scores was determined using the Spearman rank sum test (ρ). Subgingival bacteria were cultured and the association between bacterial species and gingivitis score was evaluated using a Fisher's exact test. The average gingivitis, DCT, and DCC scores for the caudal maxillary teeth were higher for the caudal mandibular teeth and more severe for the 3rd premolar, 4th premolar, and 1st molar teeth than for the canine teeth. A strong relationship between average DCT or DCC score and average gingivitis score was found (ρ = 0.96 and 1, respectively). Aerobic and anaerobic bacterial infections were identified in a large number of cats with periodontal disease (71.1% and 28.9%, respectively). In conclusion, severe gingivitis scores were associated with anaerobic bacterial infection. The caudal teeth are affected with more severe gingivitis, DCT, and DCC than the other teeth. Antibiotic prophylaxis should be prescribed in cats with periodontal disease.

Assessing the growth and recovery of Salmonella Enteritidis SE86 after sodium dichloroisocyanurate exposure

PubMed Central

Ferreira, Fernanda Stoduto; Horvath, Mariana Bandeira; Tondo, Eduardo Cesar

2013-01-01

The objective of the present study was to assess the growth and the recovery of Salmonella (S.) Enteritidis SE86 in different diluents, culture media and using different plating methods after the exposure to 200 mg/kg sodium dichloroisocyanurate (NaDCC). Before and after NaDCC exposure, SE86 was cultured at 30 °C and 7 °C in the following diluents: Peptone water (P), Saline solution (SaS), Peptone water+Saline solution (P+SaS), Peptone water+Tween 80+Lecithin+Sodium thiosulfate (P+N) and Saline solution+Tween 80+Lecithin+Sodium thiosulfate (SaS+N). The SaS diluent was chosen because it was able to maintain cells viable without growth and was further used for plating SE86 on non selective medium (Tryptic Soy Agar-TSA) and on selective media (Mannitol Lysine Crystal Violet Brilliant Green Agar-MLCB; Brilliant Green Agar-BGA; Salmonella Shigella Agar-SS and Xylose Lysine Dextrose–XLD). The Thin Agar Layer method (TAL) i.e., selective media overlayed with non selective TSA was also evaluated. Results indicated that SE86 not exposed to NaDCC was able to grow in P, P+N, SaS+N and P+SaS, but not in SaS, that was able to maintain cells viable. SE86 exposed to NaDCC demonstrated similar counts after dilution in SaS and the plating on non selective TSA, selective media MLCB, BGA, SS and XLD and on TAL media. SE86, S. Typhimurium and S. Bredeney, exposed or not exposed to NaDCC, showed no significant differences in counts on TSA, XLD and XLD overlayed with TSA, suggesting that all those media may be used to quantify NaDCC-exposed Salmonella by plating method. PMID:24516446

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment‐Based Drug Design Facilitated by Dynamic Combinatorial Chemistry

PubMed Central

Mondal, Milon; Radeva, Nedyalka; Fanlo‐Virgós, Hugo; Otto, Sijbren; Klebe, Gerhard

2016-01-01

Abstract Fragment‐based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit‐identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X‐ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis‐acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240‐fold improvement in potency compared to the parent hits. Subsequent X‐ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit‐identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit‐to‐lead optimization. PMID:27400756

Sodium Dichloroisocyanurate Tablets for Routine Treatment of Household Drinking Water in Periurban Ghana: A Randomized Controlled Trial

PubMed Central

Jain, Seema; Sahanoon, Osman K.; Blanton, Elizabeth; Schmitz, Ann; Wannemuehler, Kathleen A.; Hoekstra, Robert M.; Quick, Robert E.

2010-01-01

We conducted a randomized, placebo-controlled, triple-blinded trial to determine the health impact of daily use of sodium dichloroisocyanurate (NaDCC) tablets for household drinking water treatment in periurban Ghana. We randomized 240 households (3,240 individuals) to receive either NaDCC or placebo tablets. All households received a 20-liter safe water storage vvessel. Over 12 weeks, 446 diarrhea episodes (2.2%) occurred in intervention and 404 (2.0%) in control households (P = 0.38). Residual free chlorine levels indicated appropriate tablet use. Escherichia coli was found in stored water at baseline in 96% of intervention and 88% of control households and at final evaluation in 8% of intervention and 54% of control households (P = 0.002). NaDCC use did not prevent diarrhea but improved water quality. Diarrhea rates were low and water quality improved in both groups. Safe water storage vessels may have been protective. A follow-up health impact study of NaDCC tablets is warranted. PMID:20064989

Disinfection By-Product Formation and Mitigation Strategies in Point-of-Use Chlorination with Sodium Dichloroisocyanurate in Tanzania

PubMed Central

Lantagne, Daniele S.; Cardinali, Fred; Blount, Ben C.

2010-01-01

Almost a billion persons lack access to improved drinking water, and diarrheal diseases cause an estimated 1.87 million deaths per year. Sodium dichloroisocyanurate (NaDCC) tablets are widely recommended for household water treatment to reduce diarrhea. Because NaDCC is directly added to untreated water sources, concerns have been raised about the potential health impact of disinfection by-products. This study investigated trihalomethane (THM) production in water from six sources used for drinking (0.6–888.5 nephelometric turbidity units) near Arusha, Tanzania. No sample collected at 1, 8, and 24 hours after NaDCC addition exceeded the World Health Organization guideline values for either individual or total THMs. Ceramic filtration, sand filtration, cloth filtration, and settling and decanting were not effective mitigation strategies to reduce THM formation. Chlorine residual and THM formation were not significantly different in NaDCC and sodium hypochlorite treatment. Household chlorination of turbid and non-turbid waters did not create THM concentrations that exceeded health risk guidelines. PMID:20595492

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.

Rapid, economical qualitative method for separation of aflatoxins B-1, B-2 & G-1, G-2 by dry column chromatography.

PubMed

Megalla, S E

1983-12-01

A good correlation of four components of aflatoxins was accomplished by using the dry column chromatography method. The decolorization process of interfering substances, by 0.01 N KOH and defatting the extract with petroleum ether yields a clean residue for DCC separation. It is clear that the dry column chromatography is a very simple and time-saving procedure for separation of aflatoxins. DCC columns are more economical than precoated 'thick layer' preparative plates and, in DCC, no large developing tanks need to be used. Hazards associated with the use of large volumes of flammable solvents are greatly reduced.

Immunological Prevention of Spontaneous Mammary Carcinoma in Transgenic Mice

DTIC Science & Technology

1999-08-01

and their multiplication. The period between the 22nd and the 28th week appears to be of critical importance, as the ൤-week-old" protocol confers a...sustain their relatively low rate of proliferation. By contrast, blood supply is a critical factor for most fast-growing transplantable tumors, even...Piffanelli A, Fumero S, Pelizzola D, Berruto GP, Ricci L, and Science 244:707-712. Giovannini G (1982). Protocollo del metodo con Charcoal-destrano (DCC) per

GTC and Swift observations of SN 2017dcc: Revised redshift & X-ray upper limit

NASA Astrophysics Data System (ADS)

Kann, D. A.; Izzo, L.; Cano, Z.; Postigo, A. de Ugarte; Thoene, C. C.; Schulze, S.

2017-04-01

We obtained observations of the broad-lined type Ic SN 2017dcc (Guiterrez et al., ATel #10313) with the 10.4m GTC on La Palma, Canary Islands, Spain, as well as with XRT and UVOT on the Swift space telescope.

Germline cytotoxic lymphocytes defective mutations in Chinese patients with lymphoma.

PubMed

Chen, Xue; Zhang, Yang; Wang, Fang; Wang, Mangju; Teng, Wen; Lin, Yuehui; Han, Xiangping; Jin, Fangyuan; Xu, Yuanli; Cao, Panxiang; Fang, Jiancheng; Zhu, Ping; Tong, Chunrong; Liu, Hongxing

2017-11-01

Certain patients with lymphoma may harbor mutations in perforin 1 (PRF1), unc-13 homolog D (UNC13D), syntaxin 11 (STX11), STXBP2 (syntaxin binding protein 2) or SH2 domain containing 1A (SH2D1A), which causes functional defects of cytotoxic lymphocytes. Data regarding the association between genetic defects and the development of lymphoma in Chinese patients are limited to date. In the present study, 90 patients with lymphoma were analyzed for UNC13D, PRF1, STXBP2, STX11, SH2D1A and X-linked inhibitor of apoptosis. Mutations were observed in 24 (26.67%) patients; 16 patients exhibited mutations in UNC13D, 7 exhibited PRF1 mutations, and 1 exhibited monoallelic mutation in STX11. UNC13D c.2588G>A/p.G863D mutation was detected in 9 patients (10.00%) and in 4/210 controls (1.90%). This mutation was predicted to be pathogenic and it predominantly existed in the Chinese population. These findings suggest that impaired cytotoxic machinery may represent a predisposing factor for the development of lymphoma. Furthermore, these data describe a distinct mutation spectrum in Chinese patients with lymphoma, whereby UNC13D is the most frequently mutated gene. In addition, these findings suggest UNC13D c.2588G>A mutation is a founder mutation in Chinese patients.

Germline cytotoxic lymphocytes defective mutations in Chinese patients with lymphoma

PubMed Central

Chen, Xue; Zhang, Yang; Wang, Fang; Wang, Mangju; Teng, Wen; Lin, Yuehui; Han, Xiangping; Jin, Fangyuan; Xu, Yuanli; Cao, Panxiang; Fang, Jiancheng; Zhu, Ping; Tong, Chunrong; Liu, Hongxing

2017-01-01

Certain patients with lymphoma may harbor mutations in perforin 1 (PRF1), unc-13 homolog D (UNC13D), syntaxin 11 (STX11), STXBP2 (syntaxin binding protein 2) or SH2 domain containing 1A (SH2D1A), which causes functional defects of cytotoxic lymphocytes. Data regarding the association between genetic defects and the development of lymphoma in Chinese patients are limited to date. In the present study, 90 patients with lymphoma were analyzed for UNC13D, PRF1, STXBP2, STX11, SH2D1A and X-linked inhibitor of apoptosis. Mutations were observed in 24 (26.67%) patients; 16 patients exhibited mutations in UNC13D, 7 exhibited PRF1 mutations, and 1 exhibited monoallelic mutation in STX11. UNC13D c.2588G>A/p.G863D mutation was detected in 9 patients (10.00%) and in 4/210 controls (1.90%). This mutation was predicted to be pathogenic and it predominantly existed in the Chinese population. These findings suggest that impaired cytotoxic machinery may represent a predisposing factor for the development of lymphoma. Furthermore, these data describe a distinct mutation spectrum in Chinese patients with lymphoma, whereby UNC13D is the most frequently mutated gene. In addition, these findings suggest UNC13D c.2588G>A mutation is a founder mutation in Chinese patients. PMID:29113160

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.

Optimization of a Deep Convective Cloud Technique in Evaluating the Long-Term Radiometric Stability of MODIS Reflective Solar Bands

NASA Technical Reports Server (NTRS)

Mu, Qiaozhen; Wu, Aisheng; Xiong, Xiaoxiong; Doelling, David R.; Angal, Amit; Chang, Tiejun; Bhatt, Rajendra

2017-01-01

MODIS reflective solar bands are calibrated on-orbit using a solar diffuser and near-monthly lunar observations. To monitor the performance and effectiveness of the on-orbit calibrations, pseudo-invariant targets such as deep convective clouds (DCCs), Libya-4, and Dome-C are used to track the long-term stability of MODIS Level 1B product. However, the current MODIS operational DCC technique (DCCT) simply uses the criteria set for the 0.65- m band. We optimize several critical DCCT parameters including the 11- micrometer IR-band Brightness Temperature (BT11) threshold for DCC identification, DCC core size and uniformity to help locate DCCs at convection centers, data collection time interval, and probability distribution function (PDF) bin increment for each channel. The mode reflectances corresponding to the PDF peaks are utilized as the DCC reflectances. Results show that the BT11 threshold and time interval are most critical for the Short Wave Infrared (SWIR) bands. The Bidirectional Reflectance Distribution Function model is most effective in reducing the DCC anisotropy for the visible channels. The uniformity filters and PDF bin size have minimal impacts on the visible channels and a larger impact on the SWIR bands. The newly optimized DCCT will be used for future evaluation of MODIS on-orbit calibration by MODIS Characterization Support Team.

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

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.

Growth phase-dependent activation of the DccRS regulon of Campylobacter jejuni

USDA-ARS?s Scientific Manuscript database

Two-component systems are widespread prokaryotic signal transduction devices which allow the regulation of cellular functions in response to changing environmental conditions. The two-component system DccRS (Cj1223-Cj1222) of Campylobacter jejuni is important for the colonization of chickens. Here w...

Marketing Segmentation Analysis.

ERIC Educational Resources Information Center

Weeks, Ann A.

A study was conducted to differentiate by cities and towns the various demographic characteristics of students that Dutchess Community College (DCC) was receiving from its major service area, Dutchess County, in order to ascertain if DCC was receiving its expected share of students from these cities and towns. All the students enrolling at DCC…

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.

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.

The Balanced Regulation of Hsc70 by DNJ-13 and UNC-23 Is Required for Muscle Functionality*

PubMed Central

Papsdorf, Katharina; Sacherl, Julia; Richter, Klaus

2014-01-01

The molecular chaperone Hsc70 assists in the folding of non-native proteins together with its J domain- and BAG domain-containing cofactors. In Caenorhabditis elegans, two BAG domain-containing proteins can be identified, one of them being UNC-23, whose mutation induces severe motility dysfunctions. Using reporter strains, we find that the full-length UNC-23, in contrast to C-terminal fragments, localizes specifically to the muscular attachment sites. C-terminal fragments of UNC-23 instead perform all Hsc70-related functions, like ATPase stimulation and regulation of folding activity, albeit with lower affinity than BAG-1. Interestingly, overexpression of CFP-Hsc70 can induce muscular defects in wild-type nematodes that phenocopy the knockout of its cofactor UNC-23. Strikingly, the motility dysfunction in the unc-23 mutated strain can be cured specifically by down-regulation of the antagonistic Hsc70 cochaperone DNJ-13, implying that the severe phenotype is caused by misregulation of the Hsc70 cycle. These findings point out that the balanced action of cofactors in the ATP-driven cycle of Hsc70 is crucial for the contribution of Hsc70 to muscle functionality. PMID:25053410

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

Pervasive and largely lineage-specific adaptive protein evolution in the dosage compensation complex of Drosophila melanogaster.

PubMed

Levine, Mia T; Holloway, Alisha K; Arshad, Umbreen; Begun, David J

2007-11-01

Dosage compensation refers to the equalization of X-linked gene transcription among heterogametic and homogametic sexes. In Drosophila, the dosage compensation complex (DCC) mediates the twofold hypertranscription of the single male X chromosome. Loss-of-function mutations at any DCC protein-coding gene are male lethal. Here we report a population genetic analysis suggesting that four of the five core DCC proteins--MSL1, MSL2, MSL3, and MOF--are evolving under positive selection in D. melanogaster. Within these four proteins, several domains that range in function from X chromosome localization to protein-protein interactions have elevated, D. melanogaster-specific, amino acid divergence.

An investigation of the speeding-related crash designation through crash narrative reviews sampled via logistic regression.

PubMed

Fitzpatrick, Cole D; Rakasi, Saritha; Knodler, Michael A

2017-01-01

Speed is one of the most important factors in traffic safety as higher speeds are linked to increased crash risk and higher injury severities. Nearly a third of fatal crashes in the United States are designated as "speeding-related", which is defined as either "the driver behavior of exceeding the posted speed limit or driving too fast for conditions." While many studies have utilized the speeding-related designation in safety analyses, no studies have examined the underlying accuracy of this designation. Herein, we investigate the speeding-related crash designation through the development of a series of logistic regression models that were derived from the established speeding-related crash typologies and validated using a blind review, by multiple researchers, of 604 crash narratives. The developed logistic regression model accurately identified crashes which were not originally designated as speeding-related but had crash narratives that suggested speeding as a causative factor. Only 53.4% of crashes designated as speeding-related contained narratives which described speeding as a causative factor. Further investigation of these crashes revealed that the driver contributing code (DCC) of "driving too fast for conditions" was being used in three separate situations. Additionally, this DCC was also incorrectly used when "exceeding the posted speed limit" would likely have been a more appropriate designation. Finally, it was determined that the responding officer only utilized one DCC in 82% of crashes not designated as speeding-related but contained a narrative indicating speed as a contributing causal factor. The use of logistic regression models based upon speeding-related crash typologies offers a promising method by which all possible speeding-related crashes could be identified. Published by Elsevier Ltd.

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

Alumni Survey, 1973-1983.

ERIC Educational Resources Information Center

Weeks, Ann A.; Sillin, Andrew

A study was conducted at Dutchess Community College (DCC) to provide a broad picture of the further education and employment status of DCC alumni several years after graduation and to determine how satisfied alumni were with the education and services provided by the college. Survey questionnaires were mailed to a random sample of 20% of DCC…

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.

PubMed

Mondal, Milon; Radeva, Nedyalka; Fanlo-Virgós, Hugo; Otto, Sijbren; Klebe, Gerhard; Hirsch, Anna K H

2016-08-01

Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

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

Compliant Buckled Foam Actuators and Application in Patient-Specific Direct Cardiac Compression.

PubMed

Mac Murray, Benjamin C; Futran, Chaim C; Lee, Jeanne; O'Brien, Kevin W; Amiri Moghadam, Amir A; Mosadegh, Bobak; Silberstein, Meredith N; Min, James K; Shepherd, Robert F

2018-02-01

We introduce the use of buckled foam for soft pneumatic actuators. A moderate amount of residual compressive strain within elastomer foam increases the applied force ∼1.4 × or stroke ∼2 × compared with actuators without residual strain. The origin of these improved characteristics is explained analytically. These actuators are applied in a direct cardiac compression (DCC) device design, a type of implanted mechanical circulatory support that avoids direct blood contact, mitigating risks of clot formation and stroke. This article describes a first step toward a pneumatically powered, patient-specific DCC design by employing elastomer foam as the mechanism for cardiac compression. To form the device, a mold of a patient's heart was obtained by 3D printing a digitized X-ray computed tomography or magnetic resonance imaging scan into a solid model. From this model, a soft, robotic foam DCC device was molded. The DCC device is compliant and uses compressed air to inflate foam chambers that in turn apply compression to the exterior of a heart. The device is demonstrated on a porcine heart and is capable of assisting heart pumping at physiologically relevant durations (∼200 ms for systole and ∼400 ms for diastole) and stroke volumes (∼70 mL). Although further development is necessary to produce a fully implantable device, the material and processing insights presented here are essential to the implementation of a foam-based, patient-specific DCC design.

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

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

DARPA Improving Warfighter Information Intake Under Stress -- Augmented Cognition. Volume 1. Phase 2: Concept Validation Experiment

DTIC Science & Technology

2006-09-01

trademark of the Boeing Company. Mercedes - Benz ® is a registered trademark of DaimlerChrysler AG Corporation. Released by R. J. Smillie, Head...Team DCC CLIP architecture. 2.2.4 Methodology The test conditions for the DCC team consisted of an instrumented Mercedes Benz ® S class vehicle

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.

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

Radiation patterns of dual concentric conductor microstrip antennas for superficial hyperthermia.

PubMed

Stauffer, P R; Rossetto, F; Leoncini, M; Gentilli, G B

1998-05-01

The finite difference time domain (FDTD) method has been used to calculate electromagnetic radiation patterns from 915-MHz dual concentric conductor (DCC) microwave antennas that are constructed from thin and flexible printed circuit board (PCB) materials. Radiated field distributions are calculated in homogeneous lossy muscle tissue loads located under variable thickness coupling bolus layers. This effort extends the results of previous investigations to consider more realistic applicator configurations with smaller 2-cm-square apertures and different coupling bolus materials and thicknesses, as well as various spacings of multiple-element arrays. Results are given for practical applicator designs with microstrip feedlines etched on the backside of the PCB antenna array instead of previously tested bulky coaxial-cable feedline connections to each radiating aperture. The results demonstrate that for an optimum coupling bolus thickness of 2.5-5 mm, the thin, flexible, and lightweight DCC antennas produce effective heating to the periphery of each aperture to a depth of approximately 1 cm, and may be combined into arrays for uniform heating of large area superficial tissue regions with the 50% power deposition contour conforming closely to the outer perimeter of the array.

Multi-Protein Dynamic Combinatorial Chemistry: A Novel Strategy that Leads to Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3.

PubMed

Das, Mohua; Tianming, Yang; Jinghua, Dong; Prasetya, Fransisca; Yiming, Xie; Wong, Kendra; Cheong, Adeline; Woon, Esther C Y

2018-06-19

Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically-templated DCC employ only a single biomolecule in directing the self-assembly process. To expand the scope and potential of DCC, herein, we developed a novel multi-protein DCC strategy which combines the discriminatory power of zwitterionic 'thermal-tag' with the sensitivity of differential scanning fluorimetry. This strategy enables the discovery of ligands against several proteins of interest concurrently. It is remarkably sensitive and could differentiate the binding of ligands to structurally-similar subfamily members, which is extremely challenging to achieve. Through this approach, we were able to simultaneously identify subfamily-selective probes against two clinically important epigenetic enzymes, FTO (7; IC₅₀ = 2.6 µM) and ALKBH3 (8; IC₅₀ = 3.7 µM). To our knowledge, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins, thus it shall be of widespread scientific interest. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The urgent neurological consultation in the population of the province of Ferrara, Italy.

PubMed

Govoni, Vittorio; Della Coletta, Elena; Fallica, Elisa; Cesnik, Edward

2018-05-01

In the province of Ferrara, Italy, the urgent neurological consultation (UNC) cases in the population correspond to the resident outpatients who undergo a UNC in the ER of the university hospital of Ferrara (UHFe). Thanks to this health organization a retrospective survey identified 612 UNC cases (range of age 7-102 years, median 67,5 years) in the study period giving a period prevalence rate of 173 per 100,000 (95% CI 159.3-187.3) which increased with age (χ 2 for trend = 178.4 p < 0.001). The daily UNC cases (range 0-14, mean = 7.3, 95% CI 7.1-7.5) followed the Poisson distribution (goodness-of-fit test: λ = 7.3, χ 2  = 8082, 12 freedom degrees, p > 0.70). The prevalence rate decreased with the distance between the patients' residence and the UHFe (χ 2 for trend = 82.9, p < 0.001). The commonest clinical conditions requiring UNCs were acute cerebrovascular disorders (28%), headache (14%), and vertigo (9%). The hospital admission rate was 32.5% which increased with age (χ 2 for trend = 35.8, p < 0.001). The commonest discharge diagnoses of the admitted cases were ischemic stroke (57.3%), epilepsy (7%), TIA (6%), and intraparenchymal hemorrhage (5.5%). Acute cerebrovascular disease accounted for 69% of the discharge diagnoses. The survey showed that the UNCs' demand was higher than previous Italian data confirming that acute cerebrovascular disease is the most frequent acute neurological condition requiring attention in the ER. It also suggested that the UNCs could be poorly appropriate. These findings would require the healthcare administrators attention.

Dual function of the UNC-45b chaperone with myosin and GATA4 in cardiac development

PubMed Central

Chen, Daisi; Li, Shumin; Singh, Ram; Spinette, Sarah; Sedlmeier, Reinhard; Epstein, Henry F.

2012-01-01

Summary Cardiac development requires interplay between the regulation of gene expression and the assembly of functional sarcomeric proteins. We report that UNC-45b recessive loss-of-function mutations in C3H and C57BL/6 inbred mouse strains cause arrest of cardiac morphogenesis at the formation of right heart structures and failure of contractile function. Wild-type C3H and C57BL/6 embryos at the same stage, E9.5, form actively contracting right and left atria and ventricles. The known interactions of UNC-45b as a molecular chaperone are consistent with diminished accumulation of the sarcomeric myosins, but not their mRNAs, and the resulting decreased contraction of homozygous mutant embryonic hearts. The novel finding that GATA4 accumulation is similarly decreased at the protein but not mRNA levels is also consistent with the function of UNC-45b as a chaperone. The mRNAs of known downstream targets of GATA4 during secondary cardiac field development, the cardiogenic factors Hand1, Hand2 and Nkx-2.5, are also decreased, consistent with the reduced GATA4 protein accumulation. Direct binding studies show that the UNC-45b chaperone forms physical complexes with both the alpha and beta cardiac myosins and the cardiogenic transcription factor GATA4. Co-expression of UNC-45b with GATA4 led to enhanced transcription from GATA promoters in naïve cells. These novel results suggest that the heart-specific UNC-45b isoform functions as a molecular chaperone mediating contractile function of the sarcomere and gene expression in cardiac development. PMID:22553207

RESRAD for Radiological Risk Assessment. Comparison with EPA CERCLA Tools - PRG and DCC Calculators

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

Yu, C.; Cheng, J. -J.; Kamboj, S.

The purpose of this report is two-fold. First, the risk assessment methodology for both RESRAD and the EPA’s tools is reviewed. This includes a review of the EPA’s justification for 2 using a dose-to-risk conversion factor to reduce the dose-based protective ARAR from 15 to 12 mrem/yr. Second, the models and parameters used in RESRAD and the EPA PRG and DCC Calculators are compared in detail, and the results are summarized and discussed. Although there are suites of software tools in the RESRAD family of codes and the EPA Calculators, the scope of this report is limited to the RESRADmore » (onsite) code for soil contamination and the EPA’s PRG and DCC Calculators also for soil contamination.« less

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

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

The first new application of the mathematical theory of stochastic processes to lunar and planetary science: topography profile diagrams of Mars

NASA Astrophysics Data System (ADS)

Salamuniccar, G.

The Mathematical Statistics Theory (MST) and the Mathematical Theory of Stochastic Processes (MTSP) are different branches of the more general Mathematical Probability Theory (MPT) that represents different aspects of some physical processes we can analyze using mathematics. Each model of a stochastic process according to MTSP can provide one or more interpretations in MST domain. Large body of work on the impact crater statistics according to MST was already done many years ago, for e.g., where Cratering Chronology Diagrams (CCD) were shown in log/log scale, showing Cum. Crater Frequency [N km-2] that is the function of Age [years] for some particular crater diameter. However, all this is only one possible representation in MST domain, of the bombardment of the planetary surface modeled as stochastic process according to MTSP. The idea that other representations in MST domain of the same stochastic process from MTSP are possible was recently presented [G. Salamuniæcar, Adv. Space Res. in press]. The importance of the approach is that each such interpretation can provide large amount of new information. Topography Profile Diagrams (TPDs) are one example, that with MOLA data provide us with large amount of new information regarding history of Mars. TPDs consists of [34thLPS #1403]: (1) Topography-Profile Curve (TPC) that is representation of the planet topography, (2) Density-of-Craters Curve (DCC) that represents density of craters, (3) Filtered-DCC (FDCC) that represents DCC filtered by a low-pass filter included with the purpose of reducing the noise and (4) Level-of-Substance-Over-Time Curve (LSOTC). While definition of TPC uniquely corresponds to way we will compute it, the same is not also the case with DCC and FDCC. While DCC depends on algorithms for computing crater altitude according to the topography, center coordinates and radius of impact crater [34thLPS #1409], FDCC depends on the architecture of the custom designed low-pass filter for filtering DCC [34thLPS #1415]. However all variations of DCC and FDCC including the different input craters data-sets confirmed correlation between density of craters and topographic altitude over 70˜ 80% of the planet surface. For the assumption that ocean primarily caused noted correlation, LSOTC additionally for the first time offers mathematical approach how to compute how level of ocean was changing over time [6thMars #3187]. Accordingly, conclusion is that TPDs are the first new practical application of MTSP to the Lunar and Planetary Science (LPS).

On the Early-Time Excess Emission in Hydrogen-Poor Superluminous Supernovae

NASA Technical Reports Server (NTRS)

Vreeswijk, Paul M.; Leloudas, Giorgos; Gal-Yam, Avishay; De Cia, Annalisa; Perley, Daniel A.; Quimby, Robert M.; Waldman, Roni; Sullivan, Mark; Yan, Lin; Ofek, Eran O.;

On The Early-Time Excess Emission In Hydrogen-Poor Superluminous Supernovae

DOE PAGES

Vreeswijk, Paul M.; Leloudas, Giorgos; Gal-Yam, Avishay; ...

2017-01-18

Here, we present the light curves of the hydrogen-poor superluminous supernovae (SLSNe I) PTF 12dam and iPTF 13dcc, discovered by the (intermediate) Palomar Transient Factory. Both show excess emission at early times and a slowly declining light curve at late times. The early bump in PTF 12dam is very similar in duration (~10 days) and brightness relative to the main peak (2-3 mag fainter) compared to that observed in other SLSNe I. In contrast, the long-duration ( > 30 days) early excess emission in iPTF 13dcc, whose brightness competes with that of the main peak, appears to be of amore » different nature. We construct bolometric light curves for both targets, and fit a variety of light-curve models to both the early bump and main peak in an attempt to understand the nature of these explosions. Even though the slope of the late-time decline in the light curves of both SLSNe is suggestively close to that expected from the radioactive decay of 56Ni and 56Co, the amount of nickel required to power the full light curves is too large considering the estimated ejecta mass. The magnetar model including an increasing escape fraction provides a reasonable description of the PTF 12dam observations. However, neither the basic nor the double-peaked magnetar model is capable of reproducing the light curve of iPTF 13dcc. A model combining a shock breakout in an extended envelope with late-time magnetar energy injection provides a reasonable fit to the iPTF 13dcc observations. Finally, we find that the light curves of both PTF 12dam and iPTF 13dcc can be adequately fit with the model involving interaction with the circumstellar medium.« less

Dual-mode antenna design for microwave heating and noninvasive thermometry of superficial tissue disease.

PubMed

Jacobsen, S; Stauffer, P R; Neuman, D G

2000-11-01

Hyperthermia therapy of superficial skin disease has proven clinically useful, but current heating equipment is somewhat clumsy and technically inadequate for many patients. The present effort describes a dual-purpose, conformal microwave applicator that is fabricated from thin, flexible, multilayer printed circuit board (PCB) material to facilitate heating of surface areas overlaying contoured anatomy. Preliminary studies document the feasibility of combining Archimedean spiral microstrip antennas, located concentrically within the central region of square dual concentric conductor (DCC) annular slot antennas. The motivation is to achieve homogeneous tissue heating simultaneously with noninvasive thermometry by radiometric sensing of blackbody radiation from the target tissue under the applicator. Results demonstrate that the two antennas have complimentary regions of influence. The DCC ring antenna structure produces a peripherally enhanced power deposition pattern with peaks in the outer corners of the aperture and a broad minimum around 50% of maximum centrally. In contrast, the Archimedean spiral radiates (or receives) energy predominantly along the boresight axis of the spiral, thus confining the region of influence to tissue located within the central broad minimum of the DCC pattern. Analysis of the temperature-dependent radiometer signal (brightness temperature) showed linear correlation of radiometer output with test load temperature using either the spiral or DCC structure as the receive antenna. The radiometric performance of the broadband Archimedean antenna was superior compared to the DCC, providing improved temperature resolution (0.1 degree C-0.2 degree C) and signal sensitivity (0.3 degree C-0.8 degree C/degree C) at all four 500 MHz integration bandwidths tested within the frequency range from 1.2 to 3.0 GHz.

ON THE EARLY-TIME EXCESS EMISSION IN HYDROGEN-POOR SUPERLUMINOUS SUPERNOVAE

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

Vreeswijk, Paul M.; Leloudas, Giorgos; Gal-Yam, Avishay

2017-01-20

We present the light curves of the hydrogen-poor superluminous supernovae (SLSNe I) PTF 12dam and iPTF 13dcc, discovered by the (intermediate) Palomar Transient Factory. Both show excess emission at early times and a slowly declining light curve at late times. The early bump in PTF 12dam is very similar in duration (∼10 days) and brightness relative to the main peak (2–3 mag fainter) compared to that observed in other SLSNe I. In contrast, the long-duration (>30 days) early excess emission in iPTF 13dcc, whose brightness competes with that of the main peak, appears to be of a different nature. Wemore » construct bolometric light curves for both targets, and fit a variety of light-curve models to both the early bump and main peak in an attempt to understand the nature of these explosions. Even though the slope of the late-time decline in the light curves of both SLSNe is suggestively close to that expected from the radioactive decay of {sup 56}Ni and {sup 56}Co, the amount of nickel required to power the full light curves is too large considering the estimated ejecta mass. The magnetar model including an increasing escape fraction provides a reasonable description of the PTF 12dam observations. However, neither the basic nor the double-peaked magnetar model is capable of reproducing the light curve of iPTF 13dcc. A model combining a shock breakout in an extended envelope with late-time magnetar energy injection provides a reasonable fit to the iPTF 13dcc observations. Finally, we find that the light curves of both PTF 12dam and iPTF 13dcc can be adequately fit with the model involving interaction with the circumstellar medium.« less

Presence of Pathogenic Bacteria and Viruses in the Daycare Environment.

PubMed

Ibfelt, Tobias; Engelund, Eva Hoy; Permin, Anders; Madsen, Jonas Stenløkke; Schultz, Anna Charlotte; Andersen, Leif Percival

2015-10-01

The number of children in daycare centers (DCCs) is rising. This increases exposure to microorganisms and infectious diseases. Little is known about which bacteria and viruses are present in the DCC environment and where they are located. In the study described in this article, the authors set out to determine the prevalence of pathogenic bacteria and viruses and to find the most contaminated fomites in DCCs. Fifteen locations in each DCC were sampled for bacteria, respiratory viruses, and gastrointestinal viruses. The locations were in the toilet, kitchen, and playroom areas and included nursery pillows, toys, and tables, among other things. Coliform bacteria were primarily found in the toilet and kitchen areas whereas nasopharyngeal bacteria were found mostly on toys and fabric surfaces in the playroom. Respiratory viruses were omnipresent in the DCC environment, especially on the toys.

Mechanical gating of a mechanochemical reaction cascade

NASA Astrophysics Data System (ADS)

Wang, Junpeng; Kouznetsova, Tatiana B.; Boulatov, Roman; Craig, Stephen L.

2016-11-01

Covalent polymer mechanochemistry offers promising opportunities for the control and engineering of reactivity. To date, covalent mechanochemistry has largely been limited to individual reactions, but it also presents potential for intricate reaction systems and feedback loops. Here we report a molecular architecture, in which a cyclobutane mechanophore functions as a gate to regulate the activation of a second mechanophore, dichlorocyclopropane, resulting in a mechanochemical cascade reaction. Single-molecule force spectroscopy, pulsed ultrasonication experiments and DFT-level calculations support gating and indicate that extra force of >0.5 nN needs to be applied to a polymer of gated gDCC than of free gDCC for the mechanochemical isomerization gDCC to proceed at equal rate. The gating concept provides a mechanism by which to regulate stress-responsive behaviours, such as load-strengthening and mechanochromism, in future materials designs.

Removal of detergents from protein extracts using activated charcoal prior to immunological analysis.

PubMed

Malhas, Ashraf N; Abuknesha, Ramadan A; Price, Robert G

2002-06-01

The use of dextran-coated activated charcoal (DCC) powder to absorb solubilising detergents from cell lysates is described. Normal embryonic epithelial cells were lysed in the presence of sodium dodecyl sulphate (SDS). The detergent was then absorbed with DCC to facilitate analysis of polycystin-1 with antibody-based methods. Polycystin-1 is a membrane protein that is involved in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). The adverse effect of SDS on antibody-polycystin-1 binding was studied and the improvement resulting from its removal demonstrated using enzyme-linked immunosorbent assays (ELISAs). The results indicate that DCC can be used in a simple manner to remove highly reactive membrane-solubilising reagents from protein mixtures prior to immunological analysis. This procedure may be relevant to a variety of other techniques that are normally affected by detergents.

Three-Dimensional Color Code Thresholds via Statistical-Mechanical Mapping

NASA Astrophysics Data System (ADS)

Kubica, Aleksander; Beverland, Michael E.; Brandão, Fernando; Preskill, John; Svore, Krysta M.

2018-05-01

Three-dimensional (3D) color codes have advantages for fault-tolerant quantum computing, such as protected quantum gates with relatively low overhead and robustness against imperfect measurement of error syndromes. Here we investigate the storage threshold error rates for bit-flip and phase-flip noise in the 3D color code (3DCC) on the body-centered cubic lattice, assuming perfect syndrome measurements. In particular, by exploiting a connection between error correction and statistical mechanics, we estimate the threshold for 1D stringlike and 2D sheetlike logical operators to be p3DCC (1 )≃1.9 % and p3DCC (2 )≃27.6 % . We obtain these results by using parallel tempering Monte Carlo simulations to study the disorder-temperature phase diagrams of two new 3D statistical-mechanical models: the four- and six-body random coupling Ising models.

Exploring the formation pathways of donor-acceptor catenanes in aqueous dynamic combinatorial libraries.

PubMed

Cougnon, Fabien B L; Au-Yeung, Ho Yu; Pantoş, G Dan; Sanders, Jeremy K M

2011-03-09

The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.

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.

Target Detection and Identification Using Canonical Correlations Analysis and Subspace Partitioning

DTIC Science & Technology

2008-04-01

Fig. 2. ROCs for DCC, DCC-P, NNLS, and NNLSP (Present chemical=t1, background= t56 , SNR= 5 dB) alarm, or 1−specificity, and PD is the probability of...discrimination values are given in each ROC plot. In Fig. 2, we use t56 as the background, and t1 as the target chemical. The SNR is 5 dB. For each

NEURAL NETWORK MODELLING OF CARDIAC DOSE CONVERSION COEFFICIENT FOR ARBITRARY X-RAY SPECTRA.

PubMed

Kadri, O; Manai, K

2016-12-01

In this article, an approach to compute the dose conversion coefficients (DCCs) is described for the computational voxel phantom 'High-Definition Reference Korean-Man' (HDRK-Man) using artificial neural networks (ANN). For this purpose, the voxel phantom was implemented into the Monte Carlo (MC) transport toolkit GEANT4, and the DCCs for more than 30 tissues and organs, due to a broad parallel beam of monoenergetic photons with energy ranging from 15 to 150 keV by a step of 5 keV, were calculated. To study the influence of patient size on DCC values, DCC calculation was performed, for a representative body size population, using five different sizes covering the range of 80-120 % magnification of the original HDRK-Man. The focus of the present study was on the computation of DCC for the human heart. ANN calculation and MC simulation results were compared, and good agreement was observed showing that ANNs can be used as an efficient tool for modelling DCCs for the computational voxel phantom. ANN approach appears to be a significant advance over the time-consuming MC methods for DCC calculation. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Product Distribution from Precursor Bite Angle Variation in Multitopic Alkyne Metathesis: Evidence for a Putative Kinetic Bottleneck.

PubMed

Moneypenny, Timothy P; Yang, Anna; Walter, Nathan P; Woods, Toby J; Gray, Danielle L; Zhang, Yang; Moore, Jeffrey S

2018-05-02

In the dynamic synthesis of covalent organic frameworks and molecular cages, the typical synthetic approach involves heuristic methods of discovery. While this approach has yielded many remarkable products, the ability to predict the structural outcome of subjecting a multitopic precursor to dynamic covalent chemistry (DCC) remains a challenge in the field. The synthesis of covalent organic cages is a prime example of this phenomenon, where precursors designed with the intention of affording a specific product may deviate dramatically when the DCC synthesis is attempted. As such, rational design principles are needed to accelerate discovery in cage synthesis using DCC. Herein, we test the hypothesis that precursor bite angle contributes significantly to the energy landscape and product distribution in multitopic alkyne metathesis (AM). By subjecting a series of precursors with varying bite angles to AM, we experimentally demonstrate that the product distribution, and convergence toward product formation, is strongly dependent on this geometric attribute. Surprisingly, we discovered that precursors with the ideal bite angle (60°) do not afford the most efficient pathway to the product. The systematic study reported here illustrates how seemingly minor adjustments in precursor geometry greatly affect the outcome of DCC systems. This research illustrates the importance of fine-tuning precursor geometric parameters in order to successfully realize desirable targets.

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

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

Heat Transfer Analysis of an Optimized, Flexible Holder System for Freeze-Drying in Dual Chamber Cartridges Using Different State-of-the-Art PAT Tools.

PubMed

Korpus, Christoph; Pikal, Michael; Friess, Wolfgang

2016-11-01

The aim of this study was to determine the heat transfer characteristics of an optimized flexible holder device, using Tunable Diode Laser Absorption Spectroscopy, the Pressure Rise Test, and the gravimetric procedure. Two different controlled nucleation methods were tested, and an improved sublimation process, "preheated plate," was developed. Tunable Diode Laser Absorption Spectroscopy identified an initial sublimation burst phase. Accordingly, steady-state equations were adapted for the gravimetric procedure, to account for this initial non-steady-state period. The heat transfer coefficient, K DCC , describing the transfer from the holder to the DCC, was the only heat transfer coefficient showing a clear pressure dependence with values ranging from 3.81E-04 cal/(g·cm 2 ·K) at 40 mTorr to 7.38E-04 cal/(g·cm 2 ·K) at 200 mTorr. The heat transfer coefficient, K tot , reflecting the overall energy transfer via the holder, increased by around 24% from 40 to 200 mTorr. This resulted in a pressure-independent sublimation rate of around 42 ± 1.06 mg/h over the whole pressure range. Hence, this pressure-dependent increase in energy transfer completely compensated the decrease in driving force of sublimation. The "flexible holder" shows a substantially reduced impact of atypical radiation, improved drying homogeneity, and ultimately a better transferability of the freeze-drying cycle for process optimization. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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

A uniform geostationary visible calibration approach to achieve a climate quality dataset

NASA Astrophysics Data System (ADS)

Haney, C.; Doelling, D.; Bhatt, R.; Scarino, B. R.; Gopalan, A.

2013-12-01

The geostationary (GEO) weather satellite visible and IR image record has surpassed 30 years. They have been preserved in the ISCCP-B1U 3-hourly dataset and other archives such as McIDAS, EUMETSAT, and NOAA CLASS. Since they were designed to aid in weather forecasting, long-term calibration stability was not a high priority. All GEO imagers lack onboard visible calibration and suffer from optical degradation after they are launched. In order to piece together the 35+ GEO satellite record both in time and space, a uniform calibration approach is desired to remove individual GEO temporal trends, as well as GEO spectral band differences. Otherwise, any artificial discontinuities caused by sequential GEO satellite records or spurious temporal trends caused by optical degradation may be interpreted as a change in climate. The approach relies on multiple independent methods to reduce the overall uncertainty of the GEO calibration coefficients. Consistency among methods validates the approach. During the MODIS record (2000 to the present) the GEO satellites are inter-calibrated against MODIS using ray-matched or bore-sighted radiance pairs. The MODIS and the VIIRS follow on instruments are equipped with onboard calibration thereby providing a stable calibration reference. The GEO spectral band differences are accounted for using a Spectral Band Adjustment Factor (SBAF) based on hyper-spectral SCIAMACHY data. During the pre-MODIS era, invariant earth targets of deserts and deep convective clouds (DCC) are used. Since GEO imagers have maintained their imaging scan schedules, GEO desert and DCC bidirectional reflectance distribution functions (BRDF) can be constructed and validated during the MODIS era. The BRDF models can then be applied to historical GEO imagers. Consistency among desert and DCC GEO calibration gains validates the approach. This approach has been applied to the GEO record beginning in 1985 and the results will be presented at the meeting.

Effect of gamma irradiation and its convergent treatment for control of postharvest Botrytis cinerea of cut roses

NASA Astrophysics Data System (ADS)

Chu, Eun-Hee; Shin, Eun-Jung; Park, Hae-Jun; Jeong, Rae-Dong

2015-10-01

Postharvest diseases cause considerable losses to harvested crops. Among them, gray mold (Botrytis cinerea) is a major problem of exporting to cut rose flowers into Korea. Irradiation treatment is an alternative to phytosanitary purposes and a useful nonchemical approach to the control of postharvest diseases. Gamma irradiation was evaluated for its in vitro and in vivo antifungal activity against B. cinerea on cut rose varieties, 'Shooting Star' and 'Babe'. The irradiating dose required to reduce the population by 90%, D10, was 0.99 kGy. Gamma irradiation showed complete inhibition of spore germination and mycelial growth of B. cinerea, especially 4.0 kGy in vitro. Antifungal activity of gamma irradiation on rose B. cinerea is a dose-dependent manner. A significant phytotoxicity such as bent neck in cut rose quality was shown from gamma irradiation at over 0.4 kGy (p<0.05) in both varieties. Although there is no significant difference in both varieties for fresh weight, in the case of flower rate, 'Babe' shows more sensitivity than 'Shooting Star'. In vivo assays demonstrated that established doses in in vitro, over 4 kGy, could completely inactive fungal pathogens, but such high doses can cause severe flowers damage. Thus, to eliminate negative impact on their quality, gamma irradiation was evaluated at lower doses in combination with an eco-friendly chemical, sodium dichloroisocyanurate (NaDCC) to examine the inhibition of B. cinerea. Intriguingly, only the combined treatment with 0.2 kGy of gamma irradiation and 70 ppm of NaDCC exhibited significant synergistic antifungal activity against blue mold decay in both varieties. Together, these results suggest that a synergistic effect of the combined treatment with gamma irradiation and NaDCC can be efficiently used to control the postharvest diseases in cut rose flowers, and will provide a promising technology for horticulture products for exportation.

Impact of delayed umbilical cord clamping on public cord blood donations: can we help future patients and benefit infant donors?

PubMed

Ciubotariu, Rodica; Scaradavou, Andromachi; Ciubotariu, Ilinca; Tarnawski, Michal; Lloyd, Sara; Albano, Maria; Dobrila, Ludy; Rubinstein, Pablo; Grunebaum, Amos

2018-03-25

Cord blood (CB) is a widely accepted stem cell source and its clinical utilization depends, to a great extent, on its cell content. Birth-to-clamping (BTC) time of umbilical cord determines placental transfusion to the newborn, and the remaining blood that can be collected and banked. The 2017 Committee Opinion of the American College of Obstetrics and Gynecologists (ACOG) recommends a delay of "at least 30-60 seconds" before clamping the cord for all newborns to ensure adequate iron stores. The impact of delayed cord clamping (DCC) on public CB banking can be substantial. Cord blood units (CBUs) collected from 1210 mothers at one hospital were evaluated for total nucleated cells (TNCs) and weight/volume based on time to clamping. Bank staff recorded BTC time in seconds as reported by obstetricians; collections were performed ex utero. Immediate clamping was defined as BTC of less than 30 seconds, whereas DCC was defined as BTC of 30 seconds or more. Cord clamping was immediate in 903 (75%) and delayed in 307 (25%) deliveries. Successful recovery (% clinical CBUs) decreased 10-fold with DCC of more than 60 seconds (22% vs. 2.4%, p < 0.001). CBUs collected after DCC of more than 60 seconds had significantly lower TNC counts than those after DCC of less than 60 seconds (p < 0.0001). Furthermore, 38% to 46% of CBUs after DCC of more than 60 seconds had volume of less than 40 mL. Our study indicates that DCC of 30 to 60 seconds has a small negative impact on collection of high-TNC-count CBUs. However, increasing BTC to more than 60 seconds decreases significantly both TNC content and volume, reducing drastically the chances of obtaining clinically useful CBUs. © 2018 AABB.

Netrin-1 controls sympathetic arterial innervation.

PubMed

Brunet, Isabelle; Gordon, Emma; Han, Jinah; Cristofaro, Brunella; Broqueres-You, Dong; Liu, Chun; Bouvrée, Karine; Zhang, Jiasheng; del Toro, Raquel; Mathivet, Thomas; Larrivée, Bruno; Jagu, Julia; Pibouin-Fragner, Laurence; Pardanaud, Luc; Machado, Maria J C; Kennedy, Timothy E; Zhuang, Zhen; Simons, Michael; Levy, Bernard I; Tessier-Lavigne, Marc; Grenz, Almut; Eltzschig, Holger; Eichmann, Anne

2014-07-01

Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.

Netrin-1 controls sympathetic arterial innervation

PubMed Central

Brunet, Isabelle; Gordon, Emma; Han, Jinah; Cristofaro, Brunella; Broqueres-You, Dong; Liu, Chun; Bouvrée, Karine; Zhang, Jiasheng; del Toro, Raquel; Mathivet, Thomas; Larrivée, Bruno; Jagu, Julia; Pibouin-Fragner, Laurence; Pardanaud, Luc; Machado, Maria J.C.; Kennedy, Timothy E.; Zhuang, Zhen; Simons, Michael; Levy, Bernard I.; Tessier-Lavigne, Marc; Grenz, Almut; Eltzschig, Holger; Eichmann, Anne

2014-01-01

Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type–specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs. PMID:24937433

Paraffin section immunocytochemistry and cytosol-based ligand-binding assays for ER and PR detection in breast cancer: the time has come for more objectivity.

PubMed

Goussard, J

1998-10-23

The importance of the receptor level in breast cancer as an indicator of hormone response has been extensively studied for more than 20 years. Besides cytosol-based ligand-binding assays (dextran-coated charcoal assay, DCC), new methods using monoclonal antibodies raised against estrogen and progesterone receptors allow for the detection of receptors both in cytosol extracts (enzyme immunoassay, EIA) and in tissue sections (immunocytochemical assay, ICA). The biochemical assays (DCC and EIA) as well as the immunochemical detection (ICA) have specific qualities and produce original information which is useful for the therapeutic decision. While DCC gives a measure of the receptor level, whatever the real source of synthesis (normal and/or neoplastic tissue), ICA locates the positive cells and their relative proportion in the tumor. Both methods present their own advantages and disadvantages which are summarized in this study.

Three-Dimensional Color Code Thresholds via Statistical-Mechanical Mapping.

PubMed

Kubica, Aleksander; Beverland, Michael E; Brandão, Fernando; Preskill, John; Svore, Krysta M

2018-05-04

Three-dimensional (3D) color codes have advantages for fault-tolerant quantum computing, such as protected quantum gates with relatively low overhead and robustness against imperfect measurement of error syndromes. Here we investigate the storage threshold error rates for bit-flip and phase-flip noise in the 3D color code (3DCC) on the body-centered cubic lattice, assuming perfect syndrome measurements. In particular, by exploiting a connection between error correction and statistical mechanics, we estimate the threshold for 1D stringlike and 2D sheetlike logical operators to be p_{3DCC}^{(1)}≃1.9% and p_{3DCC}^{(2)}≃27.6%. We obtain these results by using parallel tempering Monte Carlo simulations to study the disorder-temperature phase diagrams of two new 3D statistical-mechanical models: the four- and six-body random coupling Ising models.

Treatment of patients waitlisted for liver transplant with all-oral direct-acting antivirals is a cost-effective treatment strategy in the United States.

PubMed

Ahmed, Aijaz; Gonzalez, Stevan A; Cholankeril, George; Perumpail, Ryan B; McGinnis, Justin; Saab, Sammy; Beckerman, Rachel; Younossi, Zobair M

2017-07-01

All-oral direct acting antivirals (DAAs) have been shown to have high safety and efficacy in treating patients with hepatitis C virus (HCV) awaiting liver transplant (LT). However, there is limited empirical evidence comparing the health and economic outcomes associated with treating patients pre-LT versus post-LT. The objective of this study was to analyze the cost-effectiveness of pre-LT versus post-LT treatment with an all-oral DAA regimen among HCV patients with hepatocellular carcinoma (HCC) or decompensated cirrhosis (DCC). We constructed decision-analytic Markov models of the natural disease progression of HCV in HCC patients and DCC patients waitlisted for LT. The model followed hypothetical cohorts of 1,000 patients with a mean age of 50 over a 30-year time horizon from a third-party US payer perspective and estimated their health and cost outcomes based on pre-LT versus post-LT treatment with an all-oral DAA regimen. Transition probabilities and utilities were based on the literature and hepatologist consensus. Sustained virological response rates were sourced from ASTRAL-4, SOLAR-1, and SOLAR-2. Costs were sourced from RedBook, Medicare fee schedules, and published literature. In the HCC analysis, the pre-LT treatment strategy resulted in 11.48 per-patient quality-adjusted life years and $365,948 per patient lifetime costs versus 10.39 and $283,696, respectively, in the post-LT arm. In the DCC analysis, the pre-LT treatment strategy resulted in 9.27 per-patient quality-adjusted life years and $304,800 per patient lifetime costs versus 8.7 and $283,789, respectively, in the post-LT arm. As such, the pre-LT treatment strategy was found to be the most cost-effective in both populations with an incremental cost-effectiveness ratio of $74,255 (HCC) and $36,583 (DCC). Sensitivity and scenario analyses showed that results were most sensitive to the utility of patients post-LT, treatment sustained virological response rates, LT costs, and baseline Model for End-Stage Liver Disease score (DCC analysis only). The timing of initiation of antiviral treatment for HCV patients with HCC or DCC relative to LT is an important area of clinical and policy research; our results indicate that pre-LT treatment with a highly effective, all-oral DAA regimen provides the best health outcomes and is the most cost-effective strategy for the treatment of HCV patients with HCC or DCC waitlisted for LT. (Hepatology 2017;66:46-56). © 2017 by the American Association for the Study of Liver Diseases.

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

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.

Characterizing Response Versus Scan-Angle for MODIS Reflective Solar Bands Using Deep Convective Clouds

NASA Technical Reports Server (NTRS)

Bhatt, Rajendra; Doelling, David R.; Angal, Amit; Xiong, Xiaoxiong; Scarino, Benjamin; Gopalan, Arun; Haney, Conor; Wu, Aisheng

2017-01-01

MODIS consists of a cross-track, two-sided scan mirror, whose reflectance is not uniform but is a function of angle of incidence (AOI). This feature, known as response versusscan-angle (RVS), was characterized for all reflective solar bands of both MODIS instruments prior to launch. The RVS characteristic has changed on orbit, which must be tracked precisely over time to ensure the quality of MODIS products. The MODIS characterization support team utilizes the onboard calibrators and the earth view responses from multiple pseudo invariant desert sites to track the RVS changes at different AOIs. The drawback of using deserts is the assumption that these sites are radiometrically stable during the monitoring period. In addition, the 16-day orbit repeat cycle of MODIS allows for only a limited set of AOIs over a given desert. We propose a novel and robust approach of characterizing the MODIS RVS using tropical deep convective clouds (DCC). The method tracks the monthly DCC response at specified sets of AOIs to compute the temporal RVS changes. Initial results have shown that the Aqua-MODIS collection 6 band 1 level 1B radiances show considerable residual RVS dependencies, with long-term drifts up to 2.3 at certain AOIs.

Characterizing response versus scan-angle for MODIS reflective solar bands using deep convective clouds

NASA Astrophysics Data System (ADS)

Bhatt, Rajendra; Doelling, David R.; Angal, Amit; Xiong, Xiaoxiong; Scarino, Benjamin; Gopalan, Arun; Haney, Conor; Wu, Aisheng

2017-01-01

MODIS consists of a cross-track, two-sided scan mirror, whose reflectance is not uniform but is a function of angle of incidence (AOI). This feature, known as response versus scan-angle (RVS), was characterized for all reflective solar bands of both MODIS instruments prior to launch. The RVS characteristic has changed on orbit, which must be tracked precisely over time to ensure the quality of MODIS products. The MODIS characterization support team utilizes the onboard calibrators and the earth view responses from multiple pseudoinvariant desert sites to track the RVS changes at different AOIs. The drawback of using deserts is the assumption that these sites are radiometrically stable during the monitoring period. In addition, the 16-day orbit repeat cycle of MODIS allows for only a limited set of AOIs over a given desert. We propose a novel and robust approach of characterizing the MODIS RVS using tropical deep convective clouds (DCC). The method tracks the monthly DCC response at specified sets of AOIs to compute the temporal RVS changes. Initial results have shown that the Aqua-MODIS collection 6 band 1 level 1B radiances show considerable residual RVS dependencies, with long-term drifts up to 2.3% at certain AOIs.

Rapid Biodegradation of the Herbicide 2,4-Dichlorophenoxyacetic Acid by Cupriavidus gilardii T-1.

PubMed

Wu, Xiangwei; Wang, Wenbo; Liu, Junwei; Pan, Dandan; Tu, Xiaohui; Lv, Pei; Wang, Yi; Cao, Haiqun; Wang, Yawen; Hua, Rimao

2017-05-10

Phytotoxicity and environmental pollution of residual herbicides have caused much public concern during the past several decades. An indigenous bacterial strain capable of degrading 2,4-dichlorophenoxyacetic acid (2,4-D), designated T-1, was isolated from soybean field soil and identified as Cupriavidus gilardii. Strain T-1 degraded 2,4-D 3.39 times more rapidly than the model strain Cupriavidus necator JMP134. T-1 could also efficiently degrade 2-methyl-4-chlorophenoxyacetic acid (MCPA), MCPA isooctyl ester, and 2-(2,4-dichlorophenoxy)propionic acid (2,4-DP). Suitable conditions for 2,4-D degradation were pH 7.0-9.0, 37-42 °C, and 4.0 mL of inoculums. Degradation of 2,4-D was concentration-dependent. 2,4-D was degraded to 2,4-dichlorophenol (2,4-DCP) by cleavage of the ether bond and then to 3,5-dichlorocatechol (3,5-DCC) via hydroxylation, followed by ortho-cleavage to cis-2-dichlorodiene lactone (CDL). The metabolites 2,4-DCP or 3,5-DCC at 10 mg L -1 were completely degraded within 16 h. Fast degradation of 2,4-D and its analogues highlights the potential for use of C. gilardii T-1 in bioremediation of phenoxyalkanoic acid herbicides.

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.

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.

Alkylating Derivatives of Vitamin D Hormone for Prostate Cancer

DTIC Science & Technology

2006-10-01

Acetic Anhydride / Pyridine/ 40C 1. UV / Toluene 2. EtOH - Reflux TBDMSCl / Imidazole /DMF BrCH2COOH / DCC / DMAP / CH2Cl2 1,25(OH)2D3-3-BE Figure 1...BE OH SO2 OTBDMS OH OTBDMS 1. Liq. SO2 / Reflux 2. TBDMSCl / Imidazole /DMF NaHCO3 / EtOH / Reflux NMO / SeO2 / CH2Cl2 / Reflux OH OTBDMSHO OTHP...containing 200 mg of 25-hydroxyvitamin D3 in a flask fitted with a trap that was cooled with dry ice-acetone (-780C). The yellow solution was refluxed

Lyophilization Cycle Design for Dual Chamber Cartridges and a Method for Online Process Control: The "DCC LyoMate" Procedure.

PubMed

Korpus, Christoph; Friess, Wolfgang

2017-08-01

Freeze-drying process design is a challenging task that necessitates a profound understanding of the complex interrelation among critical process parameters (e.g., shelf temperature and chamber pressure), heat transfer characteristics of the involved materials (e.g., product containers and holder devices), and critical quality attributes of the product (e.g., collapse temperatures). The Dual Chamber Cartridge "(DCC) LyoMate" (from lyophilization and automated) is a manometric temperature measurement-based process control strategy that was developed within this study to streamline this complicated task. It was successfully applied using 5% sucrose formulations with 0.5 and 1 mL fill volumes. The system was further challenged using 2, 20, and 100 mg/mL monoclonal antibody formulations. The DCC LyoMate method did not only produce pharmaceutically acceptable cakes but was also able to maintain the desired product temperature irrespective of formulation and protein content. It enabled successful process design even at high protein concentrations and aided the design and online control of the lyophilization process for drying in DCCs within a single development run. Thus, it helps to reduce development cost and the DCC LyoMate can also be easily installed on every freeze-dryer capable of performing a manometric temperature measurement, without the need for hardware modification. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Distinct Impacts of Aerosols on an Evolving Continental Cloud Complex during the RACORO Field Campaign

DOE PAGES

Lin, Yun; Wang, Yuan; Pan, Bowen; ...

2016-08-26

In this study, a continental cloud complex, consisting of shallow cumuli, a deep convective cloud (DCC), and stratus, is simulated by a cloud-resolving Weather Research and Forecasting Model to investigate the aerosol microphysical effect (AME) and aerosol radiative effect (ARE) on the various cloud regimes and their transitions during the Department of Energy Routine Atmospheric Radiation Measurement Aerial Facility Clouds with Low Optical Water Depths Optical Radiative Observations (RACORO) campaign. Under an elevated aerosol loading with AME only, a reduced cloudiness for the shallow cumuli and stratus resulted from more droplet evaporation competing with suppressed precipitation, but an enhanced cloudinessmore » for the DCC is attributed to more condensation. With the inclusion of ARE, the shallow cumuli are suppressed owing to the thermodynamic effects of light-absorbing aerosols. The responses of DCC and stratus to aerosols are monotonic with AME only but nonmonotonic with both AME and ARE. The DCC is invigorated because of favorable convection and moisture conditions at night induced by daytime ARE, via the so-called aerosol-enhanced conditional instability mechanism. Finally, the results reveal that the overall aerosol effects on the cloud complex are distinct from the individual cloud types, highlighting that the aerosol–cloud interactions for diverse cloud regimes and their transitions need to be evaluated to assess the regional and global climatic impacts.« less

SnoVault and encodeD: A novel object-based storage system and applications to ENCODE metadata.

PubMed

Hitz, Benjamin C; Rowe, Laurence D; Podduturi, Nikhil R; Glick, David I; Baymuradov, Ulugbek K; Malladi, Venkat S; Chan, Esther T; Davidson, Jean M; Gabdank, Idan; Narayana, Aditi K; Onate, Kathrina C; Hilton, Jason; Ho, Marcus C; Lee, Brian T; Miyasato, Stuart R; Dreszer, Timothy R; Sloan, Cricket A; Strattan, J Seth; Tanaka, Forrest Y; Hong, Eurie L; Cherry, J Michael

2017-01-01

The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a comprehensive catalog of functional elements initiated shortly after the completion of the Human Genome Project. The current database exceeds 6500 experiments across more than 450 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the H. sapiens and M. musculus genomes. All ENCODE experimental data, metadata, and associated computational analyses are submitted to the ENCODE Data Coordination Center (DCC) for validation, tracking, storage, unified processing, and distribution to community resources and the scientific community. As the volume of data increases, the identification and organization of experimental details becomes increasingly intricate and demands careful curation. The ENCODE DCC has created a general purpose software system, known as SnoVault, that supports metadata and file submission, a database used for metadata storage, web pages for displaying the metadata and a robust API for querying the metadata. The software is fully open-source, code and installation instructions can be found at: http://github.com/ENCODE-DCC/snovault/ (for the generic database) and http://github.com/ENCODE-DCC/encoded/ to store genomic data in the manner of ENCODE. The core database engine, SnoVault (which is completely independent of ENCODE, genomic data, or bioinformatic data) has been released as a separate Python package.

SnoVault and encodeD: A novel object-based storage system and applications to ENCODE metadata

PubMed Central

Podduturi, Nikhil R.; Glick, David I.; Baymuradov, Ulugbek K.; Malladi, Venkat S.; Chan, Esther T.; Davidson, Jean M.; Gabdank, Idan; Narayana, Aditi K.; Onate, Kathrina C.; Hilton, Jason; Ho, Marcus C.; Lee, Brian T.; Miyasato, Stuart R.; Dreszer, Timothy R.; Sloan, Cricket A.; Strattan, J. Seth; Tanaka, Forrest Y.; Hong, Eurie L.; Cherry, J. Michael

2017-01-01

The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a comprehensive catalog of functional elements initiated shortly after the completion of the Human Genome Project. The current database exceeds 6500 experiments across more than 450 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the H. sapiens and M. musculus genomes. All ENCODE experimental data, metadata, and associated computational analyses are submitted to the ENCODE Data Coordination Center (DCC) for validation, tracking, storage, unified processing, and distribution to community resources and the scientific community. As the volume of data increases, the identification and organization of experimental details becomes increasingly intricate and demands careful curation. The ENCODE DCC has created a general purpose software system, known as SnoVault, that supports metadata and file submission, a database used for metadata storage, web pages for displaying the metadata and a robust API for querying the metadata. The software is fully open-source, code and installation instructions can be found at: http://github.com/ENCODE-DCC/snovault/ (for the generic database) and http://github.com/ENCODE-DCC/encoded/ to store genomic data in the manner of ENCODE. The core database engine, SnoVault (which is completely independent of ENCODE, genomic data, or bioinformatic data) has been released as a separate Python package. PMID:28403240

Piezoelectric ceramic (PZT) modulates axonal guidance growth of rat cortical neurons via RhoA, Rac1, and Cdc42 pathways.

PubMed

Wen, Jianqiang; Liu, Meili

2014-03-01

Electrical stimulation is critical for axonal connection, which can stimulate axonal migration and deformation to promote axonal growth in the nervous system. Netrin-1, an axonal guidance cue, can also promote axonal guidance growth, but the molecular mechanism of axonal guidance growth under indirect electric stimulation is still unknown. We investigated the molecular mechanism of axonal guidance growth under piezoelectric ceramic lead zirconate titanate (PZT) stimulation in the primary cultured cortical neurons. PZT induced marked axonal elongation. Moreover, PZT activated the excitatory postsynaptic currents (EPSCs) by increasing the frequency and amplitude of EPSCs of the cortical neurons in patch clamp assay. PZT downregulated the expression of Netrin-1 and its receptor Deleted in Colorectal Cancer (DCC). Rho GTPase signaling is involved in interactions of Netrin-1 and DCC. PZT activated RhoA. Dramatic decrease of Cdc42 and Rac1 was also observed after PZT treatment. RhoA inhibitor Clostridium botulinum C3 exoenzyme (C3-Exo) prevented the PZT-induced downregulation of Netrin-1 and DCC. We suggest that PZT can promote axonal guidance growth by downregulation of Netrin-1 and DCC to mediate axonal repulsive responses via the Rho GTPase signaling pathway. Obviously, piezoelectric materials may provide a new approach for axonal recovery and be beneficial for clinical therapy in the future.

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

Goven, A.J.; Fitzpatrick, L.C.; Eyambe, G.S.

Acute toxicity in earthworms (Lumbricus terrestris) was assayed immediately after 5-d filter paper exposure to the polychlorinated biphenyl (PCB) Aroclor 1254, using coelomocyte viability, total extruded cell counts (ECC), differential cell counts (DCC), and formation of erythrocyte (ER) and secretory rosettes (SR) with, and phagocytosis of, antigenic rabbit red blood cells (RRBC). Chronic toxicity was assayed using rates by which earthworms replaced viable immunoactive coelomocytes, removed noninvasively immediately after exposure, over an 18-week depuration period. All cytological parameters, except ECC, were acutely affected immediately after exposure, when tissue concentrations were ([anti X] [plus minus] SE) 91.2 [plus minus] 8.19 [mu]gmore » PCB per gram dry mass. Replacement of viable immunoactive coelomocytes occurred within six weeks in unexposed control earthworms. Exposed earthworms showed significant alteration in viability, ECC, DCC, ER, and SR formation, and phagocytosis at 6 and 12 weeks when PCB tissue concentrations were 41 [plus minus] 0.31 and 30.2 [plus minus] 0.88 [mu]g/g dry mass, respectively. Replacement of extruded coelomocytes with normal DCC of viable immunocompetent cells was not observed until week 18, when PCB had decreased to 15.7 [plus minus] 0.83 [mu]g/g dry mass. Low inherent natural variability in coelomocyte viability, ECC, DCC, rosette formation, and phagocytosis, and their sensitivity to sublethal PCB body burdens, indicated that earthworm coelomocytes have potential as nonmammalian biomarkers for assaying acute and chronic sublethal toxicity of xenobiotics.« less

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.

Current umbilical cord clamping practices and attitudes of obstetricians and midwives toward delayed cord clamping in Saudi Arabia.

PubMed

Ibrahim, Nadia O; Sukkarieh, Hatouf H; Bustami, Rami T; Alshammari, Elaf A; Alasmari, Lama Y; Al-Kadri, Hanan M

2017-01-01

In Saudi Arabia, as in many countries, there is usually no clear definition of the timing of umbilical cord clamping (UCC) in the policies and procedures used by hospitals. The World Health Organization (WHO) recommends delayed cord clamping (DCC) ( > 1 minute after birth) as it can significantly improve hemodynamics and long-term neurodevelopment. To investigate current practices of healthcare professionals on the timing of UCC in Saudi Arabia. Cross-sectional survey. Five tertiary hospitals in Riyadh, Saudi Arabia, during May to October 2016. Obstetricians and midwives completed a widely-used questionnaire on UCC practices. Current UCC practices and attitudes of obstetricians and midwives toward DCC. Eighty-two obstetricians and 75 midwives completed the questionnaire for a response rate of 80%. The majority of respondents were aged 30 years or older (81%) and 84% were females. Most respondents were non-Saudi (66%) and had an educational level of bachelor's degree or higher (72%). Only 42% of respondents reported the existence of UCC guidelines in their practice; 38% reported the existence of a set time for UCC when the neonate was term and healthy, and only 32% had a set time for UCC in preterm neonates. While lower levels of agreement were reported among obstetricians and midwives on the benefits of DCC for babies requiring positive pressure ventilation, the majority of respondents (69-71%) thought that DCC was generally good for both term and preterm babies and that its benefits extend beyond the neonatal period. While the majority of obstetricians and midwives that participated in this study had a positive perception toward DCC, this did not translate to their daily practice as most of these professionals reported a lack of existing UCC guidelines in their institutions. Further studies are warranted to confirm these findings. Participant selection by convenience sampling.

Ubiquitylation of the acetyltransferase MOF in Drosophila melanogaster

PubMed Central

Schunter, Sarah; Villa, Raffaella; Flynn, Victoria; Heidelberger, Jan B.; Classen, Anne-Kathrin; Beli, Petra; Becker, Peter B.

2017-01-01

The nuclear acetyltransferase MOF (KAT8 in mammals) is a subunit of at least two multi-component complexes involved in transcription regulation. In the context of complexes of the ‘Non-Specific-Lethal’ (NSL) type it controls transcription initiation of many nuclear housekeeping genes and of mitochondrial genes. While this function is conserved in metazoans, MOF has an additional, specific function in Drosophila in the context of dosage compensation. As a subunit of the male-specific-lethal dosage compensation complex (MSL-DCC) it contributes to the doubling of transcription output from the single male X chromosome by acetylating histone H4. Proper dosage compensation requires finely tuned levels of MSL-DCC and an appropriate distribution of MOF between the regulatory complexes. The amounts of DCC formed depends directly on the levels of the male-specific MSL2, which orchestrates the assembly of the DCC, including MOF recruitment. We found earlier that MSL2 is an E3 ligase that ubiquitylates most MSL proteins, including MOF, suggesting that ubiquitylation may contribute to a quality control of MOF’s overall levels and folding state as well as its partitioning between the complex entities. We now used mass spectrometry to map the lysines in MOF that are ubiquitylated by MSL2 in vitro and identified in vivo ubiquitylation sites of MOF in male and female cells. MSL2-specific ubiquitylation in vivo could not be traced due to the dominance of other, sex-independent ubiquitylation events and conceivably may be rare or transient. Expressing appropriately mutated MOF derivatives we assessed the importance of the ubiquitylated lysines for dosage compensation by monitoring DCC formation and X chromosome targeting in cultured cells, and by genetic complementation of the male-specific-lethal mof2 allele in flies. Our study provides a comprehensive analysis of MOF ubiquitylation as a reference for future studies. PMID:28510597

Ubiquitylation of the acetyltransferase MOF in Drosophila melanogaster.

PubMed

Schunter, Sarah; Villa, Raffaella; Flynn, Victoria; Heidelberger, Jan B; Classen, Anne-Kathrin; Beli, Petra; Becker, Peter B

2017-01-01

The nuclear acetyltransferase MOF (KAT8 in mammals) is a subunit of at least two multi-component complexes involved in transcription regulation. In the context of complexes of the 'Non-Specific-Lethal' (NSL) type it controls transcription initiation of many nuclear housekeeping genes and of mitochondrial genes. While this function is conserved in metazoans, MOF has an additional, specific function in Drosophila in the context of dosage compensation. As a subunit of the male-specific-lethal dosage compensation complex (MSL-DCC) it contributes to the doubling of transcription output from the single male X chromosome by acetylating histone H4. Proper dosage compensation requires finely tuned levels of MSL-DCC and an appropriate distribution of MOF between the regulatory complexes. The amounts of DCC formed depends directly on the levels of the male-specific MSL2, which orchestrates the assembly of the DCC, including MOF recruitment. We found earlier that MSL2 is an E3 ligase that ubiquitylates most MSL proteins, including MOF, suggesting that ubiquitylation may contribute to a quality control of MOF's overall levels and folding state as well as its partitioning between the complex entities. We now used mass spectrometry to map the lysines in MOF that are ubiquitylated by MSL2 in vitro and identified in vivo ubiquitylation sites of MOF in male and female cells. MSL2-specific ubiquitylation in vivo could not be traced due to the dominance of other, sex-independent ubiquitylation events and conceivably may be rare or transient. Expressing appropriately mutated MOF derivatives we assessed the importance of the ubiquitylated lysines for dosage compensation by monitoring DCC formation and X chromosome targeting in cultured cells, and by genetic complementation of the male-specific-lethal mof2 allele in flies. Our study provides a comprehensive analysis of MOF ubiquitylation as a reference for future studies.

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

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

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

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 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

Role of the DIP Molecules in DCC Signaling

DTIC Science & Technology

1999-09-01

to policies of applicable Federal Law 45 CFR 46. N/A In conducting research utilizing recombinant DNA technology , the investigator(s) adhered to...for 1 h, then with 0.1 mg/ml of proteinase K, 0.1% SDS at 50’C Ihle, 1995; Fraser and Evan, 1996). These molecules overnight. Samples were extracted ...incubated with 20 yg/ml of anti-DCC antibody diluted in PBS-0.1% saponin for 1 h, washed with PBS, blocked Western blotting with 5% normal donkey serum for 1

Modelling of volatility in monetary transmission mechanism

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

Dobešová, Anna; Klepáč, Václav; Kolman, Pavel

2015-03-10

The aim of this paper is to compare different approaches to modeling of volatility in monetary transmission mechanism. For this purpose we built time-varying parameter VAR (TVP-VAR) model with stochastic volatility and VAR-DCC-GARCH model with conditional variance. The data from three European countries are included in the analysis: the Czech Republic, Germany and Slovakia. Results show that VAR-DCC-GARCH system captures higher volatility of observed variables but main trends and detected breaks are generally identical in both approaches.

A dehydrogenative cross-coupling reaction between aromatic aldehydes or ketones and dialkyl H-phosphonates for formyl or acylphenylphosphonates.

PubMed

Huang, Xing-Fen; Wu, Qing-Lai; He, Jian-Shi; Huang, Zhi-Zhen

2015-04-21

A novel DCC reaction between aromatic aldehydes or ketones and H-phosphonates has been developed for the synthesis of p-formyl or p-acylphenylphosphonates. The synthetic method has excellent para regioselectivities, good yields, and broad substrate scopes and is more benign to the environment. The DCC reaction also tolerates many functional groups, and results in a series of new p-formyl and p-acylphenylphosphonates, which should be important building blocks for the synthesis of versatile arylphosphonate derivatives.

Misplaced Priorities and Barrett’s Esophagus

Cancer.gov

Nicholas J. Shaheen, MD, MPH is 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. His research and clinical interests center on gastroesophageal reflux disease, and pre-cancerous and cancerous conditions of the esophagus. He has a clinical and research interest in early detection and treatment of cancerous and precancerous lesions of the esophagus. He has authored greater than 300 publications in these areas. Dr. Shaheen is author of multiple national guidelines in Barrett’s esophagus, GERD and eosinophilic esophagitis. He has served as senior associate editor for the American Journal of Gastroenterology, and on multiple other editorial boards. Dr. Shaheen receives research funding from the National Institutes of Health, multiple societies, and private and public foundations.

Investigation of High-Level Synthesis tools’ applicability to data acquisition systems design based on the CMS ECAL Data Concentrator Card example

NASA Astrophysics Data System (ADS)

HUSEJKO, Michal; EVANS, John; RASTEIRO DA SILVA, Jose Carlos

2015-12-01

High-Level Synthesis (HLS) for Field-Programmable Logic Array (FPGA) programming is becoming a practical alternative to well-established VHDL and Verilog languages. This paper describes a case study in the use of HLS tools to design FPGA-based data acquisition systems (DAQ). We will present the implementation of the CERN CMS detector ECAL Data Concentrator Card (DCC) functionality in HLS and lessons learned from using HLS design flow. The DCC functionality and a definition of the initial system-level performance requirements (latency, bandwidth, and throughput) will be presented. We will describe how its packet processing control centric algorithm was implemented with VHDL and Verilog languages. We will then show how the HLS flow could speed up design-space exploration by providing loose coupling between functions interface design and functions algorithm implementation. We conclude with results of real-life hardware tests performed with the HLS flow-generated design with a DCC Tester system.

Tail dependence and information flow: Evidence from international equity markets

NASA Astrophysics Data System (ADS)

Al Rahahleh, Naseem; Bhatti, M. Ishaq; Adeinat, Iman

2017-05-01

Bhatti and Nguyen (2012) used the copula approach to measure the tail dependence between a number of international markets. They observed that some country pairs exhibit only left-tail dependence whereas others show only right-tail. However, the flow of information from uni-dimensional (one-tail) to bi-dimensional (two-tails) between various markets was not accounted for. In this study, we address the flow of information of this nature by using the dynamic conditional correlation (DCC-GARCH) model. More specifically, we use various versions of the DCC models to explain the nexus between the information flow of international equity and to explain the stochastic forward vs. backward dynamics of financial markets based on data for a 15-year period comprising 3,782 observations. We observed that the information flow between the US and Hong Kong markets and between the US and Australian markets are bi-directional. We also observed that the DCC model captures a wider co-movement structure and inter-connectedness compared to the symmetric Joe-Clayton copula.

The Diesel Combustion Collaboratory: Combustion Researchers Collaborating over the Internet

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

C. M. Pancerella; L. A. Rahn; C. Yang

2000-02-01

The Diesel Combustion Collaborator (DCC) is a pilot project to develop and deploy collaborative technologies to combustion researchers distributed throughout the DOE national laboratories, academia, and industry. The result is a problem-solving environment for combustion research. Researchers collaborate over the Internet using DCC tools, which include: a distributed execution management system for running combustion models on widely distributed computers, including supercomputers; web-accessible data archiving capabilities for sharing graphical experimental or modeling data; electronic notebooks and shared workspaces for facilitating collaboration; visualization of combustion data; and video-conferencing and data-conferencing among researchers at remote sites. Security is a key aspect of themore » collaborative tools. In many cases, the authors have integrated these tools to allow data, including large combustion data sets, to flow seamlessly, for example, from modeling tools to data archives. In this paper the authors describe the work of a larger collaborative effort to design, implement and deploy the DCC.« less

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

Biota Modeling in EPA's Preliminary Remediation Goal and Dose Compliance Concentration Calculators for Use in EPA Superfund Risk Assessment: Explanation of Intake Rate Derivation, Transfer Factor Compilation, and Mass Loading Factor Sources

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

Manning, Karessa L.; Dolislager, Fredrick G.; Bellamy, Michael B.

The Preliminary Remediation Goal (PRG) and Dose Compliance Concentration (DCC) calculators are screening level tools that set forth Environmental Protection Agency's (EPA) recommended approaches, based upon currently available information with respect to risk assessment, for response actions at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) sites, commonly known as Superfund. The screening levels derived by the PRG and DCC calculators are used to identify isotopes contributing the highest risk and dose as well as establish preliminary remediation goals. Each calculator has a residential gardening scenario and subsistence farmer exposure scenarios that require modeling of the transfer of contaminants frommore » soil and water into various types of biota (crops and animal products). New publications of human intake rates of biota; farm animal intakes of water, soil, and fodder; and soil to plant interactions require updates be implemented into the PRG and DCC exposure scenarios. Recent improvements have been made in the biota modeling for these calculators, including newly derived biota intake rates, more comprehensive soil mass loading factors (MLFs), and more comprehensive soil to tissue transfer factors (TFs) for animals and soil to plant transfer factors (BV's). New biota have been added in both the produce and animal products categories that greatly improve the accuracy and utility of the PRG and DCC calculators and encompass greater geographic diversity on a national and international scale.« less

Randomised control trial showed that delayed cord clamping and milking resulted in no significant differences in iron stores and physical growth parameters at one year of age.

PubMed

Agarwal, Shivam; Jaiswal, Vijay; Singh, Dharamveer; Jaiswal, Prateek; Garg, Amit; Upadhyay, Amit

2016-11-01

Placental redistribution has been shown to improve haematological outcomes in the immediate neonatal period and early infancy. This study compared the effects of delayed cord clamping (DCC) and umbilical cord milking (UCM) on haematological and growth parameters at 12 months of age. This was a follow-up study of a randomised control trial, conducted in a tertiary care paediatric centre from August 2013 to August 2014. We studied 200 apparently healthy Indian infants randomised at birth to receive DCC for 60-90 seconds or UCM. The outcome measures were iron status and physical growth parameters at 12 months. Of the 200 babies, 161 completed the follow-up and baseline characteristics were comparable in both groups. The mean haemoglobin in the DCC group (102.2 (17.2) g/L and serum ferritin 16.44 (2.77) μg/L) showed no significant differences to the UCM group (98.6 (17.1) g/L and 18.2 (2.8) μg/L) at one year. In addition, there were no significant differences in weight, height and mid-upper arm circumference in the two groups. Term-born Indian infants who had DCC at 60-90 seconds or UCM showed no significant differences in ferritin and haemoglobin levels and growth parameters at 12 months of age. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

User-Friendly Data-Sharing Practices for Fostering Collaboration within a Research Network: Roles of a Vanguard Center for a Community-Based Study

PubMed Central

Lee, Jae Eun; Sung, Jung Hye; Barnett, M. Edwina; Norris, Keith

2015-01-01

Although various attempts have been made to build collaborative cultures for data sharing, their effectiveness is still questionable. The Jackson Heart Study (JHS) Vanguard Center (JHSVC) at the NIH-funded Research Centers in Minority Institutions (RCMI) Translational Research Network (RTRN) Data Coordinating Center (DCC) may be a new concept in that the data are being shared with a research network where a plethora of scientists/researchers are working together to achieve their common goal. This study describes the current practices to share the JHS data through the mechanism of JHSVC. The JHS is the largest single-site cohort study to prospectively investigate the determinants of cardiovascular disease among African-Americans. It has adopted a formal screened access method through a formalized JHSVC mechanism, in which only a qualified scientist(s) can access the data. The role of the DCC was to help RTRN researchers explore hypothesis-driven ideas to enhance the output and impact of JHS data through customized services, such as feasibility tests, data querying, manuscript proposal development and data analyses for publication. DCC has implemented these various programs to facilitate data utility. A total of 300 investigators attended workshops and/or received training booklets. DCC provided two online and five onsite workshops and developed/distributed more than 250 copies of the booklet to help potential data users understand the structure of and access to the data. Information on data use was also provided through the RTRN website. The DCC efforts led to the production of five active manuscript proposals, seven completed publications, 11 presentations and four NIH grant proposals. These outcomes resulted from activities during the first four years; over the last couple of years, there were few new requests. Our study suggested that DCC-customized services enhanced the accessibility of JHS data and their utility by RTRN researchers and helped to achieve the principal goal of JHSVC of scientific productivity. In order to achieve long-term success, the following, but not limited to these, should be addressed in the current data sharing practices: preparation of new promotional strategies in response to changes in technology and users’ needs, collaboration with the Network statisticians, harmonization of the JHS data with the other local-based heart datasets to meet the needs of the potential users from the broader geographical areas, adoption of the RTRN comprehensive data-sharing policy to broaden the variety of research topics and implementation of an ongoing monitoring program to evaluate its success. PMID:26703645

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).…

Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr-/-) mouse model with hepato-biliary pathology.

PubMed

Bodewes, Frank A J A; van der Wulp, Mariëtte Y M; Beharry, Satti; Doktorova, Marcela; Havinga, Rick; Boverhof, Renze; James Phillips, M; Durie, Peter R; Verkade, Henkjan J

2015-07-01

Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice. We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice. We found no differences between the total biliary bile salt or lipid concentrations of Cftr(-/-) and controls. Compared to controls, Cftr(-/-) mice had a ~30% higher bile production and a low bile hydrophobicity, related to a ~7 fold higher concentration of the choleretic and hydrophilic bile salt ursocholate. These findings coexisted with a significantly smaller quantity of fecal Bacteroides bacteria. Liver pathology in Cftr(-/-tm1Unc) is not related to increased bile hydrophobicity. Cftr(-/-) mice do however display a biliary phenotype characterized by increased bile production and decreased biliary hydrophobicity. Our findings suggest Cftr dependent, alterations in intestinal bacterial biotransformation of bile salts. Copyright © 2014. Published by Elsevier B.V.

Utilizing the Antarctic Master Directory to find orphan datasets

NASA Astrophysics Data System (ADS)

Bonczkowski, J.; Carbotte, S. M.; Arko, R. A.; Grebas, S. K.

2011-12-01

While most Antarctic data are housed at an established disciplinary-specific data repository, there are data types for which no suitable repository exists. In some cases, these "orphan" data, without an appropriate national archive, are served from local servers by the principal investigators who produced the data. There are many pitfalls with data served privately, including the frequent lack of adequate documentation to ensure the data can be understood by others for re-use and the impermanence of personal web sites. For example, if an investigator leaves an institution and the data moves, the link published is no longer accessible. To ensure continued availability of data, submission to long-term national data repositories is needed. As stated in the National Science Foundation Office of Polar Programs (NSF/OPP) Guidelines and Award Conditions for Scientific Data, investigators are obligated to submit their data for curation and long-term preservation; this includes the registration of a dataset description into the Antarctic Master Directory (AMD), http://gcmd.nasa.gov/Data/portals/amd/. The AMD is a Web-based, searchable directory of thousands of dataset descriptions, known as DIF records, submitted by scientists from over 20 countries. It serves as a node of the International Directory Network/Global Change Master Directory (IDN/GCMD). The US Antarctic Program Data Coordination Center (USAP-DCC), http://www.usap-data.org/, funded through NSF/OPP, was established in 2007 to help streamline the process of data submission and DIF record creation. When data does not quite fit within any existing disciplinary repository, it can be registered within the USAP-DCC as the fallback data repository. Within the scope of the USAP-DCC we undertook the challenge of discovering and "rescuing" orphan datasets currently registered within the AMD. In order to find which DIF records led to data served privately, all records relating to US data within the AMD were parsed. After identifying the records containing a URL leading to a national data center or other disciplinary data repository, the remaining records were individually inspected for data type, format, and quality of metadata and then assessed to determine how best to preserve. Of the records reviewed, those for which appropriate repositories could be identified were submitted. An additional 35 were deemed acceptable in quality of metadata to register in the USAP-DCC. The content of these datasets were varied in nature, ranging from penguin counts to paleo-geologic maps to results of meteorological models all of which are discoverable through our search interface, http://www.usap-data.org/search.php. The remaining 40 records linked to either no data or had inadequate documentation for preservation highlighting the danger of serving datasets on local servers where minimal metadata standards can not be enforced and long-term access can not be ensured.

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.

Pivot/Remote: a distributed database for remote data entry in multi-center clinical trials.

PubMed

Higgins, S B; Jiang, K; Plummer, W D; Edens, T R; Stroud, M J; Swindell, B B; Wheeler, A P; Bernard, G R

1995-01-01

1. INTRODUCTION. Data collection is a critical component of multi-center clinical trials. Clinical trials conducted in intensive care units (ICU) are even more difficult because the acute nature of illnesses in ICU settings requires that masses of data be collected in a short time. More than a thousand data points are routinely collected for each study patient. The majority of clinical trials are still "paper-based," even if a remote data entry (RDE) system is utilized. The typical RDE system consists of a computer housed in the CC office and connected by modem to a centralized data coordinating center (DCC). Study data must first be recorded on a paper case report form (CRF), transcribed into the RDE system, and transmitted to the DCC. This approach requires additional monitoring since both the paper CRF and study database must be verified. The paper-based RDE system cannot take full advantage of automatic data checking routines. Much of the effort (and expense) of a clinical trial is ensuring that study data matches the original patient data. 2. METHODS. We have developed an RDE system, Pivot/Remote, that eliminates the need for paper-based CRFs. It creates an innovative, distributed database. The database resides partially at the study clinical centers (CC) and at the DCC. Pivot/Remote is descended from technology introduced with Pivot [1]. Study data is collected at the bedside with laptop computers. A graphical user interface (GUI) allows the display of electronic CRFs that closely mimic the normal paper-based forms. Data entry time is the same as for paper CRFs. Pull-down menus, displaying the possible responses, simplify the process of entering data. Edit checks are performed on most data items. For example, entered dates must conform to some temporal logic imposed by the study. Data must conform to some acceptable range of values. Calculations, such as computing the subject's age or the APACHE II score, are automatically made as the data is entered. Data that is collected serially (BP, HR, etc.) can be displayed graphically in a trend form along with other related variables. An audit trail is created that automatically tracks all changes to the original data, making it possible to reconstruct the CRF to any point in time. On-line help provides information on the study protocol as well as assistance with the use of the system. Electronic security makes it possible to lock certain parts of the CRF once it has been monitored. Completed CRFs are transmitted to the DCC via electronic mail where it is reviewed and merged into the study database. Questions about subject data are transmitted back to the CC via electronic mail. This approach to maintaining the study database is unique in that the study data files are distributed among the CC and DCC. Until a subject's CRF is monitored (verified against the original patient data residing in the hospital record), it logically resides at the CC where it was collected. Copies are transmitted to the DCC and are only read there. Any pre-monitoring changes must be made to the data at the CC. Once the subject's CRF is monitored, it logically moves to the DCC, and any subsequent changes are made at the DCC with copies of the CRF flowing back to the CC. 3. DISCUSSION. Pivot/Remote eliminates the need for paper forms by utilizing portable computers that can be used at the patient bedside. A GUI makes it possible to quickly enter data. Because the user gets instant feedback on possible error conditions, time is saved because the original data is close at hand. The ability to display trended data or variables in the context of other data allows detection of erroneous conditions beyond simple range checks. The logical construction of the database minimizes the problem of managing dual databases (at the CC and DCC) and keeps CC personnel in the loop until all changes are made.

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

Costs and absence of HCV-infected employees by disease stage.

PubMed

Baran, Robert W; Samp, Jennifer C; Walker, David R; Smeeding, James E; Young, Jacob W; Kleinman, Nathan L; Brook, Richard A

2015-01-01

Quantify the costs and absenteeism associated with stages of the Hepatitis C virus (HCV). Retrospective analysis of the HCMS integrated database from multiple geographically diverse, US-based employers with employee information on medical, prescription, and absenteeism claims. Employee data were extracted from July 2001-March 2013. Employees with HCV were identified by ICD-9-CM codes and classified into disease severity cohorts using diagnosis/procedure codes assigning the first date of most severe claim as the index date. Non-HCV employees (controls) were assigned random index dates. Inclusion required 6-month pre-/post-index eligibility. Medical, prescription, and absenteeism cost and time were analyzed using two-part regression (logistic/generalized linear) models, controlling for potentially confounding factors. Costs were inflation adjusted to September 2013. All direct costs comparisons were statistically significant (p ≤ 0.05) with mean medical costs of $1813 [SE = $3] for controls (n = 727,588), $4611 [SE = $211] for non-cirrhotic (n = 1007), $4646 [SE = $721] for compensated cirrhosis (CC, n = 87), $12,384 [SE = $1122] for decompensated cirrhosis (DCC, n = 256), $33,494 [SE = $11,753] for hepatocellular carcinoma (HCC, n = 17) and $97,724 [SE = $32,437] for liver transplant (LT, n = 19) cohorts. Mean short-term disability days/costs were significantly greater for the non-cirrhotic (days = 2.03 [SE = 0.36]; $299 [SE = $53]), DCC (days = 6.20 [SE = 1.36]; $763 [SE = $169]), and LT cohorts (days = 21.98 [SE = 8.21]; $2537 [SE = $972]) compared to controls (days = 1.19 [SE = 0.01]; $155 [SE = $1]). Mean sick leave costs were significantly greater for non-cirrhotic ($373 [SE = $22]) and DCC ($460 [SE = $54]) compared to controls ($327 [SE = $1]). Employees with HCV were shown to have greater direct and indirect costs compared to non-HCV employee controls. Costs progressively increased in the more severe HCV disease categories. Slowing or preventing disease progression may avert the costs of more severe liver disease stages and enable employees with HCV to continue as productive members of the workforce.

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

Advanced Stirling Convertor Dual Convertor Controller Testing at NASA Glenn Research Center in the Radioisotope Power Systems System Integration Laboratory

NASA Technical Reports Server (NTRS)

Dugala, Gina M.; Taylor, Linda M.; Bell, Mark E.; Dolce, James L.; Fraeman, Martin; Frankford, David P.

2015-01-01

NASA Glenn Research Center developed a nonnuclear representation of a Radioisotope Power System (RPS) consisting of a pair of Advanced Stirling Convertors (ASCs), Dual Convertor Controller (DCC) EMs (engineering models) 2 and 3, and associated support equipment, which were tested in the Radioisotope Power Systems System Integration Laboratory (RSIL). The DCC was designed by the Johns Hopkins University Applied Physics Laboratory (JHU/APL) to actively control a pair of ASCs. The first phase of testing included a Dual Advanced Stirling Convertor Simulator (DASCS), which was developed by JHU/APL and simulates the operation and electrical behavior of a pair of ASCs in real time via a combination of hardware and software. RSIL provides insight into the electrical interactions between a representative radioisotope power generator, its associated control schemes, and realistic electric system loads. The first phase of integration testing included the following spacecraft bus configurations: capacitive, battery, and super-capacitor. A load profile, created based on data from several missions, tested the RPS's and RSIL's ability to maintain operation during load demands above and below the power provided by the RPS. The integration testing also confirmed the DCC's ability to disconnect from the spacecraft when the bus voltage dipped below 22 volts or exceeded 36 volts. Once operation was verified with the DASCS, the tests were repeated with actual operating ASCs. The goal of this integration testing was to verify operation of the DCC when connected to a spacecraft and to verify the functionality of the newly designed RSIL. The results of these tests are presented in this paper.

Promoter hypermethylation in Indian primary oral squamous cell carcinoma

PubMed Central

Kaur, Jatinder; Demokan, Semra; Tripathi, Satyendra Chandra; Macha, Muzafar Ahmad; Begum, Shahnaz; Califano, Joseph A.; Ralhan, Ranju

2010-01-01

We evaluated promoter hypermethylation of a panel of tumor suppressor genes as a means to detect epigenetic alterations in oral squamous cell carcinomas (OSCC) of Indian-origin and compare with North-American head and neck squamous cell carcinomas (HNSCC). Quantitative-methylation-specific PCR was used to investigate the promoter methylation status of DCC, EDNRB, p16INK4a and KIF1A in 92 OSCC, and compared to 48 paired normal tissues and 30 saliva and sera samples from healthy control subjects. Aberrant methylation of at-least one of these genes was detected in 74/92 (80.4%) OSCC; 72.8% at EDNRB, 71.7% at KIF1A, 47.8% at p16INK4a and 58.7% at DCC; and in 5 of 48 (10.4%) normal oral tissues. None of the saliva and sera samples from controls exhibited DNA methylation in these four target genes. Thirty-two of 72 node positive cases harbored p16INK4a and DCC hypermethylation (p = 0.005). Thus, promoter hypermethylation in genes analyzed herein is a common event in Indian OSCC and may represent promising markers for the molecular staging of OSCC patients. We found higher frequency of p16INK4a methylation (47.8%) in this Indian cohort in comparison with a North-American cohort (37.5%). In conclusion, aberrant methylation of EDNRB, KIF1A, DCC and p16INK4a genes is a common event in Indian OSCC, suggesting that epigenetic alterations of these genes warrant validation in larger studies for their potential use as biomarkers. PMID:20473870

The dynamic pattern of PLIN3 in pig oocytes and cumulus cells during in vitro maturation.

PubMed

Xu, Mingzhu; Zeng, Yaqiong; Chi, Daming; Si, Linan; Qu, Xiao; Li, Juan

2018-02-01

Lipid droplets (LDs) are the main energy resource for porcine preimplantation embryonic development. PLIN3 has been implicated in LD formation and regulation. Therefore, this study aimed to detect the dynamic pattern of PLIN3 in pig oocytes and cumulus cells (CC) during in vitro maturation (IVM), and to determine the relationship between PLIN3 and LD content. IVM with cumulus-enclosed oocytes (CEO), cumulus-denuded oocytes (DO) and the CCs denuded from the corresponding oocytes (DCC) was performed in porcine follicular fluid (PFF) or PFF-free optimized medium. DO and the DCC were cultured together under the same conditions as described above, while the DO was named DTO and the DCC was named DTCC in this group. Firstly, our results revealed LDs distributed widely in oocytes and CC, while the PLIN3 protein coated these LDs and spread out ubiquitously in the cytoplasm. Secondly, not only the mRNA level but also at protein level of PLIN3 in immature naked oocytes (IO) was higher than that in matured CEO, DO and DTO. Although PLIN3 was expressed at lower levels in CC from immature oocytes (ICC), the protein level of PLIN3 was comparably higher in the ECC and DCC groups. The triglyceride (TG) content in CEO and DO was significantly less abundant compared with that in IO. Therefore, our results indicated that co-culturing of oocytes and CC might affect PLIN3 expression levels in CC but not in oocytes. Lipid accumulation in pig oocytes during maturation might be affected by PLIN3 cross-talk between oocytes and CC.

"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…

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...

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

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

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

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.

Repulsive Guidance Molecules (RGMs) and Neogenin in Bone Morphogenetic Protein (BMP) signaling

PubMed Central

Tian, Chenxi; Liu, Jun

2015-01-01

Summary Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGFβ) superfamily. BMPs mediate a highly conserved signal transduction cascade through the type I and type II serine/threonine kinase receptors and intracellular Smad proteins. The BMP pathway regulates multiple developmental and homeostatic processes. Mutations in this pathway can cause various diseases in humans, such as skeletal disorders, cardiovascular diseases and various cancers. Multiple levels of regulation, including extracellular regulation, help to ensure proper spatiotemporal control of BMP signaling in the right cellular context. The family of repulsive guidance molecules (RGMs) and the type I trans-membrane protein neogenin, a paralog of DCC (Deleted in Colorectal Cancer), have been implicated in modulating the BMP pathway. In this review, we discuss the properties and functions of RGM proteins and neogenin, focusing on their roles in the modulation of BMP signal transduction. PMID:23740870

Advanced Stirling Convertor Dual Convertor Controller Testing at NASA Glenn Research Center in the Radioisotope Power Systems System Integration Laboratory

NASA Technical Reports Server (NTRS)

Dugala, Gina M.; Taylor, Linda M.; Bell, Mark E.; Dolce, James L.; Fraeman, Martin; Frankford, David P.

2015-01-01

NASA Glenn Research Center (GRC) developed a non-nuclear representation of a Radioisotope Power System (RPS) consisting of a pair of Advanced Stirling Convertors (ASC), a Dual Convertor Controller (DCC) EM (engineering model) 2 & 3, and associated support equipment, which were tested in the Radioisotope Power Systems System Integration Laboratory (RSIL). The DCC was designed by the Johns Hopkins University/Applied Physics Laboratory (JHU/APL) to actively control a pair of Advanced Stirling Convertors (ASC). The first phase of testing included a Dual Advanced Stirling Convertor Simulator (DASCS) which was developed by JHU/APL and simulates the operation and electrical behavior of a pair of ASC's in real time via a combination of hardware and software. RSIL provides insight into the electrical interactions between a representative radioisotope power generator, its associated control schemes, and realistic electric system loads. The first phase of integration testing included the following spacecraft bus configurations: capacitive, battery, and supercapacitor. A load profile, created based on data from several missions, tested the RPS and RSIL ability to maintain operation during load demands above and below the power provided by the RPS. The integration testing also confirmed the DCC's ability to disconnect from the spacecraft when the bus voltage dipped below 22 V or exceeded 36 V. Once operation was verified with the DASCS, the tests were repeated with actual operating ASC's. The goal of this integration testing was to verify operation of the DCC when connected to a spacecraft and to verify the functionality of the newly designed RSIL. The results of these tests are presented in this paper.

Effect of indoor air quality of day care centers in children with different predisposition for asthma.

PubMed

Carreiro-Martins, Pedro; Papoila, Ana Luisa; Caires, Iolanda; Azevedo, Susana; Cano, Maria Manuela; Virella, Daniel; Leiria-Pinto, Paula; Teixeira, João Paulo; Rosado-Pinto, José; Annesi-Maesano, Isabella; Neuparth, Nuno

2016-05-01

Scarce information is available about the relationships between indoor air quality (IAQ) at day care centers (DCC), the estimated predisposition for asthma, and the actual wheezing susceptibility. In the Phase II of ENVIRH study, 19 DCC were recruited after cluster analysis. Children were evaluated firstly using the ISAAC questionnaire and later by a follow-up questionnaire about recent wheezing. A positive asthma predictive index (API) was considered as predisposition for asthma. Every DCC was audited for IAQ and monitored for chemical and biologic contaminants. We included 1191 children, with a median age of 43 (P25 -P75 : 25-58) months. Considering the overall sample, in the first questionnaire, associations were found between CO2 concentration (increments of 200 ppm) and diagnosis of asthma (OR: 1.10; 95% CI: 1.00-1.20). Each increment of 100 μg/m(3) of total volatile organic compounds (TVOC) and 1 μg of Der p1/g of dust were associated with wheezing in the previous 12 months (OR: 1.06; 95% CI: 1.01-1.11 and OR: 1.06; 95% CI: 0.99-1.12, respectively). In the follow-up questionnaire, TVOC were again associated with wheezing (OR: 1.05; 95% CI: 1.00-1.11). Children exposed to fungal concentration above the 75th percentile had also higher odds of wheezing at follow-up. TVOC were associated with wheezing in children with either negative or positive API. IAQ in DCC seems to be associated with wheezing, in children with and without predisposition for asthma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The burden of hepatitis C to the United States Medicare system in 2009: Descriptive and economic characteristics.

PubMed

Rein, David B; Borton, Joshua; Liffmann, Danielle K; Wittenborn, John S

2016-04-01

The aim of this work was to estimate and describe the Medicare beneficiaries diagnosed with hepatitis C virus (HCV) in 2009, incremental annual costs by disease stage, incremental total Medicare HCV payments in 2009 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data covering the years 2002 to 2009. We weighted the 2009 SEER-Medicare data to create estimates of the number of patients with an HCV diagnosis, used an inverse probability-weighted two-part, probit, and generalized linear model to estimate incremental per patient per month costs, and used simulation to estimate annual 2009 Medicare burden, presented in 2014 dollars. We summarized patient characteristics, diagnoses, and costs from SEER-Medicare files into a person-year panel data set. We estimated there were 407,786 patients with diagnosed HCV in 2009, of whom 61.4% had one or more comorbidities defined by the study. In 2009, 68% of patients were diagnosed with chronic HCV only, 9% with cirrhosis, 12% with decompensated cirrhosis (DCC), 2% with liver cancer, 2% with a history of transplant, and 8% who died. Annual costs for patients with chronic infection only and DCC were higher than the values used in many previous cost-effectiveness studies, and treatment of DCC accounted for 63.9% of total Medicare's HCV expenditures. Medicare paid $2.7 billion (credible interval: $0.7-$4.6 billion) in incremental costs for HCV in 2009. The costs of HCV to Medicare in 2009 were substantial and expected to increase over the next decade. Annual costs for patients with chronic infection only and DCC were higher than values used in many cost-effectiveness analyses. © 2015 by the American Association for the Study of Liver Diseases.

Feasibility of a cardiologist-only approach to sedation for electrical cardioversion of atrial fibrillation: a randomized, open-blinded, prospective study.

PubMed

Guerra, Federico; Pavoni, Ilaria; Romandini, Andrea; Baldetti, Luca; Matassini, Maria Vittoria; Brambatti, Michela; Luzi, Mario; Pupita, Giuseppe; Capucci, Alessandro

2014-10-20

Sedation with propofol should be administered by personnel trained in advanced airway management. To overcome this limitation, the use of short acting benzodiazepines by cardiologists spread widely, causing concerns about the safety of this procedure in the absence of anesthesiology assistance. The aim of the study was to compare feasibility of a cardiologist-only approach with an anesthesiologist-assisted sedation protocol during elective direct-current cardioversion (DCC) of persistent atrial fibrillation (AF). This prospective, open-blinded, randomized study included 204 patients, which were admitted for scheduled cardioversion of persistent AF, and randomized in a 1:1 fashion to either propofol or midazolam treatment arm. Patients in the propofol group underwent DCC with anesthesiologist assistance, while patients in the midazolam group saw the cardiologist as the only responsible for both sedation and DCC. Twenty-three adverse events occurred: 13 in the propofol group and 10 in the midazolam group (p=NS). Most of them were related to bradyarrhythmias and respiratory depressions. There was no need of intubation or other advanced resuscitation techniques in any of these patients. No differences were found regarding procedure tolerability and safety endpoints between the two groups. DCC procedures with anesthesiology support were burdened by higher delay from scheduled time and higher costs. Sedation with midazolam administered by cardiologist-only appears to be as safe as sedation with propofol and anesthesiologist assistance. Adverse events were few in both groups and easily handled by the cardiologist alone. A cardiologist-only approach to sedation provides less procedural delay, thus being easier to schedule and correlated with fewer costs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Decellularized Cartilage May Be a Chondroinductive Material for Osteochondral Tissue Engineering

PubMed Central

Sutherland, Amanda J.; Beck, Emily C.; Dennis, S. Connor; Converse, Gabriel L.; Hopkins, Richard A.; Berkland, Cory J.; Detamore, Michael S.

2015-01-01

Extracellular matrix (ECM)-based materials are attractive for regenerative medicine in their ability to potentially aid in stem cell recruitment, infiltration, and differentiation without added biological factors. In musculoskeletal tissue engineering, demineralized bone matrix is widely used, but recently cartilage matrix has been attracting attention as a potentially chondroinductive material. The aim of this study was thus to establish a chemical decellularization method for use with articular cartilage to quantify removal of cells and analyze the cartilage biochemical content at various stages during the decellularization process, which included a physically devitalization step. To study the cellular response to the cartilage matrix, rat bone marrow-derived mesenchymal stem cells (rBMSCs) were cultured in cell pellets containing cells only (control), chondrogenic differentiation medium (TGF-β), chemically decellularized cartilage particles (DCC), or physically devitalized cartilage particles (DVC). The chemical decellularization process removed the vast majority of DNA and about half of the glycosaminoglycans (GAG) within the matrix, but had no significant effect on the amount of hydroxyproline. Most notably, the DCC group significantly outperformed TGF-β in chondroinduction of rBMSCs, with collagen II gene expression an order of magnitude or more higher. While DVC did not exhibit a chondrogenic response to the extent that DCC did, DVC had a greater down regulation of collagen I, collagen X and Runx2. A new protocol has been introduced for cartilage devitalization and decellularization in the current study, with evidence of chondroinductivity. Such bioactivity along with providing the ‘raw material’ building blocks of regenerating cartilage may suggest a promising role for DCC in biomaterials that rely on recruiting endogenous cell recruitment and differentiation for cartilage regeneration. PMID:25965981

VizieR Online Data Catalog: PTF 12dam & iPTF 13dcc follow-up (Vreeswijk+, 2017)

NASA Astrophysics Data System (ADS)

Vreeswijk, P. M.; Leloudas, G.; Gal-Yam, A.; De Cia, A.; Perley, D. A.; Quimby, R. M.; Waldman, R.; Sullivan, M.; Yan, L.; Ofek, E. O.; Fremling, C.; Taddia, F.; Sollerman, J.; Valenti, S.; Arcavi, I.; Howell, D. A.; Filippenko, A. V.; Cenko, S. B.; Yaron, O.; Kasliwal, M. M.; Cao, Y.; Ben-Ami, S.; Horesh, A.; Rubin, A.; Lunnan, R.; Nugent, P. E.; Laher, R.; Rebbapragada, U. D.; Wozniak, P.; Kulkarni, S. R.

2017-08-01

Spectroscopic follow-up observations of PTF 12dam were performed with the Kast Spectrograph at the Lick 3m Shane telescope, and the Low Resolution Imaging Spectrograph (LRIS) at the Keck-I 10m telescope (on Mauna Kea, Hawaii) on 2012 May 20, 21, and 22. The full spectroscopic sequence of PTF 12dam will be presented by R. M. Quimby et al. (2016, in preparation). PTF 12dam was imaged with the Palomar Oschin 48 inch (P48) (i)PTF survey telescope in the Mould R filter, the Palomar 60 inch (P60) and CCD camera in Johnson B and Sloan Digital Sky Survey (SDSS) gri, the Las Cumbres Observatory Global Telescope Network (LCOGT) in SDSS r, and LRIS mounted on the 10m Keck-I telescope in Rs. iPTF 13dcc has not had any exposure in the literature yet. It was flagged as a transient source on 2013 August 29. Spectroscopic follow-up observations spanning 2013 Nov 26 to 2014 Jan 16 were performed with the Double Spectrograph (DBSP) at the Palomar 200 inch (P200), LRIS at Keck-I, and the Inamori-Magellan Areal Camera & Spectrograph (IMACS) at the Magellan Baade telescope, showing iPTF 13dcc to be an SLSN at z=0.4305. iPTF 13dcc was imaged with the P48 Oschin (i)PTF survey telescope in the Mould R filter, the P60 in SDSS gri, the 4.3m Discovery Channel Telescope (DCT, at Lowell Observatory, Arizona) with the Large Monolithic Imager (LMI) in SDSS ri, and finally with the Hubble Space Telescope (HST) Advanced Camera for Surveys (ACS) Wide-Field Camera using filter F625W (under program GO-13858; P.I. A. De Cia). (3 data files).

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

Microphysical effects determine macrophysical response for aerosol impacts on deep convective clouds

NASA Astrophysics Data System (ADS)

Fan, Jiwen; Leung, L. Ruby; Rosenfeld, Daniel; Chen, Qian; Li, Zhanqing; Zhang, Jinqiang; Yan, Hongru

2013-11-01

Deep convective clouds (DCCs) play a crucial role in the general circulation, energy, and hydrological cycle of our climate system. Aerosol particles can influence DCCs by altering cloud properties, precipitation regimes, and radiation balance. Previous studies reported both invigoration and suppression of DCCs by aerosols, but few were concerned with the whole life cycle of DCC. By conducting multiple monthlong cloud-resolving simulations with spectral-bin cloud microphysics that capture the observed macrophysical and microphysical properties of summer convective clouds and precipitation in the tropics and midlatitudes, this study provides a comprehensive view of how aerosols affect cloud cover, cloud top height, and radiative forcing. We found that although the widely accepted theory of DCC invigoration due to aerosol's thermodynamic effect (additional latent heat release from freezing of greater amount of cloud water) may work during the growing stage, it is microphysical effect influenced by aerosols that drives the dramatic increase in cloud cover, cloud top height, and cloud thickness at the mature and dissipation stages by inducing larger amounts of smaller but longer-lasting ice particles in the stratiform/anvils of DCCs, even when thermodynamic invigoration of convection is absent. The thermodynamic invigoration effect contributes up to ∼27% of total increase in cloud cover. The overall aerosol indirect effect is an atmospheric radiative warming (3-5 Wṡm-2) and a surface cooling (-5 to -8 Wṡm-2). The modeling findings are confirmed by the analyses of ample measurements made at three sites of distinctly different environments.

Microphysical effects determine macrophysical response for aerosol impacts on deep convective clouds.

PubMed

Fan, Jiwen; Leung, L Ruby; Rosenfeld, Daniel; Chen, Qian; Li, Zhanqing; Zhang, Jinqiang; Yan, Hongru

2013-11-26

Deep convective clouds (DCCs) play a crucial role in the general circulation, energy, and hydrological cycle of our climate system. Aerosol particles can influence DCCs by altering cloud properties, precipitation regimes, and radiation balance. Previous studies reported both invigoration and suppression of DCCs by aerosols, but few were concerned with the whole life cycle of DCC. By conducting multiple monthlong cloud-resolving simulations with spectral-bin cloud microphysics that capture the observed macrophysical and microphysical properties of summer convective clouds and precipitation in the tropics and midlatitudes, this study provides a comprehensive view of how aerosols affect cloud cover, cloud top height, and radiative forcing. We found that although the widely accepted theory of DCC invigoration due to aerosol's thermodynamic effect (additional latent heat release from freezing of greater amount of cloud water) may work during the growing stage, it is microphysical effect influenced by aerosols that drives the dramatic increase in cloud cover, cloud top height, and cloud thickness at the mature and dissipation stages by inducing larger amounts of smaller but longer-lasting ice particles in the stratiform/anvils of DCCs, even when thermodynamic invigoration of convection is absent. The thermodynamic invigoration effect contributes up to ~27% of total increase in cloud cover. The overall aerosol indirect effect is an atmospheric radiative warming (3-5 W m(-2)) and a surface cooling (-5 to -8 W m(-2)). The modeling findings are confirmed by the analyses of ample measurements made at three sites of distinctly different environments.

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.

Seasonality and Dynamic Spatial Contagion of Air Pollution in 42 Chinese Cities

PubMed Central

He, Zhanqiong; Sriboonchita, Songsak; He, Min

2013-01-01

To monitor and improve the urban air quality, the Chinese government has begun to make many efforts, and the interregional cooperation to cut and improve air quality has been required. In this paper, we focus on the seasonality of the first and second moments of the daily air pollution indexes (APIs) of 42 Chinese sample cities over 10 years, from June 5, 2000 to March 4, 2010, and investigate the dynamic correlation of air pollution indexes (APIs) between 42 Chinese cities and their corresponding regional and national levels; comparison with the model without seasonal consideration is made. By adopting a DCC-GARCH model that accounts for the seasonality, we found that (i) the transformed DCC-GARCH model including seasonality dummies improves the estimation result in this study; (ii) the seasonality feature of the second moment follows that of the first moment, with the condition mean and variance of the second and autumn significantly lower than spring, whereas that of winter is higher than spring; (iii) the correlation between local APIs and their corresponding regional and national levels is dynamic; (iv) comparing with the DCC-GARCH model estimation, the transformed model does not change the feature of the dynamic correlations very much. PMID:23533348

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.

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

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.

On the Use of Deep Convective Clouds to Characterize Response versus Scan-angle for MODIS Reflective Solar Bands

NASA Astrophysics Data System (ADS)

Bhatt, R.; Doelling, D. R.; Scarino, B. R.; Gopalan, A.; Haney, C.

2016-12-01

MODIS is a cross-track scanning radiometer with a two-sided scan mirror that images the Earth with an angular field of view of 55° on either side of the nadir. The reflectance of the scan mirror is not uniform and is a function of angle of incidence (AOI), as well as wavelength. This feature of the scan mirror is described by response versus scan-angle (RVS), and was characterized for all reflective solar bands (RSBs), for both MODIS instruments prior to launch. The RVS characteristic of the two MODIS instruments has changed on orbit and, therefore, must be tracked precisely over time to ensure high-quality data in the MODIS products. The MODIS Characterization Support Team (MCST) utilizes the onboard solar diffuser (SD) and lunar measurements to track the RVS changes at two fixed AOIs. The RVS at the remaining AOIs is characterized using the earth view (EV) responses from multiple pseudo-invariant desert sites located in Northern Africa. The drawback of this approach is the assumption that all of the desert sites imaged by the MODIS sensors at different AOIs are radiometrically stable during the same period of time. In addition, the desert samples do not always have continuous AOI coverage as they are limited by the 16-day repeat cycle of the satellite orbit, and by clear-sky conditions over the deserts. This paper proposes a novel and robust approach of characterizing the MODIS RVS using tropical deep convective clouds (DCCs) as an invariant calibration target. The method tracks the monthly DCC response at specified sets of AOIs to compute the temporal RVS changes. Because DCCs are distributed across the entirety of the tropics, they provide a continuum of AOI measurements. Initial results have shown that the Aqua-MODIS Collection 6 band 1 level 1b radiances show considerable residual, or artifact, RVS dependencies, especially on the left side of the cross-track scan. Long-term drifts, up to 2.3%, have been observed at certain AOIs. Temporal correction factors are computed using the DCC trends from 12 scan intervals encompassing all AOIs, and their effectiveness in correcting the observed RVS artifact is evaluated using the Libya-1 pseudo-invariant desert site. The desert and DCC temporal scan dependent trends are reduced to less than 1 standard error after the RVS correction.

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.

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.

Modeling inflation rates and exchange rates in Ghana: application of multivariate GARCH models.

PubMed

Nortey, Ezekiel Nn; Ngoh, Delali D; Doku-Amponsah, Kwabena; Ofori-Boateng, Kenneth

2015-01-01

This paper was aimed at investigating the volatility and conditional relationship among inflation rates, exchange rates and interest rates as well as to construct a model using multivariate GARCH DCC and BEKK models using Ghana data from January 1990 to December 2013. The study revealed that the cumulative depreciation of the cedi to the US dollar from 1990 to 2013 is 7,010.2% and the yearly weighted depreciation of the cedi to the US dollar for the period is 20.4%. There was evidence that, the fact that inflation rate was stable, does not mean that exchange rates and interest rates are expected to be stable. Rather, when the cedi performs well on the forex, inflation rates and interest rates react positively and become stable in the long run. The BEKK model is robust to modelling and forecasting volatility of inflation rates, exchange rates and interest rates. The DCC model is robust to model the conditional and unconditional correlation among inflation rates, exchange rates and interest rates. The BEKK model, which forecasted high exchange rate volatility for the year 2014, is very robust for modelling the exchange rates in Ghana. The mean equation of the DCC model is also robust to forecast inflation rates in Ghana.

The influence of day care centres for people with dementia on family caregivers: an integrative review of the literature.

PubMed

Tretteteig, Signe; Vatne, Solfrid; Rokstad, Anne Marie Mork

2016-01-01

Day care centres (DCC) for people with dementia (PWD) have received increased attention recently, due to a shift in policy from the use of residential care towards home-based services. The aim of this study is to provide an extended understanding of the influence of DCCs on family caregivers (FCs). An integrative review including 19 studies was used: qualitative (n = 2), quantitative non-randomised (n = 8), quantitative descriptive studies (n = 7), and with mixed-method design (n = 2). The quality of the studies was evaluated by the mixed-methods appraisal tool (MMAT). FC experienced the DCC both as a respite service, and to some extent as a support service, improving their competence in caring for the PWD. The quality of the DCC influenced its use, and the FC's motivation to care for the PWD. FC's gender, role, individual needs, PWD behavioural problems and need for assistance played an important role. As a respite and support service, DCCs have the potential to give FCs a feeling of safety and relief, reduce the caregiver's burden, and increase their motivation towards their role as caregivers. These outcomes depend on the quality of treatment, and how the service meets the FC's needs for flexibility, support, information, and responsibility sharing.

Interaction of Bacillus subtilis spores with sodium hypochlorite, sodium dichloroisocyanurate and chloramine-T.

PubMed

Bloomfield, S F; Arthur, M

1992-02-01

Solutions of chlorine-releasing agents (CRAs) show varying activity against Bacillus subtilis spores; sodium hypochlorite (NaOCl) shows higher activity than sodium dichloroisocyanurate (NaDCC) which is more active than chloramine-T. Investigations with coat- and cortex-extracted spores indicate that resistance to CRAs depends not only on the spore coat but also the cortex. Whereas extraction of alkali-soluble coat protein increased sensitivity to NaOCl and NaDCC, degradation of coat and cortex material was required to achieve significant activity with chloramine-T. NaOCl (in the presence and absence of NaOH) and NaDCC (in the presence of NaOH only) produced degradation of spore coat and cortex material which may be related to their rapid sporicidal action at low concentrations under these conditions. By contrast, chloramine-T produced no degradation of cortex peptidoglycan and was only effective against normal and alkali-treated spores at high concentrations, requiring extraction of peptidoglycan with urea/dithiothreitol/sodium lauryl sulphate (UDS) or UDS/lysozyme to achieve significant activity at low concentrations. Results suggest that the sporicidal action of CRAs is associated with spore coat and cortex degradation causing rehydration of the protoplast allowing diffusion to the site of action on the underlying protoplast.

Microphysical effects determine macrophysical response for aerosol impacts on deep convective clouds

PubMed Central

Fan, Jiwen; Leung, L. Ruby; Rosenfeld, Daniel; Chen, Qian; Li, Zhanqing; Zhang, Jinqiang; Yan, Hongru

2013-01-01

Deep convective clouds (DCCs) play a crucial role in the general circulation, energy, and hydrological cycle of our climate system. Aerosol particles can influence DCCs by altering cloud properties, precipitation regimes, and radiation balance. Previous studies reported both invigoration and suppression of DCCs by aerosols, but few were concerned with the whole life cycle of DCC. By conducting multiple monthlong cloud-resolving simulations with spectral-bin cloud microphysics that capture the observed macrophysical and microphysical properties of summer convective clouds and precipitation in the tropics and midlatitudes, this study provides a comprehensive view of how aerosols affect cloud cover, cloud top height, and radiative forcing. We found that although the widely accepted theory of DCC invigoration due to aerosol’s thermodynamic effect (additional latent heat release from freezing of greater amount of cloud water) may work during the growing stage, it is microphysical effect influenced by aerosols that drives the dramatic increase in cloud cover, cloud top height, and cloud thickness at the mature and dissipation stages by inducing larger amounts of smaller but longer-lasting ice particles in the stratiform/anvils of DCCs, even when thermodynamic invigoration of convection is absent. The thermodynamic invigoration effect contributes up to ∼27% of total increase in cloud cover. The overall aerosol indirect effect is an atmospheric radiative warming (3–5 W⋅m−2) and a surface cooling (−5 to −8 W⋅m−2). The modeling findings are confirmed by the analyses of ample measurements made at three sites of distinctly different environments. PMID:24218569

Spatial Segregation of γ-Secretase and Substrates in Distinct Membrane Domains*

PubMed Central

Vetrivel, Kulandaivelu S.; Cheng, Haipeng; Kim, Seong-Hun; Chen, Ying; Barnes, Natalie Y.; Parent, Ange‘le T.; Sisodia, Sangram S.; Thinakaran, Gopal

2005-01-01

γ-Secretase facilitates the regulated intramembrane proteolysis of select type I membrane proteins that play diverse physiological roles in multiple cell types and tissue. In this study, we used biochemical approaches to examine the distribution of amyloid precursor protein (APP) and several additional γ-secretase substrates in membrane microdomains. We report that APP C-terminal fragments (CTFs) and γ-secretase reside in Lubrol WX detergent-insoluble membranes (DIM) of cultured cells and adult mouse brain. APP CTFs that accumulate in cells lacking γ-secretase activity preferentially associate with DIM. Cholesterol depletion and magnetic im-munoisolation studies indicate recruitment of APP CTFs into cholesterol- and sphingolipid-rich lipid rafts, and co-residence of APP CTFs, PS1, and syntaxin 6 in DIM patches derived from the trans-Golgi network. Photoaffinity cross-linking studies provided evidence for the preponderance of active γ-secretase in lipid rafts of cultured cells and adult brain. Remarkably, unlike the case of APP, CTFs derived from Notch1, Jagged2, deleted in colorectal cancer (DCC), and N-cadherin remain largely detergent-soluble, indicative of their spatial segregation in non-raft domains. In embryonic brain, the majority of PS1 and nicastrin is present in Lubrol WX-soluble membranes, wherein the CTFs derived from APP, Notch1, DCC, and N-cadherin also reside. We suggest that γ-secretase residence in non-raft membranes facilitates proteolysis of diverse substrates during embryonic development but that the translocation of γ-secretase to lipid rafts in adults ensures processing of certain substrates, including APP CTFs, while limiting processing of other potential substrates. PMID:15886206

Spatial segregation of gamma-secretase and substrates in distinct membrane domains.

PubMed

Vetrivel, Kulandaivelu S; Cheng, Haipeng; Kim, Seong-Hun; Chen, Ying; Barnes, Natalie Y; Parent, Angèle T; Sisodia, Sangram S; Thinakaran, Gopal

2005-07-08

Gamma-secretase facilitates the regulated intramembrane proteolysis of select type I membrane proteins that play diverse physiological roles in multiple cell types and tissue. In this study, we used biochemical approaches to examine the distribution of amyloid precursor protein (APP) and several additional gamma-secretase substrates in membrane microdomains. We report that APP C-terminal fragments (CTFs) and gamma-secretase reside in Lubrol WX detergent-insoluble membranes (DIM) of cultured cells and adult mouse brain. APP CTFs that accumulate in cells lacking gamma-secretase activity preferentially associate with DIM. Cholesterol depletion and magnetic immunoisolation studies indicate recruitment of APP CTFs into cholesterol- and sphingolipid-rich lipid rafts, and co-residence of APP CTFs, PS1, and syntaxin 6 in DIM patches derived from the trans-Golgi network. Photoaffinity cross-linking studies provided evidence for the preponderance of active gamma-secretase in lipid rafts of cultured cells and adult brain. Remarkably, unlike the case of APP, CTFs derived from Notch1, Jagged2, deleted in colorectal cancer (DCC), and N-cadherin remain largely detergent-soluble, indicative of their spatial segregation in non-raft domains. In embryonic brain, the majority of PS1 and nicastrin is present in Lubrol WX-soluble membranes, wherein the CTFs derived from APP, Notch1, DCC, and N-cadherin also reside. We suggest that gamma-secretase residence in non-raft membranes facilitates proteolysis of diverse substrates during embryonic development but that the translocation of gamma-secretase to lipid rafts in adults ensures processing of certain substrates, including APP CTFs, while limiting processing of other potential substrates.

Assessment of MODIS RSB Detector Uniformity Using Deep Convective Clouds

NASA Technical Reports Server (NTRS)

Chang, Tiejun; Xiong, Xiaoxiong (Jack); Angal, Amit; Mu, Qiaozhen

2016-01-01

For satellite sensor, the striping observed in images is typically associated with the relative multiple detector gain difference derived from the calibration. A method using deep convective cloud (DCC) measurements to assess the difference among detectors after calibration is proposed and demonstrated for select reflective solar bands (RSBs) of the Moderate Resolution Imaging Spectroradiometer (MODIS). Each detector of MODIS RSB is calibrated independently using a solar diffuser (SD). Although the SD is expected to accurately characterize detector response, the uncertainties associated with the SD degradation and characterization result in inadequacies in the estimation of each detector's gain. This work takes advantage of the DCC technique to assess detector uniformity and scan mirror side difference for RSB. The detector differences for Terra MODIS Collection 6 are less than 1% for bands 1, 3-5, and 18 and up to 2% for bands 6, 19, and 26. The largest difference is up to 4% for band 7. Most Aqua bands have detector differences less than 0.5% except bands 19 and 26 with up to 1.5%. Normally, large differences occur for edge detectors. The long-term trending shows seasonal oscillations in detector differences for some bands, which are correlated with the instrument temperature. The detector uniformities were evaluated for both unaggregated and aggregated detectors for MODIS band 1 and bands 3-7, and their consistencies are verified. The assessment results were validated by applying a direct correction to reflectance images. These assessments can lead to improvements to the calibration algorithm and therefore a reduction in striping observed in the calibrated imagery.

Healthy Living Partnerships to Prevent Diabetes (HELP PD): Design and Methods

PubMed Central

Katula, Jeffrey A.; Vitolins, Mara Z.; Rosenberger, Erica L.; Blackwell, Caroline; Espeland, Mark A.; Lawlor, Michael S.; Rejeski, W. Jack; Goff, David C.

2009-01-01

Although the Diabetes Prevention Program (DPP) developed a lifestyle weight loss intervention that has been demonstrated to prevent type 2 diabetes in high-risk individuals, it has yet to be widely adopted at the community level. The Healthy Living Partnership to Prevent Diabetes study (HELP PD) was designed to translate the DPP approach for use in community settings as a cost-effective intervention led by Community Health Workers (CHW's) and administered through a Diabetes Care Center (DCC). Approximately 300 overweight and obese (BMI 25-40 kg/m2) individuals with prediabetes (fasting blood glucose 95-124 mg/dl) were randomly assigned to either a lifestyle weight loss intervention (LW) or an enhanced usual care comparison condition (UC). The goal of LW is ≥7% weight loss achieved through increases in physical activity (180 min/wk) and decreases in caloric intake (approximately 1500 kcal/day). The intervention consists of CHW-led group-mediated cognitive behavioral meetings that occur weekly for 6 months and monthly thereafter for 18 months. UC consists of 2 individual meetings with a registered dietitian and a monthly newsletter. The primary outcome is change in fasting blood glucose. Secondary outcomes include cardiovascular risk factors, health-related quality of life, and social cognitive variables. Outcomes are masked and are collected every 6 months. The cost-effectiveness of the program will also be assessed. A community-based program that is administered through local DCC's and that harnesses the experience of community members (CHW's) may be a promising strategy for the widespread dissemination of interventions effective at preventing type 2 diabetes in high risk individuals. PMID:19758580

X-Chromosome dosage compensation.

PubMed

Meyer, Barbara J

2005-06-25

In mammals, flies, and worms, sex is determined by distinctive regulatory mechanisms that cause males (XO or XY) and females (XX) to differ in their dose of X chromosomes. In each species, an essential X chromosome-wide process called dosage compensation ensures that somatic cells of either sex express equal levels of X-linked gene products. The strategies used to achieve dosage compensation are diverse, but in all cases, specialized complexes are targeted specifically to the X chromosome(s) of only one sex to regulate transcript levels. In C. elegans, this sex-specific targeting of the dosage compensation complex (DCC) is controlled by the same developmental signal that establishes sex, the ratio of X chromosomes to sets of autosomes (X:A signal). Molecular components of this chromosome counting process have been defined. Following a common step of regulation, sex determination and dosage compensation are controlled by distinct genetic pathways. C. elegans dosage compensation is implemented by a protein complex that binds both X chromosomes of hermaphrodites to reduce transcript levels by one-half. The dosage compensation complex resembles the conserved 13S condensin complex required for both mitotic and meiotic chromosome resolution and condensation, implying the recruitment of ancient proteins to the new task of regulating gene expression. Within each C. elegans somatic cell, one of the DCC components also participates in the separate mitotic/meiotic condensin complex. Other DCC components play pivotal roles in regulating the number and distribution of crossovers during meiosis. The strategy by which C. elegans X chromosomes attract the condensin-like DCC is known. Small, well-dispersed X-recognition elements act as entry sites to recruit the dosage compensation complex and to nucleate spreading of the complex to X regions that lack recruitment sites. In this manner, a repressed chromatin state is spread in cis over short or long distances, thus establishing the global, epigenetic regulation of X chromosomes that is maintained throughout the lifetime of hermaphrodites.

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.

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.

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

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

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

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

Over-expression of GFP-FEZ1 causes generation of multi-lobulated nuclei mediated by microtubules in HEK293 cells

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

Lanza, Daniel C.F.; Trindade, Daniel M.; Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP

2008-06-10

FEZ1 (Fasciculation and elongation protein zeta 1) is an ortholog of the Caenorhabditis elegans protein UNC-76, involved in neuronal development and axon outgrowth, in that worm. Mammalian FEZ1 has already been reported to cooperate with PKC-zeta in the differentiation and polarization of PC12 neuronal cells. Furthermore, FEZ1 is associated with kinesin 1 and JIP1 to form a cargo-complex responsible for microtubule based transport of mitochondria along axons. FEZ1 can also be classified as a hub protein, since it was reported to interact with over 40 different proteins in yeast two-hybrid screens, including at least nine nuclear proteins. Here, we transientlymore » over-expressed GFP-FEZ1full in human HEK293 and HeLa cells in order to study the sub-cellular localization of GFP-FEZ1. We observed that over 40% of transiently transfected cells at 3 days post-transfection develop multi-lobulated nuclei, which are also called flower-like nuclei. We further demonstrated that GFP-FEZ1 localizes either to the cytoplasm or the nuclear fraction, and that the appearance of the flower-like nuclei depends on intact microtubule function. Finally, we show that FEZ1 co-localizes with both, {alpha}- and especially with {gamma}-tubulin, which localizes as a centrosome like structure at the center of the multiple lobules. In summary, our data suggest that FEZ1 has an important centrosomal function and supply new mechanistic insights to the formation of flower-like nuclei, which are a phenotypical hallmark of human leukemia cells.« less

Co-movement measure of information transmission on international equity markets

NASA Astrophysics Data System (ADS)

Al Rahahleh, Naseem; Bhatti, M. Ishaq

2017-03-01

Recently, Bhatti and Nguyen (2012) used EVT and various stochastic copulas to study the cross-country co-movements diversification and asset pricing allocation. Weiss (2013) observed that Dynamic Conditional Correlation (DCC) models outperform various copula models. This paper attempts to contribute to the literature on multivariate models for capturing forward and backward return co-movement, spillover effects and volatility linkages. It reflects cross-country forward and backward co-movements more clearly among various coupled international stock markets relating to information transmission and price discovery for making investment decisions. Given the reality of fat-tail or skewed distribution of financial data, this paper proposes the use of VECM-DCC and VAR-DCC models which capture dynamic dependences between the Australian and other selected international financial stock markets. We observe that the return co-movement effects between Australian and Asian countries are bidirectional ((AUS ↔ Hong Kong), (AUS ↔ Japan)) with the exception of Taiwan (AUS → Taiwan). We also observe that the volatility spillover between the Australian and both the UK and the US markets are bidirectional with a larger volatility spillover from both toward the AUS market. Further, the UK market has a higher volatility spillover on the Australian market compared to the US market and the US market has a higher volatility spillover on the UK than that of the Australian market.

Deep convective cloud characterizations from both broadband imager and hyperspectral infrared sounder measurements

NASA Astrophysics Data System (ADS)

Ai, Yufei; Li, Jun; Shi, Wenjing; Schmit, Timothy J.; Cao, Changyong; Li, Wanbiao

2017-02-01

Deep convective storms have contributed to airplane accidents, making them a threat to aviation safety. The most common method to identify deep convective clouds (DCCs) is using the brightness temperature difference (BTD) between the atmospheric infrared (IR) window band and the water vapor (WV) absorption band. The effectiveness of the BTD method for DCC detection is highly related to the spectral resolution and signal-to-noise ratio (SNR) of the WV band. In order to understand the sensitivity of BTD to spectral resolution and SNR for DCC detection, a BTD to noise ratio method using the difference between the WV and IR window radiances is developed to assess the uncertainty of DCC identification for different instruments. We examined the case of AirAsia Flight QZ8501. The brightness temperatures (Tbs) over DCCs from this case are simulated for BTD sensitivity studies by a fast forward radiative transfer model with an opaque cloud assumption for both broadband imager (e.g., Multifunction Transport Satellite imager, MTSAT-2 imager) and hyperspectral IR sounder (e.g., Atmospheric Infrared Sounder) instruments; we also examined the relationship between the simulated Tb and the cloud top height. Results show that despite the coarser spatial resolution, BTDs measured by a hyperspectral IR sounder are much more sensitive to high cloud tops than broadband BTDs. As demonstrated in this study, a hyperspectral IR sounder can identify DCCs with better accuracy.

The impact of physicians' communication styles on evaluation of physicians and information processing: A randomized study with simulated video consultations on contraception with an intrauterine device.

PubMed

Bientzle, Martina; Fissler, Tim; Cress, Ulrike; Kimmerle, Joachim

2017-10-01

This study aimed at examining the impact of different types of physicians' communication styles on people's subsequent evaluation of physician attributes as well as on their information processing, attitude and decision making. In a between-group experiment, 80 participants watched one of three videos in which a gynaecologist displayed a particular communication style in a consultation situation on contraception with an intrauterine device. We compared doctor-centred communication (DCC) vs patient-centred communication (PCC) vs patient-centred communication with need-orientation (PCC-N). In the PCC condition, participants perceived the physician to be more empathetic and more competent than in the DCC condition. In the DCC condition, participants showed less attitude change compared to the other conditions. In the PCC-N condition, the physician was perceived as more empathetic and more socially competent than in the other conditions. However, participants acquired less knowledge in the PCC-N condition. We conclude that appropriate application of particular communication styles depends on specific consultation goals. Our results suggest that patients' needs should be addressed if the main goal is to build a good relationship, whereas a traditional PCC style appears to be more effective in communicating factual information. © 2016 The Authors Health Expectations Published by John Wiley & Sons Ltd.

Effectiveness of the Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) dissemination project: a science to prenatal care practice partnership.

PubMed

Windsor, Richard; Clark, Jeannie; Cleary, Sean; Davis, Amanda; Thorn, Stephanie; Abroms, Lorien; Wedeles, John

2014-01-01

This study evaluated the effectiveness of the Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) Program selected by the West Virginia-Right From The Start Project for state-wide dissemination. A process evaluation documented the fidelity of SCRIPT delivery by Designated Care Coordinators (DCC), licensed nurses and social workers who provide home-based case management to Medicaid-eligible clients in all 55 counties. We implemented a quasi-experimental, non-randomized, matched Comparison (C) Group design. The SCRIPT Experimental E Group (N = 259) were all clients in 2009-2010 that wanted to quit, provided a screening carbon monoxide (CO), and received a SCRIPT home visit. The (C) Group was derived from all clients in 2006-2007 who had the same CO assessments as E Group clients and reported receiving cessation counseling. We stratified the baseline CO of E Group clients into 10 strata, and randomly selected the same number of (C) Group clients (N = 259) from each matched strata to evaluate the effectiveness of the SCRIPT Program. There were no significant baseline differences in the E and (C) Group. A Process Evaluation documented a significant increase in the fidelity of DCC delivery of SCRIPT Program procedures: from 63 % in 2006 to 74 % in 2010. Significant increases were documented in the E Group cessation rate (+9.3 %) and significant reduction rate (+4.5 %), a ≥50 % reduction from a baseline CO. Perinatal health case management staff can deliver the SCRIPT Program, and Medicaid-supported clients can change smoking behavior, even very late in pregnancy. When multiple biases were analyzed, we concluded the SCRIPT Dissemination Project was the most plausible reason for the significant changes in behavior.

Transformation products and human metabolites of triclocarban and tricllosan in sewage sludge across the United States

USGS Publications Warehouse

Pycke, Benny F.G.; Roll, Isaac B.; Brownawell, Bruce J.; Kinney, Chad A.; Furlong, Edward T.; Kolpin, Dana W.; Halden, Rolf U.

2014-01-01

Removal of triclocarban (TCC) and triclosan (TCS) from wastewater is a function of adsorption, abiotic degradation, and microbial mineralization or transformation, reactions that are not currently controlled or optimized in the pollution control infrastructure of standard wastewater treatment. Here, we report on the levels of eight transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in raw and treated sewage sludge. Two sample sets were studied: samples collected once from 14 wastewater treatment plants (WWTPs) representing nine states, and multiple samples collected from one WWTP monitored for 12 months. Time-course analysis of significant mass fluxes (α = 0.01) indicate that transformation of TCC (dechlorination) and TCS (methylation) occurred during sewage conveyance and treatment. Strong linear correlations were found between TCC and the human metabolite 2′-hydroxy-TCC (r = 0.84), and between the TCC-dechlorination products dichlorocarbanilide (DCC) and monochlorocarbanilide (r = 0.99). Mass ratios of DCC-to-TCC and of methyl-triclosan (MeTCS)-to-TCS, serving as indicators of transformation activity, revealed that transformation was widespread under different treatment regimes across the WWTPs sampled, though the degree of transformation varied significantly among study sites (α = 0.01). The analysis of sludge sampled before and after different unit operation steps (i.e., anaerobic digestion, sludge heat treatment, and sludge drying) yielded insights into the extent and location of TCC and TCS transformation. Results showed anaerobic digestion to be important for MeTCS transformation (37–74%), whereas its contribution to partial TCC dechlorination was limited (0.4–2.1%). This longitudinal and nationwide survey is the first to report the occurrence of transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in sewage sludge.

A Consistent EPIC Visible Channel Calibration Using VIIRS and MODIS as a Reference.

NASA Astrophysics Data System (ADS)

Haney, C.; Doelling, D. R.; Minnis, P.; Bhatt, R.; Scarino, B. R.; Gopalan, A.

2017-12-01

The Earth Polychromatic Imaging Camera (EPIC) aboard the Deep Space Climate Observatory (DSCOVR) satellite constantly images the sunlit disk of Earth from the Lagrange-1 (L1) point in 10 spectral channels spanning the UV, VIS, and NIR spectrums. Recently, the DSCOVR EPIC team has publicly released version 2 dataset, which has implemented improved navigation, stray-light correction, and flat-fielding of the CCD array. The EPIC 2-year data record must be well-calibrated for consistent cloud, aerosol, trace gas, land use and other retrievals. Because EPIC lacks onboard calibrators, the observations made by EPIC channels must be calibrated vicariously using the coincident measurements from radiometrically stable instruments that have onboard calibration systems. MODIS and VIIRS are best-suited instruments for this task as they contain similar spectral bands that are well-calibrated onboard using solar diffusers and lunar tracking. We have previously calibrated the EPIC version 1 dataset by using EPIC and VIIRS angularly matched radiance pairs over both all-sky ocean and deep convective clouds (DCC). We noted that the EPIC image required navigations adjustments, and that the EPIC stray-light correction provided an offset term closer to zero based on the linear regression of the EPIC and VIIRS ray-matched radiance pairs. We will evaluate the EPIC version 2 navigation and stray-light improvements using the same techniques. In addition, we will monitor the EPIC channel calibration over the two years for any temporal degradation or anomalous behavior. These two calibration methods will be further validated using desert and DCC invariant Earth targets. The radiometric characterization of the selected invariant targets is performed using multiple years of MODIS and VIIRS measurements. Results of these studies will be shown at the conference.

Transformation products and human metabolites of triclocarban and triclosan in sewage sludge across the United States.

PubMed

Pycke, Benny F G; Roll, Isaac B; Brownawell, Bruce J; Kinney, Chad A; Furlong, Edward T; Kolpin, Dana W; Halden, Rolf U

2014-07-15

Removal of triclocarban (TCC) and triclosan (TCS) from wastewater is a function of adsorption, abiotic degradation, and microbial mineralization or transformation, reactions that are not currently controlled or optimized in the pollution control infrastructure of standard wastewater treatment. Here, we report on the levels of eight transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in raw and treated sewage sludge. Two sample sets were studied: samples collected once from 14 wastewater treatment plants (WWTPs) representing nine states, and multiple samples collected from one WWTP monitored for 12 months. Time-course analysis of significant mass fluxes (α=0.01) indicate that transformation of TCC (dechlorination) and TCS (methylation) occurred during sewage conveyance and treatment. Strong linear correlations were found between TCC and the human metabolite 2'-hydroxy-TCC (r=0.84), and between the TCC-dechlorination products dichlorocarbanilide (DCC) and monochlorocarbanilide (r=0.99). Mass ratios of DCC-to-TCC and of methyl-triclosan (MeTCS)-to-TCS, serving as indicators of transformation activity, revealed that transformation was widespread under different treatment regimes across the WWTPs sampled, though the degree of transformation varied significantly among study sites (α=0.01). The analysis of sludge sampled before and after different unit operation steps (i.e., anaerobic digestion, sludge heat treatment, and sludge drying) yielded insights into the extent and location of TCC and TCS transformation. Results showed anaerobic digestion to be important for MeTCS transformation (37-74%), whereas its contribution to partial TCC dechlorination was limited (0.4-2.1%). This longitudinal and nationwide survey is the first to report the occurrence of transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in sewage sludge.

Transformation Products and Human Metabolites of Triclocarban and Triclosan in Sewage Sludge Across the United States

PubMed Central

2015-01-01

Removal of triclocarban (TCC) and triclosan (TCS) from wastewater is a function of adsorption, abiotic degradation, and microbial mineralization or transformation, reactions that are not currently controlled or optimized in the pollution control infrastructure of standard wastewater treatment. Here, we report on the levels of eight transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in raw and treated sewage sludge. Two sample sets were studied: samples collected once from 14 wastewater treatment plants (WWTPs) representing nine states, and multiple samples collected from one WWTP monitored for 12 months. Time-course analysis of significant mass fluxes (α = 0.01) indicate that transformation of TCC (dechlorination) and TCS (methylation) occurred during sewage conveyance and treatment. Strong linear correlations were found between TCC and the human metabolite 2′-hydroxy-TCC (r = 0.84), and between the TCC-dechlorination products dichlorocarbanilide (DCC) and monochlorocarbanilide (r = 0.99). Mass ratios of DCC-to-TCC and of methyl-triclosan (MeTCS)-to-TCS, serving as indicators of transformation activity, revealed that transformation was widespread under different treatment regimes across the WWTPs sampled, though the degree of transformation varied significantly among study sites (α = 0.01). The analysis of sludge sampled before and after different unit operation steps (i.e., anaerobic digestion, sludge heat treatment, and sludge drying) yielded insights into the extent and location of TCC and TCS transformation. Results showed anaerobic digestion to be important for MeTCS transformation (37–74%), whereas its contribution to partial TCC dechlorination was limited (0.4–2.1%). This longitudinal and nationwide survey is the first to report the occurrence of transformation products, human metabolites, and manufacturing byproducts of TCC and TCS in sewage sludge. PMID:24932693

A Consistent EPIC Visible Channel Calibration using VIIRS and MODIS as a Reference

NASA Technical Reports Server (NTRS)

Haney, C. O.; Doelling, D. R.; Minnis, P.; Bhatt, R.; Scarino, B. R.; Gopalan, A.

2017-01-01

The Earth Polychromatic Imaging Camera (EPIC) aboard the Deep Space Climate Observatory (DSCOVR) satellite constantly images the sunlit disk of Earth from the Lagrange-1 (L1) point in 10 spectral channels spanning the UV, VIS, and NIR spectrums. Recently, the DSCOVR EPIC team has publicly released version 2 dataset, which has implemented improved navigation, stray-light correction, and flat-fielding of the CCD array. The EPIC 2-year data record must be well-calibrated for consistent cloud, aerosol, trace gas, land use and other retrievals. Because EPIC lacks onboard calibrators, the observations made by EPIC channels must be calibrated vicariously using the coincident measurements from radiometrically stable instruments that have onboard calibration systems. MODIS and VIIRS are best-suited instruments for this task as they contain similar spectral bands that are well-calibrated onboard using solar diffusers and lunar tracking. We have previously calibrated the EPIC version 1 dataset by using EPIC and VIIRS angularly matched radiance pairs over both all-sky ocean and deep convective clouds (DCC). We noted that the EPIC image required navigations adjustments, and that the EPIC stray-light correction provided an offset term closer to zero based on the linear regression of the EPIC and VIIRS ray-matched radiance pairs. We will evaluate the EPIC version 2 navigation and stray-light improvements using the same techniques. In addition, we will monitor the EPIC channel calibration over the two years for any temporal degradation or anomalous behavior. These two calibration methods will be further validated using desert and DCC invariant Earth targets. The radiometric characterization of the selected invariant targets is performed using multiple years of MODIS and VIIRS measurements. Results of these studies will be shown at the conference.

Vaccination of day-care center attendees reduces carriage of Streptococcus pneumoniae among their younger siblings.

PubMed

Givon-Lavi, Noga; Fraser, Drora; Dagan, Ron

2003-06-01

We conducted a study to determine whether administration of a pneumococcal conjugate vaccine to toddlers attending day-care centers (DCCs) could prevent acquisition of Streptococcus pneumoniae of the vaccine serotypes (VT) by their younger siblings. In a double blind study, 262 DCC attendees ages 12 to 35 months were randomized to receive a 9-valent pneumococcal conjugate vaccine (PnCRM9; n = 132), or a control vaccine (meningococcus C vaccine; n = 130). It was planned to follow the groups for 2 years with monthly nasopharyngeal pneumococcal cultures during the first follow-up year and every 2 months during the second year. Forty-six younger siblings of the above described children, age <18 months (23 siblings of the PnCRM9 recipients and 23 of the controls), were also enrolled, and nasopharyngeal cultures were obtained monthly until the children reached the age of 18 months or started to attend DCC, if before the age of 18 months. Pneumococcal isolates were serotyped and tested for antibiotic susceptibility. Of the 3748 cultures obtained from the DCC attendees, 2450 (65%) were positive for S. pneumoniae. Of 306 cultures obtained from the younger siblings, 151 (49%) were positive. Among the PnCRM9 recipients, cultures were significantly less frequently positive for the VT S. pneumoniae than among the controls (13% vs. 21%, respectively; P < 0.001). The same pattern was seen in the younger siblings of PnCRM9 recipients vs. the siblings of controls (21% vs. 34%, respectively; P = 0.017). The reverse trend was seen for non-VT strains in both the DCC attendees (44% vs. 34%, respectively; P < 0.001) and their younger siblings (19% vs. 13%, respectively; P = 0.15). There was a significant decrease in the carriage rate of antibiotic-resistant S. pneumoniae in both the PnCRM9 recipients and their younger siblings. The relative risks (and 95% confidence intervals) to carry S. pneumoniae penicillin-nonsusceptible, resistant to > or =1, > or =2 and > or =3 antibiotic categories among younger siblings of PnCRM9 recipients vs. siblings of controls were 0.47 (0.31 to 0.70), 0.49 (0.33 to 0.71), 0.46 (0.30 to 0.73) and 0.49 (0.21 to 1.17), respectively. When acquired, VT and antibiotic-resistant S. pneumoniae were carried for a significantly shorter period of time among siblings of PnCRM9 recipients than in siblings of controls. The marked effect of PnCRM9 administration to DCC attendees on carriage of VT and antibiotic-resistant S. pneumoniae among their younger household close contacts demonstrates a herd effect of the vaccine.

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

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.

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.

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

PHISICS/RELAP5-3D RESULTS FOR EXERCISES II-1 AND II-2 OF THE OECD/NEA MHTGR-350 BENCHMARK

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

Strydom, Gerhard

2016-03-01

The Idaho National Laboratory (INL) Advanced Reactor Technologies (ART) High-Temperature Gas-Cooled Reactor (HTGR) Methods group currently leads the Modular High-Temperature Gas-Cooled Reactor (MHTGR) 350 benchmark. The benchmark consists of a set of lattice-depletion, steady-state, and transient problems that can be used by HTGR simulation groups to assess the performance of their code suites. The paper summarizes the results obtained for the first two transient exercises defined for Phase II of the benchmark. The Parallel and Highly Innovative Simulation for INL Code System (PHISICS), coupled with the INL system code RELAP5-3D, was used to generate the results for the Depressurized Conductionmore » Cooldown (DCC) (exercise II-1a) and Pressurized Conduction Cooldown (PCC) (exercise II-2) transients. These exercises require the time-dependent simulation of coupled neutronics and thermal-hydraulics phenomena, and utilize the steady-state solution previously obtained for exercise I-3 of Phase I. This paper also includes a comparison of the benchmark results obtained with a traditional system code “ring” model against a more detailed “block” model that include kinetics feedback on an individual block level and thermal feedbacks on a triangular sub-mesh. The higher spatial fidelity that can be obtained by the block model is illustrated with comparisons of the maximum fuel temperatures, especially in the case of natural convection conditions that dominate the DCC and PCC events. Differences up to 125 K (or 10%) were observed between the ring and block model predictions of the DCC transient, mostly due to the block model’s capability of tracking individual block decay powers and more detailed helium flow distributions. In general, the block model only required DCC and PCC calculation times twice as long as the ring models, and it therefore seems that the additional development and calculation time required for the block model could be worth the gain that can be obtained in the spatial resolution« less

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.

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

Dynamic combinatorial libraries: from exploring molecular recognition to systems chemistry.

PubMed

Li, Jianwei; Nowak, Piotr; Otto, Sijbren

2013-06-26

Dynamic combinatorial chemistry (DCC) is a subset of combinatorial chemistry where the library members interconvert continuously by exchanging building blocks with each other. Dynamic combinatorial libraries (DCLs) are powerful tools for discovering the unexpected and have given rise to many fascinating molecules, ranging from interlocked structures to self-replicators. Furthermore, dynamic combinatorial molecular networks can produce emergent properties at systems level, which provide exciting new opportunities in systems chemistry. In this perspective we will highlight some new methodologies in this field and analyze selected examples of DCLs that are under thermodynamic control, leading to synthetic receptors, catalytic systems, and complex self-assembled supramolecular architectures. Also reviewed are extensions of the principles of DCC to systems that are not at equilibrium and may therefore harbor richer functional behavior. Examples include self-replication and molecular machines.

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.

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.

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.

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.

A financial network perspective of financial institutions' systemic risk contributions

NASA Astrophysics Data System (ADS)

Huang, Wei-Qiang; Zhuang, Xin-Tian; Yao, Shuang; Uryasev, Stan

2016-08-01

This study considers the effects of the financial institutions' local topology structure in the financial network on their systemic risk contribution using data from the Chinese stock market. We first measure the systemic risk contribution with the Conditional Value-at-Risk (CoVaR) which is estimated by applying dynamic conditional correlation multivariate GARCH model (DCC-MVGARCH). Financial networks are constructed from dynamic conditional correlations (DCC) with graph filtering method of minimum spanning trees (MSTs). Then we investigate dynamics of systemic risk contributions of financial institution. Also we study dynamics of financial institution's local topology structure in the financial network. Finally, we analyze the quantitative relationships between the local topology structure and systemic risk contribution with panel data regression analysis. We find that financial institutions with greater node strength, larger node betweenness centrality, larger node closeness centrality and larger node clustering coefficient tend to be associated with larger systemic risk contributions.

Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target.

PubMed

Frei, Priska; Pang, Lijuan; Silbermann, Marleen; Eriş, Deniz; Mühlethaler, Tobias; Schwardt, Oliver; Ernst, Beat

2017-08-25

Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neutrino-induced meson productions off nucleon at forward limit in nucleon resonance region

NASA Astrophysics Data System (ADS)

Nakamura, S. X.; Kamano, H.; Lee, T.-S. H.; Sato, T.

2015-05-01

We study forward neutrino-induced meson production off the nucleon in the resonance region. Our calculation is based on a dynamical coupled-channels (DCC) model that reasonably describes π(γ)N → πN, ηN, KΛ, KΣ data in the resonance region. We apply the PCAC hypothesis to the DCC model to relate the πN reaction amplitude to the forward neutrino reaction amplitude. In this way, we give a prediction for νN → πN, ππN, ηN, KΛ, KΣ reaction cross sections. The predicted νN → ππN, ηN, KΛ, KΣ cross sections are, for the first time, based on a model extensively tested by data. We compare our results with those from the Rein-Sehgal model that has been very often used in the existing Monte Carlo simulators for neutrino experiments. We find a significant difference between them.

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.

Lotus birth, a holistic approach on physiological cord clamping.

PubMed

Zinsser, Laura A

2018-04-01

The positive effects of delayed cord clamping (DCC) has been extensively researched. DCC means: waiting at least one minute after birth before clamping and cutting the cord or till the pulsation has stopped. With physiological clamping and cutting (PCC) the clamping and cutting can happen at the earliest after the pulsation has stopped. With a Lotus birth, no clamping and cutting of the cord is done. A woman called Clair Lotus Day imitated the holistic approach of PCC from an anthropoid ape in 1974. The chimpanzee did not separate the placenta from the newborn. The aim of this case report is to discuss and learn a different approach in the third stage of labour. Three cases of Lotus birth by human beings were observed. All three women gave birth in an out-of-hospital setting and had ambulant postnatal care. The placenta was washed, salted and herbs were put on 2-3h post partum. The placenta was wrapped in something that absorbs the moisture. The salting was repeated with a degreasing frequency depending on moistness of the placenta. On life day six all three Lotus babies experiences a natural separation of the cord. All three Lotus birth cases were unproblematic, no special incidence occurred. One should differentiate between early cord clamping (ECC), delayed cord clamping (DCC) and physiological cord clamping (PCC). Lotus birth might lead to an optimisation of the bonding and attachment. Research is needed in the areas of both PCC and Lotus birth. Copyright © 2017 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.

Environment and Health in Children Day Care Centres (ENVIRH) - Study rationale and protocol.

PubMed

Araújo-Martins, J; Carreiro Martins, P; Viegas, J; Aelenei, D; Cano, M M; Teixeira, J P; Paixão, P; Papoila, A L; Leiria-Pinto, P; Pedro, C; Rosado-Pinto, J; Annesi-Maesano, I; Neuparth, N

2014-01-01

Indoor air quality (IAQ) is considered an important determinant of human health. The association between exposure to volatile organic compounds, particulate matter, house dust mite, molds and bacteria in day care centers (DCC) is not completely clear. The aim of this project was to study these effects. This study comprised two phases. Phase I included an evaluation of 45 DCCs (25 from Lisbon and 20 from Oporto, targeting 5161 children). In this phase, building characteristics, indoor CO2 and air temperature/relative humidity, were assessed. A children's respiratory health questionnaire derived from the ISAAC (International Study on Asthma and Allergies in Children) was also distributed. Phase II encompassed two evaluations and included 20 DCCs selected from phase I after a cluster analysis (11 from Lisbon and 9 from Oporto, targeting 2287 children). In this phase, data on ventilation, IAQ, thermal comfort parameters, respiratory and allergic health, airway inflammation biomarkers, respiratory virus infection patterns and parental and child stress were collected. In Phase I, building characteristics, occupant behavior and ventilation surrogates were collected from all DCCs. The response rate of the questionnaire was 61.7% (3186 children). Phase II included 1221 children. Association results between DCC characteristics, IAQ and health outcomes will be provided in order to support recommendations on IAQ and children's health. A building ventilation model will also be developed. This paper outlines methods that might be implemented by other investigators conducting studies on the association between respiratory health and indoor air quality at DCC. Copyright © 2013 Sociedade Portuguesa de Pneumologia. Published by Elsevier España. All rights reserved.

Quantitative Reactivity Scales for Dynamic Covalent and Systems Chemistry.

PubMed

Zhou, Yuntao; Li, Lijie; Ye, Hebo; Zhang, Ling; You, Lei

2016-01-13

Dynamic covalent chemistry (DCC) has become a powerful tool for the creation of molecular assemblies and complex systems in chemistry and materials science. Herein we developed for the first time quantitative reactivity scales capable of correlation and prediction of the equilibrium of dynamic covalent reactions (DCRs). The reference reactions are based upon universal DCRs between imines, one of the most utilized structural motifs in DCC, and a series of O-, N-, and S- mononucleophiles. Aromatic imines derived from pyridine-2-carboxyaldehyde exhibit capability for controlling the equilibrium through distinct substituent effects. Electron-donating groups (EDGs) stabilize the imine through quinoidal resonance, while electron-withdrawing groups (EWGs) stabilize the adduct by enhancing intramolecular hydrogen bonding, resulting in curvature in Hammett analysis. Notably, unique nonlinearity induced by both EDGs and EWGs emerged in Hammett plot when cyclic secondary amines were used. This is the first time such a behavior is observed in a thermodynamically controlled system, to the best of our knowledge. Unified quantitative reactivity scales were proposed for DCC and defined by the correlation log K = S(N) (R(N) + R(E)). Nucleophilicity parameters (R(N) and S(N)) and electrophilicity parameters (R(E)) were then developed from DCRs discovered. Furthermore, the predictive power of those parameters was verified by successful correlation of other DCRs, validating our reactivity scales as a general and useful tool for the evaluation and modeling of DCRs. The reactivity parameters proposed here should be complementary to well-established kinetics based parameters and find applications in many aspects, such as DCR discovery, bioconjugation, and catalysis.

Non-Intrusive Velocity Measurements with MTV During DCC Event in the HTTF

NASA Technical Reports Server (NTRS)

Andre, M. A.; Bardet, P. M.; Cadell, S. R.; Woods, B.; Burns, R. A.; Danehy, P. M.

2017-01-01

Velocity profiles are measured using molecular tagging velocimetry (MTV) in the high temperature test facility (HTTF) at Oregon State University during a depressurized conduction cooldown (DCC) event. The HTTF is a quarter scale electrically heated nuclear reactor simulator designed to replicate various accident scenarios. During a DCC, a double ended guillotine break results in the reactor pressure vessel (RPV) depressurizing into the reactor cavity and ultimately leading to air ingress in the reactor core (lock-exchange and gas diffusion). It is critical to understand the resulting buoyancy-driven flow to characterize the reactor self-cooling capacity through natural circulation. During tests conducted at ambient pressure and temperature, the RPV containing helium is opened (via the hot and cold legs) to a large vessel filled with nitrogen to simulate the atmosphere. The velocity profile on the hot leg pipe centerline is recorded at 10 Hz with MTV based on NO tracers. The precision of the velocimetry was measured to be 0.02 m/s in quiescent flow prior to the tests. A helium flow from the RPV is initially observed in the top quarter of the pipe. During the first 20 seconds of the event, helium flows out of the RPV with a maximum velocity below 2 m/s. The velocity profile transitions from parabolic to linear in character and decays slowly over the rest of the recording; peak velocities of 0.2 m/s are observed after 30 min. A counter-flow of nitrogen is also observed intermittently, which occurs at lower velocities (>0.1 m/s).

Comparing airborne and satellite retrievals of cloud optical thickness and particle effective radius using a spectral radiance ratio technique: two case studies for cirrus and deep convective clouds

NASA Astrophysics Data System (ADS)

Krisna, Trismono C.; Wendisch, Manfred; Ehrlich, André; Jäkel, Evelyn; Werner, Frank; Weigel, Ralf; Borrmann, Stephan; Mahnke, Christoph; Pöschl, Ulrich; Andreae, Meinrat O.; Voigt, Christiane; Machado, Luiz A. T.

2018-04-01

Solar radiation reflected by cirrus and deep convective clouds (DCCs) was measured by the Spectral Modular Airborne Radiation Measurement System (SMART) installed on the German High Altitude and Long Range Research Aircraft (HALO) during the Mid-Latitude Cirrus (ML-CIRRUS) and the Aerosol, Cloud, Precipitation, and Radiation Interaction and Dynamic of Convective Clouds System - Cloud Processes of the Main Precipitation Systems in Brazil: A Contribution to Cloud Resolving Modelling and to the Global Precipitation Measurement (ACRIDICON-CHUVA) campaigns. On particular flights, HALO performed measurements closely collocated with overpasses of the Moderate Resolution Imaging Spectroradiometer (MODIS) aboard the Aqua satellite. A cirrus cloud located above liquid water clouds and a DCC topped by an anvil cirrus are analyzed in this paper. Based on the nadir spectral upward radiance measured above the two clouds, the optical thickness τ and particle effective radius reff of the cirrus and DCC are retrieved using a radiance ratio technique, which considers the cloud thermodynamic phase, the vertical profile of cloud microphysical properties, the presence of multilayer clouds, and the heterogeneity of the surface albedo. For the cirrus case, the comparison of τ and reff retrieved on the basis of SMART and MODIS measurements yields a normalized mean absolute deviation of up to 1.2 % for τ and 2.1 % for reff. For the DCC case, deviations of up to 3.6 % for τ and 6.2 % for reff are obtained. The larger deviations in the DCC case are mainly attributed to the fast cloud evolution and three-dimensional (3-D) radiative effects. Measurements of spectral upward radiance at near-infrared wavelengths are employed to investigate the vertical profile of reff in the cirrus. The retrieved values of reff are compared with corresponding in situ measurements using a vertical weighting method. Compared to the MODIS observations, measurements of SMART provide more information on the vertical distribution of particle sizes, which allow reconstructing the profile of reff close to the cloud top. The comparison between retrieved and in situ reff yields a normalized mean absolute deviation, which ranges between 1.5 and 10.3 %, and a robust correlation coefficient of 0.82.

Design and implementation of co-operative control strategy for hybrid AC/DC microgrids

NASA Astrophysics Data System (ADS)

Mahmud, Rasel

This thesis is mainly divided in two major sections: 1) Modeling and control of AC microgrid, DC microgrid, Hybrid AC/DC microgrid using distributed co-operative control, and 2) Development of a four bus laboratory prototype of an AC microgrid system. At first, a distributed cooperative control (DCC) for a DC microgrid considering the state-of-charge (SoC) of the batteries in a typical plug-in-electric-vehicle (PEV) is developed. In DC microgrids, this methodology is developed to assist the load sharing amongst the distributed generation units (DGs), according to their ratings with improved voltage regulation. Subsequently, a DCC based control algorithm for AC microgrid is also investigated to improve the performance of AC microgrid in terms of power sharing among the DGs, voltage regulation and frequency deviation. The results validate the advantages of the proposed methodology as compared to traditional droop control of AC microgrid. The DCC-based control methodology for AC microgrid and DC microgrid are further expanded to develop a DCC-based power management algorithm for hybrid AC/DC microgrid. The developed algorithm for hybrid microgrid controls the power flow through the interfacing converter (IC) between the AC and DC microgrids. This will facilitate the power sharing between the DGs according to their power ratings. Moreover, it enables the fixed scheduled power delivery at different operating conditions, while maintaining good voltage regulation and improved frequency profile. The second section provides a detailed explanation and step-by-step design and development of an AC/DC microgrid testbed. Controllers for the three-phase inverters are designed and tested on different generation units along with their corresponding inductor-capacitor-inductor (LCL) filters to eliminate the switching frequency harmonics. Electric power distribution line models are developed to form the microgrid network topology. Voltage and current sensors are placed in the proper positions to achieve a full visibility over the microgrid. A running average filter (RAF) based enhanced phase-locked-loop (EPLL) is designed and implemented to extract frequency and phase angle information. A PLL-based synchronizing scheme is also developed to synchronize the DGs to the microgrid. The developed laboratory prototype runs on dSpace platform for real time data acquisition, communication and controller implementation.

Comparison of Promoter Hypermethylation Pattern in Salivary Rinses Collected with and without an Exfoliating Brush from Patients with HNSCC

PubMed Central

Sun, Wenyue; Zaboli, David; Liu, Yan; Arnaoutakis, Demetri; Khan, Tanbir; Wang, Hao; Koch, Wayne; Khan, Zubair; Califano, Joseph A.

2012-01-01

Background Salivary rinses have been recently proposed as a valuable resource for the development of epigenetic biomarkers for detection and monitoring of head and neck squamous cell carcinoma (HNSCC). Both salivary rinses collected with and without an exfoliating brush from patients with HNSCC are used in detection of promoter hypermethylation, yet their correlation of promoter hypermethylation has not been evaluated. This study was to evaluate the concordance of promoter hypermethylation between salivary rinses collected with and without an exfoliating brush from patients with HNSCC. Methodolgy 57 paired salivary rinses collected with or without an exfoliating brush from identical HNSCC patients were evaluated for promoter hypermethylation status using Quantitative Methylation-Specific PCR. Target tumor suppressor gene promoter regions were selected based on our previous studies describing a panel for HNSCC screening and surveillance, including P16, CCNA1, DCC, TIMP3, MGMT, DAPK and MINT31. Principal Findings In salivary rinses collected with and without brush, frequent methylation was detected in P16 (8.8% vs. 5.2%), CCNA1 (26.3% vs. 22.8%), DCC (33.3% vs. 29.8%), TIMP3 (31.6% vs. 36.8%), MGMT (29.8% vs. 38.6%), DAPK (14.0% vs. 19.2%), and MINT31 (10.5% vs. 8.8%). Spearman's rank correlation coefficient showed a positive correlation between salivary rinses collected with and without brush for P16 (ρ = 0.79), CCNA1 (ρ = 0.61), DCC (ρ = 0.58), TIMP3 (ρ = 0.10), MGMT (ρ = 0.70), DAPK (ρ = 0.51) and MINT31 (ρ = 0.72) (P<0.01). The percent agreement of promoter methylation between salivary rinses with brush and without brush were 96.5% for P16, 82.5% for CCNA1, 78.9% for DCC, 59.7% for TIMP3, 84.2% for MGMT, 84.2% for DAPK, and 94.7% for MINT31. Conclusions Our study demonstrated strong correlations of gene promoter hypermethylation between salivary rinses collected with and without an exfoliating brush. Salivary rinse collection without using an exfoliating brush may offer a cost effective, rapid, non-invasive, and reliable means for development of epigenetic salivary rinse biomarkers. PMID:22438973

Attenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells.

PubMed

Liu, Norika Mengchia; Siu, Kin Lung; Youn, Ji Youn; Cai, Hua

2017-03-01

Restenosis after angioplasty is a serious clinical problem that can result in re-occlusion of the coronary artery. Although current drug-eluting stents have proved to be more effective in reducing restenosis, they have drawbacks of inhibiting reendothelialization to promote thrombosis. New treatment options are in urgent need. We have shown that netrin-1, an axon-guiding protein, promotes angiogenesis and cardioprotection via production of nitric oxide (NO). The present study examined whether and how netrin-1 attenuates neointimal formation in a femoral wire injury model. Infusion of netrin-1 into C57BL/6 mice markedly attenuated neointimal formation following wire injury of femoral arteries, measured by intimal to media ratio (from 1.94 ± 0.55 to 0.45 ± 0.86 at 4 weeks). Proliferation of VSMC in situ was largely reduced. This protective effect was absent in DCC +/- animals. NO production was increased by netrin-1 in both intact and injured femoral arteries, indicating netrin-1 stimulation of endogenous NO production from intact endothelium and remaining endothelial cells post-injury. VSMC migration was abrogated by netrin-1 via a NO/cGMP/p38 MAPK pathway, while timely EPC homing was induced. Injection of netrin-1 preconditioned wild-type EPCs, but not EPCs of DCC +/- animals, substantially attenuated neointimal formation. EPC proliferation, NO production, and resistance to oxidative stress induced apoptosis were augmented by netrin-1 treatment. In conclusion, our data for the first time demonstrate that netrin-1 is highly effective in reducing neointimal formation following vascular endothelial injury, which is dependent on DCC, and attributed to inhibition of VSMC proliferation and migration, as well as improved EPC function. These data may support usage of netrin-1 and netrin-1 preconditioned EPCs as novel therapies for post angioplasty restenosis. Netrin-1 attenuates neointimal formation following post endothelial injury via DCC and NO. Netrin-1 inhibits VSMC proliferation in situ following endothelial injury. Netrin-1 inhibits VSMC migration via a NO/cGMP/p38 MAPK pathway. Netrin-1 augments proliferation of endothelial progenitor cells (EPCs) and EPC eNOS/NO activation. Netrin-1 enhances resistance of EPCs to oxidative stress, improving re-endothelialization following injury.

Multifunctional Polymers and Composites for Self-Healing Applications

DTIC Science & Technology

2006-09-30

DCC) was obtained from Avocado . Reagent grade ether was purchased from Malinckrodt and anhydrous methylene chloride was purchased from Acros and...We have worked with several companies through sponsored research agreements to transition self-healing technology into the commercial market . These

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.

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.

Detection of triclocarban and two co-contaminating chlorocarbanilides in US aquatic environments using isotope dilution liquid chromatography tandem mass spectrometry.

PubMed

Sapkota, Amir; Heidler, Jochen; Halden, Rolf U

2007-01-01

The antimicrobial compound triclocarban (TCC; 3,4,4'-trichlorocarbanilide; CAS# 101-20-2) is a high-production-volume chemical, recently suggested to cause widespread contamination of US water resources. To test this hypothesis, we developed an isotope dilution liquid chromatography electrospray ionization tandem mass spectrometry method for ultratrace analysis of TCC (0.9 ng/L detection limit) and analyzed low-volume water samples (200 mL) along with primary sludge samples from across the United States. All river water samples (100%) collected downstream of wastewater treatment plants had detectable levels of TCC, as compared to 56% of those taken upstream. Concentrations of TCC (mean+/-standard deviation) downstream of sewage treatment plants (84+/-110 ng/L) were significantly higher (P<0.05; Wilcoxon rank sum test) than those of samples taken upstream (12+/-15 ng/L). Compared to surface water, mean TCC concentrations found in dried, primary sludge obtained from municipal sewage treatment plants in five states were six orders of magnitude greater (19,300+/-7100 microg/kg). Several river samples contained a co-contaminant, identified based on its chromatographic retention time, molecular base ion, and MS/MS fragmentation behavior as 4,4'-dichlorocarbanilide (DCC; CAS# 1219-99-4). In addition to TCC and DCC, municipal sludge contained a second co-contaminant, 3,3',4,4'-tetrachlorocarbanilide (TetraCC; CAS# 4300-43-0). Both newly detected compounds were present as impurities (0.2%(w/w) each) in technical grade TCC (99%). Application of the new method for chlorocarbanilide analysis yielded TCC occurrence data for 13 US states, confirmed the role of sewage treatment plants as environmental inputs of TCC, and identified DCC and TetraCC as previously unrecognized pollutants released into the environment alongside TCC.

Comparative varicella vaccine effectiveness during outbreaks in day-care centres.

PubMed

Spackova, M; Wiese-Posselt, M; Dehnert, M; Matysiak-Klose, D; Heininger, U; Siedler, A

2010-01-08

Routine varicella vaccination for children >11 months was introduced in Germany in 2004 with three different vaccine brands available. In 2008 and 2009, we investigated seven varicella outbreaks in day-care centres (DCC). Varicella disease and vaccination status of 1084 children was reviewed to evaluate vaccination coverage (VC), brand-specific varicella vaccine effectiveness (VE), and risk factors of breakthrough varicella (BV, >42 days after vaccination). A case was defined as a child with acute onset of varicella attending one of the respective DCC at the time of outbreak. Children with a previous history of varicella, age<11 months, vaccinated at age<11 months or <42 days before disease onset or during the outbreak were excluded from VE and BV risk factors analyses (adjusted for gender, age and DCC). Of 631 children with available vaccination information, 392 (62%) were vaccinated at least once. Overall VE among 352 children eligible was 71% (95% confidence interval (CI) 57-81, p<0.001) and differed significantly by disease severity and number of doses administered. Risk for BV was higher for 1 dose of Varilrix (RR=2.8, 95%CI 1.0-7.8, p=0.05) or Priorix-Tetra (RR=2.4, 95%CI 0.7-8.3, p=0.18) but lower for 2 doses of Priorix-Tetra (RR=0.5, 95%CI 0.1-2.7, p=0.41) than for 1 dose of Varivax. Enhanced efforts to increase VC in Germany and 2 doses varicella vaccine might be successful to reduce the risk for BV. The evidence that VE and risk of BV are associated with vaccine brand needs further investigation.

Assessment of MODIS On-Orbit Calibration Using a Deep Convective Cloud Technique

NASA Technical Reports Server (NTRS)

Mu, Qiaozhen; Wu, Aisheng; Chang, Tiejun; Angal, Amit; Link, Daniel; Xiong, Xiaoxiong; Doelling, David R.; Bhatt, Rajendra

2016-01-01

The MODerate Resolution Imaging Spectroradiometer (MODIS) sensors onboard Terra and Aqua satellites are calibrated on-orbit with a solar diffuser (SD) for the reflective solar bands (RSB). The MODIS sensors are operating beyond their designed lifetime and hence present a major challenge to maintain the calibration accuracy. The degradation of the onboard SD is tracked by a solar diffuser stability monitor (SDSM) over a wavelength range from 0.41 to 0.94 micrometers. Therefore, any degradation of the SD beyond 0.94 micrometers cannot be captured by the SDSM. The uncharacterized degradation at wavelengths beyond this limit could adversely affect the Level 1B (L1B) product. To reduce the calibration uncertainties caused by the SD degradation, invariant Earth-scene targets are used to monitor and calibrate the MODIS L1B product. The use of deep convective clouds (DCCs) is one such method and particularly significant for the short-wave infrared (SWIR) bands in assessing their long-term calibration stability. In this study, we use the DCC technique to assess the performance of the Terra and Aqua MODIS Collection-6 L1B for RSB 1 3- 7, and 26, with spectral coverage from 0.47 to 2.13 micrometers. Results show relatively stable trends in Terra and Aqua MODIS reflectance for most bands. Careful attention needs to be paid to Aqua band 1, Terra bands 3 and 26 as their trends are larger than 1% during the study time period. We check the feasibility of using the DCC technique to assess the stability in MODIS bands 17-19. The assessment test on response versus scan angle (RVS) calibration shows substantial trend difference for Aqua band 1between different angles of incidence (AOIs). The DCC technique can be used to improve the RVS calibration in the future.

Tumor suppressor function of Betaig-H3 gene in radiation carcinogenesis

NASA Astrophysics Data System (ADS)

Zhao, Y. L.; Piao, C. Q.; Hei, T. K.

Interaction between cell and extracellular matrix (ECM) plays a crucial role in tumor invasiveness and metastasis. Using an immortalized human bronchial epithelial (BEP2D) cell model, we showed previously that expression of a list of genes including Betaig-h3 (induced by transforming growth factor-β) DCC (deleted in colorectal cancer), p21 cip1, c-fos , Heat shock protein (HSP27) and cytokeratin 14 were differentially expressed in several independently generated, radiation-induced tumor cell lines (TL1-TL5) relative to parental BEP2D cells. Our previous data further demonstrated that loss of tumor suppressor gene(s) as a likely mechanism of radiation carcinogenesis. In the present study, we chose Betaig-h3 and DCC that were downregulated in tumorigenic cells for further study. Restored expression of Betaig-h3 gene, not DCC gene, by transfecting cDNA into tumor cells resulted in a significant reduction in tumor growth. While integrin receptor α5β1 was overexpressed in tumor cells, its expression was corrected to the level found in control BEP2D cells after Betaig-h3 transfection. These data suggest that Betaig-h3 gene is involved in tumor progression by regulating integrin α5β1 receptor. Furthermore, exogenous TGF-β1 induced expression of Betaig-h3 gene and inhibited the growth of both control and tumorigenic BEP2D cells. Therefore, downregulation of Betaig-h3 gene may results from the decreased expression of upstream mediators such as TGF-β. The findings provide strong evidence that the Betaig-h3 gene has tumor suppressor function in radiation-induced tumorigenic human bronchial epithelial cells and suggest a potential target for interventional therapy.

Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene.

PubMed

Zauber, Peter; Marotta, Stephen; Sabbath-Solitare, Marlene

2016-03-12

Changes in the number of alleles of a chromosome may have an impact upon gene expression. Loss of heterozygosity (LOH) indicates that one allele of a gene has been lost, and knowing the exact copy number of the gene would indicate whether duplication of the remaining allele has occurred. We were interested to determine the copy number of the Adenomatous Polyposis Coli (APC) gene in sporadic colorectal cancers with LOH. We selected 38 carcinomas with LOH for the APC gene region of chromosome 5, as determined by amplification of the CA repeat region within the D5S346 loci. The copy number status of APC was ascertained using the SALSA® MLPA® P043-B1 APC Kit. LOH for the DCC gene, KRAS gene mutation, and microsatellite instability were also evaluated for each tumor, utilizing standard polymerase chain reaction methods. No tumor demonstrated microsatellite instability. LOH of the DCC gene was also present in 33 of 36 (91.7%) informative tumors. A KRAS gene mutation was present in 16 of the 38 (42.1%) tumors. Twenty-four (63.2%) of the tumors were copy number neutral, 10 (26.3%) tumors demonstrated major loss, while two (5.3%) showed partial loss. Two tumors (5.3%) had copy number gain. Results of APC and DCC LOH, KRAS and microsatellite instability indicate our colorectal cancer cases were typical of sporadic cancers following the 'chromosomal instability' pathway. The majority of our colorectal carcinomas with LOH for APC gene are copy number neutral. However, one-third of our cases showed copy number loss, suggesting that duplication of the remaining allele is not required for the development of a colorectal carcinoma.

An Apprenticeship Rotation Teaches Chief Residents Nontechnical Skills and ACGME Core Competencies.

PubMed

Kwakye, Gifty; Chen, Xiaodong Phoenix; Havens, Joaquim M; Irani, Jennifer L; Yule, Steven; Smink, Douglas S

2015-01-01

Traditionally, surgical training has used an apprenticeship model but has more recently moved to a service-based model, with groups of residents working with groups of attending surgeons. We developed an apprenticeship rotation to enhance one-on-one interaction between chief residents and selected faculty. We hypothesized that the apprenticeship rotation would be effective for teaching nontechnical skills (NTS) and core competencies. An apprenticeship rotation was created at a university-based surgery residency in which each chief resident selected a single attending surgeon with whom to work exclusively with for a 4-week period. Emphasis was placed on teaching intraoperative NTS as well as the 4 difficult-to-teach Accreditation Council for Graduate Medical Education core competencies (DCC): Interpersonal and Communication Skills, Practice-Based Learning and Improvement, Professionalism, and Systems-Based Practice. Participants were surveyed afterwards about their rotation using a 5-point Likert scale. A Wilcoxon signed rank test was used to compare differences depending on data distribution. All (13/13) the chief residents and 67% (8/12) faculty completed the survey. Overall, 85% of residents and 87.5% of faculty would recommend the rotation to other residents/faculty members. Both residents and faculty reported improvement in trainees' technical skills and NTS. Residents reported improvement in all 4 DCC, particularly, Practice-Based Learning and Improvement, Professionalism, and Interpersonal and Communication Skills. The apprenticeship rotation is an effective means of teaching residents both NTS and DCC essential for independent practice. Consideration should be given to introducing this program into surgical curricula nationally. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

LCRE and SNAP 50-DR-1 programs. Engineering progress report, October 1, 1962--December 31, 1962

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

None

Declassified 5 Sep 1973. Information is presented concerning LCRE specifications, reactor kinetics, fuel elements, primary coolant circuit, secondary coolant circuit, materials development, and fabrication; and SNAP50-DR- 1 specifications, primary pump, and materials development. (DCC)

LCRE and SNAP 50-DR-1 programs. Engineering progress report, January 1, 1963--March 31, 1963

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

None

Declassified 5 Sep 1973. Information is presented concerning LCRE specifications, primary coolant circuit, aaxiliary systems, fuel elements, instrumentation, materials development, and fabrication; and SNAP-50DR-1 specifications, fuel elements, pumps, steam generator, and materials development. (DCC)

Interactions between deep convective clouds and aerosols as observed by satellites

NASA Astrophysics Data System (ADS)

Yuan, T.; Li, Z. I.; Remer, L.; Martins, V.

2008-12-01

Major uncertainties regarding interactions between deep convective clouds (DCC) exist due partly to observational difficulty and partly to the entanglement among remotely sensed properties of aerosols and clouds and entanglement between meteorology and possible aerosol signals. In this study we adopt a novel, physically sound relationship between cloud crystal effective radius(CER) and brightness temperature (BT) and utilize ample sampling opportunity provided by MODIS instrument. We reveal aerosol impacts on DCCs by analyzing an ensemble data. Through a conceptual model we demonstrate how aerosol may affect DCC properties. We outline a few scenarios where aerosol signals are best separated and pronounced. Based on our results, anthropogenic pollutions and smokes are shown to effectively decrease CER and to elevate glaciation level of DCCs. On the other hand, dust particles from local sources have the opposite effects, namely, increasing cloud ice particle size and enhancing glaciation by acting possibly as giant CCN or IN. Implications of these effects for aerosols are discussed along with feedbacks of these effects to dynamics.

Theoretical and Experimental Study on Wide Range Optical Fiber Turbine Flow Sensor.

PubMed

Du, Yuhuan; Guo, Yingqing

2016-07-15

In this paper, a novel fiber turbine flow sensor was proposed and demonstrated for liquid measurement with optical fiber, using light intensity modulation to measure the turbine rotational speed for converting to flow rate. The double-circle-coaxial (DCC) fiber probe was introduced in frequency measurement for the first time. Through the divided ratio of two rings light intensity, the interference in light signals acquisition can be eliminated. To predict the characteristics between the output frequency and flow in the nonlinear range, the turbine flow sensor model was built. Via analyzing the characteristics of turbine flow sensor, piecewise linear equations were achieved in expanding the flow measurement range. Furthermore, the experimental verification was tested. The results showed that the flow range ratio of DN20 turbine flow sensor was improved 2.9 times after using piecewise linear in the nonlinear range. Therefore, combining the DCC fiber sensor and piecewise linear method, it can be developed into a strong anti-electromagnetic interference(anti-EMI) and wide range fiber turbine flowmeter.

Theoretical and Experimental Study on Wide Range Optical Fiber Turbine Flow Sensor

PubMed Central

Du, Yuhuan; Guo, Yingqing

2016-01-01

In this paper, a novel fiber turbine flow sensor was proposed and demonstrated for liquid measurement with optical fiber, using light intensity modulation to measure the turbine rotational speed for converting to flow rate. The double-circle-coaxial (DCC) fiber probe was introduced in frequency measurement for the first time. Through the divided ratio of two rings light intensity, the interference in light signals acquisition can be eliminated. To predict the characteristics between the output frequency and flow in the nonlinear range, the turbine flow sensor model was built. Via analyzing the characteristics of turbine flow sensor, piecewise linear equations were achieved in expanding the flow measurement range. Furthermore, the experimental verification was tested. The results showed that the flow range ratio of DN20 turbine flow sensor was improved 2.9 times after using piecewise linear in the nonlinear range. Therefore, combining the DCC fiber sensor and piecewise linear method, it can be developed into a strong anti-electromagnetic interference(anti-EMI) and wide range fiber turbine flowmeter. PMID:27428976

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

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

Developing Customized Programs for Steel and Other Heavy Industries.

ERIC Educational Resources Information Center

Day, Philip R., Jr.

1984-01-01

Describes Dundalk Community College's (DCC's) customized training programs for local industries. Looks at employment problems and outlook in Baltimore County, the development of a training agreement with Bethlehem Steel, the use of the Developing a Curriculum (DACUM) process to develop skill profiles, and future directions. (DMM)

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

The Dye Sensitized Photoelectrosynthesis Cell (DSPEC) for Solar Water Splitting and CO2 Reduction

NASA Astrophysics Data System (ADS)

Meyer, Thomas; Alibabaei, Leila; Sherman, Benjamin; Sheridan, Matthew; Ashford, Dennis; Lapides, Alex; Brennaman, Kyle; Nayak, Animesh; Roy, Subhangi; Wee, Kyung-Ryang; Gish, Melissa; Meyer, Jerry; Papanikolas, John

The dye-sensitized photoelectrosynthesis cell (DSPEC) integrates molecular level light absorption and catalysis with the bandgap properties of stable oxide materials such as TiO2 and NiO. Excitation of surface-bound chromophores leads to excited state formation and rapid electron or hole injection into the conduction or valence bands of n or p-type oxides. Addition of thin layers of TiO2 or NiO on the surfaces of mesoscopic, nanoparticle films of semiconductor or transparent conducting oxides to give core/shell structures provides a basis for accumulating multiple redox equivalents at catalysts for water oxidation or CO2 reduction. UNC EFRC Center for Solar Fuels, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DE-SC0001011.

NEW Work for Women: A Model Program for Nontraditional Careers.

ERIC Educational Resources Information Center

de Wit, Kathleen S.

The NEW (Nontraditional Employment for Women Act) Work for Women project at Dundalk Community College (DCC) encourages and assists women in entering nontraditional fields, especially the building and construction trades. The program provides comprehensive services in outreach and awareness of nontraditional careers, career counseling, education,…

LCRE and SNAP 50-DR-1 programs. Engineering and progress report, April 1, 1963--June 30, 1963

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

None

BS>Declassified 6 Sep 1973. Information is presented concerning the LCRE kinetics, auxiliary systems, fuel, primary cooling system components, instrumentation, secondary cooling system, materials development, and fabrication; and SNAP-50/SPUR kinetics, fuel, primary system pump, steam generator, and materials development. (DCC)

The Cutting Edge, 1999-2000.

ERIC Educational Resources Information Center

Cutting Edge, 2000

2000-01-01

The Cutting Edge is a bimonthly newsletter of the Regional Center for Applied Technology and Training at Danville Community College (DCC) (Virginia) that provides the latest information on a wide range of issues including technology, business, employment trends, and new legislation. Articles from the first five issues discuss: (1) the July 2000…

Air traffic control : good progress on interim replacement for outage-plagued system, but risks can be further reduced

DOT National Transportation Integrated Search

1996-10-01

Certain air traffic control(ATC) centers experienced a series of major outages, : some of which were caused by the Display Channel Complex or DCC-a mainframe : computer system that processes radar and other data into displayable images on : controlle...

Evaluation of the Virgin Mechanical and Thermal Properties of AVCO 3DCC Heatshield Materials

DTIC Science & Technology

1977-03-01

alumina or zirconia powder . Surrounding the guard is an annulus of distomaceous earth enclosed in an aluminum or transite shell. The specimens and...pa.-ked with either copper granules, graphite or zirconia powder . This packing provides a positive method for centering the calorimeter within the

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.

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.

78 FR 28859 - National Institute of Diabetes and Digestive and Kidney Diseases Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-16

... Diabetes and Digestive and Kidney Diseases Notice of Closed Meetings Pursuant to section 10(d) of the... Diabetes and Digestive and Kidney Diseases Special Emphasis Panel; DCC MAPP Network. Date: June 12, 2013... Digestive and Kidney Diseases Special Emphasis Panel; NIDDK Bioengineering Interdisciplinary Training for...

77 FR 52750 - National Institute of Diabetes and Digestive and Kidney Diseases; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-30

... Diabetes and Digestive and Kidney Diseases; Notice of Closed Meetings Pursuant to section 10(d) of the... Diabetes and Digestive and Kidney Diseases Special Emphasis Panel HALT-PKD DCC. Date: October 17, [email protected] . Name of Committee: National Institute of Diabetes and Digestive and Kidney Diseases...

The Economic Impact of Dutchess Community College.

ERIC Educational Resources Information Center

Dutchess Community Coll., Poughkeepsie, NY. Office of Planning and Institutional Research.

In an effort to measure the economic impact of Dutchess Community College (DCC), in Poughkeepsie, New York, on Dutchess County, a study was undertaken of expenditures and jobs created in the county during fiscal year 1991-92. To measure the tangible economic impact, three major financial components were examined: direct expenditures by the college…

Developing Clinical Leaders in Primary Care: The US Air Force Diabetes Champion Course

DTIC Science & Technology

2017-04-03

The US Air Force Diabetes Center of Excellence designed the Diabetes Champion Course (DCC), a semi-annual, 3-day course, to train primary care teams ...and patient flow in a team -based setting. Each team is tasked to identify local deficits and make a Plan of Action (POA) for implementation.

Bossier Parish Community College and Delgado Community College Collaborative Pharmacy Technician Program Distance Education Initiative.

ERIC Educational Resources Information Center

Bossier Parish Community Coll., Bossier City, LA.

Two Louisiana community colleges--Bossier Parish Community College (BPCC) and Delgado Community College (DCC)--proposed, developed, and implemented a collaborative Pharmacy Technician program for delivery through the use of two-way interactive video. The new program was inspired by new certification requirements instituted by the state of…

Impact Measures for a Marketing Intervention Strategy at a Two-Year College.

ERIC Educational Resources Information Center

Donsky, Aaron P.; And Others

In fall 1983, Dutchess Community College (DCC), Poughkeepsie, New York, implemented a strategic planning process which ultimately resulted in the development of short- and long-range marketing plans. The initial marketing approach began in spring 1985 and was directed toward a pilot project to affect summer 1985 enrollments utilizing a market…

Chromosome-wide mechanisms to decouple gene expression from gene dose during sex-chromosome evolution

PubMed Central

Wheeler, Bayly S; Anderson, Erika; Frøkjær-Jensen, Christian; Bian, Qian; Jorgensen, Erik; Meyer, Barbara J

2016-01-01

Changes in chromosome number impair fitness by disrupting the balance of gene expression. Here we analyze mechanisms to compensate for changes in gene dose that accompanied the evolution of sex chromosomes from autosomes. Using single-copy transgenes integrated throughout the Caenorhabditis elegans genome, we show that expression of all X-linked transgenes is balanced between XX hermaphrodites and XO males. However, proximity of a dosage compensation complex (DCC) binding site (rex site) is neither necessary to repress X-linked transgenes nor sufficient to repress transgenes on autosomes. Thus, X is broadly permissive for dosage compensation, and the DCC acts via a chromosome-wide mechanism to balance transcription between sexes. In contrast, no analogous X-chromosome-wide mechanism balances transcription between X and autosomes: expression of compensated hermaphrodite X-linked transgenes is half that of autosomal transgenes. Furthermore, our results argue against an X-chromosome dosage compensation model contingent upon rex-directed positioning of X relative to the nuclear periphery. DOI: http://dx.doi.org/10.7554/eLife.17365.001 PMID:27572259

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.

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.

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.

Molecular and cytogenetic analysis of human diploid fibroblast cells transformed by simian virus 40: What causes immortalization

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

Patsalis, P.C.

1993-01-01

Transformation of human diploid fibroblasts (HF) with SV40 can result in extension of life span beyond the normal limit of senescence and in a minority of cases, immortalization. This study used comparison of matched parental (diploid) and immortalized cell lines to determine if any single genetic factor could be related to the immortalization phenomena. The integration site of SV40 was shown to be at chromosome 5q21 by cytologic hybridization. A comparison of mortal and immortal cells showed no alterations involving the integrated SV40 genome per se. Karyotypic analysis of matched cell lines identified a specific chromosomal breakpoint (6q21) in immortalizedmore » cells that was not present in the parental line. Hybridization analysis confirmed that sequences on the distal portion of 6q are lost in immortalized cells. Two single copy DNAs which flank the breakpoint were identified and used to further define the exact breakpoint on 6q13. FISH analysis demonstrated the region 6q13 [yields] 21 as belonging to another chromosome and confirmed the 6q13 breakpoint. A survey of random translocations and other anomalies occurring in the immortalized lines was also made. Some of these are regions known to contain oncogenes and transforming proteins. The MCC tumor suppressor gene was rearranged and deregulated. The genes DCC, Bel-2, APC were also found to be deregulated. The authors propose that deletion of specific sequences due to breakage of chromosome 6q represent one of the mutational events responsible for immortalization of SV40 transformed HF. In addition, the MCC and possibly other genes are involved in the progression of immortalization.« less

Bypass Mechanisms of the Androgen Receptor Pathway in Therapy-Resistant Prostate Cancer Cell Models

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van Weerden, Wytske M.; Jenster, Guido

2010-01-01

Background Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. Methodology/Principal Findings Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10−7). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression. Conclusions/Significance Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets. PMID:20976069

Inhibitory effect of gamma irradiation and its application for control of postharvest green mold decay of Satsuma mandarins.

PubMed

Jeong, Rae-Dong; Chu, Eun-Hee; Lee, Gun Woong; Cho, Chuloh; Park, Hae-Jun

2016-10-03

Gamma irradiation has been shown to be effective for the control of postharvest fungi in vitro, but little is known regarding antifungal action, responses to gamma irradiation, and its application to fresh produce. Gamma irradiation was evaluated for its in vitro and in vivo antifungal activity against Penicillium digitatum on Satsuma mandarin fruits. Green mold was inhibited in a dose-dependent manner. Gamma irradiation showed a complete inhibition of spore germination, germ tube elongation, and mycelial growth of P. digitatum, particularly at 1.0kGy. To further investigate the mechanisms by which gamma irradiation inhibits fungal growth, the membrane integrity and cellular leakage of conidia were tested, indicating that gamma irradiation results in the loss of plasma membrane integrity, causing the release of intracellular contents such as soluble proteins. In vivo assays demonstrated that established doses can completely inhibit the growth of fungal pathogens, but such high doses cause severe fruit damage. Thus, to eliminate the negative impact on fruit quality, gamma irradiation at lower doses was evaluated for inhibition of P. digitatum, in combination with a chlorine donor, sodium dichloro-s-triazinetrione (NaDCC). Interestingly, only a combined treatment with 0.4kGy of gamma irradiation and 10ppm of NaDCC exhibited significant synergistic antifungal activity against green mold decay. The mechanisms by which the combined treatment decreased the green mold decay of mandarin fruits can be directly associated with the disruption of cell membrane of the fungal pathogen, which resulted in a loss of cytoplasmic material from the hyphae. These findings suggest that a synergistic effect of combining treatment with gamma irradiation with NaDCC has potential as an antifungal approach to reduce the severity of green mold in mandarin fruits. Copyright © 2016 Elsevier B.V. All rights reserved.

Loss of Chromosome 18 in Neuroendocrine Tumors of the Small Intestine: The Enigma Remains.

PubMed

Nieser, Maike; Henopp, Tobias; Brix, Joachim; Stoß, Laura; Sitek, Barbara; Naboulsi, Wael; Anlauf, Martin; Schlitter, Anna M; Klöppel, Günter; Gress, Thomas; Moll, Roland; Bartsch, Detlef K; Heverhagen, Anna E; Knoefel, Wolfram T; Kaemmerer, Daniel; Haybaeck, Johannes; Fend, Falko; Sperveslage, Jan; Sipos, Bence

2017-01-01

Neuroendocrine tumors of the small intestine (SI-NETs) exhibit an increasing incidence and high mortality rate. Until now, no fundamental molecular event has been linked to the tumorigenesis and progression of these tumors. Only the loss of chromosome 18 (Chr18) has been shown in up to two thirds of SI-NETs, whereby the significance of this alteration is still not understood. We therefore performed the first comprehensive study to identify Chr18-related events at the genetic, epigenetic and gene/protein expression levels. We did expression analysis of all seven putative Chr18-related tumor suppressors by quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. Next-generation exome sequencing and SNP array analysis were performed with five SI-NETs with (partial) loss of Chr18. Finally, we analyzed all microRNAs (miRNAs) located on Chr18 by qRT-PCR, comparing Chr18+/- and Chr18+/+ SI-NETs. Only DCC (deleted in colorectal cancer) revealed loss of/greatly reduced expression in 6/21 cases (29%). No relevant loss of SMAD2, SMAD4, elongin A3 and CABLES was detected. PMAIP1 and maspin were absent at the protein level. Next-generation sequencing did not reveal relevant recurrent somatic mutations on Chr18 either in an exploratory cohort of five SI-NETs, or in a validation cohort (n = 30). SNP array analysis showed no additional losses. The quantitative analysis of all 27 Chr18-related miRNAs revealed no difference in expression between Chr18+/- and Chr18+/+ SI-NETs. DCC seems to be the only Chr18-related tumor suppressor affected by the monoallelic loss of Chr18 resulting in a loss of DCC protein expression in one third of SI-NETs. No additional genetic or epigenetic alterations were present on Chr18. © 2016 S. Karger AG, Basel.

The Interface Between Chemical and Oxide Materials in the DSPEC

NASA Astrophysics Data System (ADS)

Meyer, Thomas; Alibabaei, Leila; Sherman, Benjamin; Sheridan, Matthew; Ashford, Dennis; Lapides, Alex; Brennaman, Kyle; Nayak, Animesh; Roy, Subhangi

Significant challenges exist for both chemical and oxide materials in the Dye Sensitized Photoelectrosynthesis Cell (DSPEC) for water oxidation or CO2 reduction. They arise from light absorption, the energetics of electron or hole injection, the accumulation of multiple redox equivalents at catalysts for water oxidation or water/CO2 reduction in competition with back electron transfer, and sustained, long term performance. These challenges are being met by the use of a variety of chromophores (metal complexes, organic dyes, porphyrins), broad application of nanoparticle mesoscopic oxide films, atomic layer deposition (ALD) to prepare core/shell and stabilizing overlayer structures, and recent advances in the molecular catalysis of water oxidation and CO2 reduction. UNC EFRC Center for Solar Fuels, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DE-SC0001011.

Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers

PubMed Central

2017-01-01

Conspectus Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular biodynamers are commonly produced in aqueous media under mild or even physiological conditions to suit their biorelated applications. In contrast to static biopolymers emphasizing structural stability and unity by using irreversible covalent bonds, molecular biodynamers are seeking relative structural adaptability and diversity through the formation of reversible covalent bonds. Based on these considerations, molecular biodynamers are capable of reorganizing their monomers, generating, identifying, and amplifying the fittest structures in response to environmental factors. Hence, molecular biodynamers have received considerable research attention over the past decades. Accordingly, the construction of molecular biodynamers through equilibrium polymerization of nucleobase-, carbohydrate- or amino-acid-based monomers can lead to the fabrication of dynamic analogues of nucleic acids (DyNAs), polysaccharides (glycodynamers), or proteins (dynamic proteoids), respectively. In this Account, we summarize recent advances in developing different types of molecular biodynamers as structural or functional biomimetics of biopolymers, including DyNAs, glycodynamers, and dynamic proteoids. We introduce how chemists utilize various reversible reactions to generate molecular biodynamers with specific sequences and well-ordered structures in aqueous medium. We also discuss and list their potential applications in various research fields, such as drug delivery, drug discovery, gene sensing, cancer diagnosis, and treatment. PMID:28169527

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.

State Articulated Instructional Objectives Guide for Occupational Education Programs. State Pilot Model for Automotive Mechanics (DCC V-003) and Automotive Mechanics (High School).

ERIC Educational Resources Information Center

North Carolina State Dept. of Community Colleges, Raleigh.

This articulation instructional objective guide for automotive mechanics contains summary information on fifteen blocks (courses) of instruction. They are introduction to automotive technology; lubrication and vehicle operating maintenance; cooling system maintenance and repair; automobile heater maintenance and repair; braking system maintenance…

ESBL/AmpC-producing Enterobacteriaceae in households with children of preschool age: prevalence, risk factors and co-carriage.

PubMed

van den Bunt, G; Liakopoulos, A; Mevius, D J; Geurts, Y; Fluit, A C; Bonten, M J M; Mughini-Gras, L; van Pelt, W

2017-02-01

ESBL/AmpC-producing Enterobacteriaceae are an emerging public health concern. As households with preschool children may substantially contribute to the community burden of antimicrobial resistance, we determined the prevalence, risk factors and co-carriage of ESBL/AmpC-producing bacteria in preschool children and their parents. From April 2013 to January 2015, each month 2000 preschool children were randomly selected from Dutch population registries. The parents were invited to complete an epidemiological questionnaire and to obtain and send a faecal sample from the selected child and from one parent. Samples were tested for ESBL/AmpC-producing bacteria. Logistic regression was used to identify risk factors for ESBL/AmpC carriage in children and parents, and findings were internally validated by bootstrapping. In total, 1016 families were included and ESBL/AmpC prevalence was 4.0% (95% CI 3.2%-5.0%); 3.5% (95% CI 2.5%-4.8%) in children and 4.5% (95% CI 3.4%-6.0%) in parents. Attending a daycare centre (DCC) was the only significant risk factor for children (OR 2.1, 95% CI 1.0-4.3). For parents, the only significant risk factor was having one or more children attending DCCs (OR 2.2, 95% CI 1.2-4.8). For parents of ESBL/AmpC-positive children the OR for ESBL/AmpC carriage was 19.7 (95% CI 9.2-42.4). Co-carriage of specific ESBL/AmpC genotypes in child and parent occurred more often than expected by chance (14.6% versus 1.1%, P < 0.001). In this study, intestinal carriage with ESBL/AmpCs was detected in ∼4% of households with preschool children. DCC attendance was a risk factor in both children and parents and co-carriage of specific genotypes frequently occurred in child-parent pairs. These findings suggest household transmission or/and family-specific exposure to common sources of ESBL/AmpC-producing bacteria. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

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.

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.

Linear pi-Acceptor-Templated Dynamic Clipping to Macrobicycles and[2]Rotaxanes

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

Klivansky, Liana M.; Koshkakaryan, Gayane; Cao, Dennis

2009-04-30

Functional rotaxanes are one of the representative nanoscale molecular machines that have found applications in many areas, including molecular electronics, nanoelectromechanical systems (NEMS), photo controllable smart surfaces, and nanovalves. With the advent of molecular recognition and self-assembly, such molecular compounds can now be obtained efficiently through template-directed synthesis. One of the common strategies of making [2]rotaxanes involves the clipping of a macrocycle around a preformed dumbbell-shaped template in a [1+1] or [2+2] manner. While early examples were based on irreversible kinetic pathway through covalent bond formation, recent advances on reversible dynamic covalent chemistry (DCC) has attracted great attention to thismore » field. By virtue of thermodynamically controlled equilibria, DCC has provided highly efficient and versatile synthetic routes in the selection of specific products from a complex system. Among the several reversible reactions in the category of DCC reactions, the imine formation has proven to be very versatile in macrocyclization to give complex interlocked molecular compounds. Cryptands are three dimensional bicyclic hosts with preorganized cavities capable of inclusion of ions and small molecules. Replacing the nitrogen bridgeheads in common cryptands with aromatic ring systems gives cyclophane-based macrobicycles. The introduction of aromatic ring systems into a preorganized cage-like geometry facilitates ion-{pi} interactions and {pi}-{pi} interactions, resulting in novel metal sandwiches, fluoride receptors, and host-guest complexes. In particular, the seminal work by Gibson, Huang and coworkers on cryptand complexation with paraquat and diquat guests have resulted in the efficient synthesis of mechanically interlocked rotaxanes. The synthesis of cyclophane-based macrobicycles, however, was mostly realized through multiple reaction steps and in high-dilution conditions, which often suffered from low yield and tedious workup. Thus, a one-step, five-component [2+3] clipping reaction that can give the desired macrobicycle is highly desirable. We are motivated by a {pi}-guest templating protocol, because not only {pi}-{pi} interactions can contribute to the formation of macrobicycles, but also the resulting host-guest system holds great promise as a forerunner in the construction of interlocked molecules. (Scheme 1c) Very simple precursors, namely 1,3,5-benzenetrialdehyde (1) and 2,2{prime}-(ethylenedioxy)diethylamine (2) were chosen as the components for desired macrobicycle. (Scheme 2) The formation of six imine bonds would connect the five components to give a macrobicycle while extending the conjugation in the C{sub 3}-symmetric aromatic 'ceiling' and 'floor', which is suitable for enhancing the {pi}-{pi} interactions with a complementary aromatic template. Meanwhile, the ethylene glycol 'pillars' can provide sufficient flexibility, proper spacing, and polar binding sites to assist guest encapsulation. Initial screening of ?-templates engaged several C{sub 3} symmetric aromatic compounds in order to match the symmetry of the desired macrobicycle, which only resulted in nonspecific mixtures. It was found instead that linear bipyridinium (BPY) containing guests effectively templated the [2+3] clipping reaction. Based on this protocol, a [2]rotaxane was successfully assembled as the single product from the six-component reaction.« less

Comparison of convective clouds observed by spaceborne W-band radar and simulated by cloud-resolving atmospheric models

NASA Astrophysics Data System (ADS)

Dodson, Jason B.

Deep convective clouds (DCCs) play an important role in regulating global climate through vertical mass flux, vertical water transport, and radiation. For general circulation models (GCMs) to simulate the global climate realistically, they must simulate DCCs realistically. GCMs have traditionally used cumulus parameterizations (CPs). Much recent research has shown that multiple persistent unrealistic behaviors in GCMs are related to limitations of CPs. Two alternatives to CPs exist: the global cloud-resolving model (GCRM), and the multiscale modeling framework (MMF). Both can directly simulate the coarser features of DCCs because of their multi-kilometer horizontal resolutions, and can simulate large-scale meteorological processes more realistically than GCMs. However, the question of realistic behavior of simulated DCCs remains. How closely do simulated DCCs resemble observed DCCs? In this study I examine the behavior of DCCs in the Nonhydrostatic Icosahedral Atmospheric Model (NICAM) and Superparameterized Community Atmospheric Model (SP-CAM), the latter with both single-moment and double-moment microphysics. I place particular emphasis on the relationship between cloud vertical structure and convective environment. I also emphasize the transition between shallow clouds and mature DCCs. The spatial domains used are the tropical oceans and the contiguous United States (CONUS), the latter of which produces frequent vigorous convection during the summer. CloudSat is used to observe DCCs, and A-Train and reanalysis data are used to represent the large-scale environment in which the clouds form. The CloudSat cloud mask and radar reflectivity profiles for CONUS cumuliform clouds (defined as clouds with a base within the planetary boundary layer) during boreal summer are first averaged and compared. Both NICAM and SP-CAM greatly underestimate the vertical growth of cumuliform clouds. Then they are sorted by three large-scale environmental variables: total preciptable water (TPW), surface air temperature (SAT), and 500hPa vertical velocity (W500), representing the dynamical and thermodynamical environment in which the clouds form. The sorted CloudSat profiles are then compared with NICAM and SP-CAM profiles simulated with the Quickbeam CloudSat simulator. Both models have considerable difficulty representing the relationship of SAT and clouds over CONUS. For TPW and W500, shallow clouds transition to DCCs at higher values than observed. This may be an indication of the models' inability to represent the formation of DCCs in marginal convective environments. NICAM develops tall DCCs in highly favorable environments, but SP-CAM appears to be incapable of developing tall DCCs in almost any environment. The use of double moment microphysics in SP-CAM improves the frequency of deep clouds and their relationship with TPW, but not SAT. Both models underpredict radar reflectivity in the upper cloud of mature DCCs. SP-CAM with single moment microphysics has a particularly unrealistic DCC reflectivity profile, but with double moment microphysics it improves substantially. SP-CAM with double-moment microphysics unexpectedly appears to weaken DCC updraft strength as TPW increases, but otherwise both NICAM and SP-CAM represent the environment-versus-DCC relationships fairly realistically.

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...

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.

Report on Users' Satisfaction with Services Provided by Institutional Research. Research Report.

ERIC Educational Resources Information Center

Bashford, Joanne

The Office of Institutional Research (IR) at Miami-Dade Community College (M-DCC) (Florida) offers the results of a survey regarding the use of the office's services. Instead of using hard copy format as in the past, the current survey was conducted online. An e-mail message requesting participation was sent to the 3,498 employees with e-mail…

Quantification of Methane and Ammonia Emissions in a Naturally Ventilated Barn by Using Defined Criteria to Calculate Emission Rates.

PubMed

Schmithausen, Alexander J; Schiefler, Inga; Trimborn, Manfred; Gerlach, Katrin; Südekum, Karl-Heinz; Pries, Martin; Büscher, Wolfgang

2018-05-16

Extensive experimentation on individual animals in respiration chambers has already been carried out to evaluate the potential of dietary changes and opportunities to mitigate CH₄ emissions from ruminants. Although it is difficult to determine the air exchange rate of open barn spaces, measurements at the herd level should provide similarly reliable and robust results. The primary objective of this study was (1) to define a validity range (data classification criteria (DCC)) for the variables of wind velocity and wind direction during long-term measurements at barn level; and (2) to apply this validity range to a feeding trial in a naturally cross-flow ventilated dairy barn. The application of the DCC permitted quantification of CH₄ and NH₃ emissions during a feeding trial consisting of four periods. Differences between the control group (no supplement) and the experimental group fed a ration supplemented with condensed Acacia mearnsii tannins (CT) became apparent. Notably, CT concentrations of 1% and 3% of ration dry matter did not reduce CH₄ emissions. In contrast, NH₃ emissions decreased 34.5% when 3% CT was supplemented. The data confirm that quantification of trace gases in a naturally ventilated barn at the herd level is possible.

[Receptor status (ER and PgR) determined with histochemical and biochemical methods in breast carcinoma].

PubMed

Simone, G; Paradiso, A; Cirillo, R; Mangia, A; Rella, G; Wiesel, S; Petroni, S; De Benedictis, G; De Lena, M

1991-01-01

Recently, a method similar to ER.ICA has been proposed for the progesterone receptor (PgR) using two monoclonal antibodies, JZB39 and KD68, specific for human PgR and characterized by a molecular weight of 95 and 120 Kd, respectively. A series of 73 breast cancer patients was studied with regards to ER and PgR using both immunocytochemical (ICA) and biochemical (DCC) assays. Results showed no substantial differences between the two methods when considering common clinical-pathological parameters. Overall agreement between ICA and DCC methods was found: 79% for PgR and 78% for ER. A slight quantitative correlation was also observed between the "score values" of the ICA method and the Fmol content of ER and PgR using the Brave-Pearson test (r = 0.49 for PgR; r = 0.43 for ER). Specificity of PgR.ICA method was 77% for PgR and 72% for ER; sensitivity was 82% and 83%, respectively. The ICA method is a reliable technique to assess PgR presence as well as ER. Further studies are necessary to evaluate the prognostic role of nuclear PgR.

Dichlorocarbene-Functionalized Fluorographene: Synthesis and Reaction Mechanism.

PubMed

Lazar, Petr; Chua, Chun Kiang; Holá, Kateřina; Zbořil, Radek; Otyepka, Michal; Pumera, Martin

2015-08-01

Halogen functionalization of graphene is an important branch of graphene research as it provides opportunities to tailor the band gap and catalytic properties of graphene. Monovalent C-X bond obviates pitfalls of functionalization with atoms of groups 13, 15, and 16, which can introduce various poorly defined groups. Here, the preparation of functionalized graphene containing both fluorine and chlorine atoms is shown. The starting material, fluorographite, undergoes a reaction with dichlorocarbene to provide dichlorocarbene-functionalized fluorographene (DCC-FG). The material is characterized by X-ray photoelectron spectroscopy, Raman spectroscopy, and high-resolution transmission electron microscopy with X-ray dispersive spectroscopy. It is found that the chlorine atoms in DCC-FG are distributed homogeneously over the entire area of the fluorographene sheet. Further density functional theory calculations show that the mechanism of dichlorocarbene attack on fluorographene sheet is a two-step process. Dichlorocarbene detaches fluorine atoms from fluorographene sheet and subsequently adds to the newly formed sp(2) carbons. Halogenated graphene consisting of two (or eventually three) types of halogen atoms is envisioned to find its way as new graphene materials with tailored properties. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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).

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.

Optimization of the Microwave-Assisted Ethanosolv Extraction of Lignocellulosic Compounds from the Bagasse of Agave angustifolia Haw Using the Response Methodology.

PubMed

Hernández, Yuliana Rosas; García Serrano, Luz Arcelia; Maruri, Daniel Tapia; Jiménez Aparicio, Antonio Ruperto; Camacho Díaz, Brenda Hildeliza; Arenas Ocampo, Martha Lucía

2018-04-04

The main objective of this work was to optimize the process of fractionation of the bagasse of Agave angustifolia Haw, applying organosolv assisted with microwaves. The DCC was used to evaluate the effect of independent variables such as ethanol concentration (40, 50, and 60%) and reaction time (1, 1.5, and 2 h) on yield, cellulose and lignin percentages. Lignocellulosic fractions (F1 and F2) were obtained by means of organosolv assisted with microwave in an open system (atmospheric pressure) and a closed system (controlled pressure). The lignocellulosic fractions were microstructurally characterized. The highest extraction yields (70.39%) were reached in the open system at 50% ethanol for 1.5 h. The highest percentages of LK (5.05%) were obtained in the closed system at 60% ethanol for 2 h. The SEM photomicrograph showed that the microstructure of F1 was retained even after treatment with 60% ethanol for 2 h, and the exposure of the fibrillar part was observed obtaining the disposition of pectin.

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.

The Geometry of Selected U.S. Tidal Inlets.

DTIC Science & Technology

1980-05-01

wrong cluster. Table 6. Descriminant analysis results for three variables (DCC, EM2, and EM3). a. Coefficients for di i iminant functions based on three...47.95/ 3 07.72 0.975, 4,1 0 .310. 1 C1297 0,)1r, 55,94 o, D, C 24.07: 1. C5, 75 Iable-9. Descriminant analysis results for six variables (DMX, DMA, W

An Application of Singularity Analysis to a Heavy Precipitation Event

DTIC Science & Technology

1993-01-01

difference in this plot. 61 NORMAN RADAR ELEVATION: 3.094 DATE 28 MAY 87 TIM 005342 GUT Cumin a 10 Tpam c CD low am am Io CID e0UC 100 "CC C d~Cc 100...element of fluid shaped like a sphere. Assuming the fluid is friction- less, no tangential stresses or forces are applied to its surface. The pressure

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.

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.

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.

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

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

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

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...

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...

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...

Adhesion and Early Colonization of S. Mutans on Lithium Disilicate Reinforced Glass-Ceramics, Monolithic Zirconia and Dual Cure Resin Cement.

PubMed

Viitaniemi, L; Abdulmajeed, A; Sulaiman, T; Söderling, E; Närhi, T

2017-12-01

Monolithic zirconia and glass ceramics are increasingly used in implant crowns. Limited data is available on bacterial adhesion and early biofilm formation on these materials. Four different materials were investigated: (1) Lithium disilicate glass-ceramics (LDS), (2) Fully stabilized zirconia (FSZ), (3) Partially stabilized zirconia (PSZ), and (4) Dual curing cement (DCC). The materials' surfaces were characterized with spinning disc confocal microscopy and by water contact angle and surface free energy (SFE) measurements. For the adhesion tests the materials were rolled in suspensions of Streptococcus mutans. Early biofilm formation was studied on the materials and allowing the biofilms to form for 24 h. S. mutans cell counts were determined by plate culturing. ANOVA and post-hoc Tukey's tests (p⟨0.05) were used for statistical evaluation. The LDS surfaces were clearly hydrophilic with the highest SFE value (p⟨0.001). For S. mutans adhesion, the ranking of the materials from lowest to highest was: LDS = FSZ ⟨ DCC ⟨ PSZ (p⟨0.05). No significant differences among the materials were noticed in biofilm formation. LDS has lower S.mutans adhesion than other materials examined in this study, but the difference was not reflected in early biofilm formation. Copyright© 2017 Dennis Barber Ltd.

Cartilage extracellular matrix as a biomaterial for cartilage regeneration.

PubMed

Kiyotake, Emi A; Beck, Emily C; Detamore, Michael S

2016-11-01

The extracellular matrix (ECM) of various tissues possesses the model characteristics that biomaterials for tissue engineering strive to mimic; however, owing to the intricate hierarchical nature of the ECM, it has yet to be fully characterized and synthetically fabricated. Cartilage repair remains a challenge because the intrinsic properties that enable its durability and long-lasting function also impede regeneration. In the last decade, cartilage ECM has emerged as a promising biomaterial for regenerating cartilage, partly because of its potentially chondroinductive nature. As this research area of cartilage matrix-based biomaterials emerged, investigators facing similar challenges consequently developed convergent solutions in constructing robust and bioactive scaffolds. This review discusses the challenges, emerging trends, and future directions of cartilage ECM scaffolds, including a comparison between two different forms of cartilage matrix: decellularized cartilage (DCC) and devitalized cartilage (DVC). To overcome the low permeability of cartilage matrix, physical fragmentation greatly enhances decellularization, although the process itself may reduce the chondroinductivity of fabricated scaffolds. The less complex processing of a scaffold composed of DVC, which has not been decellularized, appears to have translational advantages and potential chondroinductive and mechanical advantages over DCC, without detrimental immunogenicity, to ultimately enhance cartilage repair in a clinically relevant way. © 2016 New York Academy of Sciences.

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

Poenkae, A.

The weekly changes in ambient sulfur dioxide, nitrogen dioxide, and temperature were compared with the figures for respiratory infection in children and adults and for absenteeism from day-care centers (DCC), schools, and workplaces during a 1-year period in Helsinki. The annual average level of sulfur dioxide was 21 micrograms/m3 and of nitrogen dioxide 47 micrograms/m3; the average temperature was +3.1 degrees C. The levels of these pollutants and the temperature were significantly correlated with the number of upper respiratory infections reported from health centers. Low temperature also correlated with increased frequency of acute tonsillitis, of lower respiratory tract infection amongmore » DCC children, and of absenteeism from day-care centers, schools and workplaces. Furthermore, a significant association was found between levels of sulfur dioxide and absenteeism. After statistical standardization for temperature, no other correlations were observed apart from that between high levels of sulfur dioxide and numbers of upper respiratory tract infections diagnosed at health centers (P = 0.04). When the concentrations of sulfur dioxide were above the mean, the frequency of the upper respiratory tract infections was 15% higher than that during the periods of low concentration. The relative importance of the effects of low-level air pollution and low temperature on health is difficult to assess.« less

Initial Stability Assessment of S-NPP VIIRS Reflective Solar Band Calibration Using Invariant Desert and Deep Convective Cloud Targets

NASA Technical Reports Server (NTRS)

Bhatt, Rajendra; Doelling, David R.; Wu, Aisheng; Xiong, Xiaoxiong (Jack); Scarino, Benjamin R.; Haney, Conor O.; Gopalan, Arun

2014-01-01

The latest CERES FM-5 instrument launched onboard the S-NPP spacecraft will use the VIIRS visible radiances from the NASA Land Product Evaluation and Analysis Tool Elements (PEATE) product for retrieving the cloud properties associated with its TOA flux measurement. In order for CERES to provide climate quality TOA flux datasets, the retrieved cloud properties must be consistent throughout the record, which is dependent on the calibration stability of the VIIRS imager. This paper assesses the NASA calibration stability of the VIIRS reflective solar bands using the Libya-4 desert and deep convective clouds (DCC). The invariant targets are first evaluated for temporal natural variability. It is found for visible (VIS) bands that DCC targets have half of the variability of Libya-4. For the shortwave infrared (SWIR) bands, the desert has less variability. The brief VIIRS record and target variability inhibits high confidence in identifying any trends that are less than 0.6yr for most VIS bands, and 2.5yr for SWIR bands. None of the observed invariant target reflective solar band trends exceeded these trend thresholds. Initial assessment results show that the VIIRS data have been consistently calibrated and that the VIIRS instrument stability is similar to or better than the MODIS instrument.

Establishment of apoptotic regulatory network for genetic markers of colorectal cancer and optimal selection of traditional Chinese medicine target.

PubMed

Tian, Tongde; Chen, Chuanliang; Yang, Feng; Tang, Jingwen; Pei, Junwen; Shi, Bian; Zhang, Ning; Zhang, Jianhua

2017-03-01

The paper aimed to screen out genetic markers applicable to early diagnosis for colorectal cancer and establish apoptotic regulatory network model for colorectal cancer, and to analyze the current situation of traditional Chinese medicine (TCM) target, thereby providing theoretical evidence for early diagnosis and targeted therapy of colorectal cancer. Taking databases including CNKI, VIP, Wanfang data, Pub Med, and MEDLINE as main sources of literature retrieval, literatures associated with genetic markers that are applied to early diagnosis of colorectal cancer were searched and performed comprehensive and quantitative analysis by Meta analysis, hence screening genetic markers used in early diagnosis of colorectal cancer. KEGG analysis was employed to establish apoptotic regulatory network model based on screened genetic markers, and optimization was conducted on TCM targets. Through Meta analysis, seven genetic markers were screened out, including WWOX, K-ras, COX-2, P53, APC, DCC and PTEN, among which DCC has the highest diagnostic efficiency. Apoptotic regulatory network was built by KEGG analysis. Currently, it was reported that TCM has regulatory function on gene locus in apoptotic regulatory network. The apoptotic regulatory model of colorectal cancer established in this study provides theoretical evidence for early diagnosis and TCM targeted therapy of colorectal cancer in clinic.

Occurrence of triclosan, triclocarban, and its lesser chlorinated congeners in Minnesota freshwater sediments collected near wastewater treatment plants

USGS Publications Warehouse

Venkatesan, Arjun K.; Pycke, Benny F.G.; Barber, Larry B.; Lee, Kathy E.; Halden, Rolf U.

2012-01-01

The antimicrobial agents triclosan (TCS), triclocarban (TCC) and their associated transformation products are of increasing concern as environmental pollutants due to their potential adverse effects on humans and wildlife, including bioaccumulation and endocrine-disrupting activity. Analysis by tandem mass spectrometry of 24 paired freshwater bed sediment samples (top 10 cm) collected by the U.S. Geological Survey near 12 wastewater treatment plants (WWTPs) in Minnesota revealed TCS and TCC concentrations of up to 85 and 822 ng/g dry weight (dw), respectively. Concentrations of TCS and TCC in bed sediments collected downstream of WWTPs were significantly greater than upstream concentrations in 58% and 42% of the sites, respectively. Dichloro- and non-chlorinated carbanilides (DCC and NCC) were detected in sediments collected at all sites at concentrations of up to 160 and 1.1 ng/g dw, respectively. Overall, antimicrobial concentrations were significantly higher in lakes than in rivers and creeks, with relative abundances decreasing from TCC > TCS > DCC > NCC. This is the first statewide report on the occurrence of TCS, TCC and TCC transformation products in freshwater sediments. Moreover, the results suggest biological or chemical TCC dechlorination products to be ubiquitous in freshwater environments of Minnesota, but whether this transformation occurs in the WWTP or bed sediment remains to be determined.

Evaluating Dynamic Bivariate Correlations in Resting-state fMRI: A comparison study and a new approach

PubMed Central

Lindquist, Martin A.; Xu, Yuting; Nebel, Mary Beth; Caffo, Brain S.

2014-01-01

To date, most functional Magnetic Resonance Imaging (fMRI) studies have assumed that the functional connectivity (FC) between time series from distinct brain regions is constant across time. However, recently, there has been increased interest in quantifying possible dynamic changes in FC during fMRI experiments, as it is thought this may provide insight into the fundamental workings of brain networks. In this work we focus on the specific problem of estimating the dynamic behavior of pair-wise correlations between time courses extracted from two different regions of the brain. We critique the commonly used sliding-windows technique, and discuss some alternative methods used to model volatility in the finance literature that could also prove useful in the neuroimaging setting. In particular, we focus on the Dynamic Conditional Correlation (DCC) model, which provides a model-based approach towards estimating dynamic correlations. We investigate the properties of several techniques in a series of simulation studies and find that DCC achieves the best overall balance between sensitivity and specificity in detecting dynamic changes in correlations. We also investigate its scalability beyond the bivariate case to demonstrate its utility for studying dynamic correlations between more than two brain regions. Finally, we illustrate its performance in an application to test-retest resting state fMRI data. PMID:24993894

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. ...

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...

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...

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...

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...

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 ...

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…

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,…

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...

Coupled thermal-fluid analysis with flowpath-cavity interaction in a gas turbine engine

NASA Astrophysics Data System (ADS)

Fitzpatrick, John Nathan

This study seeks to improve the understanding of inlet conditions of a large rotor-stator cavity in a turbofan engine, often referred to as the drive cone cavity (DCC). The inlet flow is better understood through a higher fidelity computational fluid dynamics (CFD) modeling of the inlet to the cavity, and a coupled finite element (FE) thermal to CFD fluid analysis of the cavity in order to accurately predict engine component temperatures. Accurately predicting temperature distribution in the cavity is important because temperatures directly affect the material properties including Young's modulus, yield strength, fatigue strength, creep properties. All of these properties directly affect the life of critical engine components. In addition, temperatures cause thermal expansion which changes clearances and in turn affects engine efficiency. The DCC is fed from the last stage of the high pressure compressor. One of its primary functions is to purge the air over the rotor wall to prevent it from overheating. Aero-thermal conditions within the DCC cavity are particularly challenging to predict due to the complex air flow and high heat transfer in the rotating component. Thus, in order to accurately predict metal temperatures a two-way coupled CFD-FE analysis is needed. Historically, when the cavity airflow is modeled for engine design purposes, the inlet condition has been over-simplified for the CFD analysis which impacts the results, particularly in the region around the compressor disc rim. The inlet is typically simplified by circumferentially averaging the velocity field at the inlet to the cavity which removes the effect of pressure wakes from the upstream rotor blades. The way in which these non-axisymmetric flow characteristics affect metal temperatures is not well understood. In addition, a constant air temperature scaled from a previous analysis is used as the simplified cavity inlet air temperature. Therefore, the objectives of this study are: (a) model the DCC cavity with a more physically representative inlet condition while coupling the solid thermal analysis and compressible air flow analysis that includes the fluid velocity, pressure, and temperature fields; (b) run a coupled analysis whose boundary conditions come from computational models, rather than thermocouple data; (c) validate the model using available experimental data; and (d) based on the validation, determine if the model can be used to predict air inlet and metal temperatures for new engine geometries. Verification with experimental results showed that the coupled analysis with the 3D no-bolt CFD model with predictive boundary conditions, over-predicted the HP6 offtake temperature by 16k. The maximum error was an over-prediction of 50k while the average error was 17k. The predictive model with 3D bolts also predicted cavity temperatures with an average error of 17k. For the two CFD models with predicted boundary conditions, the case without bolts performed better than the case with bolts. This is due to the flow errors caused by placing stationary bolts in a rotating reference frame. Therefore it is recommended that this type of analysis only be attempted for drive cone cavities with no bolts or shielded bolts.

PET Radiotracers for Imaging the Proliferation Status of Breast Tumors

DTIC Science & Technology

2004-12-01

390 627 ±244 12,900±111 8.2± 1.415 58.8± 13.7 2.1 ±0.4 809±66 75.0±4.1 75-85% yield. Reduction with either lithium aluminum 16 107.0± 19.0 10.2±5.3 751... hexafluorophosphate (BOP) or 1,3- dicyclohexylcarbodiimide (DCC) and 2.5 equivalents of triethylamine were added, and the solution was allowed to warm

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…

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…

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...

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...

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.

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.

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

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

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

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.

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.

The genome architecture of the Collaborative Cross mouse genetic reference population.

PubMed

2012-02-01

The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.

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.

People, poverty and the Earth Summit.

PubMed

Wheeler, J

1992-01-01

UNCED is about human beings managing their affairs so that all can achieve a reasonably good life without destroying the life-supporting environment. Currently human activities are approaching an upset of environmental balance through production of greenhouse gases, depletion of the ozone layer, and reduction of natural resources. Equity is the right to a decent life for the current human population of 5.5 billion and the future 10 billion expected within the next 50 years. A minimum use of environmental space/person is required. The Earth Summit will be a broad statement of environmental policy. Agenda 21 includes 115 action programs within 40 chapters. Separate conventions will be held on climate and biodiversity. The secretariat of UNCED has been working primarily with Agenda 21. Population issues are emphasized in Chapter 5 ("Demographic Dynamics and Sustainability") of the first section in Agenda 21 on Social and Economic Dimensions. The program areas include 1) research on the links between population, the environment, and development; 2) formulation by governments of integrated national policies on environment and development, which account for demographic trends, and promotion of population literacy; and 3) implementation of local level programs to ensure access to education and information and services in order to plan families freely and responsibly. Increases in funding for the population program are anticipated to be US $9 billion by the year 2000 and about US $7 billion/year until then. The year 2000 will bring with it a doubling of urban population in developing countries. There are challenges and opportunities to expand private sector job creation, education, clean water, and family health services. In addition to managing human settlements, there is also management of fragile ecosystems, which means relieving the pressure on these lands through urban migration or relocation to richer agricultural areas. The goal for agriculture is to triple food outputs over the next 50 years without increasing land use; improved soil and management systems are needed. Ocean/seas protection from pollution and provision of an adequate, clean water supply are other challenges. Demographic transition must be completed in order to improve global development success.

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.

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

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

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.