Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication.

PubMed

Ren, Xiaodi; Siegel, Rachael; Kim, Unkyu; Roeder, Robert G

2011-05-06

B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in Igh promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated Igh promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3' enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3' enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. Copyright © 2011 Elsevier Inc. All rights reserved.

Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication

PubMed Central

Ren, Xiaodi; Siegel, Rachael; Kim, Unkyu; Roeder, Robert G.

2011-01-01

Summary B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in IgH promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated IgH promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3′enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3′enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. PMID:21549311

The effects of oral appliance therapy on occlusal function in patients with obstructive sleep apnea: a short-term prospective study.

PubMed

Otsuka, Ryo; Almeida, Fernanda Ribeiro; Lowe, Alan A

2007-02-01

The aim of this study was to objectively and prospectively assess whether oral appliances (OAs) alter occlusal function in patients treated for snoring or obstructive sleep apnea. The occlusal contact area (OCA) and bite force (Bf) of 12 patients who used OAs were measured with pressure-sensitive sheets in the morning and evening with the Dental Prescale Occluzer System. OCA and Bf were compared in each measurement period by using ANOVA. Percentage changes in the morning relative to the evening (OCA(M-E) and Bf(M-E)) were compared between the 2 periods by using the Wilcoxon signed rank test. Correlations between percentage changes in pretreatment and posttitration ((Pre-Post)OCA and (Pre-Post)Bf), age, and cephalometric variables were also assessed. Patients showed significant decreases in OCA and Bf when posttitration readings were compared with corresponding pretreatment measurements. OCA(M-E) and Bf(M-E) were significantly different between pretreatment and posttitration, suggesting that OCA and Bf tend to be smaller in the morning with OA use. (Pre-Post)Bf measured in the evening correlated with age. Effects on occlusal function after OA use were observed. These results suggest that practitioners should pay attention to the possible side effects of OAs on the dentition when treating patients with snoring or obstructive sleep apnea.

A Genetic Mechanism for Convergent Skin Lightening during Recent Human Evolution.

PubMed

Yang, Zhaohui; Zhong, Hua; Chen, Jing; Zhang, Xiaoming; Zhang, Hui; Luo, Xin; Xu, Shuhua; Chen, Hua; Lu, Dongsheng; Han, Yinglun; Li, Jinkun; Fu, Lijie; Qi, Xuebin; Peng, Yi; Xiang, Kun; Lin, Qiang; Guo, Yan; Li, Ming; Cao, Xiangyu; Zhang, Yanfeng; Liao, Shiyu; Peng, Yingmei; Zhang, Lin; Guo, Xiaosen; Dong, Shanshan; Liang, Fan; Wang, Jun; Willden, Andrew; Seang Aun, Hong; Serey, Bun; Sovannary, Tuot; Bunnath, Long; Samnom, Ham; Mardon, Graeme; Li, Qingwei; Meng, Anming; Shi, Hong; Su, Bing

2016-05-01

Skin lightening among Eurasians is thought to have been a convergence occurring independently in Europe and East Asia as an adaptation to high latitude environments. Among Europeans, several genes responsible for such lightening have been found, but the information available for East Asians is much more limited. Here, a genome-wide comparison between dark-skinned Africans and Austro-Asiatic speaking aborigines and light-skinned northern Han Chinese identified the pigmentation gene OCA2, showing unusually deep allelic divergence between these groups. An amino acid substitution (His615Arg) of OCA2 prevalent in most East Asian populations-but absent in Africans and Europeans-was significantly associated with skin lightening among northern Han Chinese. Further transgenic and targeted gene modification analyses of zebrafish and mouse both exhibited the phenotypic effect of the OCA2 variant manifesting decreased melanin production. These results indicate that OCA2 plays an important role in the convergent skin lightening of East Asians during recent human evolution. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Identification of two novel mutations in the SLC45A2 gene in a Hungarian pedigree affected by unusual OCA type 4.

PubMed

Tóth, Lola; Fábos, Beáta; Farkas, Katalin; Sulák, Adrienn; Tripolszki, Kornélia; Széll, Márta; Nagy, Nikoletta

2017-03-15

Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities. OCA type IV (OCA4, OMIM 606574) develops due to homozygous or compound heterozygous mutations in the solute carrier family 45, member 2 (SLC45A2) gene. This gene encodes a membrane-associated transport protein, which regulates tyrosinase activity and, thus, melanin content by changing melanosomal pH and disrupting the incorporation of copper into tyrosinase. Here we report two Hungarian siblings affected by an unusual OCA4 phenotype. After genomic DNA was isolated from peripheral blood of the patients, the coding regions of the SLC45A2 gene were sequenced. In silico tools were applied to identify the functional impact of the newly detected mutations. Direct sequencing of the SLC45A2 gene revealed two novel, heterozygous mutations, one missense (c.1226G > A, p.Gly409Asp) and one nonsense (c.1459C > T, p.Gln437*), which were present in both patients, suggesting the mutations were compound heterozygous. In silico tools suggest that these variations are disease causing mutations. The newly identified mutations may affect the transmembrane domains of the protein, and could impair transport function, resulting in decreases in both melanosomal pH and tyrosinase activity. Our study provides expands on the mutation spectrum of the SLC45A2 gene and the genetic background of OCA4.

Interaction of the B cell-specific transcriptional coactivator OCA-B and galectin-1 and a possible role in regulating BCR-mediated B cell proliferation.

PubMed

Yu, Xin; Siegel, Rachael; Roeder, Robert G

2006-06-02

OCA-B is a B cell-specific transcriptional coactivator for OCT factors during the activation of immunoglobulin genes. In addition, OCA-B is crucial for B cell activation and germinal center formation. However, the molecular mechanisms for OCA-B function in these processes are not clear. Our previous studies documented two OCA-B isoforms and suggested a novel mechanism for the function of the myristoylated, membrane-bound form of OCA-B/p35 as a signaling molecule. Here, we report the identification of galectin-1, and related galectins, as a novel OCA-B-interacting protein. The interaction of OCA-B and galectin-1 can be detected both in vivo and in vitro. The galectin-1 binding domain in OCA-B has been localized to the N terminus of OCA-B. In B cells lacking OCA-B expression, increased galectin-1 expression, secretion, and cell surface association are observed. Consistent with these observations, and a reported inhibitory interaction of galectin-1 with CD45, the phosphatase activity of CD45 is reduced modestly, but significantly, in OCA-B-deficient B cells. Finally, galectin-1 is shown to negatively regulate B cell proliferation and tyrosine phosphorylation upon BCR stimulation. Together, these results raise the possibility that OCA-B may regulate BCR signaling through an association with galectin-1.

The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosinase.

PubMed

Toyofuku, Kazutomo; Valencia, Julio C; Kushimoto, Tsuneto; Costin, Gertrude-E; Virador, Victoria M; Vieira, Wilfred D; Ferrans, Victor J; Hearing, Vincent J

2002-06-01

Oculocutaneous albinism (OCA) is caused by reduced or deficient melanin pigmentation in the skin, hair, and eyes. OCA has different phenotypes resulting from mutations in distinct pigmentation genes involved in melanogenesis. OCA type 2 (OCA2), the most common form of OCA, is an autosomal recessive disorder caused by mutations in the P gene, the function(s) of which is controversial. In order to elucidate the mechanism(s) involved in OCA2, our group used several antibodies specific for various melanosomal proteins (tyrosinase, Tyrp1, Dct, Pmel17 and HMB45), including a specific set of polyclonal antibodies against the p protein. We used confocal immunohistochemistry to compare the processing and distribution of those melanosomal proteins in wild type (melan-a) and in p mutant (melan-p1) melanocytes. Our results indicate that the melanin content of melan-p1 melanocytes was less than 50% that of wild type melan-a melanocytes. In contrast, the tyrosinase activities were similar in extracts of wild type and p mutant melanocytes. Confocal microscopy studies and pulse-chase analyses showed altered processing and sorting of tyrosinase, which is released from melan-p1 cells to the medium. Processing and sorting of Tyrp1 was also altered to some extent. However, Dct and Pmel17 expression and subcellular localization were similar in melan-a and in melan-p1 melanocytes. In melan-a cells, the p protein showed mainly a perinuclear pattern with some staining in the cytoplasm where some co-localization with HMB45 antibody was observed. These findings suggest that the p protein plays a major role in modulating the intracellular transport of tyrosinase and a minor role for Tyrp1, but is not critically involved in the transport of Dct and Pmel17. This study provides a basis to understand the relationship of the p protein with tyrosinase function and melanin synthesis, and also provides a rational approach to unveil the consequences of P gene mutations in the pathogenesis of OCA2.

Fresh Osteochondral Allograft Transplantation for Fractures of the Knee.

PubMed

Gracitelli, Guilherme C; Tirico, Luis Eduardo Passarelli; McCauley, Julie C; Pulido, Pamela A; Bugbee, William D

2017-04-01

Objective The purpose of this study was to evaluate functional outcomes and allograft survivorship among patients with knee fracture who underwent fresh osteochondral allograft (OCA) transplantation as a salvage treatment option. Design Retrospective analysis of prospectively collected data. Setting Department of Orthopaedic Surgery at one hospital. Patients Fresh OCAs were implanted for osteochondral lesions after knee fracture in 24 males and 15 females with an average age of 34 years. Twenty-nine lesions (74%) were tibial plateau fractures, 6 (15%) were femoral condyle fractures, and 4 (10%) were patella fractures. Main Outcome Measurements Clinical evaluation included modified Merle d'Aubigné-Postel (18-point), International Knee Documentation Committee, and Knee Society function scores, and patient satisfaction. Failure of OCA was defined as revision OCA or conversion to total knee arthroplasty (TKA). Results Nineteen of 39 knees (49%) had further surgery. Ten knees (26%) were considered OCA failures (3 OCA revisions, 6 TKA, and 1 patellectomy). Survivorship of the OCA was 82.6% at 5 years and 69.6% at 10 years. Among the 29 knees (74%) that had the OCA still in situ, median follow-up was 6.6 years. Pain and function improved from preoperative to latest follow-up; 83% of patients reported satisfaction with OCA results. Conclusion OCA transplantation is a useful salvage treatment option for osteochondral lesions caused by knee fracture. Although the reoperation rate was high, successful outcome was associated with significant clinical improvement.

FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver.

PubMed

Papazyan, Romeo; Liu, Xueqing; Liu, Jingwen; Dong, Bin; Plummer, Emily M; Lewis, Ronald D; Roth, Jonathan D; Young, Mark A

2018-06-01

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism.

PubMed

Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya; Leeb, Tosso

2017-01-01

We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G). The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5'-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1). Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2) in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5'-splice site of the first intron of the canine OCA2 gene.

Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-Induced NASH (DIN) hamster model.

PubMed

Briand, François; Brousseau, Emmanuel; Quinsat, Marjolaine; Burcelin, Rémy; Sulpice, Thierry

2018-01-05

The use of rat and mouse models limits the translation to humans for developing novel drugs targeting nonalcoholic steatohepatitis (NASH). Obeticholic acid (OCA) illustrates this limitation since its dyslipidemic effect in humans cannot be observed in these rodents. Conversely, Golden Syrian hamsters have a lipoprotein metabolism mimicking human dyslipidemia since it does express the cholesteryl ester transfer protein (CETP). We therefore developed a Diet-Induced NASH (DIN) hamster model and evaluated the impact of OCA. Compared with chow fed controls, hamsters fed for 20 weeks with a free-choice (FC) diet, developed obesity, insulin resistance, dyslipidemia and NASH (microvesicular steatosis, inflammation, hepatocyte ballooning and perisinusoidal to bridging fibrosis). After 20 weeks of diet, FC fed hamsters were treated without or with obeticholic acid (15mg/kg/day) for 5 weeks. Although a non-significant trend towards higher dietary caloric intake was observed, OCA significantly lowered body weight after 5 weeks of treatment. OCA significantly increased CETP activity and LDL-C levels by 20% and 27%, and reduced HDL-C levels by 20%. OCA blunted hepatic gene expression of Cyp7a1 and Cyp8b1 and reduced fecal bile acids mass excretion by 64% (P < 0.05). Hamsters treated with OCA showed a trend towards higher scavenger receptor Class B type I (SR-BI) and lower LDL-receptor hepatic protein expression. OCA reduced NAS score for inflammation (P < 0.01) and total NAS score, although not significantly. Compared to mouse and rat models, the DIN hamster replicates benefits and side effects of OCA as observed in humans, and should be useful for evaluating novel drugs targeting NASH. Copyright © 2017 Elsevier B.V. All rights reserved.

Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.

PubMed

Mudaliar, Sunder; Henry, Robert R; Sanyal, Arun J; Morrow, Linda; Marschall, Hanns-Ulrich; Kipnes, Mark; Adorini, Luciano; Sciacca, Cathi I; Clopton, Paul; Castelloe, Erin; Dillon, Paul; Pruzanski, Mark; Shapiro, David

2013-09-01

Obeticholic acid (OCA; INT-747, 6α-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7α-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma.

PubMed

Jannot, Anne-Sophie; Meziani, Roubila; Bertrand, Guylene; Gérard, Benedicte; Descamps, Vincent; Archimbaud, Alain; Picard, Catherine; Ollivaud, Laurence; Basset-Seguin, Nicole; Kerob, Delphine; Lanternier, Guy; Lebbe, Celeste; Saiag, P; Crickx, Beatrice; Clerget-Darpoux, Françoise; Grandchamp, Bernard; Soufir, Nadem; Melan-Cohort

2005-08-01

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

Quantitative computed tomography applied to interstitial lung diseases.

PubMed

Obert, Martin; Kampschulte, Marian; Limburg, Rebekka; Barańczuk, Stefan; Krombach, Gabriele A

2018-03-01

To evaluate a new image marker that retrieves information from computed tomography (CT) density histograms, with respect to classification properties between different lung parenchyma groups. Furthermore, to conduct a comparison of the new image marker with conventional markers. Density histograms from 220 different subjects (normal = 71; emphysema = 73; fibrotic = 76) were used to compare the conventionally applied emphysema index (EI), 15 th percentile value (PV), mean value (MV), variance (V), skewness (S), kurtosis (K), with a new histogram's functional shape (HFS) method. Multinomial logistic regression (MLR) analyses was performed to calculate predictions of different lung parenchyma group membership using the individual methods, as well as combinations thereof, as covariates. Overall correct assigned subjects (OCA), sensitivity (sens), specificity (spec), and Nagelkerke's pseudo R 2 (NR 2 ) effect size were estimated. NR 2 was used to set up a ranking list of the different methods. MLR indicates the highest classification power (OCA of 92%; sens 0.95; spec 0.89; NR 2 0.95) when all histogram analyses methods were applied together in the MLR. Highest classification power among individually applied methods was found using the HFS concept (OCA 86%; sens 0.93; spec 0.79; NR 2 0.80). Conventional methods achieved lower classification potential on their own: EI (OCA 69%; sens 0.95; spec 0.26; NR 2 0.52); PV (OCA 69%; sens 0.90; spec 0.37; NR 2 0.57); MV (OCA 65%; sens 0.71; spec 0.58; NR 2 0.61); V (OCA 66%; sens 0.72; spec 0.53; NR 2 0.66); S (OCA 65%; sens 0.88; spec 0.26; NR 2 0.55); and K (OCA 63%; sens 0.90; spec 0.16; NR 2 0.48). The HFS method, which was so far applied to a CT bone density curve analysis, is also a remarkable information extraction tool for lung density histograms. Presumably, being a principle mathematical approach, the HFS method can extract valuable health related information also from histograms from complete different areas. Copyright © 2018 Elsevier B.V. All rights reserved.

Oct1 and OCA-B are selectively required for CD4 memory T cell function.

PubMed

Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean

2015-11-16

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. © 2015 Shakya et al.

Oct1 and OCA-B are selectively required for CD4 memory T cell function

PubMed Central

Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N.; Snook, Jeremy; Kuchroo, Vijay K.; Yosef, Nir; Chan, Raymond C.; Regev, Aviv

2015-01-01

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4+ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4+ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4+ T cell memory. PMID:26481684

Differential recognition of a dileucine-based sorting signal by AP-1 and AP-3 reveals a requirement for both BLOC-1 and AP-3 in delivery of OCA2 to melanosomes

PubMed Central

Sitaram, Anand; Dennis, Megan K.; Chaudhuri, Rittik; De Jesus-Rojas, Wilfredo; Tenza, Danièle; Setty, Subba Rao Gangi; Wood, Christopher S.; Sviderskaya, Elena V.; Bennett, Dorothy C.; Raposo, Graça; Bonifacino, Juan S.; Marks, Michael S.

2012-01-01

Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adaptors, but the relative contribution of each adaptor to cargo recognition and their functional interactions with other effectors during transport to melanosomes are not clear. Here we exploit targeted mutagenesis of the acidic dileucine–based sorting signal in the pigment cell–specific protein OCA2 to dissect the relative roles of AP-1 and AP-3 in transport to melanosomes. We show that binding to AP-1 or AP-3 depends on the primary sequence of the signal and not its position within the cytoplasmic domain. Mutants that preferentially bound either AP-1 or AP-3 each trafficked toward melanosomes and functionally complemented OCA2 deficiency, but AP-3 binding was necessary for steady-state melanosome localization. Unlike tyrosinase, which also engages AP-3 for optimal melanosomal delivery, both AP-1– and AP-3–favoring OCA2 variants required BLOC-1 for melanosomal transport. These data provide evidence for distinct roles of AP-1 and AP-3 in OCA2 transport to melanosomes and indicate that BLOC-1 can cooperate with either adaptor during cargo sorting to LROs. PMID:22718909

Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico.

PubMed

Santiago Borrero, Pedro J; Rodríguez-Pérez, Yolanda; Renta, Jessicca Y; Izquierdo, Natalio J; Del Fierro, Laura; Muñoz, Daniel; Molina, Norma López; Ramírez, Sonia; Pagán-Mercado, Glorivee; Ortíz, Idith; Rivera-Caragol, Enid; Spritz, Richard A; Cadilla, Carmen L

2006-01-01

Hermansky-Pudlak syndrome (HPS) (MIM #203300) is a heterogeneous group of autosomal recessive disorders characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal dysfunction. HPS is very common in Puerto Rico (PR), particularly in the northwest part of the island, with a frequency of approximately 1:1,800. Two HPS genes and mutations have been identified in PR, a 16-base pair (bp) duplication in HPS1 and a 3,904-bp deletion in HPS3. In Puerto Ricans with more typical OCA, the most common mutation of the tyrosinase (TYR) (human tyrosinase (OCA1) gene) gene was G47D. We describe screening 229 Puerto Rican OCA patients for these mutations, and for mutations in the OCA2 gene. We found the HPS1 mutation in 42.8% of cases, the HPS3 deletion in 17%, the TYR G47D mutation in 3.0%, and a 2.4-kb deletion of the OCA2 gene in 1.3%. Among Puerto Rican newborns, the frequency of the HPS1 mutation is highest in northwest PR (1:21; 4.8%) and lower in central PR (1:64; 1.6%). The HPS3 gene deletion is most frequent in central PR (1:32; 3.1%). Our findings provide insights into the genetics of albinism and HPS in PR, and provide the basis for genetic screening for these disorders in this minority population.

Genetic Testing for Oculocutaneous Albinism Type 1 and 2 and Hermansky–Pudlak Syndrome Type 1 and 3 Mutations in Puerto Rico

PubMed Central

Santiago Borrero, Pedro J.; Rodríguez-Pérez, Yolanda; Renta, Jessicca Y.; Izquierdo, Natalio J.; del Fierro, Laura; Muñoz, Daniel; Molina, Norma López; Ramírez, Sonia; Pagán-Mercado, Glorivee; Ortíz, Idith; Rivera-Caragol, Enid; Spritz, Richard A.; Cadilla, Carmen L.

2013-01-01

Hermansky–Pudlak syndrome (HPS) (MIM #203300) is a heterogeneous group of autosomal recessive disorders characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal dysfunction. HPS is very common in Puerto Rico (PR), particularly in the northwest part of the island, with a frequency of ~1:1,800. Two HPS genes and mutations have been identified in PR, a 16-base pair (bp) duplication in HPS1 and a 3,904-bp deletion in HPS3. In Puerto Ricans with more typical OCA, the most common mutation of the tyrosinase (TYR) (human tyrosinase (OCA1) gene) gene was G47D. We describe screening 229 Puerto Rican OCA patients for these mutations, and for mutations in the OCA2 gene. We found the HPS1 mutation in 42.8% of cases, the HPS3 deletion in 17%, the TYR G47D mutation in 3.0%, and a 2.4-kb deletion of the OCA2 gene in 1.3%. Among Puerto Rican newborns, the frequency of the HPS1 mutation is highest in northwest PR (1:21; 4.8%) and lower in central PR (1:64; 1.6%). The HPS3 gene deletion is most frequent in central PR (1:32; 3.1%). Our findings provide insights into the genetics of albinism and HPS in PR, and provide the basis for genetic screening for these disorders in this minority population. PMID:16417222

Fresh Osteochondral Allograft Transplantation: Is Graft Storage Time Associated With Clinical Outcomes and Graft Survivorship?

PubMed

Schmidt, Kenneth J; Tírico, Luís E; McCauley, Julie C; Bugbee, William D

2017-08-01

Regulatory concerns and the popularity of fresh osteochondral allograft (OCA) transplantation have led to a need for prolonged viable storage of osteochondral grafts. Tissue culture media allow a longer storage time but lead to chondrocyte death within the tissue. The long-term clinical consequence of prolonged storage is unknown. Patients transplanted with OCAs with a shorter storage time would have lower failure rates and better clinical outcomes than those transplanted with OCAs with prolonged storage. Cohort study; Level of evidence, 3. A matched-pair study was performed of 75 patients who received early release grafts (mean storage, 6.3 days [range, 1-14 days]) between 1997 and 2002, matched 1:1 by age, diagnosis, and graft size, with 75 patients who received late release grafts (mean storage time, 20.0 days [range, 16-28 days]) from 2002 to 2008. The mean age was 33.5 years, and the median graft size was 6.3 cm 2 . All patients had a minimum 2-year follow-up. Evaluations included pain, satisfaction, function, failures, and reoperations. Outcome measures included the modified Merle d'Aubigné-Postel (18-point) scale, International Knee Documentation Committee (IKDC) form, and Knee Society function (KS-F) scale. Clinical failure was defined as revision OCA transplantation or conversion to arthroplasty. Among patients with grafts remaining in situ, the mean follow-up was 11.9 years (range, 2.0-16.8 years) and 7.8 years (range, 2.3-11.1 years) for the early and late release groups, respectively. OCA failure occurred in 25.3% (19/75) of patients in the early release group and 12.0% (9/75) of patients in the late release group ( P = .036). The median time to failure was 3.5 years (range, 1.7-13.8 years) and 2.7 years (range, 0.3-11.1 years) for the early and late release groups, respectively. The 5-year survivorship of OCAs was 85% for the early release group and 90% for the late release group ( P = .321). No differences in postoperative pain and function were noted between the groups. Ninety-one percent of the early release group and 93% of the late release group reported satisfaction with OCA results. The transplantation of OCA tissue with prolonged storage is safe and effective for large osteochondral lesions of the knee and has similar clinical outcomes and satisfaction to the transplantation of early release grafts.

OCA-B regulation of B-cell development and function.

PubMed

Teitell, Michael A

2003-10-01

The transcriptional co-activator OCA-B [for Oct co-activator from B cells, also known as OBF-1 (OCT-binding factor-1) and Bob1] is not required for B-cell genesis but does regulate subsequent B-cell development and function. OCA-B deficient mice show strain-specific, partial blocks at multiple stages of B-cell maturation and a complete disruption of germinal center formation in all strains, causing humoral immune deficiency and susceptibility to infection. OCA-B probably exerts its effects through the regulation of octamer-motif controlled gene expression. The OCA-B gene encodes two proteins of distinct molecular weight, designated p34 and p35. The p34 isoform localizes in the nucleus, whereas the p35 isoform is myristoylated and is bound to the cytoplasmic membrane. p35 can traffic to the nucleus and probably activates octamer-dependent transcription, although this OCA-B isoform might regulate B cells through membrane-related signal transduction.

Outcomes of Osteochondral Allograft Transplantation With and Without Concomitant Meniscus Allograft Transplantation: A Comparative Matched Group Analysis.

PubMed

Frank, Rachel M; Lee, Simon; Cotter, Eric J; Hannon, Charles P; Leroux, Timothy; Cole, Brian J

2018-03-01

Osteochondral allograft transplantation (OCA) is often performed with concomitant meniscus allograft transplantation (MAT) as a strategy for knee joint preservation, although to date, the effect of concomitant MAT on outcomes and failure rates after OCA has not been assessed. To determine clinical outcomes for patients undergoing OCA with MAT as compared with a matched cohort of patients undergoing isolated OCA. Control study; Level of evidence, 3. Patients who underwent OCA of the medial or lateral femoral condyle without concomitant MAT by a single surgeon were compared with a matched group of patients who underwent OCA with concomitant MAT (ipsilateral compartment). The patients were matched per age, sex, body mass index, and number of previous ipsilateral knee operations ±1. Patient-reported outcomes, complications, reoperations, and survival rates were compared between groups. One hundred patients undergoing OCA (50 isolated, 50 with MAT) with a mean ± SD follow-up of 4.9 ± 2.7 years (minimum, 2 years) were included (age, 31.7 ± 9.8 years; 52% male). Significantly more patients underwent OCA to the medial femoral condyle (n = 59) than the lateral femoral condyle (n = 41, P < .0001). Patients underwent 2.7 ± 1.7 operations on the ipsilateral knee before OCA. There were no significant differences between the groups regarding reoperation rate (n = 18 for OCA with MAT, n = 17 for OCA without MAT, P = .834), time to reoperation (2.2 ± 2.4 years for OCA with MAT, 3.4 ± 2.7 years for OCA without MAT, P = .149), or failure rates (n = 7 [14%] for OCA with MAT, n = 7 [14%] for OCA without MAT, P > .999). There were no significant differences in patient-reported clinical outcome scores between the groups at final follow-up. There was no significant difference in failure rates between patients undergoing medial femoral condyle OCA (n = 12, 15.3%) and lateral femoral condyle OCA (n = 5, 12.2%, P = .665). These results imply that with appropriate surgical indications to address meniscus deficiency in patients otherwise indicated for OCA and despite the added surgical time and complexity of concomitant MAT, outcomes are favorable, with an 86% OCA graft survivorship at 5 years. This information can be used to counsel patients undergoing OCA with concomitant MAT as part of a knee joint preservation strategy.

DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in Molecular Diagnostics

PubMed Central

Simeonov, Dimitre R.; Wang, Xinjing; Wang, Chen; Sergeev, Yuri; Dolinska, Monika; Bower, Matthew; Fischer, Roxanne; Winer, David; Dubrovsky, Genia; Balog, Joan Z.; Huizing, Marjan; Hart, Rachel; Zein, Wadih M.; Gahl, William A.; Brooks, Brian P.; Adams, David R.

2014-01-01

Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA, caused by mutations in TYR (OCA-1), OCA2 (OCA-2), TYRP1 (OCA-3), or SLC45A2 (OCA-4). Here we report 22 novel mutations; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and 8 from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations, along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 25% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation. PMID:23504663

Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes.

PubMed

Zhang, Yuanyuan; Jackson, Jonathan P; St Claire, Robert L; Freeman, Kimberly; Brouwer, Kenneth R; Edwards, Jeffrey E

2017-08-01

Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose-dependently increased fibroblast growth factor-19 (FGF-19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8-fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OST α ) and OST β increased by 6.4 ± 0.2-fold and 42.9 ± 7.9-fold, respectively. The upregulation of BSEP and OST α and OST β, by OCA reduced the intracellular concentrations of d 8 -TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid-induced toxicity observed in cholestatic diseases. © 2017 Intercept Pharmaceuticals. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

A Partial Gene Deletion of SLC45A2 Causes Oculocutaneous Albinism in Doberman Pinscher Dogs

PubMed Central

Winkler, Paige A.; Gornik, Kara R.; Ramsey, David T.; Dubielzig, Richard R.; Venta, Patrick J.; Petersen-Jones, Simon M.; Bartoe, Joshua T.

2014-01-01

The first white Doberman pinscher (WDP) dog was registered by the American Kennel Club in 1976. The novelty of the white coat color resulted in extensive line breeding of this dog and her offspring. The WDP phenotype closely resembles human oculocutaneous albinism (OCA) and clinicians noticed a seemingly high prevalence of pigmented masses on these dogs. This study had three specific aims: (1) produce a detailed description of the ocular phenotype of WDPs, (2) objectively determine if an increased prevalence of ocular and cutaneous melanocytic tumors was present in WDPs, and (3) determine if a genetic mutation in any of the genes known to cause human OCA is causal for the WDP phenotype. WDPs have a consistent ocular phenotype of photophobia, hypopigmented adnexal structures, blue irides with a tan periphery and hypopigmented retinal pigment epithelium and choroid. WDPs have a higher prevalence of cutaneous melanocytic neoplasms compared with control standard color Doberman pinschers (SDPs); cutaneous tumors were noted in 12/20 WDP (<5 years of age: 4/12; >5 years of age: 8/8) and 1/20 SDPs (p<0.00001). Using exclusion analysis, four OCA causative genes were investigated for their association with WDP phenotype; TYR, OCA2, TYRP1 and SLC45A2. SLC45A2 was found to be linked to the phenotype and gene sequencing revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4∶77,062,968–77,067,051). This mutation is highly likely to be the cause of the WDP phenotype and is supported by a lack of detectable SLC45A2 transcript levels by reverse transcriptase PCR. The WDP provides a valuable model for studying OCA4 visual disturbances and melanocytic neoplasms in a large animal model. PMID:24647637

Combined osteochondral allograft and meniscal allograft transplantation: a survivorship analysis.

PubMed

Getgood, Alan; Gelber, Jonathon; Gortz, Simon; De Young, Alison; Bugbee, William

2015-04-01

The efficacy of meniscal allograft transplantation (MAT) and osteochondral allografting (OCA) as individual treatment modalities for select applications is well established. MAT and OCA are considered symbiotic procedures due to a complementary spectrum of indications and reciprocal contraindications. However, few outcomes of concomitant MAT and OCA have been reported. This study is a retrospective review of patients who received simultaneous MAT and OCA between 1983 and 2011. Forty-eight (twenty-nine male: nineteen female) patients with a median age of 35.8 years (15-66) received combined MAT and OCA procedures between 1983 and 2011. Forty-three patients had received previous surgery with a median of 3 procedures (1-11 procedures). The underlying diagnosis was trauma (tibial plateau fracture) in 33 % with osteoarthritis predominating in 54.2 % of cases. Thirty-one patients received a lateral meniscus, 16 received a medial meniscus and one patient received bilateral MAT. The median number of OCAs was two per patient (1-5 grafts), with a median graft area of 15 cm(2) (0.7-41 cm(2)). There were 21 unipolar, 24 bipolar (tibiofemoral) and three multifocal lesions. Thirty-six MATs constituted a compound tibial plateau OCA with native meniscus attached. At follow-up, failure was defined as any procedure resulting in removal or revision of one or more of the grafts. Patients completed the modified Merle d'Aubigné and Postel (18-point) scale, Knee Society Function (KS-F) score, and subjective International Knee Documentation Committee (IKDC) scores. Patient satisfaction was also captured. Twenty-six of 48 patients (54.2 %) required reoperation, but only 11 patients (22.9 %) were noted to have failed (10 MAT and 11 OCA). The mean time to failure was 3.2 years (95 % CI 1.5-4.9 years) and 2.7 years (95 % CI 1.3-4.2 years) for MAT and OCA, respectively. The 5-year survivorship was 78 and 73 % for MAT and OCA respectively, and 69 and 68 % at 10 years. Six of the failures were in the OA cases and one was an OCD lesion where bipolar grafts were utilized. The OCD case underwent a revision OCA and remains intact. The others were converted to knee arthroplasty. One case failed due to early deep infection, ultimately requiring arthrodesis. Of those with grafts still intact, the mean clinical follow-up was 6.8 years (1.7-17.1 years). Statistically significant improvements in all outcome scores were noted between baseline and the latest follow-up. In total, 90 % of those responding would have the surgery again and 78 % were either extremely satisfied or satisfied with the outcome. The overall success rate of concomitant MAT and OCA was comparable with reported results for either procedure in isolation. A trend towards  a worse outcome was observed with bipolar tibiofemoral grafts in the setting of OA. Comparatively better results in less advanced, unipolar disease could suggest a benefit to early intervention that might merit a lower treatment threshold for combined MAT and OCA. IV.

Lesion Size Does Not Predict Outcomes in Fresh Osteochondral Allograft Transplantation.

PubMed

Tírico, Luis E P; McCauley, Julie C; Pulido, Pamela A; Bugbee, William D

2018-03-01

Cartilage repair algorithms use lesion size to choose surgical techniques when selecting a cartilage repair procedure. The association of fresh osteochondral allograft (OCA) size with graft survivorship and subjective patient outcomes is still unknown. To determine if lesion size (absolute or relative) affects outcomes after OCA transplantation. Cohort study; Level of evidence, 3. The study included 156 knees in 143 patients who underwent OCA transplantation from 1998 to 2014 for isolated femoral condyle lesions. The mean age was 29.6 ± 11.4 years, and 62.9% were male. The majority of patients (62.2%) presented for cartilage repair because of osteochondritis dissecans. The mean graft area, used as a surrogate for absolute size of the lesion, was 6.4 cm 2 (range, 2.3-11.5 cm 2 ). The relative size of the lesion was calculated as the tibial width ratio (TWR; ratio of graft area to tibial width) and affected femoral condyle ratio (AFCR; ratio of graft area to affected femoral condyle width) using preoperative radiographs. All patients had a minimum follow-up of 2 years. Further surgical procedures were documented, and graft failure was defined as revision OCA transplantation or conversion to arthroplasty. International Knee Documentation Committee (IKDC) pain, function, and total scores were obtained. Satisfaction with OCA transplantation was assessed. The mean follow-up among patients with grafts remaining in situ was 6.0 years (range, 1.9-16.5 years). The OCA failure rate was 5.8%. Overall survivorship of the graft was 97.2% at 5 years and 93.5% at 10 years. No difference in postoperative outcomes between groups was found in absolute or relative size. Change in IKDC scores (from preoperative to latest follow-up) was greater for knees with large lesions compared to knees with small lesions, among all measurement methods. Overall satisfaction with the results of OCA transplantation was 89.8%. The size of the lesion, either absolute or relative, does not influence outcomes after OCA transplantation for isolated femoral condyle lesions of the knee.

Long-term clinical impact and cost-effectiveness of obeticholic acid for the treatment of primary biliary cholangitis.

PubMed

Samur, Sumeyye; Klebanoff, Matthew; Banken, Reiner; Pratt, Daniel S; Chapman, Rick; Ollendorf, Daniel A; Loos, Anne M; Corey, Kathleen; Hur, Chin; Chhatwal, Jagpreet

2017-03-01

Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune liver disease that mainly affects middle-aged women. Obeticholic acid (OCA), which was recently approved by the Food and Drug Administration for PBC treatment, has demonstrated positive effects on biochemical markers of liver function. Our objective was to evaluate the long-term clinical impact and cost-effectiveness of OCA as a second-line treatment for PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA. We developed a mathematical model to simulate the lifetime course of PBC patients treated with OCA+UDCA versus UDCA alone. Efficacy data were derived from the phase 3 PBC OCA International Study of Efficacy trial, and the natural history of PBC was informed by published clinical studies. Model outcomes were validated using the PBC Global Study. We found that in comparison with UDCA, OCA+UDCA could decrease the 15-year cumulative incidences of decompensated cirrhosis from 12.2% to 4.5%, hepatocellular carcinoma from 9.1% to 4.0%, liver transplants from 4.5% to 1.2%, and liver-related deaths from 16.2% to 5.7% and increase 15-year transplant-free survival from 61.1% to 72.9%. The lifetime cost of PBC treatment would increase from $63,000 to $902,000 (1,330% increment). The discounted quality-adjusted life years with UDCA and OCA+UDCA were 10.74 and 11.78, respectively, and the corresponding costs were $142,300 and $633,900, resulting in an incremental cost-effectiveness ratio of $473,400/quality-adjusted life year gained. The results were most sensitive to the cost of OCA. OCA is a promising new therapy to substantially improve the long-term outcomes of PBC patients, but at its current annual price of $69,350, it is not cost-effective using a willingness-to-pay threshold of $100,000/quality-adjusted life year; pricing below $18,450/year is needed to make OCA cost-effective. (Hepatology 2017;65:920-928). © 2016 by the American Association for the Study of Liver Diseases.

Identification of transcription coactivator OCA-B-dependent genes involved in antigen-dependent B cell differentiation by cDNA array analyses.

PubMed

Kim, Unkyu; Siegel, Rachael; Ren, Xiaodi; Gunther, Cary S; Gaasterland, Terry; Roeder, Robert G

2003-07-22

The tissue-specific transcriptional coactivator OCA-B is required for antigen-dependent B cell differentiation events, including germinal center formation. However, the identity of OCA-B target genes involved in this process is unknown. This study has used large-scale cDNA arrays to monitor changes in gene expression patterns that accompany mature B cell differentiation. B cell receptor ligation alone induces many genes involved in B cell expansion, whereas B cell receptor and helper T cell costimulation induce genes associated with B cell effector function. OCA-B expression is induced by both B cell receptor ligation alone and helper T cell costimulation, suggesting that OCA-B is involved in B cell expansion as well as B cell function. Accordingly, several genes involved in cell proliferation and signaling, such as Lck, Kcnn4, Cdc37, cyclin D3, B4galt1, and Ms4a11, have been identified as OCA-B-dependent genes. Further studies on the roles played by these genes in B cells will contribute to an understanding of B cell differentiation.

The Optic Canal: A Bottleneck for Cerebrospinal Fluid Dynamics in Normal-Tension Glaucoma?

PubMed

Pircher, Achmed; Montali, Margherita; Berberat, Jatta; Remonda, Luca; Killer, Hanspeter E

2017-01-01

To report on the optic canal cross-sectional area (OCA) in Caucasian patients with normal-tension glaucoma (NTG) compared with Caucasian control subjects without known optic nerve (ON) diseases. Retrospective analysis of computed tomographic images of the cranium and orbits in 56 NTG patients (30 females and 26 males; 99 of 112 eyes; mean age 67.7 ± 11.1 years). Fifty-six age- and gender-matched subjects (mean age: 68.0 ± 11.2 years) without known ON diseases served as controls. The OCA at the orbital opening was measured in square millimeters by using the tool "freehand." Statistical analysis was performed by using the independent two-tailed t -test. The mean orbital opening OCA in NTGs measured 14.5 ± 3.5 mm 2 (right OCA: 14.4 ± 3.6 mm 2 , left OCA: 14.5 ± 3.4 mm 2 ) and in controls measured 18.3 ± 2.6 mm 2 (right OCA: 18.5 ± 2.7 mm 2 , left OCA: 18.1 ± 2.5 mm 2 ). The difference between NTG and controls was statistically significant ( p  < 0.000 for the right OCA, p  < 0.000 for the left OCA). This study demonstrates narrower OCAs in Caucasian NTG patients compared with Caucasian control subjects without known ON diseases. Narrower OCAs might contribute to a discontinuity of the cerebrospinal fluid flow between the intracranial and orbital subarachnoid space in NTG patients. This might have an influence onto the pathophysiology in NTG.

Identification of Five Novel Variants in Chinese Oculocutaneous Albinism by Targeted Next-Generation Sequencing.

PubMed

Qiu, Biyuan; Ma, Tao; Peng, Chunyan; Zheng, Xiaoqin; Yang, Jiyun

2018-04-01

The diagnosis of oculocutaneous albinism (OCA) is established using clinical signs and symptoms. OCA is, however, a highly genetically heterogeneous disease with mutations identified in at least nineteen unique genes, many of which produce overlapping phenotypic traits. Thus, differentiating genetic OCA subtypes for diagnoses and genetic counseling is challenging, based on clinical presentation alone, and would benefit from a comprehensive molecular diagnostic. To develop and validate a more comprehensive, targeted, next-generation-sequencing-based diagnostic for the identification of OCA-causing variants. The genomic DNA samples from 28 OCA probands were analyzed by targeted next-generation sequencing (NGS), and the candidate variants were confirmed through Sanger sequencing. We observed mutations in the TYR, OCA2, and SLC45A2 genes in 25/28 (89%) patients with OCA. We identified 38 pathogenic variants among these three genes, including 5 novel variants: c.1970G>T (p.Gly657Val), c.1669A>C (p.Thr557Pro), c.2339-2A>C, and c.1349C>G (p.Thr450Arg) in OCA2; c.459_470delTTTTGCTGCCGA (p.Ala155_Phe158del) in SLC45A2. Our findings expand the mutational spectrum of OCA in the Chinese population, and the assay we developed should be broadly useful as a molecular diagnostic, and as an aid for genetic counseling for OCA patients.

Noise-immune complex correlation for vasculature imaging based on standard and Jones-matrix optical coherence tomography

NASA Astrophysics Data System (ADS)

Makita, Shuichi; Kurokawa, Kazuhiro; Hong, Young-Joo; Li, En; Miura, Masahiro; Yasuno, Yoshiaki

2016-03-01

A new optical coherence angiography (OCA) method, called correlation mapping OCA (cmOCA), is presented by using the SNR-corrected complex correlation. An SNR-correction theory for the complex correlation calculation is presented. The method also integrates a motion-artifact-removal method for the sample motion induced decorrelation artifact. The theory is further extended to compute more reliable correlation by using multi- channel OCT systems, such as Jones-matrix OCT. The high contrast vasculature imaging of in vivo human posterior eye has been obtained. Composite imaging of cmOCA and degree of polarization uniformity indicates abnormalities of vasculature and pigmented tissues simultaneously.

Two Variants in SLC24A5 Are Associated with “Tiger-Eye” Iris Pigmentation in Puerto Rican Paso Fino Horses

PubMed Central

Mack, Maura; Kowalski, Elizabeth; Grahn, Robert; Bras, Dineli; Penedo, Maria Cecilia T.; Bellone, Rebecca

2017-01-01

A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino (PRPF) horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study (GWAS) with 24 individuals identified a locus on ECA 1 reaching genome-wide significance (Pcorrected = 1.32 × 10−5). This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium/Calcium Exchanger), Member 5 (SLC24A5), with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism (OCA) type 6 (OCA6), which is characterized by dilute skin, hair, and eye pigmentation, as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a nonsynonymous mutation in exon 2 (p.Phe91Tyr) of SLC24A5 (called here Tiger-eye 1), which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628 bp deletion encompassing all of exon 7 of SLC24A5 (c.875-340_1081+82del), which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye-associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds not known to have the tiger-eye phenotype. Here, we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2) does not appear to cause ocular anomalies or a change in coat color in the PRPF horse. PMID:28655738

TYPES OF ALBINISM IN THE BLACK SOUTHERN AFRICA POPULATION.

PubMed

Kromberg, J G R; Bothwell, J; Kidson, S H; Manga, P; Kerr, R; Jenkins, T

2012-01-01

Oculocutaneous albinism (OCA) is the most common inherited disorder in Southern African blacks and several types have been described. Molecular techniques, where available, can be used to confirm a clinical diagnosis and the type of OCA, if necessary, and for prenatal diagnosis. To investigate and classify the different types of albinism commonly found and to determine the clinical implications for each type. A descriptive survey. Gauteng province, South Africa, and Lesotho. Three groups of subjects with OCA (96 from a genetics clinic, 62 from a dermatology clinic, and 31 from community surveys) from the black African population participated. Subjects underwent clinical and/or dermatological examinations and were then classified according to type of OCA. Four forms of OCA were identified: most (82%) subjects had OCA2 (a tyrosinase- positive type) with three sub-types: those without large freckles (ephelides) on exposed areas (named OCA 2a in this study), those with such freckles (named OCA 2b), and those with brown albinism (BOCA); the remainder had red/rufous albinism, ROCA (OCA 3). The four forms could be distinguished from each other clinically without using molecular genetic testing. The most common types of albinism found in the black population of Southern Africa are OCA2 and OCA3. Given the high prevalence of the disorder, together with the high risk of skin cancer, and the recent persecution of affected individuals in certain East African countries, these findings and their clinical implications have significance in terms of both education and awareness for health professionals and lay people caring for those with albinism.

Diagnostic Capability of Peripapillary Retinal Volume Measurements in Glaucoma.

PubMed

Simavli, Huseyin; Poon, Linda Yi-Chieh; Que, Christian J; Liu, Yingna; Akduman, Mustafa; Tsikata, Edem; de Boer, Johannes F; Chen, Teresa C

2017-06-01

To determine the diagnostic capability of spectral domain optical coherence tomography peripapillary retinal volume (RV) measurements. A total of 156 patients, 89 primary open-angle glaucoma and 67 normal subjects, were recruited. Spectral domain optical coherence tomography peripapillary RV was calculated for 4 quadrants using 3 annuli of varying scan circle diameters: outer circumpapillary annuli of circular grids 1, 2, and 3 (OCA1, OCA2, OCA3). Area under the receiver operating characteristic curves and pairwise comparisons of receiver operating characteristic (ROC) curves were performed to determine which quadrants were best for diagnosing primary open-angle glaucoma. The pairwise comparisons of the best ROC curves for RV and retinal nerve fiber layer (RNFL) were performed. The artifact rates were analyzed. Pairwise comparisons showed that the smaller annuli OCA1 and OCA2 had better diagnostic performance than the largest annulus OCA3 (P<0.05 for all quadrants). OCA1 and OCA2 had similar diagnostic performance, except for the inferior quadrant which was better for OCA1 (P=0.0033). The pairwise comparisons of the best ROC curves for RV and RNFL were not statistically significant. RV measurements had lower rates of artifacts at 7.4% while RNFL measurements had higher rates at 42.9%. Peripapillary RV measurements have excellent ability for diagnosing not only glaucoma patients but also a subset of early glaucoma patients. The inferior quadrant of peripapillary annulus OCA1 demonstrated the best diagnostic capability for both glaucoma and early glaucoma. The diagnostic ability of RV is comparable with that of RNFL parameters in glaucoma but with lower artifact rates.

Diagnostic Capability of Peripapillary Retinal Volume Measurements in Glaucoma

PubMed Central

Simavli, Huseyin; Poon, Linda Yi-Chieh; Que, Christian John; Liu, Yingna; Akduman, Mustafa; Tsikata, Edem; de Boer, Johannes F.; Chen, Teresa C.

2017-01-01

Purpose To determine the diagnostic capability of spectral domain optical coherence tomography (SD-OCT) peripapillary retinal volume (RV) measurements. Materials and Methods A total of 156 patients, 89 primary open angle (POAG) and 67 normal subjects, were recruited. SD-OCT peripapillary RV was calculated for four quadrants using 3 annuli of varying scan circle diameters: outer circumpapillary annuli of circular grids 1, 2, and 3 (OCA1, OCA2, OCA3). Area under the receiver operating characteristic (AUROC) curves and pairwise comparisons of receiver operating characteristic (ROC) curves were performed to determine which quadrants were best for diagnosing POAG. The pairwise comparisons of the best ROC curves for RV and RNFL were performed. The artifact rates were analyzed. Results Pairwise comparisons showed that the smaller annuli OCA1 and OCA2 had better diagnostic performance than the largest annulus OCA3 (p<0.05 for all quadrants). OCA1 and OCA2 had similar diagnostic performance, except for the inferior quadrant which was better for OCA1 (p=0.0033).The pairwise comparisons of the best ROC curves for RV and RNFL were not statistically significant. Retinal volume measurements had lower rates of artifacts at 7.4% while RNFL measurements had higher rates at 42.9%. Conclusion Peripapillary RV measurements have excellent ability for diagnosing not only glaucoma patients but also a subset of early glaucoma patients. The inferior quadrant of peripapillary annulus OCA1 demonstrated the best diagnostic capability for both glaucoma and early glaucoma. The diagnostic ability of RV is comparable to that of RNFL parameters in glaucoma but with lower artifact rates. PMID:28079657

Sutureless circumcision using 2-Octyl cyanoacrylate results in more rapid and less painful procedures with excellent cosmetic satisfaction.

PubMed

Van Haute, C; Tailly, T; Klockaerts, K; Ringoir, Y

2015-06-01

Circumcision is the most common surgical procedure in male children in the world and is performed because of cultural, religious or medical reasons. Traditionally, interrupted sutures are used to close the wound, but 2-Octyl cyanoacrylate (2-OCA) tissue glue can be used as an alternative method to close the circumcision wound. To compare the use of 2-OCA with absorbable sutures in circumcision wound closure in prepubescent patients in terms of operative time, complication rate, postoperative pain and cosmetic results. We retrospectively evaluated 662 circumcision procedures using sutures and 609 procedures using 2-OCA for wound closure in prepubescent boys. All circumcision procedures were performed by 2 surgeons in a single centre. Operative time was collected from the hospital surgical software system. 62% of the patients in the suture group and 59% of the patients in the 2-OCA group presented for a postoperative check-up 6 weeks after the circumcision. Data regarding postoperative pain, need for analgesia, cosmetic satisfaction and the ease of wound care were collected through questionnaires completed by 25% of the boy's parents in the suture group and 53% of the parents in the 2-OCA group. Mean operative time was significantly shorter in the 2-OCA group (13 min) than in the suture group (17 min). Complications were comparable and mostly minor. Reintervention was only required in 3 cases. According to the parents, the degree of postoperative pain and the postoperative need for analgesics was significantly lower in the 2-OCA group. Wounds closed with 2-OCA were easier to care for. The cosmetic results after 1 day, after 1 week and after 1 month in the 2-OCA group were significantly superior than in the suture group, according to the parents' evaluation. The use of 2-OCA in circumcision wound closure has been reported before. Previous studies with mainly limited patient numbers report less pain, shorter procedure times and a higher surgeon satisfaction in terms of cosmetic results. This study is the largest study comparing the use of 2-OCA and interrupted sutures in circumcision wound closure. The retrospective character of the study, the lack of a validated questionnaire tool for the cosmetic evaluation and the use of the parent's evaluation are the limitations of this study. The use of 2-OCA in circumcision wound closure results in a shorter operative time, in less postoperative pain, in easy postoperative wound care and in excellent cosmesis when compared to interrupted absorbable sutures. 2-OCA is our current technique of choice in circumcision wound closure. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Osteochondral Allograft Transplantation of the Knee in Patients with an Elevated Body Mass Index.

PubMed

Wang, Dean; Rebolledo, Brian J; Dare, David M; Pais, Mollyann D; Cohn, Matthew R; Jones, Kristofer J; Williams, Riley J

2018-02-01

Objective To characterize the graft survivorship and clinical outcomes of osteochondral allograft transplantation (OCA) of the knee in patients with an elevated body mass index (BMI). Design Prospective data on 38 consecutive patients with a BMI ≥30 kg/m 2 treated with OCA from 2000 to 2015 were reviewed. Complications, reoperations, and patient responses to validated outcome measures were examined. Failures were defined by any removal/revision of the allograft or conversion to arthroplasty. Results Thirty-one knees in 31 patients (mean age, 35.4 years [range, 17-61 years]; 87% male) met the inclusion criteria. Mean BMI was 32.9 kg/m 2 (range, 30-39 kg/m 2 ). Mean chondral defect size was 6.4 cm 2 (range, 1.0-15.3 cm 2 ). Prior to OCA, 23 patients (74%) had undergone previous surgery to the ipsilateral knee. Mean duration of follow-up was 4.1 years (range, 2-11 years). After OCA, 5 knees (13%) underwent conversion to unicompartmental (1) or total (4) knee arthroplasty. Two- and 5-year graft survivorship were 87% and 83%, respectively. At final follow-up, clinically significant improvements were noted in the pain (49.3-72.6) and physical functioning (52.9-81.3) subscales of the Short Form-36 ( P ≤ 0.001), International Knee Documentation Committee subjective form (43.5-67.0; P = 0.002), Knee Outcome Survey-Activities of Daily Living (58.2-80.4; P = 0.002), and overall condition subscale of the Cincinnati Knee Rating System (4.7-6.9; P = 0.046). Conclusions OCA can be a successful midterm treatment option for focal cartilage defects of the knee in select patients with a BMI ≥30 kg/m 2 .

Cardiopulmonary protective effects of the selective FXR agonist obeticholic acid in the rat model of monocrotaline-induced pulmonary hypertension.

PubMed

Vignozzi, Linda; Morelli, Annamaria; Cellai, Ilaria; Filippi, Sandra; Comeglio, Paolo; Sarchielli, Erica; Maneschi, Elena; Vannelli, Gabriella Barbara; Adorini, Luciano; Maggi, Mario

2017-01-01

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the effects of OCA treatment (3, 10 or 30mg/kg, daily for 5days a week, for 7 and/or 28 days) on inflammation, tissue remodeling and fibrosis in the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model. Treatment with OCA attenuated MCT-induced increased pulmonary arterial wall thickness and right ventricular hypertrophy, by i) blunting pathogenic inflammatory mechanisms (downregulation of interleukin 6, IL-6, and monocyte chemoattractant protein-1, MCP-1) and ii) enhancing protective mechanisms counteracting fibrosis and endothelial/mesenchymal transition. MCT-injected rats also showed a marked decrease of pulmonary artery responsiveness to both endothelium-dependent and independent relaxant stimuli, such as acetylcholine and a nitric oxide donor, sodium nitroprusside. Administration of OCA (30mg/kg) normalized this decreased responsiveness. Accordingly, OCA treatment induced profound beneficial effects on lung histology. In particular, both OCA doses markedly reduced the MCT-induced medial wall thickness increase in small pulmonary arteries. To evaluate the objective functional improvement by OCA treatment of MCT-induced PAH, we performed a treadmill test and measured duration of exercise. MCT significantly reduced, and OCA normalized treadmill endurance. Results with OCA were similar, or even superior, to those obtained with tadalafil, a well-established treatment of PAH. In conclusion, OCA treatment demonstrates cardiopulmonary protective effects, modulating lung vascular remodeling, reducing right ventricular hypertrophy and significantly improving exercise capacity. Thus, OCA can restore the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Condyle-Specific Matching Does Not Improve Midterm Clinical Outcomes of Osteochondral Allograft Transplantation in the Knee.

PubMed

Wang, Dean; Jones, Kristofer J; Eliasberg, Claire D; Pais, Mollyann D; Rodeo, Scott A; Williams, Riley J

2017-10-04

Condyle-specific matching for osteochondral allograft transplantation (OCA) pairs donor and recipient condyles in an attempt to minimize articular incongruity. While the majority of cartilage defects are located on the medial femoral condyle, lateral femoral condyles are more commonly available as a graft source. The purpose of this study was to compare the clinical outcomes of patients treated with non-orthotopic (lateral-to-medial condyle or medial-to-lateral condyle) OCA with those treated with traditional orthotopic (medial-to-medial condyle or lateral-to-lateral condyle) OCA. We hypothesized that clinical outcomes would be similar between groups at midterm follow-up. A retrospective review of prospectively collected data on patients treated with OCA from 2000 to 2014 was conducted. Seventy-seven patients with a full-thickness cartilage defect of a femoral condyle were treated with either orthotopic (n = 50) or non-orthotopic (n = 27) OCA. A minimum follow-up of 2 years was required for analysis. Patients in each group were matched according to sex, age, and total chondral defect size. Reoperations and patient responses to validated outcome measures were reviewed. Failure was defined as any revision cartilage procedure or conversion to knee arthroplasty. The mean duration of follow-up was 4.0 years (range, 2 to 16 years). The orthotopic and non-orthotopic OCA groups were comparable in terms of demographics, the mean number of prior ipsilateral knee operations, and the percentage of concomitant procedures at baseline. Reoperation (p = 0.427) and failure (p = 0.917) rates did not differ significantly between groups. Both groups demonstrated significant increases in the Short Form-36 (SF-36) physical functioning and pain, International Knee Documentation Committee (IKDC), and Knee Outcome Survey-Activities of Daily Living (KOS-ADL) scores compared with baseline (p < 0.004). Outcome scores (baseline and postoperative) and change scores did not differ significantly between groups. Clinical outcomes do not differ between patients treated with orthotopic OCA and those treated with non-orthotopic OCA, suggesting that condyle-specific matching may not be necessary. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Diagnostic Capability of Peripapillary Retinal Thickness in Glaucoma Using 3D Volume Scans

PubMed Central

Simavli, Huseyin; Que, Christian John; Akduman, Mustafa; Rizzo, Jennifer L.; Tsikata, Edem; de Boer, Johannes F.; Chen, Teresa C.

2015-01-01

Purpose To determine the diagnostic capability of spectral domain optical coherence tomography (SD-OCT) peripapillary retinal thickness (RT) measurements from 3-dimensional (3D) volume scans for primary open angle glaucoma (POAG). Design Cross-sectional study. Methods Setting Institutional Study population 156 patients (89 POAG and 67 normal subjects) Observation procedures One eye of each subject was included. SD-OCT peripapillary RT values from 3D volume scans were calculated for four quadrants of three different sized annuli. Peripapillary retinal nerve fiber layer (RNFL) thickness values were also determined. Main outcome measures Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. Results The top five RT AUROCs for all glaucoma patients and for a subset of early glaucoma patients were for the inferior quadrant of outer circumpapillary annulus of circular grid (OCA) 1 (0.959, 0.939), inferior quadrant of OCA2 (0.945, 0.921), superior quadrant of OCA1 (0.890, 0.811), inferior quadrant of OCA3 (0.887, 0.854), and superior quadrant of OCA2 (0.879, 0.807). Smaller RT annuli OCA1 and OCA2 consistently showed better diagnostic performance than the larger RT annulus OCA3. For both RNFL and RT measurements, best AUROC values were found for inferior RT OCA1 and OCA2, followed by inferior and overall RNFL thickness. Conclusion Peripapillary RT measurements from 3D volume scans showed excellent diagnostic performance for detecting both glaucoma and early glaucoma patients. Peripapillary RT values have the same or better diagnostic capability compared to peripapillary RNFL thickness measurements, while also having fewer algorithm errors. PMID:25498354

Anti-fibrotic effects of chronic treatment with the selective FXR agonist obeticholic acid in the bleomycin-induced rat model of pulmonary fibrosis.

PubMed

Comeglio, Paolo; Filippi, Sandra; Sarchielli, Erica; Morelli, Annamaria; Cellai, Ilaria; Corcetto, Francesca; Corno, Chiara; Maneschi, Elena; Pini, Alessandro; Adorini, Luciano; Vannelli, Gabriella Barbara; Maggi, Mario; Vignozzi, Linda

2017-04-01

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated. Lung function was assessed by measuring airway resistance to inflation. In the acute phase (7days), bleomycin promoted an initial thickening and fibrosis of the lung interstitium, with upregulation of genes related to epithelial proliferation, tissue remodeling and hypoxia. At 28days, an evident increase in the deposition of collagen in the lungs was observed. This excessive deposition was accompanied by an upregulation of transcripts related to the extracellular matrix (TGFβ1, SNAI1 and SNAI2), indicating lung fibrosis. Administration of OCA protected against bleomycin-induced lung damage by suppressing molecular mechanisms related to epithelial-to-mesenchymal transition (EMT), inflammation and collagen deposition, with a dose-dependent reduction of proinflammatory cytokines such as IL-1β and IL-6, as well as TGF-β1 and SNAI1 expression. Pirfenidone, a recently approved treatment for idiopathic pulmonary fibrosis (IPF), significantly counteracted bleomycin-induced pro-fibrotic genes expression, but did not exert significant effects on IL-1β and IL-6. OCA treatment in bleomycin-challenged rats also improved pulmonary function, by effectively normalizing airway resistance to inflation and lung stiffness in vivo. Results with OCA were similar, or even superior, to those obtained with pirfenidone. In conclusion, our results suggest an important protective effect of OCA against bleomycin-induced lung fibrosis by blunting critical mediators in the pathogenesis of IPF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Homozygosity Mapping and Whole Exome Sequencing to Detect SLC45A2 and G6PC3 Mutations in a Single Patient with Oculocutaneous Albinism and Neutropenia

PubMed Central

Cullinane, Andrew R.; Vilboux, Thierry; O’Brien, Kevin; Curry, James A.; Maynard, Dawn M.; Carlson-Donohoe, Hannah; Ciccone, Carla; Markello, Thomas C.; Gunay-Aygun, Meral; Huizing, Marjan; Gahl, William A.

2011-01-01

We evaluated a 32 year-old woman whose oculocutaneous albinism, bleeding diathesis, neutropenia, and history of recurrent infections prompted consideration of the diagnosis of Hermansky-Pudlak syndrome type 2 (HPS-2). This was ruled out due to the presence of platelet delta granules and absence of AP3B1 mutations. Since parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping, followed by whole exome sequencing, to identify two candidate disease-causing genes, SLC45A2 and G6PC3. Conventional di-deoxy sequencing confirmed pathogenic mutations in SLC45A2, associated with oculocutaneous albinism type 4 (OCA-4), and G6PC3, associated with neutropenia. The substantial reduction of SLC45A2 protein in the patient’s melanocytes caused the mis-localization of tyrosinase from melanosomes to the plasma membrane and also led to the incorporation of tyrosinase into exosomes and secretion into the culture medium, explaining the hypopigmentation in OCA-4. Our patient’s G6PC3 mRNA expression level was also reduced, leading to increased apoptosis of her fibroblasts under ER stress. This report describes the first North American patient with OCA-4, the first culture of human OCA-4 melanocytes, and the use of homozygosity mapping followed by whole exome sequencing to identify disease-causing mutations in multiple genes in a single affected individual. PMID:21677667

Extended fatigue life of a catalyst-free self-healing acrylic bone cement using microencapsulated 2-octyl cyanoacrylate

PubMed Central

Brochu, Alice B.W.; Matthys, Oriane B.; Craig, Stephen L.; Reichert, William M.

2014-01-01

The tissue adhesive 2-octyl cyanoacrylate (OCA) was encapsulated in polyurethane microshells and incorporated into bone cement to form a catalyst free, self-healing bone cement comprised of all clinically approved components. The bending strength, modulus, and fatigue lifetime were investigated in accordance with ASTM and ISO standards for the testing of PMMA bone cement. The bending strength of bone cement specimens decreased with increasing wt% capsules content for capsules without or with OCA, with specimens of < 5 wt% capsule content showing minimal effect. In contrast, bone cement bending modulus was insensitive to capsule content. Load controlled fatigue testing was performed in air at room temperature on capsule free bone cement (0 wt%), bone cement with 5 wt% OCA-free capsules (5 wt% No OCA), and 5 wt% OCA-containing capsules (5 wt% OCA). Specimens were tested at a frequency of 5 Hz at maximum stresses of 90%, 80%, 70% and 50% of each specimen's bending strength until failure. The 5 wt% OCA exhibited significant self-healing at 70% and 50% of its reference strength (p < 0.05). Fatigue testing of all three specimen types in air at 22 MPa (50% of reference strength of the 5 wt% OCA specimens) showed that the cycles to failure of OCA-containing specimens was increased by two-fold compared to the OCA-free and capsule-free specimens. This study represents the first demonstration of dynamic, catalyst-free self-healing in a biomaterial formulation. PMID:24825796

Effects of boiling on chlorogenic acid and the liver protective effects of its main products against CCl₄-induced toxicity in vitro.

PubMed

Kan, Shidong; Cheung, Matt Wan Man; Zhou, Yanling; Ho, Wing Shing

2014-02-01

Chlorogenic acid (3-O-caffeoylquinic acid, CA) is the active component in several botanical beverage, vegetables, fruits, and herbal drugs. The effect of water boiling on the bioactivity of CA was studied. CA could be isomerized to 4-O-caffeoylquinic acid (4-O-CA) and 5-O-caffeoylquinic acid (5-O-CA) in decoctive extraction, and each of the isomers occupied about one-third of the total caffeoylquinic acids. A novel method, using water elution of microsphere resin, was used to purify CA and its 2 isomers. The yield of CA, 4-O-CA, and 5-O-CA was 82%, 5.6%, and 50%, with the purity of 98%, 97%, and 99%, respectively. The DPPH radical scavenging assay showed that 4-O-CA, 5-O-CA, and CA exhibited similar activity. However, there was no significant difference between 4-O-CA and 5-O-CA when used against CCl₄-induced toxicity in hepG2 cells. Our studies show that isomerization is the main transformation of CA in boiling, and the decoction could not decrease the anti-oxidant activity of CA. © 2014 Institute of Food Technologists®

Does Treatment of the Tibia Matter in Bipolar Chondral Defects of the Knee? Clinical Outcomes with Greater Than 2 Years Follow-up.

PubMed

Hannon, Charles P; Weber, Alexander E; Gitelis, Matthew; Meyer, Maximillian A; Yanke, Adam B; Cole, Brian J

2018-04-01

To compare the osteochondral allograft (OCA) outcomes of bipolar defects with isolated femoral defects and to investigate the optimal treatment of bipolar defects by comparing femoral OCA with tibial debridement to femoral OCA and tibial microfracture. A series of patients with 2-year follow-up from March 2004 to September 2015 after femoral OCA for bipolar chondral defects was identified. Group 1 contained patients with tibial defects treated with debridement and group 2 contained patients with microfractured tibial defects. A third group (group 3) with isolated femoral defects treated with OCA was identified and matched by gender, body mass index (BMI), laterality, and OCA size to groups 1 and 2. Patient-specific, defect-specific, intraoperative, and postoperative data including patient-reported outcomes were collected on all patients. The study groups were compared using analyses of variance, paired sample t tests, and χ-square analyses. Thirty-six patients who had femoral OCA for bipolar lesions were identified with 20 patients in group 1 and 16 patients in group 2. Group 3 had 20 patients. There were no differences between the 3 groups in terms of gender (P = .616), BMI (P = .271), number of previous surgeries (P = .451), femoral or tibial defect size (P = .296), and OCA size (P = .981). Preoperative to postoperative patient-reported clinical outcomes (PROs) revealed statistical and clinically meaningful improvement in all 3 groups, but did not differ between groups. Patient-specific and defect-specific factors did not correlate with PROs. The graft survivorship for group 1 was 85% at 4.5 years, 100% for group 2 at 2.5 years, and 95% for group 3 at 3.8 years. Regardless of tibial treatment, patients with bipolar defects treated with femoral OCA have clinically meaningful improvements in PROs and excellent graft survivorship comparable to isolated femoral OCAs at more than 2 years. Level III, case-control study. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation.

PubMed

Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

2017-01-01

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15ml/kg). In CCl 4 +OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis.

PubMed

Hameed, B; Terrault, N A; Gill, R M; Loomba, R; Chalasani, N; Hoofnagle, J H; Van Natta, M L

2018-03-01

In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (-2.4 vs -1.2, P<0.001) and placebo-treated patients (-1.2 vs -0.5, P = 0.03). ALT levels also improved in those with vs without weight loss in OCA- (-43 vs -34 U/L, P = 0.12) and placebo-treated patients (-29 vs -10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs -12 U/L, P<0.001), total (+13 vs -14 mg/dL, P = 0.02) and LDL cholesterol (+18 vs -12 mg/dL, P = 0.01), and HbA1c (+0.1 vs -0.4%, P = 0.01). OCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498. © 2018 John Wiley & Sons Ltd.

Bone cysts after osteochondral allograft repair of cartilage defects in goats suggest abnormal interaction between subchondral bone and overlying synovial joint tissues.

PubMed

Pallante-Kichura, Andrea L; Cory, Esther; Bugbee, William D; Sah, Robert L

2013-11-01

The efficacy of osteochondral allografts (OCAs) may be affected by osseous support of the articular cartilage, and thus affected by bone healing and remodeling in the OCA and surrounding host. Bone cysts, and their communication pathways, may be present in various locations after OCA insertion and reflect distinct pathogenic mechanisms. Previously, we analyzed the effect of OCA storage (FRESH, 4°C/14d, 4°C/28d, FROZEN) on cartilage quality in fifteen adult goats after 12months in vivo. The objectives of this study were to further analyze OCAs and contralateral non-operated (Non-Op) CONTROLS from the medial femoral condyle to (1) determine the effect of OCA storage on local subchondral bone (ScB) and trabecular bone (TB) structure, (2) characterize the location and structure of bone cysts and channels, and (3) assess the relationship between cartilage and bone properties. (1) Overall bone structure after OCAs was altered compared to Non-Op, with OCA samples displaying bone cysts, ScB channels, and ScB roughening. ScB BV/TV in FROZEN OCAs was lower than Non-Op and other OCAs. TB BV/TV in FRESH, 4°C/14d, and 4°C/28d OCAs did not vary compared to Non-Op, but BS/TV was lower. (2) OCAs contained "basal" cysts, localized to deeper regions, some "subchondral" cysts, localized near the bone-cartilage interface, and some ScB channels. TB surrounding basal cysts exhibited higher BV/TV than Non-Op. (3) Basal cysts occurred (a) in isolation, (b) with subchondral cysts and ScB channels, (c) with ScB channels, or (d) with subchondral cysts, ScB channels, and ScB erosion. Deterioration of cartilage gross morphology was strongly associated with abnormal μCT bone structure. Evidence of cartilage-bone communication following OCA repair may favor fluid intrusion as a mechanism for subchondral cyst formation, while bone resorption at the graft-host interface without affecting overall bone and cartilage structure may favor bony contusion mechanism for basal cyst formation. These findings suggest that cysts occurring after OCAs may result from aberrant mechanobiology due to (1) altered compartmentalization that normally separates overlying cartilage and subchondral bone, either from distinct ScB channels or more general ScB plate deterioration, and (2) bone resorption at the basal graft-host interface. © 2013.

Bone Cysts After Osteochondral Allograft Repair of Cartilage Defects in Goats Suggest Abnormal Interaction Between Subchondral Bone and Overlying Synovial Joint Tissues

PubMed Central

Pallante-Kichura, Andrea L.; Cory, Esther; Bugbee, William D.; Sah, Robert L.

2013-01-01

The efficacy of osteochondral allografts (OCA) may be affected by osseous support of the articular cartilage, and thus affected by bone healing and remodeling in the OCA and surrounding host. Bone cysts, and their communication pathways, may be present in various locations after OCA insertion and reflect distinct pathogenic mechanisms. Previously, we analyzed the effect of OCA storage (FRESH, 4°C/14d, 4°C/28d, FROZEN) on cartilage quality in fifteen adult goats after 12 months in vivo. The objectives of this study were to further analyze OCA and contralateral non-operated (Non-Op) CONTROLS from the medial femoral condyle to (1) determine the effect of OCA storage on local subchondral (ScB) and trabecular (TB) bone structure, (2) characterize the location and structure of bone cysts and channels, and (3) assess the relationship between cartilage and bone properties. (1) Overall bone structure after OCA was altered compared to Non-Op, with OCA samples displaying bone cysts, ScB channels, and ScB roughening. ScB BV/TV in FROZEN OCA was lower than Non-Op and other OCA. TB BV/TV in FRESH, 4°C/14d, and 4°C/28d OCA did not vary compared to Non-Op, but BS/TV was lower. (2) OCA contained “basal” cysts, localized to deeper regions, some “subchondral” cysts, localized near the bone-cartilage interface, and some ScB channels. TB surrounding basal cysts exhibited higher BV/TV than Non-Op. (3) Basal cysts occurred (a) in isolation, (b) with subchondral cysts and ScB channels, (c) with ScB channels, or (d) with subchondral cysts, ScB channels, and ScB erosion. Deterioration of cartilage gross morphology was strongly associated with abnormal μCT bone structure. Evidence of cartilage-bone communication following OCA repair may favor fluid intrusion as a mechanism for subchondral cyst formation, while bone resorption at the graft-host interface without affecting overall bone and cartilage structure may favor bony contusion mechanism for basal cyst formation. These findings suggest that cysts occurring after OCA may result from aberrant mechanobiology due to (1) altered compartmentalization that normally separates overlying cartilage and subchondral bone, either from distinct ScB channels or more general ScB plate deterioration, and (2) bone resorption at the basal graft-host interface. PMID:23958821

Role of defective Oct-2 and OCA-B expression in immunoglobulin production and Kaposi's sarcoma-associated herpesvirus lytic reactivation in primary effusion lymphoma.

PubMed

Di Bartolo, Daniel L; Hyjek, Elizabeth; Keller, Shannon; Guasparri, Ilaria; Deng, Hongyu; Sun, Ren; Chadburn, Amy; Knowles, Daniel M; Cesarman, Ethel

2009-05-01

Primary effusion lymphoma (PEL) is a distinct type of B-cell non-Hodgkin lymphoma characterized by the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8). Despite having a genotype and gene expression signature of highly differentiated B cells, PEL does not usually express surface or cytoplasmic immunoglobulin (Ig). We show the lack of Oct-2 and OCA-B transcription factors to be responsible, at least in part, for this defect in Ig production. Like Ig genes, ORF50, the key regulator of the switch from latency to lytic reactivation, contains an octamer motif within its promoter. We therefore examined the impact of Oct-2 and OCA-B on ORF50 activation. The binding of Oct-1 to the ORF50 promoter has been shown to significantly enhance ORF50 transactivation. We found that Oct-2, on the other hand, inhibited ORF50 expression and consequently lytic reactivation by competing with Oct-1 for the octamer motif in the ORF50 promoter. Our data suggest that Oct-2 downregulation in infected cells would be favorable to KSHV in allowing for efficient viral reactivation.

In Southern Africa, Brown Oculocutaneous Albinism (BOCA) Maps to the OCA2 Locus on Chromosome 15q: P-Gene Mutations Identified

PubMed Central

Manga, Prashiela; Kromberg, Jennifer G. R.; Turner, Angela; Jenkins, Trefor; Ramsay, Michele

2001-01-01

In southern Africa, brown oculocutaneous albinism (BOCA) is a distinct pigmentation phenotype. In at least two cases, it has occurred in the same families as tyrosinase-positive oculocutaneous albinism (OCA2), suggesting that it may be allelic, despite the fact that this phenotype was attributed to mutations in the TYRP1 gene in an American individual of mixed ancestry. Linkage analysis in five families mapped the BOCA locus to the same region as the OCA2 locus (maximum LOD 3.07; θ=0 using a six-marker haplotype). Mutation analysis of the human homologue of the mouse pink-eyed dilution gene (P), in 10 unrelated individuals with BOCA revealed that 9 had one copy of the 2.7-kb deletion. No other mutations were identified. Additional haplotype studies, based on closely linked markers (telomere to centromere: D15S1048, D15S1019, D15S1533, P-gene 2.7-kb deletion, D15S219, and D15S156) revealed several BOCA-associated P haplotypes. These could be divided into two core haplotypes, suggesting that a limited number of P-gene mutations give rise to this phenotype. PMID:11179026

Analyzing and designing object-oriented missile simulations with concurrency

NASA Astrophysics Data System (ADS)

Randorf, Jeffrey Allen

2000-11-01

A software object model for the six degree-of-freedom missile modeling domain is presented. As a precursor, a domain analysis of the missile modeling domain was started, based on the Feature-Oriented Domain Analysis (FODA) technique described by the Software Engineering Institute (SEI). It was subsequently determined the FODA methodology is functionally equivalent to the Object Modeling Technique. The analysis used legacy software documentation and code from the ENDOSIM, KDEC, and TFrames 6-DOF modeling tools, including other technical literature. The SEI Object Connection Architecture (OCA) was the template for designing the object model. Three variants of the OCA were considered---a reference structure, a recursive structure, and a reference structure with augmentation for flight vehicle modeling. The reference OCA design option was chosen for maintaining simplicity while not compromising the expressive power of the OMT model. The missile architecture was then analyzed for potential areas of concurrent computing. It was shown how protected objects could be used for data passing between OCA object managers, allowing concurrent access without changing the OCA reference design intent or structure. The implementation language was the 1995 release of Ada. OCA software components were shown how to be expressed as Ada child packages. While acceleration of several low level and other high operations level are possible on proper hardware, there was a 33% degradation of 4th order Runge-Kutta integrator performance of two simultaneous ordinary differential equations using Ada tasking on a single processor machine. The Defense Department's High Level Architecture was introduced and explained in context with the OCA. It was shown the HLA and OCA were not mutually exclusive architectures, but complimentary. HLA was shown as an interoperability solution, with the OCA as an architectural vehicle for software reuse. Further directions for implementing a 6-DOF missile modeling environment are discussed.

Effects of Autogenous Bone Marrow Aspirate Concentrate on Radiographic Integration of Femoral Condylar Osteochondral Allografts.

PubMed

Oladeji, Lasun O; Stannard, James P; Cook, Cristi R; Kfuri, Mauricio; Crist, Brett D; Smith, Matthew J; Cook, James L

2017-10-01

Transplantation of fresh osteochondral allografts (OCAs) is an attractive treatment option for symptomatic articular cartilage lesions in young, healthy patients. Because the lack of OCA bone integration can be a cause of treatment failure, methods for speeding and enhancing OCA bone integration to mitigate this potential complication are highly desirable. To determine if autogenous bone marrow aspirate concentrate (BMC) treatment of large femoral condylar OCAs would be associated with superior radiographic OCA bone integration compared with nontreated allografts during the critical first 6 months after surgery. Cohort study; Level of evidence, 3. A review of patients enrolled in a prospective registry who were treated with transplantation of large OCAs to one or both femoral condyles at our institution from March 12, 2013 to March 14, 2016 was performed. Patients were stratified into 2 groups based on BMC treatment versus no BMC treatment; the treatment was nonrandomized and was rooted in a shift in practice and a continuing effort to optimize OCA transplantation at our institution. Patients were excluded if they did not have orthogonal view radiographs performed at 6 weeks, 3 months, and 6 months postoperatively. Each condyle undergoing OCA transplantation was assessed individually by an independent musculoskeletal radiologist, who was blinded to the treatment group and time point. OCAs were assessed with respect to graft integration (0%-100%; 0 = no integration, 100 = complete integration) and degree of sclerosis (0-3; 0 = normal, 1 = mild sclerosis, 2 = moderate sclerosis, and 3 = severe sclerosis) of the graft at each time point. This study identified 17 condyles in 15 patients who underwent OCA transplantation without BMC and 29 condyles in 22 patients who underwent OCA transplantation with BMC. The BMC group had significantly ( P = .033) higher graft integration scores at 6 weeks, 3 months, and 6 months after surgery. Graft sclerosis was significantly ( P = .017) less in the BMC group at 6 weeks and 3 months, with no significant difference at 6 months after surgery. When combining the groups to examine the influence of smoking on graft integration, nonsmokers had significantly ( P = .007) higher graft integration scores at 6 months. Large femoral condylar OCAs treated with autogenous BMC before implantation showed superior radiographic integration to bone and less sclerosis during the initial 6-month postoperative period. BMC treatment of OCAs may mitigate the failure of OCA bone healing.

Effects of optical clearing agents on noninvasive blood glucose monitoring with optical coherence tomography: a pilot study

NASA Astrophysics Data System (ADS)

He, Ruoyu; Wei, Huajiang; Gu, Huimin; Zhu, Zhengguo; Zhang, Yuqing; Guo, Xiao; Cai, Tiantian

2012-10-01

Recently, the capability of optical coherence tomography (OCT) has been demonstrated for noninvasive blood glucose monitoring. In this work, we investigate the administration of chemical agents onto human skin tissue to increase the transparency of the surface of the skin, as a means of improving the capability of OCT imaging for clinically relevant applications. Eight groups of experiments were proposed, in which different optical clearing agents (OCA) were used. The results indicate that, when properly used, some OCAs perform well in promoting the capability of OCT for noninvasive blood glucose monitoring. Among the four kinds of OCA we used, 50% v/v glycerol solute turns out to be the best enhancer. Compared with the results of the experiments in which no OCA was used, when 50% glycerol was applied onto the human skin topically, the correlation coefficient between the OCT signal slope (OCTSS) and blood glucose concentration (BGC) was improved by 7.1% on average, and the lag time between changes in the OCTSS and BGC was cut by 8 min on average. The results of 10 w/v mannitol were also good, but not as pronounced.

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.

PubMed

Shahzad, Mohsin; Yousaf, Sairah; Waryah, Yar M; Gul, Hadia; Kausar, Tasleem; Tariq, Nabeela; Mahmood, Umair; Ali, Muhammad; Khan, Muzammil A; Waryah, Ali M; Shaikh, Rehan S; Riazuddin, Saima; Ahmed, Zubair M

2017-03-07

Nonsyndromic oculocutaneous Albinism (nsOCA) is clinically characterized by the loss of pigmentation in the skin, hair, and iris. OCA is amongst the most common causes of vision impairment in children. To date, pathogenic variants in six genes have been identified in individuals with nsOCA. Here, we determined the identities, frequencies, and clinical consequences of OCA alleles in 94 previously unreported Pakistani families. Combination of Sanger and Exome sequencing revealed 38 alleles, including 22 novel variants, segregating with nsOCA phenotype in 80 families. Variants of TYR and OCA2 genes were the most common cause of nsOCA, occurring in 43 and 30 families, respectively. Twenty-two novel variants include nine missense, four splice site, two non-sense, one insertion and six gross deletions. In vitro studies revealed retention of OCA proteins harboring novel missense alleles in the endoplasmic reticulum (ER) of transfected cells. Exon-trapping assays with constructs containing splice site alleles revealed errors in splicing. As eight alleles account for approximately 56% (95% CI: 46.52-65.24%) of nsOCA cases, primarily enrolled from Punjab province of Pakistan, hierarchical strategies for variant detection would be feasible and cost-efficient genetic tests for OCA in families with similar origin. Thus, we developed Tetra-primer ARMS assays for rapid, reliable, reproducible and economical screening of most of these common alleles.

A survey of occupational exposure to 4,4'-methylene-bis (2-chloroaniline) (MbOCA) in the UK.

PubMed

Cocker, J; Cain, J R; Baldwin, P; McNally, K; Jones, K

2009-07-01

The main objective of the study was to gather information about the current controls and levels of exposure to 4,4'-methylene-bis (2-chloroaniline) (MbOCA) in a representative cross section of workplaces that use it to manufacture polyurethane elastomers. The study also aimed to investigate whether controls and guidance could be improved and to investigate exposure to isocyanates in these workplaces using biological monitoring. An occupational hygienist and a field scientist visited the two UK suppliers and 20 out of the 25 workplaces known to be using MbOCA in the UK during 2005 and 2006. They collected air samples, surface wipes, gloves, and urine samples and made observations to assess exposure and the adequacy of controls. All samples were analysed for MbOCA and urine samples were additionally analysed for isocyanate metabolites. A statistical analysis was made of the results. Only 2.5% of the 80 personal inhalation exposures to MbOCA exceeded the workplace exposure limit of 5 microg m(-3) 8-h time-weighted average and 84% were below the limit of detection (LOD). Surface samples (n = 334) were collected from MbOCA users and suppliers and 60% had detectable levels of MbOCA ranging from 0.019 to 400 microg cm(-2). The highest levels were around a hopper, ovens, and the weighing and pouring areas. MbOCA was also detected in 8 of the 75 samples collected from areas not likely to be in contact with MbOCA. At the two suppliers, samples (n = 28) were collected from the outside surfaces of recently imported kegs, pallets, and the floor around kegs. Six samples had detectable levels and four of these (0.2, 0.8, 1, and 6 microg cm(-2)) were from the floor and pallets in both suppliers. The other two positive results were found on the outside rim (18 microg cm(-2)) and side (23 microg cm(-2)) of a keg at one supplier indicating contamination by the manufacturer. Urine samples (n = 79) were collected and 49% were below the LOD for MbOCA and only three samples had levels of MbOCA that exceeded the biological monitoring guidance value (BMGV) of 15 micromol mol(-1) creatinine. The highest urinary MbOCA concentrations were in samples from workers casting and moulding. The 90th percentile of the urine MbOCA results was 8.6 micromol MbOCA per mol creatinine. Urine samples were also analysed for the diamine metabolites of toluene diisocyanate and hexamethylene diisocyanate and 33% had detectable levels with 22 and 13% of results, respectively, above the BMGV for isocyanates (1 micromol isocyanate-derived diamine per mol creatinine). The maximum urinary concentration of toluene diamine and hexane diamine were 15.6 and 10.1 micromol mol(-1) creatinine, respectively. The survey found that the measures used to control exposure to MbOCA could be improved. Although air levels of MbOCA were generally low, there was evidence of spread of surface contamination and poor maintenance of controls such as local exhaust ventilation. A BMGV based on the 90th percentile of data from workplaces with good control would be less than the 90% value of 8.6 micromol mol(-1) creatinine found in this study and suggests that the current BMGV of 15 micromol mol(-1) creatinine is no longer acting as a stimulus to reduce exposure. The metabolites of isocyanates found in urine samples in this study could arise from inhalation exposure to isocyanates or from dermal exposure to either isocyanates or their diamine breakdown product and need further investigation.

Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes

PubMed Central

Cheng, Tsing; Orlow, Seth J.; Manga, Prashiela

2013-01-01

Summary Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of proapoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress. PMID:23962237

A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.

PubMed

Kowdley, Kris V; Luketic, Velimir; Chapman, Roger; Hirschfield, Gideon M; Poupon, Raoul; Schramm, Christoph; Vincent, Catherine; Rust, Christian; Parés, Albert; Mason, Andrew; Marschall, Hanns-Ulrich; Shapiro, David; Adorini, Luciano; Sciacca, Cathi; Beecher-Jones, Tessa; Böhm, Olaf; Pencek, Richard; Jones, David

2018-05-01

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902). © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

Origins of domestication and polyploidy in oca (Oxalis Tuberosa: Oxalidaceae). 2. Chloroplast-expressed glutamine synthetase data.

PubMed

Emshwiller, Eve; Doyle, Jeff J

2002-07-01

In continuing study of the origins of the octoploid tuber crop oca, Oxalis tuberosa Molina, we used phylogenetic analysis of DNA sequences of the chloroplast-active (nuclear encoded) isozyme of glutamine synthetase (ncpGS) from cultivated oca, its allies in the "Oxalis tuberosa alliance," and other Andean Oxalis. Multiple ncpGS sequences found within individuals of both the cultigen and a yet unnamed wild tuber-bearing taxon of Bolivia were separated by molecular cloning, but some cloned sequences appeared to be artifacts of polymerase chain reaction (PCR) recombination and/or Taq error. Nonetheless, three classes of nonrecombinant sequences each joined a different part of the O. tuberosa alliance clade on the ncpGS gene tree. Octoploid oca shares two sequence classes with the Bolivian tuber-bearing taxon (of unknown ploidy level). Fixed heterozygosity of these two sequence classes in all ocas sampled suggests that they represent homeologous loci and that oca is allopolyploid. A third sequence class, found in eight of nine oca plants sampled, might represent a third homeologous locus, suggesting that oca may be autoallopolyploid, and is shared with another wild tuber-bearing species, tetraploid O. picchensis of southern Peru. Thus, ncpGS data identify these two taxa as the best candidates as progenitors of cultivated oca.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

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

Zhang, Da-Gang

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatmentmore » inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.« less

Contribution of trimeric autotransporter C-terminal domains of oligomeric coiled-coil adhesin (Oca) family members YadA, UspA1, EibA, and Hia to translocation of the YadA passenger domain and virulence of Yersinia enterocolitica.

PubMed

Ackermann, Nikolaus; Tiller, Maximilian; Anding, Gisela; Roggenkamp, Andreas; Heesemann, Jürgen

2008-07-01

The Oca family is a novel class of autotransporter-adhesins with highest structural similarity in their C-terminal transmembrane region, which supposedly builds a beta-barrel pore in the outer membrane (OM). The prototype of the Oca family is YadA, an adhesin of Yersinia enterocolitica and Yersinia pseudotuberculosis. YadA forms a homotrimeric lollipop-like structure on the bacterial surface. The C-terminal regions of three YadA monomers form a barrel in the OM and translocate the trimeric N-terminal passenger domain, consisting of stalk, neck, and head region to the exterior. To elucidate the structural and functional role of the C-terminal translocator domain (TLD) and to assess its promiscuous capability with respect to transport of related passenger domains, we constructed chimeric YadA proteins, which consist of the N-terminal YadA passenger domain and C-terminal TLDs of Oca family members UspA1 (Moraxella catarrhalis), EibA (Escherichia coli), and Hia (Haemophilus influenzae). These constructs were expressed in Y. enterocolitica and compared for OM localization, surface exposure, oligomerization, adhesion properties, serum resistance, and mouse virulence. We demonstrate that all chimeric YadA proteins translocated the YadA passenger domain across the OM. Y. enterocolitica strains producing YadA chimeras or wild-type YadA showed comparable binding to collagen and epithelial cells. However, strains producing YadA chimeras were attenuated in serum resistance and mouse virulence. These results demonstrate for the first time that TLDs of Oca proteins of different origin are efficient translocators of the YadA passenger domain and that the cognate TLD of YadA is essential for bacterial survival in human serum and mouse virulence.

Biology and genetics of oculocutaneous albinism and vitiligo - common pigmentation disorders in southern Africa.

PubMed

Manga, Prashiela; Kerr, Robyn; Ramsay, Michèle; Kromberg, Jennifer G R

2013-07-29

Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of both albinism and vitiligo may herald novel treatment strategies for these disorders. 

[Influence of hormonal contraceptives on indices of zinc homeostasis and bone remodeling in young adult women].

PubMed

Simões, Tania Mara Rodrigues; Zapata, Carmiña Lucía Vargas; Donangelo, Carmen Marino

2015-09-01

To investigate the influence of the use of oral hormonal contraceptive agents (OCA) on the biochemical indices related to metabolic zinc utilization and distribution, and to bone turnover in young adult women. Cross-sectional study. Blood and urine samples from non-users (-OCA; control; n=69) and users of hormonal contraceptives for at least 3 months (+OCA; n=62) were collected under controlled conditions. Indices of zinc homeostasis and of bone turnover were analyzed in serum or plasma (total, albumin-bound and α2-macroglobulin-bound zinc, albumin and total and bone alkaline phosphatase activity), in erythrocytes (zinc and metallothionein) and in urine (zinc, calcium and hydroxyproline). The habitual zinc and calcium intakes were evaluated by a food frequency questionnaire. Dietary zinc intake was similar in both groups and on average above recommended values, whereas calcium intake was similarly sub-adequate in +OCA and -OCA. Compared to controls, +OCA had lower concentrations of total and α2-macroglobulin-bound zinc (11 and 28.5%, respectively, p<0.001), serum albumin (13%, p<0.01), total and bone-specific alkaline phosphatase activity (13 and 18%, respectively, p<0.05), erythrocyte metallothionein (13%, p<0.01), and, urinary zinc (34%, p<0.05). OCA use decreases serum zinc, alters zinc distribution in major serum fractions with possible effects on tissue uptake, enhances zinc retention in the body and decreases bone turnover. Prolonged OCA use may lead to lower peak bone mass and/or to impaired bone mass maintenance in young women, particularly in those with marginal calcium intake. The observed OCA effects were more evident in women younger than 25 years and in nulliparous women, deserving special attention in future studies.

Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.

PubMed

Cheng, Tsing; Orlow, Seth J; Manga, Prashiela

2013-11-01

Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of pro-apoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.

PubMed

Delahanty, Ryan J; Zhang, Yanfeng; Bichell, Terry Jo; Shen, Wangzhen; Verdier, Kelienne; Macdonald, Robert L; Xu, Lili; Boyd, Kelli; Williams, Janice; Kang, Jing-Qiong

2016-12-20

Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3 -/- mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Long-term Follow-up of Revision Osteochondral Allograft Transplantation of the Ankle.

PubMed

Gaul, Florian; Tírico, Luís E P; McCauley, Julie C; Bugbee, William D

2018-05-01

Osteochondral allograft (OCA) transplantation is a useful alternative for treatment of posttraumatic ankle arthritis in young patients but has a relatively high failure rate and further procedures are often required. The purpose of this study was to evaluate outcomes of patients who underwent revision OCA transplantation of the ankle after failed primary OCA transplantation. Twenty patients underwent revision OCA transplantation of the ankle between 1988 and 2015. Mean age was 44 years, 55% (11 of 20) were female. The mean time from primary to revision OCA was 3.0 ± 1.7 years. All patients had a minimum follow-up of 2 years. Outcomes included the American Academy of Orthopaedic Surgeons Foot and Ankle Module (AAOS-FAM) and questionnaires evaluating pain and satisfaction. Failure of the revision OCA was defined as a conversion to arthroplasty, arthrodesis, or amputation. Ten of 20 ankles required further surgery, of which 30% (6 of 20) were considered OCA revision failures (4 arthrodeses, 1 arthroplasty, and 1 amputation). The mean time to failure was 6.7 (range, 0.6-13.1) years. Survivorship of the revision OCA was 84% at 5 years and 65% at 10 years. The 14 patients with grafts remaining in situ had an average follow-up of 10.3 years; mean AAOS-FAM Core Score was 70.5 (range, 42.3-99). Of the patients who answered the follow-up questions, 4 of 7 reported moderate to severe pain, and 5 of 12 were satisfied with the results of the procedure. Although the results of revision ankle OCA transplantation are not inferior to primary OCA transplantation, the high rates of persistent pain, further surgery, and graft failure suggest that the indications for OCA as a revision procedure should be carefully evaluated, with proper patient selection. Considering the treatment alternatives, revising a failed OCA transplantation can be a useful treatment option, especially for young and active patients who wish to avoid arthrodesis or arthroplasty. Level IV, case series.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

PubMed

Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

A Potential Benefit of Albinism in Astyanax Cavefish: Downregulation of the oca2 Gene Increases Tyrosine and Catecholamine Levels as an Alternative to Melanin Synthesis

PubMed Central

Parkhurst, Amy; Jeffery, William R.

2013-01-01

Albinism, the loss of melanin pigmentation, has evolved in a diverse variety of cave animals but the responsible evolutionary mechanisms are unknown. In Astyanax mexicanus, which has a pigmented surface dwelling form (surface fish) and several albino cave-dwelling forms (cavefish), albinism is caused by loss of function mutations in the oca2 gene, which operates during the first step of the melanin synthesis pathway. In addition to albinism, cavefish have evolved differences in behavior, including feeding and sleep, which are under the control of the catecholamine system. The catecholamine and melanin synthesis pathways diverge after beginning with the same substrate, L-tyrosine. Here we describe a novel relationship between the catecholamine and melanin synthesis pathways in Astyanax. Our results show significant increases in L-tyrosine, dopamine, and norepinephrine in pre-feeding larvae and adult brains of Pachón cavefish relative to surface fish. In addition, norepinephrine is elevated in cavefish adult kidneys, which contain the teleost homologs of catecholamine synthesizing adrenal cells. We further show that the oca2 gene is expressed during surface fish development but is downregulated in cavefish embryos. A key finding is that knockdown of oca2 expression in surface fish embryos delays the development of pigmented melanophores and simultaneously increases L-tyrosine and dopamine. We conclude that a potential evolutionary benefit of albinism in Astyanax cavefish may be to provide surplus L-tyrosine as a precursor for the elevated catecholamine synthesis pathway, which could be important for adaptation to the challenging cave environment. PMID:24282555

A follow up study of occupational exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and isocyanates in polyurethane manufacture in the UK.

PubMed

Keen, C; Coldwell, M; McNally, K; Baldwin, P; McAlinden, J; Cocker, J

2012-08-13

This is a follow up survey of exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and isocyanates in the UK polyurethane industry. Urine samples (n=446) were collected from 90 different workers. MbOCA levels were below the limit of detection in 170 samples and 26 were above the UK Biological Monitoring Guidance Value (BMGV) of 15 μmol MbOCA/mol creatinine. Detailed advice and guidance was given to each workplace at the end of the survey in 2008 and the 90% value reduced from 10 to 3 μmol MbOCA/mol creatinine in samples collected since. There was a positive correlation between glove contamination and urinary MbOCA and levels were dependent upon individual working practices especially how gloves were used. Of the 446 samples analysed for urinary metabolites of toluene diisocyanate 280 were below the detection limit and 126 were above the BMGV (1 μmol/mol creatinine). Of the 326 urine samples that were analysed for metabolites of methylenediphenyl diisocyanate, 270 were below the detection limit and 13 were above the BMGV for isocyanates. There was no correlation between urinary levels of isocyanates and MbOCA suggesting different routes of absorption, most likely inhalation and dermal respectively. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Genetic diseases associated with an increased risk of skin cancer development in childhood.

PubMed

Fogel, Alexander L; Sarin, Kavita Y; Teng, Joyce M C

2017-08-01

Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals. In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7). Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.

In Silico Screening and Molecular Dynamics Simulation of Disease-Associated nsSNP in TYRP1 Gene and Its Structural Consequences in OCA3

PubMed Central

Kamaraj, Balu

2013-01-01

Oculocutaneous albinism type III (OCA3), caused by mutations of TYRP1 gene, is an autosomal recessive disorder characterized by reduced biosynthesis of melanin pigment in the hair, skin, and eyes. The TYRP1 gene encodes a protein called tyrosinase-related protein-1 (Tyrp1). Tyrp1 is involved in maintaining the stability of tyrosinase protein and modulating its catalytic activity in eumelanin synthesis. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and cell death. In this work we implemented computational analysis to filter the most probable mutation that might be associated with OCA3. We found R326H and R356Q as most deleterious and disease associated by using PolyPhen 2.0, SIFT, PANTHER, I-mutant 3.0, PhD-SNP, SNP&GO, Pmut, and Mutpred tools. To understand the atomic arrangement in 3D space, the native and mutant (R326H and R356Q) structures were modelled. Finally the structural analyses of native and mutant Tyrp1 proteins were investigated using molecular dynamics simulation (MDS) approach. MDS results showed more flexibility in native Tyrp1 structure. Due to mutation in Tyrp1 protein, it became more rigid and might disturb the structural conformation and catalytic function of the structure and might also play a significant role in inducing OCA3. The results obtained from this study would facilitate wet-lab researches to develop a potent drug therapies against OCA3. PMID:23862152

Ocatin. A Novel Tuber Storage Protein from the Andean Tuber Crop Oca with Antibacterial and Antifungal Activities1

PubMed Central

Flores, Teresita; Alape-Girón, Alberto; Flores-Díaz, Marietta; Flores, Hector E.

2002-01-01

The most abundant soluble tuber protein from the Andean crop oca (Oxalis tuberosa Mol.), named ocatin, has been purified and characterized. Ocatin accounts for 40% to 60% of the total soluble oca tuber proteins, has an apparent molecular mass of 18 kD and an isoelectric point of 4.8. This protein appears to be found only in tubers and is accumulated only within the cells of the pith and peridermis layers (peel) of the tuber as it develops. Ocatin inhibits the growth of several phytopathogenic bacteria (Agrobacterium tumefaciens, Agrobacterium radiobacter, Serratia marcescens, and Pseudomonas aureofaciens) and fungi (Phytophthora cinnamomi, Fusarium oxysporum, Rhizoctonia solani, and Nectria hematococcus). Ocatin displays substantial amino acid sequence similarity with a widely distributed group of intracellular pathogenesis-related proteins with a hitherto unknown biological function. Our results showed that ocatin serves as a storage protein, has antimicrobial properties, and belongs to the Betv 1/PR-10/MLP protein family. Our findings suggest that an ancient scaffolding protein was recruited in the oca tuber to serve a storage function and that proteins from the Betv 1/PR-10/MLP family might play a role in natural resistance to pathogens. PMID:11950978

Ocatin. A novel tuber storage protein from the andean tuber crop oca with antibacterial and antifungal activities.

PubMed

Flores, Teresita; Alape-Girón, Alberto; Flores-Díaz, Marietta; Flores, Hector E

2002-04-01

The most abundant soluble tuber protein from the Andean crop oca (Oxalis tuberosa Mol.), named ocatin, has been purified and characterized. Ocatin accounts for 40% to 60% of the total soluble oca tuber proteins, has an apparent molecular mass of 18 kD and an isoelectric point of 4.8. This protein appears to be found only in tubers and is accumulated only within the cells of the pith and peridermis layers (peel) of the tuber as it develops. Ocatin inhibits the growth of several phytopathogenic bacteria (Agrobacterium tumefaciens, Agrobacterium radiobacter, Serratia marcescens, and Pseudomonas aureofaciens) and fungi (Phytophthora cinnamomi, Fusarium oxysporum, Rhizoctonia solani, and Nectria hematococcus). Ocatin displays substantial amino acid sequence similarity with a widely distributed group of intracellular pathogenesis-related proteins with a hitherto unknown biological function. Our results showed that ocatin serves as a storage protein, has antimicrobial properties, and belongs to the Betv 1/PR-10/MLP protein family. Our findings suggest that an ancient scaffolding protein was recruited in the oca tuber to serve a storage function and that proteins from the Betv 1/PR-10/MLP family might play a role in natural resistance to pathogens.

Use of 2-octyl cyanoacrylate for wound closure in a modified Roberts-Bistner procedure for eyelid agenesis in five cats (nine eyes).

PubMed

Reed, Zoe; Doering, Clinton J; Barrett, Paul M

2018-01-15

CASE DESCRIPTION 5 cats (9 eyes) were evaluated for surgical correction of bilateral eyelid agenesis. CLINICAL FINDINGS All eyes lacked > 25% of the temporal upper eyelid, and all cats had clinical signs attributable to chronic ocular exposure. Abnormalities were limited to the ocular surface in the 4 female cats, whereas the sole male cat had additional abnormalities consistent with anterior segment dysgenesis. TREATMENT AND OUTCOME A modified Roberts-Bistner procedure involving 2-octyl cyanoacrylate (2OCA) was performed on 9 eyes; 1 eye was enucleated. Surgical wounds in the initial 3 eyes were closed with 2OCA plus sutures, and flaps were lined with conjunctiva. The technique was optimized for remaining eyes by use of a single suture for flap apposition, no conjunctival lining of flaps, and 2OCA alone for wound closure. Median duration of surgery was 35 minutes/eye for the initial 3 eyes versus 16 minutes/eye for the subsequent 6 eyes treated with the optimized procedure. After surgery, all cats had complete palpebral reflexes and resolution of clinical signs of ocular irritation. Minor complications in the early postoperative period included eyelid swelling (n = 9), poor cosmesis (7), and persistent epiphora (3). By the second recheck examination, swelling had resolved and cosmesis was considered excellent. Two eyes with epiphora had been treated with the initial modified procedure and required cryoepilation for resolution of epiphora. CLINICAL RELEVANCE The modified Roberts-Bistner procedure for eyelid agenesis involving 2OCA for wound closure provided functional, cosmetic eyelids that improved comfort and provided protection of the ocular surface in affected cats.

Multifocal visual evoked potentials reveal normal optic nerve projections in human carriers of oculocutaneous albinism type 1a.

PubMed

Hoffmann, Michael B; Wolynski, Barbara; Meltendorf, Synke; Behrens-Baumann, Wolfgang; Käsmann-Kellner, Barbara

2008-06-01

In albinism, part of the temporal retina projects abnormally to the contralateral hemisphere. A residual misprojection is also evident in feline carriers that are heterozygous for tyrosinase-related albinism. This study was conducted to test whether such residual abnormalities can also be identified in human carriers of oculocutaneous tyrosinase-related albinism (OCA1a). In eight carriers heterozygous for OCA1a and in eight age- and sex-matched control subjects, monocular pattern-reversal and -onset multifocal visual evoked potentials (mfVEPs) were recorded at 60 locations comprising a visual field of 44 degrees diameter (VERIS 5.01; EDI, San Mateo, CA). For each eye and each stimulus location, interhemispheric difference potentials were calculated and correlated with each other, to assess the lateralization of the responses: positive and negative correlations indicate lateralizations on the same or opposite hemispheres, respectively. Misrouted optic nerves are expected to yield negative interocular correlations. The analysis also allowed for the assessment of the sensitivity and specificity of the detection of projection abnormalities. No significant differences were obtained for the distributions of the interocular correlation coefficients of controls and carriers. Consequently, no local representation abnormalities were observed in the group of OCA1a carriers. For pattern-reversal and -onset stimulation, an assessment of the control data yielded similar specificity (97.9% and 94.6%) and sensitivity (74.4% and 74.8%) estimates for the detection of projection abnormalities. The absence of evidence for projection abnormalities in human OCA1a carriers contrasts with the previously reported evidence for abnormalities in cat-carriers of tyrosinase-related albinism. This discrepancy suggests that animal models of albinism may not provide a match to human albinism.

Noise-immune complex correlation for optical coherence angiography based on standard and Jones matrix optical coherence tomography

PubMed Central

Makita, Shuichi; Kurokawa, Kazuhiro; Hong, Young-Joo; Miura, Masahiro; Yasuno, Yoshiaki

2016-01-01

This paper describes a complex correlation mapping algorithm for optical coherence angiography (cmOCA). The proposed algorithm avoids the signal-to-noise ratio dependence and exhibits low noise in vasculature imaging. The complex correlation coefficient of the signals, rather than that of the measured data are estimated, and two-step averaging is introduced. Algorithms of motion artifact removal based on non perfusing tissue detection using correlation are developed. The algorithms are implemented with Jones-matrix OCT. Simultaneous imaging of pigmented tissue and vasculature is also achieved using degree of polarization uniformity imaging with cmOCA. An application of cmOCA to in vivo posterior human eyes is presented to demonstrate that high-contrast images of patients’ eyes can be obtained. PMID:27446673

Prevalence and outcome of patients with non-ST segment elevation myocardial infarction with occluded "culprit" artery - a systemic review and meta-analysis.

PubMed

Hung, Chi-Sheng; Chen, Ying-Hsien; Huang, Ching-Chang; Lin, Mao-Shin; Yeh, Chih-Fan; Li, Hung-Yuan; Kao, Hsien-Li

2018-02-09

The aim was to determine the prevalence and impact of an occluded "culprit" artery (OCA) in patients with non-ST segment elevation myocardial infarction (NSTEMI). We searched PubMed, EMBASE, and Web of Science, with no language restrictions, up to 1 Jul. 2016. Observational cohorts or clinical trials of adult NSTEMI were eligible for inclusion to determine the prevalence if the proportion of OCA on coronary angiography was reported. Studies were further eligible for inclusion to determine the outcome if the association between OCA and clinical endpoints was reported. Among the 60,898 patients with NSTEMI enrolled in 25 studies, 17,212 were found to have OCA. The average proportion of OCA in NSTEMI was 34% (95% CI 30-37%). Patients with OCA were more likely to have left circumflex artery as their culprit artery (odds ratio (OR) 1.65, 95% CI 1.15-2.37, p = 0.007), and this was associated with lower left ventricular ejection fraction (standard mean difference -0.29, 95% CI -0.34 to -0.34, p < 0.001), higher peak enzyme level (standard mean difference 0.43, 95% CI 0.27-0.58, p < 0.001), and higher risk for cardiogenic shock (OR 1.66, 95% CI 1.35-2.04, p < 0.001), compared with patients with a non-occlusive culprit artery. Death rate (OR 1.72, 95% CI 1.49-1.98, p < 0.001) and recurrent myocardial infarction (OR 1.7, 95% CI 1.06-2.75, p = 0.029) were also higher in patients with OCA, compared with patients with a non-occlusive culprit artery. Patients with OCA comprised a substantial portion of the NSTEMI population. These patients present with more severe symptoms and worse clinical outcome. Whether these patients should be treated with more aggressive strategy warrants further study.

Macular pigment optical density spatial distribution measured in a subject with oculocutaneous albinism.

PubMed

Putnam, Christopher M; Bland, Pauline J

2014-01-01

Previous studies of macular pigment optical density (MPOD) distribution in individuals with oculocutaneous albinism (OCA) have primarily used objective measurement techniques including fundus reflectometry and autofluorescence. We report here on a subject with OCA and their corresponding MPOD distribution assessed through heterochromatic flicker photometry (HFP). A subject with a history of OCA presented with an ocular history including strabismus surgery of the LE with persistent amblyopia and mild, latent nystagmus. Best corrected visual acuity was 20/25- RE and 20/40- LE. Spectral domain optical coherence tomography (SD-OCT) and fundus photography were also obtained. Evaluation of MPOD spatial distribution up to 8 degrees eccentricity from the fovea was performed using HFP. SD-OCT indicated a persistence of multiple inner retinal layers within the foveal region in the RE and LE including symmetric foveal thickening consistent with foveal hypoplasia. Fundus photography showed mild retinal pigmented epithelial (RPE) hypopigmentation and a poorly demarcated macula. OriginPro 9 was used to plot MPOD spatial distribution of the subject and a 33-subject sample. The OCA subject demonstrated a foveal MPOD of 0.10 with undetectable levels at 6 degrees eccentricity. The study sample showed a mean foveal MPOD of 0.34 and mean 6 degree eccentricity values of 0.03. Consistent with previous macular pigment (MP) studies of OCA, overall MPOD is reduced in our subject. Mild phenotypic expression of OCA with high functional visual acuity may represent a Henle fiber layer amenable to additional MP deposition. Further study of MP supplementation in OCA patients is warranted. Copyright © 2014 Spanish General Council of Optometry. Published by Elsevier Espana. All rights reserved.

Importance of Donor Chondrocyte Viability for Osteochondral Allografts.

PubMed

Cook, James L; Stannard, James P; Stoker, Aaron M; Bozynski, Chantelle C; Kuroki, Keiichi; Cook, Cristi R; Pfeiffer, Ferris M

2016-05-01

Osteochondral allograft (OCA) transplantation provides a biological treatment option for functional restoration of large articular cartilage defects in multiple joints. While successful outcomes after OCA transplantation have been linked to viable donor chondrocytes, the importance of donor cell viability has not been comprehensively validated. To use a canine model to determine the importance of donor chondrocyte viability at the time of implantation with respect to functional success of femoral condylar OCAs based on radiographic, gross, cell viability, histologic, biochemical, and biomechanical outcome measures. Controlled laboratory study. After approval was obtained from the institutional animal care and use committee, adult female dogs (N = 16) were implanted with 8-mm cylindrical OCAs from male dogs in the lateral and medial femoral condyles of 1 knee. OCAs were preserved for 28 or 60 days after procurement, and chondrocyte viability was quantified before implantation. Two different storage media, temperatures, and time points were used to obtain a spectrum of percentage chondrocyte viability at the time of implantation. A successful outcome was defined as an OCA that was associated with graft integration, maintenance of hyaline cartilage, lack of associated cartilage disorder, and lack of fibrillation, fissuring, or fibrous tissue infiltration of the allograft based on subjective radiographic, gross, and histologic assessments at 6 months after implantation. Chondrocyte viability ranged from 23% to 99% at the time of implantation. All successful grafts had >70% chondrocyte viability at the time of implantation, and no graft with chondrocyte viability <70% was associated with a successful outcome. Live-dead stained sections and histologic findings with respect to cell morphological features suggested that successful grafts were consistently composed of viable chondrocytes in lacunae, while grafts that were not successful were composed of nonviable chondrocytes with infiltration of fibroblasts from the surrounding recipient tissues. In situ polymerase chain reaction (fluorescence in situ hybridization [FISH]) assays were performed in an attempt to distinguish donor (male) cells from recipient (female) cells. Unfortunately, this technique was exceptionally difficult to perform on intact articular cartilage sections, and consistent, repeatable data could not be obtained from this testing. However, the data did support histologic and live-dead data, which strongly suggested that successful grafts retained viable donor (male) chondrocytes and unsuccessful grafts degraded and were replaced by fibrous tissue populated with recipient (female) fibroblasts. Viable chondrocytes in OCAs at the time of transplantation are primarily responsible for maintenance of donor articular cartilage health in the long term. Optimizing chondrocyte viability in all aspects of OCA transplantation-including procurement, processing, storage, transportation, and surgical implantation-needs to be a primary focus for OCA clinical use. © 2016 The Author(s).

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis

PubMed Central

Aldini, R; Camborata, C; Spinozzi, S; Franco, P; Cont, M; D'Errico, A; Vasuri, F; Degiovanni, A; Maroni, L; Adorini, L

2017-01-01

Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride‐induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography–mass spectrometry to measure OCA, its metabolites, and BAs at different timepoints in various organs and fluids. Plasma and hepatic concentrations of OCA and BAs were higher in cirrhotic rats than in controls. OCA and endogenous BAs had similar metabolic pathways in cirrhotic rats, although OCA hepatic and intestinal clearance were lower than in controls. BAs' qualitative and quantitative compositions were not modified by a single administration of OCA. In all the matrices studied, OCA concentrations were significantly lower than those of endogenous BAs, potentially much more cytotoxic. PMID:28411380

Genetic Architecture of Skin and Eye Color in an African-European Admixed Population

PubMed Central

Beleza, Sandra; Johnson, Nicholas A.; Candille, Sophie I.; Absher, Devin M.; Coram, Marc A.; Lopes, Jailson; Campos, Joana; Araújo, Isabel Inês; Anderson, Tovi M.; Vilhjálmsson, Bjarni J.; Nordborg, Magnus; Correia e Silva, António; Shriver, Mark D.; Rocha, Jorge

2013-01-01

Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3×10−62, SLC24A5 P = 9.6×10−9) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4×10−27, TYR P = 1.1×10−9, APBA2[OCA2] P = 1.5×10−8, SLC45A2 P = 6×10−9) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (∼44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ∼70% of the estimated heritability. PMID:23555287

Tissue adhesive skills study: the physician learning curve.

PubMed

Lin, Michelle; Coates, Wendy C; Lewis, Roger J

2004-04-01

To compare 2 educational approaches (structured group session vs. individual instruction) of learning application techniques of 2-octylcyanoacrylate (OCA) on wounds repaired in the emergency department. This prospective, nonrandomized, observational study was conducted in an urban hospital emergency department. Medical students, residents, and faculty were trained in the use of OCA either in a standardized group session or individually, based on their availability to attend the group session. Physicians completed a data collection form that included wound characteristics, type of instruction, and number of lacerations previously repaired with OCA. Impressions of time required, difficulty, and postrepair cosmesis were each recorded on a 5-point Likert scale. The 3 scales were totaled to yield a 15-point summary outcome measure. Univariate nonparametric comparisons of measures were performed between physicians with and without group instruction and between those with and without prior OCA experience. Using 35 subjects in each group, this study had a power of 0.95 to detect a difference of 1.5 points in the 15-point summary score, using alpha = 0.05. Eighty-one subjects were enrolled; the median summary score was 13 (IQR 12 to 15). There was no statistically significant difference in the summary score, nor any of its 3 components (time saved, difficulty, cosmesis), when comparing physicians with and without group instruction, nor when comparing first-time users to those with prior experience. OCA application is an easily acquired skill. Physicians were satisfied with their proficiency in OCA application, regardless of type of instruction received or number of previous lacerations repaired with OCA.

Similar Outcomes After Osteochondral Allograft Transplantation in Anterior Cruciate Ligament-Intact and -Reconstructed Knees: A Comparative Matched-Group Analysis With Minimum 2-Year Follow-Up.

PubMed

Wang, Dean; Eliasberg, Claire D; Wang, Tim; Fader, Ryan R; Coxe, Francesca R; Pais, Mollyann D; Williams, Riley J

2017-12-01

To compare failure rates and clinical outcomes of osteochondral allograft transplantation (OCA) in anterior cruciate ligament (ACL)-intact versus ACL-reconstructed knees at midterm follow-up. After a priori power analysis, a prospective registry of patients treated with OCA for focal chondral lesions ≥2 cm 2 in size with minimum 2-year follow-up was used to match ACL-reconstructed knees with ACL-intact knees by age, sex, and primary chondral defect location. Exclusion criteria included meniscus transplantation, realignment osteotomy, or other ligamentous injury. Complications, reoperations, and patient responses to validated outcome measures were reviewed. Failure was defined by any procedure involving allograft removal/revision or conversion to arthroplasty. Kaplan-Meier analysis and multivariate Cox regression were performed to evaluate the association of ACL reconstruction (ACLR) with failure. A total of 50 ACL-intact and 25 ACL-reconstructed (18 prior, 7 concomitant) OCA patients were analyzed. The mean age was 36.2 years (range, 14-62 years). Mean follow-up was 3.9 years (range, 2-14 years). Patient demographics and chondral lesion characteristics were similar between groups. ACL-reconstructed patients averaged 2.2 ± 1.9 prior surgeries on the ipsilateral knee compared with 1.4 ± 1.4 surgeries for ACL-intact patients (P = .014). Grafts used for the last ACLR included bone-patellar tendon-bone autograft, hamstring autograft, Achilles tendon allograft, and tibialis allograft (data available for only 11 of 25 patients). At final follow-up, 22% of ACL-intact and 32% of ACL-reconstructed patients had undergone reoperation. OCA survivorship was 90% and 96% at 2 years and 79% and 85% at 5 years in ACL-intact and ACL-reconstructed patients, respectively (P = .774). ACLR was not independently associated with failure. Both groups demonstrated clinically significant improvements in the Short Form-36 pain and physical functioning, International Knee Documentation Committee subjective, and Knee Outcome Survey-Activities of Daily Living scores at final follow-up (P < .001), with no significant differences in preoperative, postoperative, and change scores between groups. OCA in the setting of prior or concomitant ACLR does not portend higher failure rates or compromise clinical outcomes. Level III, retrospective comparative study. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

40 CFR 1400.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION... analysis (OCA) information means sections 2 through 5 of a risk management plan (consisting of an... consequence analysis (OCA) data elements means the results of the off-site consequence analysis conducted by a...

40 CFR 1400.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION... analysis (OCA) information means sections 2 through 5 of a risk management plan (consisting of an... consequence analysis (OCA) data elements means the results of the off-site consequence analysis conducted by a...

40 CFR 1400.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION... analysis (OCA) information means sections 2 through 5 of a risk management plan (consisting of an... consequence analysis (OCA) data elements means the results of the off-site consequence analysis conducted by a...

40 CFR 1400.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION... analysis (OCA) information means sections 2 through 5 of a risk management plan (consisting of an... consequence analysis (OCA) data elements means the results of the off-site consequence analysis conducted by a...

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis.

PubMed

Roda, A; Aldini, R; Camborata, C; Spinozzi, S; Franco, P; Cont, M; D'Errico, A; Vasuri, F; Degiovanni, A; Maroni, L; Adorini, L

2017-07-01

Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride-induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and BAs at different timepoints in various organs and fluids. Plasma and hepatic concentrations of OCA and BAs were higher in cirrhotic rats than in controls. OCA and endogenous BAs had similar metabolic pathways in cirrhotic rats, although OCA hepatic and intestinal clearance were lower than in controls. BAs' qualitative and quantitative compositions were not modified by a single administration of OCA. In all the matrices studied, OCA concentrations were significantly lower than those of endogenous BAs, potentially much more cytotoxic. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury

PubMed Central

Berardo, Clarissa; Siciliano, Veronica; Rizzo, Vittoria; Adorini, Luciano; Richelmi, Plinio

2018-01-01

Background We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. Material and methods Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. Results OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. Conclusion The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent. PMID:29346429

The bioavailability of oxalate from Oca (Oxalis tuberosa).

PubMed

Albihn, P B; Savage, G P

2001-08-01

It is believed that soluble oxalate has higher bioavailability than insoluble oxalate. Oca (Oxalis tuberosa) is moderately high in oxalate and contains oxalate in soluble form only. We estimated the bioavailability of oxalate in oca based on the urinary excretion of oxalate after oxalate loading with oca to estimate the bioavailability of oxalate in oca. We also clarified whether bioavailability differs in various oxalate loads from the same food source and studied the effect of an additional calcium source on the bioavailability of oxalate from oca. Four men and 4 women ingested 50, 100 and 150 gm. oca as well as 100 gm. oca with 100 gm. sour cream. Oxalate was measured in a 6-hour urine sample from each volunteer. The mean bioavailability of oxalate from oca plus or minus standard deviation was 1.44% +/- 1.31% during the 6-hour period after intake. There was no significant difference in oxalate bioavailability among oxalate intake levels in this study, although oca consumption with sour cream significantly decreased the uptake of oxalate (p <0.01). The variation in bioavailability among individuals was high in our study. The bioavailability of oxalate in oca appears to be similar to that in spinach. However, bioavailability varies among individuals and depends on other constituents of a combined meal.

ASSESSMENT OF BORIC ACID AND BORAX USING THE IEHR EVALUATIVE PROCESS FOR ASSESSING HUMAN DEVELOPMENT AND REPRODUCTIVE TOXICITY OF AGENTS

EPA Science Inventory

This document presents an evaluation of the reproductive and developmental effects of boric acid, H3803 (CAS Registry No. 10043-35-3) and disodium tetraborate decehydrate or borax, Na2B4O2O(CAS Registry No. 1303-96-4). he element, boron, does not exist naturally. oron always exis...

Computational screening of disease-associated mutations in OCA2 gene.

PubMed

Kamaraj, Balu; Purohit, Rituraj

2014-01-01

Oculocutaneous albinism type 2 (OCA2), caused by mutations of OCA2 gene, is an autosomal recessive disorder characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eyes. The OCA2 gene encodes instructions for making a protein called the P protein. This protein plays a crucial role in melanosome biogenesis, and controls the eumelanin content in melanocytes in part via the processing and trafficking of tyrosinase which is the rate-limiting enzyme in melanin synthesis. In this study we analyzed the pathogenic effect of 95 non-synonymous single nucleotide polymorphisms reported in OCA2 gene using computational methods. We found R305W mutation as most deleterious and disease associated using SIFT, PolyPhen, PANTHER, PhD-SNP, Pmut, and MutPred tools. To understand the atomic arrangement in 3D space, the native and mutant (R305W) structures were modeled. Molecular dynamics simulation was conducted to observe the structural significance of computationally prioritized disease-associated mutation (R305W). Root-mean-square deviation, root-mean-square fluctuation, radius of gyration, solvent accessibility surface area, hydrogen bond (NH bond), trace of covariance matrix, eigenvector projection analysis, and density analysis results showed prominent loss of stability and rise in mutant flexibility values in 3D space. This study presents a well designed computational methodology to examine the albinism-associated SNPs.

Exposure to 4,4'-methylene bis (2-chloroaniline) (MbOCA) in New South Wales, Australia

PubMed Central

Shankar, Kiran; Fung, Vivian; Seneviratne, Mahinda; O'Donnell, Gregory E

2017-01-01

Objectives: This study was conducted to determine the level of exposure of 4,4'-methylene bis (2-chloroaniline) (MbOCA) in New South Wales (NSW), Australia. Methods: An integrated occupational hygiene and biological monitoring program were used to assess the workers' exposure to MbOCA via inhalation, ingestion and dermal contact. This was conducted by personal air monitoring, static air monitoring and surface contamination monitoring of the work environment and biological monitoring of the workers' exposure to MbOCA at nine workplaces in NSW. Results: The air monitoring results for MbOCA gave a geometric mean (GM) of 0.06 μg/m3 and a geometric standard deviation (GSD) of 2.70 and a 95% confidence interval of 0.29 μg/m3. The surface contamination in the main work area showed the highest contamination with a GM of 74 ng/cm2 and a GSD of 17 and a 95% confidence interval of 7,751 ng/cm2. Biological monitoring showed a GM of 0.89 μmol/mol cr and a GSD of 11.9 and a 95% confidence interval of 52 μmol/mol cr. This indicated that 13% of the workers were over the SafeWork NSW Biological Occupational Exposure Limit of 15 μmol/mol cr. Conclusions: Workers' exposure through inhalation was minimal; however, evidence from biological monitoring of MbOCA suggested that the main contributing factor to exposure was skin absorption. This was attributed to poor housekeeping and inadequate personal protection. Improvements in these areas were recommended, and it was also recommended to improve the awareness of the workers to the adverse effects to their health of exposure to this carcinogen. PMID:28320979

Association of five SNPs with human hair colour in the Polish population.

PubMed

Siewierska-Górska, A; Sitek, A; Żądzińska, E; Bartosz, G; Strapagiel, D

2017-03-01

Twenty-two variants (single nucleotide polymorphisms - SNPs) of the genes involved in hair pigmentation (OCA2, HERC2, MC1R, SLC24A5, SLC45A2, TPCN2, TYR, TYRP1) were genotyped in a group of 186 Polish participants, representing a range of hair colours (45 red, 64 blond, 77 dark). A genotype-phenotype association analysis was performed. Using z-statistics we identified three variants highly associated with different hair colour categories (rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R). Two variants: rs1800401:C>T in OCA2 and rs16891982:C>G in SLC45A2 showed a high probability of a relation with hair colour, although that probability did not exceed the threshold of statistical significance after applying the Bonferroni correction. We created and validated mathematical logistic regression models in order to test the usefulness of the sets of polymorphisms for hair colour prediction in the Polish population. We subjected four models to stratified cross-validation. The first model consisted of three polymorphisms that proved to be important in the associative analysis. The second model included, apart from the mentioned polymorphisms, additionally rs16891982:C>G in SLC45A. The third model included, apart from the variants relevant in the associating analysis, rs1800401:C>T in OCA. The fourth model consisted of the set of polymorphisms from the first model supplemented with rs16891982:C>G in SLC45A and rs1800401:C>T in OCA. The validation of our models has shown that the inclusion of rs16891982:C>G in SLC45A and rs1800401:C>T in OCA increases the prediction of red hair in comparison with the algorithm including only rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R. The model consisting of all the five above-mentioned genetic variants has shown good prediction accuracies, expressed by the area under the curve (AUC) of the receiver operating characteristics: 0.84 for the red-haired, 0.82 for the dark-haired and 0.71 for the blond-haired. A genotype-phenotype association analysis brought results similar to those in other studies and confirmed the role of rs16891982:C>G, rs12913832:A>G, rs1805007:T>C and rs1805008:C>T in hair colour determination in the Polish population. Our study demonstrated for the first time the possibility of a share of the rs1800401:C>T SNP in the OCA2 gene in hair colour determination. Including this single nucleotide polymorphism in the actual hair colour predicting models would improve their predictive accuracy. Copyright © 2017 Elsevier GmbH. All rights reserved.

Comparing the occlusal contact area of individual teeth during low-level clenching.

PubMed

Nishimori, Hideta; Iida, Takashi; Kamiyama, Hirona; Komoda, Yoshihiro; Obara, Ryoko; Uchida, Takashi; Kawara, Misao; Komiyama, Osamu

2017-09-14

The aim of this study was to investigate the occlusal contact area (OCA) in individual teeth during low-level tooth clenching in 24 healthy participants. Before measurements were made, the 100% maximum voluntary contraction (MVC) was determined. At baseline, all subjects were instructed to close their mouth and touch the opposing teeth with minimal force. Occlusal contact was recorded during three jaw motor tasks (baseline, 20% MVC, and 40% MVC) using a blue silicone material. OCA thickness was determined from images and defined on five levels: level 1 (0-149 µm), level 2 (0-89 µm), level 3 (0-49 µm), level 4 (0-29 µm), and level 5 (0-4 µm). Premolar and molar OCAs increased significantly from baseline to 20% MVC and 40% MVC. The OCA of each anterior tooth did not change significantly with increasing clenching intensity at all levels. Our findings suggest that premolar and molar OCAs may be altered by low-intensity clenching, affecting the teeth and periodontal tissues.

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage

PubMed Central

LaCerte, C; Peyret, T; Gosselin, NH; Marier, JF; Hofmann, AF; Shapiro, D

2016-01-01

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4‐, 8‐, and 13‐fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1‐, 1.5‐, and 1.7‐fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2‐fold). PMID:27743502

NASA's OCA Mirroring System: An Application of Multiagent Systems in Mission Control

NASA Technical Reports Server (NTRS)

Sierhuis, Maarten; Clancey, William J.; vanHoof, Ron J. J.; Seah, Chin H.; Scott, Michael S.; Nado, Robert A.; Blumenberg, Susan F.; Shafto, Michael G.; Anderson, Brian L.; Bruins, Anthony C.;

Homozygosity mapping in albinism patients using a novel panel of 13 STR markers inside the nonsyndromic OCA genes: introducing 5 novel mutations.

PubMed

Khordadpoor-Deilamani, Faravareh; Akbari, Mohammad Taghi; Karimipoor, Morteza; Javadi, Gholam Reza

2016-05-01

Albinism is a heterogeneous genetic disorder of melanin synthesis that results in hypopigmented hair, skin and eyes. It is associated with decreased visual acuity, nystagmus, strabismus and photophobia. Six genes are known to be involved in nonsyndromic oculocutaneous albinism (OCA). In this study, we aimed to find the disease causing mutations in albinism patients using homozygosity mapping. Twenty three unrelated patients with nonsyndromic OCA or autosomal recessive ocular albinism were recruited in this study. All of the patients' parents had consanguineous marriage and all were screened for TYR mutations previously. At first, we performed homozygosity mapping using fluorescently labeled primers to amplify a novel panel of 13 STR markers inside the OCA genes and then the screened loci in each family were studied using PCR and cycle sequencing methods. We found five mutations including three mutations in OCA2, one mutation in SLC45A2 and one mutation in C10ORF11 genes, all of which were novel. In cases where the disease causing mutations are identical by descent due to a common ancestor, these STR markers can enable us to screen for the responsible genes.

Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome.

PubMed

Pereira-Fantini, Prue M; Lapthorne, Susan; Gahan, Cormac G M; Joyce, Susan A; Charles, Jenny; Fuller, Peter J; Bines, Julie E

2017-07-01

Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction. OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration. Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation.

Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism.

PubMed

Manga, Prashiela; Orlow, Seth J

2011-10-01

Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1-OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and increases eye and hair pigmentation.

Comparison of Techniques for Preimplantation Treatment of Osteochondral Allograft Bone.

PubMed

Baumann, Charles A; Baumann, John R; Bozynski, Chantelle C; Stoker, Aaron M; Stannard, James P; Cook, James L

2018-03-07

Articular defects are a major problem with few effective treatment options. Osteochondral allograft (OCA) transplantation can be an effective treatment; however, lack of OCA bone integration can cause failure. This controlled laboratory study was designed to compare clinically applicable methods for marrow element removal and enhanced delivery of bone marrow aspirate concentrate (BMC) to OCA bone. We hypothesized that compressed carbon dioxide (CO 2 ) treatment of OCA bone would result in significantly better marrow element removal, significantly more retention and distribution of viable osteoprogenitor cells, and significantly higher osteoinductive protein elution from OCAs compared with other preimplantation treatments. Fresh humeral heads ( n  = 24) were harvested and stored for 14 days, then randomly assigned to treatment based on marrow element removal and bone treatment: (standard of care [SOC]) ( n  = 4) - SOC high-pulse saline lavage, no BMC; (BMC) ( n  = 5) - saline lavage then canine BMC; (Drill + BMC) ( n  = 5) - 1.1 mm drill-hole immediately subchondral then saline lavage then BMC injection through drill hole; (Carb + BMC) ( n  = 5) - saline lavage then CO 2 then BMC; or (Saline-Carb + BMC) ( n  = 5) - saline lavage and CO 2 together then BMC. Treated OCAs were cultured for 14 days. On day 3, media were collected, centrifuged to isolate cells, and replaced. Cells were cultured for 11 days for colony forming unit (CFU) determination. OCA media were collected on days 7 and 14 of culture for analysis. On day 14, each graft was assessed for viable cell retention and distribution, and bone marrow element removal. BMC had significantly higher ( p  = 0.001) viable cell distribution compared with the SOC, Drill + BMC, Carb + BMC, and Saline-Carb + BMC groups. BMC and Drill + BMC had significantly higher ( p  < 0.05) CFUs than SOC, Carb + BMC, and Saline-Carb + BMC. Drill + BMC and Carb + BMC had the highest media concentrations of the osteoinductive biomarkers. The Carb + BMC and Saline-Carb + BMC groups were associated with significantly superior marrow element removal ( p  < 0.02) compared with the SOC, Drill + BMC, and BMC groups. Saline irrigation plus saturation with autogenous BMC appears to be the most advantageous preimplantation treatment for OCA transplantation. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Bioinspired polyethylene terephthalate nanocone arrays with underwater superoleophobicity and anti-bioadhesion properties

NASA Astrophysics Data System (ADS)

Liu, Wendong; Liu, Xueyao; Fangteng, Jiaozi; Wang, Shuli; Fang, Liping; Shen, Huaizhong; Xiang, Siyuan; Sun, Hongchen; Yang, Bai

2014-10-01

This paper presents a facile method to fabricate bioinspired polyethylene terephthalate (PET) nanocone arrays via colloidal lithography. The aspect ratio (AR) of the nanocones can be finely modulated ranging from 1 to 6 by regulating the etching time. The samples with the AR value of 6 can present underwater superoleophobicity with the underwater oil contact angle (OCA) of 171.8°. The as-prepared PET nanocone arrays perform anti-bioadhesion behavior, which inhibits the formation of the actin cytoskeleton when it used as the substrate for cell culture. Moreover, the oil wettability is temperature controlled after modifying the PET nanocone arrays with PNIPAAm film, and the oil wettability of the functionalized nanocone arrays can be transformed from the superoleophobic state with OCA about 151° to the oleophilic state with OCA about 25° reversibly. Due to the high-throughput, parallel fabrication and cost-efficiency of this method, it will be favourable for researchers to introduce oleophobic properties to various substrate and device surfaces. Due to the superoleophobicity and simple functionalizing properties, the PET nanocone arrays are very promising surfaces for anti-adhesion, self-cleaning and have potential applications in material, medical, and biological fields.This paper presents a facile method to fabricate bioinspired polyethylene terephthalate (PET) nanocone arrays via colloidal lithography. The aspect ratio (AR) of the nanocones can be finely modulated ranging from 1 to 6 by regulating the etching time. The samples with the AR value of 6 can present underwater superoleophobicity with the underwater oil contact angle (OCA) of 171.8°. The as-prepared PET nanocone arrays perform anti-bioadhesion behavior, which inhibits the formation of the actin cytoskeleton when it used as the substrate for cell culture. Moreover, the oil wettability is temperature controlled after modifying the PET nanocone arrays with PNIPAAm film, and the oil wettability of the functionalized nanocone arrays can be transformed from the superoleophobic state with OCA about 151° to the oleophilic state with OCA about 25° reversibly. Due to the high-throughput, parallel fabrication and cost-efficiency of this method, it will be favourable for researchers to introduce oleophobic properties to various substrate and device surfaces. Due to the superoleophobicity and simple functionalizing properties, the PET nanocone arrays are very promising surfaces for anti-adhesion, self-cleaning and have potential applications in material, medical, and biological fields. Electronic supplementary information (ESI) available: The optical microscopy image of the self-assembled 2D PS microspheres over a large area, the diameter of the PS microsphere is 580 nm; The top-view SEM image of the PET nanocone arrays over a large area, the AR of the nanocone is 6; The SEM image of the PET nanocone arrays obtained after 30 min etching; The optical image of the water droplet on the PET nanocone arrays with an AR of 6; The schematic illustration of the nanocone arrays modification with PNIPAAm; High resolution XPS spectra of the PNIPAAm modified PET nanocone arrays. See DOI: 10.1039/c4nr04471a

[Chemical characterization and quantification of fructooligosaccharides, phenolic compounds and antiradical activity of Andean roots and tubers grown in Northwest of Argentina].

PubMed

Jiménez, María Eugenia; Sammán, Norma

2014-06-01

There is great interest in consuming foods that can provide the nutrients for a good nutrition and other health beneficial compounds. The aim of this work was to determine the chemical composition of native foods of the Andean region and to quantify some functional com-ponents. Proximal composition, vitamin C, total phenolic compounds, antiradical activity (DPPH) in peel and pulp, dietary fiber soluble and insoluble, fructooligosaccharides (FOS), total and resistant starch (in tubers and raw roots, boiled and boiled and stored) of 6 varieties of Oca (Oxalis tuberosa), 4 clones of manioc (Manihot esculenta Crantz) and yacon (Smallanthus sonchifolius were determined. The results showed greater amount of bioactive compounds and antiradical activity in the skin of these products. The highest content was found in the oca peel. In all cases, the content of insoluble fiber was greater than the soluble. The manioc had higher total starch than Andean roots and tubers. The boiling process decreased the resistant starch content of ocas and maniocs, but when these are stored for 48 h at 5 ° C, the resistant starch content increased. The FOS content of the ocas was similar for all varieties (7%). The main component of yacon carbohydrates were FOS (8.89%). The maniocs did not contain FOS. It can be concluded that the roots and tubers studied, in addition to provide nutrients, contain functional compounds that confer additional helpful value for preventing no communicable diseases.

Optical clearing of the dura mater using glycerol: a reversible process to aid the post-mortem investigation of infant head injury.

PubMed

Cheshire, Emma C; Malcomson, Roger D G; Joseph, Shiju; Biggs, Mike J B; Adlam, David; Rutty, Guy N

2015-09-01

In cases of suspected abusive head trauma, a thorough and systematic study of the cranium and its contents is essential, preferably using the best available methods for observing the brain and its coverings. Building upon recent developments in skull bone removal techniques in infant autopsies, we have assessed the use of two optical clearing agents (OCAs), glycerol and mannitol, on pediatric dura mater in an attempt to increase the transparency of this tissue and thereby enhance the post-mortem assessment of infant head injuries, particularly subdural hematomas. Extracorporeal testing revealed glycerol to be the more effective OCA. Therefore, in situ investigations were commenced using glycerol during 33 pediatric post-mortem examinations. An increase in the transparency of the dura was observed in 32 of the 33 cases, within 1 min of application of the OCA. In a 2 year old with cerebral palsy, only partial optical clearance of the dura was seen, most likely due to a significantly atrophic brain, prominent gelatinous leptomeninges, and abnormally thickened dura. This technique allowed for detection of minimal amounts of subdural bleeding over the convexities, before dissection of the dura, avoiding post-mortem blood spillage from artifactually disrupted bridging veins. Optical clearing of the dura aided in the evaluation of patterns of subdural hemorrhage in three cases of non-accidental head injury, three cases of peri-natal head injury and one case of overlaying, apparently resulting in minor crush injury to the head. We have demonstrated that glycerol is an effective and easy-to-use OCA to effect the readily reversible optical clearing of human infant calvarial dura at autopsy.

Assessment of laser-induced acceleration effects in optical clearing of in vivo human skin by optical coherence tomography

NASA Astrophysics Data System (ADS)

Zhan, Zhigang; Wei, Huajiang; Jin, Ying

2015-02-01

Laser irradiation is considered to be a promising innovative technology which has been developed in an attempt to increase transdermal drug delivery. In this study, a near-infrared CW diode laser (785 nm) was applied to increase permeability of glycerol solutions in human skin in vivo and improve the optical clearing efficacy. Results show that for both 15%v/v and 30%v/v glycerol, the permeability coefficient increased significantly if the detected area of the skin tissue was treated with laser irradiation before optical clearing agents (OCAs) were applied. This study based on optical coherence tomography imaging technique and optical clearing effect finds laser irradiation a new approach for enhancing the penetration of OCAs and accelerating the rate of transdermal drug delivery.

Obeticholic Acid

PubMed Central

Smith, Susan M.; Pegram, Angela H.

2017-01-01

Objective: To review the pharmacology, efficacy, and safety of obeticholic acid (OCA) and determine its clinical role relative to other agents in the treatment of patients with primary biliary cholangitis (PBC). Data Sources: A PubMed search (1946 to November 2016) was conducted using the terms INT-747, obeticholic acid, OCA, farnesoid X receptor agonists, FXR agonists, primary biliary cirrhosis, and primary biliary cholangitis. Study Selection and Data Extraction: Phase II and III studies evaluating the use of OCA in PBC patients were included in this review. Data Synthesis: OCA, a farnesoid X receptor (FXR) agonist, is indicated for adult patients with PBC in combination with ursodeoxycholic acid (UDCA) or as monotherapy if unable to tolerate UDCA. Two clinical trials were identified evaluating OCA for the treatment of PBC. Study end points utilized biochemical markers (alkaline phosphatase [ALP] and bilirubin). A phase II study (n = 165) to determine efficacy and safety of OCA at 3 different doses (10 mg, 25 mg, 50 mg) demonstrated statistically significant reductions in ALP (P < .0001 for all OCA groups versus placebo) after 12 weeks. A phase III trial (n = 217) assessed lower OCA doses (5 mg and 10 mg) with a longer study duration (12 months). Statistically significant differences (P < .001) between the 5 to 10 mg group (46%) and the 10 mg group (47%) compared to the placebo group (10%) were found. The primary adverse effect reported in both trials was pruritus. Conclusions: OCA is the first FXR agonist approved for the treatment of PBC. Ongoing research to evaluate clinical outcomes with OCA is currently underway.

Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

PubMed

Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

2017-12-01

Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Loci associated with skin pigmentation identified in African populations

PubMed Central

Crawford, Nicholas G.; Kelly, Derek E.; Hansen, Matthew E. B.; Beltrame, Marcia H.; Fan, Shaohua; Bowman, Shanna L.; Jewett, Ethan; Ranciaro, Alessia; Thompson, Simon; Lo, Yancy; Pfeifer, Susanne P.; Jensen, Jeffrey D.; Campbell, Michael C.; Beggs, William; Hormozdiari, Farhad; Mpoloka, Sununguko Wata; Mokone, Gaonyadiwe George; Nyambo, Thomas; Meskel, Dawit Wolde; Belay, Gurja; Haut, Jake; Rothschild, Harriet; Zon, Leonard; Zhou, Yi; Kovacs, Michael A.; Xu, Mai; Zhang, Tongwu; Bishop, Kevin; Sinclair, Jason; Rivas, Cecilia; Elliot, Eugene; Choi, Jiyeon; Li, Shengchao A.; Hicks, Belynda; Burgess, Shawn; Abnet, Christian; Watkins-Chow, Dawn E.; Oceana, Elena; Song, Yun S.; Eskin, Eleazar; Brown, Kevin M.; Marks, Michael S.; Loftus, Stacie K.; Pavan, William J.; Yeager, Meredith; Chanock, Stephen; Tishkoff, Sarah

2017-01-01

Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2 and HERC2 that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in southern Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of UV response genes under selection in Eurasians. PMID:29025994

Viscous optical clearing agent for in vivo optical imaging

NASA Astrophysics Data System (ADS)

Deng, Zijian; Jing, Lijia; Wu, Ning; lv, Pengyu; Jiang, Xiaoyun; Ren, Qiushi; Li, Changhui

2014-07-01

By allowing more photons to reach deeper tissue, the optical clearing agent (OCA) has gained increasing attention in various optical imaging modalities. However, commonly used OCAs have high fluidity, limiting their applications in in vivo studies with oblique, uneven, or moving surfaces. In this work, we reported an OCA with high viscosity. We measured the properties of this viscous OCA, and tested its successful performances in the imaging of a living animal's skin with two optical imaging modalities: photoacoustic microscopy and optical coherence tomography. Our results demonstrated that the viscous OCA has a great potential in the study of different turbid tissues using various optical imaging modalities.

CD86 and beta2-adrenergic receptor signaling pathways, respectively, increase Oct-2 and OCA-B Expression and binding to the 3'-IgH enhancer in B cells.

PubMed

Podojil, Joseph R; Kin, Nicholas W; Sanders, Virginia M

2004-05-28

Stimulation of CD86 (formerly known as B7-2) and/or the beta2-adrenergic receptor on a CD40 ligand/interleukin-4-activated B cell increased the rate of mature IgG1 transcription. To identify the mechanism responsible for this effect, we determined whether CD86 and/or beta2-adrenergic receptor stimulation regulated transcription factor expression and binding to the 3'-IgH enhancer in vitro and in vivo. We showed that CD86 stimulation increased the nuclear localization of NF-kappaB1 (p50) and phosphorylated RelA (p65) and increased Oct-2 expression and binding to the 3'-IgH enhancer, in a protein kinase C-dependent manner. These effects were lost when CD86-deficient or NF-kappaB1-deficient B cells were used. CD86 stimulation also increased the level of IkappaB-alpha phosphorylation but in a protein kinase C-independent manner. Beta2-adrenergic receptor stimulation increased CREB phosphorylation, OCA-B expression, and OCA-B binding to the 3'-IgH enhancer in a protein kinase A-dependent manner, an effect lost when beta2-adrenergic receptor-deficient B cells were used. Also, the beta2-adrenergic receptor-induced increase in the level of mature IgG1 transcript was lost when OCA-B-deficient B cells were used. These data are the first to show that CD86 stimulation up-regulates the expression of the transcription factor Oct-2 in a protein kinase C- and NF-kappaB1-dependent manner, and that beta2-adrenergic receptor stimulation up-regulates the expression of the coactivator OCA-B in a protein kinase A-dependent manner to cooperate with Oct-2 binding to the 3'-IgH enhancer.

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters[S

PubMed Central

Dong, Bin; Young, Mark; Liu, Xueqing; Singh, Amar Bahadur; Liu, Jingwen

2017-01-01

The farnesoid X receptor (FXR) plays critical roles in plasma cholesterol metabolism, in particular HDL-cholesterol (HDL-C) homeostasis. Obeticholic acid (OCA) is a FXR agonist being developed for treating various chronic liver diseases. Previous studies reported inconsistent effects of OCA on regulating plasma cholesterol levels in different animal models and in different patient populations. The mechanisms underlying its divergent effects have not yet been thoroughly investigated. The scavenger receptor class B type I (SR-BI) is a FXR-modulated gene and the major receptor for HDL-C. We investigated the effects of OCA on hepatic SR-BI expression and correlated such effects with plasma HDL-C levels and hepatic cholesterol efflux in hyperlipidemic hamsters. We demonstrated that OCA induced a time-dependent reduction in serum HDL-C levels after 14 days of treatment, which was accompanied by a significant reduction of liver cholesterol content and increases in fecal cholesterol in OCA-treated hamsters. Importantly, hepatic SR-BI mRNA and protein levels in hamsters were increased to 1.9- and 1.8-fold of control by OCA treatment. Further investigations in normolipidemic hamsters did not reveal OCA-induced changes in serum HDL-C levels or hepatic SR-BI expression. We conclude that OCA reduces plasma HDL-C levels and promotes transhepatic cholesterol efflux in hyperlipidemic hamsters via a mechanism involving upregulation of hepatic SR-BI. PMID:27940481

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters.

PubMed

Dong, Bin; Young, Mark; Liu, Xueqing; Singh, Amar Bahadur; Liu, Jingwen

2017-02-01

The farnesoid X receptor (FXR) plays critical roles in plasma cholesterol metabolism, in particular HDL-cholesterol (HDL-C) homeostasis. Obeticholic acid (OCA) is a FXR agonist being developed for treating various chronic liver diseases. Previous studies reported inconsistent effects of OCA on regulating plasma cholesterol levels in different animal models and in different patient populations. The mechanisms underlying its divergent effects have not yet been thoroughly investigated. The scavenger receptor class B type I (SR-BI) is a FXR-modulated gene and the major receptor for HDL-C. We investigated the effects of OCA on hepatic SR-BI expression and correlated such effects with plasma HDL-C levels and hepatic cholesterol efflux in hyperlipidemic hamsters. We demonstrated that OCA induced a time-dependent reduction in serum HDL-C levels after 14 days of treatment, which was accompanied by a significant reduction of liver cholesterol content and increases in fecal cholesterol in OCA-treated hamsters. Importantly, hepatic SR-BI mRNA and protein levels in hamsters were increased to 1.9- and 1.8-fold of control by OCA treatment. Further investigations in normolipidemic hamsters did not reveal OCA-induced changes in serum HDL-C levels or hepatic SR-BI expression. We conclude that OCA reduces plasma HDL-C levels and promotes transhepatic cholesterol efflux in hyperlipidemic hamsters via a mechanism involving upregulation of hepatic SR-BI.

Osteochondral Allograft Transplantation in Cartilage Repair: Graft Storage Paradigm, Translational Models, and Clinical Applications

PubMed Central

Bugbee, William D.; Pallante-Kichura, Andrea L.; Görtz, Simon; Amiel, David; Sah, Robert

2016-01-01

The treatment of articular cartilage injury and disease has become an increasingly relevant part of orthopaedic care. Articular cartilage transplantation, in the form of osteochondral allografting, is one of the most established techniques for restoration of articular cartilage. Our research efforts over the last two decades have supported the transformation of this procedure from experimental “niche” status to a cornerstone of orthopaedic practice. In this Kappa Delta paper, we describe our translational and clinical science contributions to this transformation: (1) to enhance the ability of tissue banks to process and deliver viable tissue to surgeons and patients, (2) to improve the biological understanding of in vivo cartilage and bone remodeling following osteochondral allograft (OCA) transplantation in an animal model system, (3) to define effective surgical techniques and pitfalls, and (4) to identify and clarify clinical indications and outcomes. The combination of coordinated basic and clinical studies is part of our continuing comprehensive academic OCA transplant program. Taken together, the results have led to the current standards for OCA processing and storage prior to implantation and also novel observations and mechanisms of the biological and clinical behavior of OCA transplants in vivo. Thus, OCA transplantation is now a successful and increasingly available treatment for patients with disabling osteoarticular cartilage pathology. PMID:26234194

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers.

PubMed

Pencek, R; Marmon, T; Roth, J D; Liberman, A; Hooshmand-Rad, R; Young, M A

2016-09-01

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub-fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. © 2016 John Wiley & Sons Ltd.

Pennsylvania Occupational Competency Assessment Program--1983. Final Report. Vocational-Technical Education Research Report, Volume 22, Number 2. Occupational Competency Evaluation Monograph, Number 15.

ERIC Educational Resources Information Center

Walter, Richard A.

The Pennsylvania State University served as the Pennsylvania Coordinator of Occupational Competency Assessment (OCA). It managed the Pennsylvania OCA Program, which provides the secondary public schools of the state with competent vocational instructors as a component of teacher preparation at Temple University, Indiana University of Pennsylvania,…

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.

PubMed

Hirschfield, Gideon M; Mason, Andrew; Luketic, Velimir; Lindor, Keith; Gordon, Stuart C; Mayo, Marlyn; Kowdley, Kris V; Vincent, Catherine; Bodhenheimer, Henry C; Parés, Albert; Trauner, Michael; Marschall, Hanns-Ulrich; Adorini, Luciano; Sciacca, Cathi; Beecher-Jones, Tessa; Castelloe, Erin; Böhm, Olaf; Shapiro, David

2015-04-01

We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Can Competitive Athletes Return to High-Level Play After Osteochondral Allograft Transplantation of the Knee?

PubMed

McCarthy, Mark A; Meyer, Maximilian A; Weber, Alexander E; Levy, David M; Tilton, Annemarie K; Yanke, Adam B; Cole, Brian J

2017-09-01

To investigate functional outcomes among competitive athletes undergoing osteochondral allograft (OCA) transplantation of the knee, including rates of return to play (RTP), and factors preventing RTP. A retrospective review identified all competitive athletes (high school, intercollegiate, professional) undergoing isolated femoral condyle OCA from 2004 to 2013. Patient-reported outcome (PRO) questionnaires (Lysholm, International Knee Documentation Committee [IKDC], Knee Injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMasters Universities Arthritis Index [WOMAC], 12-Item Short Form Health Survey [SF-12], Tegner, and Marx) and custom RTP surveys were administered. All subsequent reoperations were documented. Thirteen athletes (4 intercollegiate, 9 high-school) were identified with an average follow-up of 5.9 ± 2.5 years. Seven athletes (54%) returned to competitive sport at an average of 7.9 ± 3.5 months, 5 of whom returned to preinjury functional levels. Of the 8 athletes who either did not return to competitive sport or failed to sustain their high level of play, the most common reasons cited were graduation from high school or college (4 patients, 50%) or fear of reinjury (3 patients, 38%). All 4 patients citing graduation as the primary factor preventing return to preinjury level of competitive sport resumed recreational sport without limitations, yielding an adjusted RTP rate of 10 patients (77%) who either returned to competitive play or believed they could return if they had not graduated. At final follow-up, athletes reported significant improvements in all PRO scores except for KOOS-Sport, WOMAC-Stiffness, and SF-12 Mental subscales. There were 3 reoperations at an average of 3.8 ± 3.3 years after the index OCA. There were no instances of graft failure. OCAs provide an adjusted RTP rate of 77% for high-level adolescent athletes. Social factors may be more likely than persistent pain to prevent return to sport. Level IV, therapeutic case series. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

In silico analysis of miRNA-mediated gene regulation in OCA and OA genes.

PubMed

Kamaraj, Balu; Gopalakrishnan, Chandrasekhar; Purohit, Rituraj

2014-12-01

Albinism is an autosomal recessive genetic disorder due to low secretion of melanin. The oculocutaneous albinism (OCA) and ocular albinism (OA) genes are responsible for melanin production and also act as a potential targets for miRNAs. The role of miRNA is to inhibit the protein synthesis partially or completely by binding with the 3'UTR of the mRNA thus regulating gene expression. In this analysis, we predicted the genetic variation that occurred in 3'UTR of the transcript which can be a reason for low melanin production thus causing albinism. The single nucleotide polymorphisms (SNPs) in 3'UTR cause more new binding sites for miRNA which binds with mRNA which leads to inhibit the translation process either partially or completely. The SNPs in the mRNA of OCA and OA genes can create new binding sites for miRNA which may control the gene expression and lead to hypopigmentation. We have developed a computational procedure to determine the SNPs in the 3'UTR region of mRNA of OCA (TYR, OCA2, TYRP1 and SLC45A2) and OA (GPR143) genes which will be a potential cause for albinism. We identified 37 SNPs in five genes that are predicted to create 87 new binding sites on mRNA, which may lead to abrogation of the translation process. Expression analysis confirms that these genes are highly expressed in skin and eye regions. It is well supported by enrichment analysis that these genes are mainly involved in eye pigmentation and melanin biosynthesis process. The network analysis also shows how the genes are interacting and expressing in a complex network. This insight provides clue to wet-lab researches to understand the expression pattern of OCA and OA genes and binding phenomenon of mRNA and miRNA upon mutation, which is responsible for inhibition of translation process at genomic levels.

75 FR 8995 - Submission for OMB Review: Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-26

... currently approved collection. Title of Collection: Occupational Code Assignment (OCA). OMB Control Number... (OCA), is provided as a public service for the states as well as for others who use occupational information. The OCA process is designed to help users relate an occupational specialty or a job title or to...

Oxalates in oca (New Zealand yam) (Oxalis tuberosa Mol.).

PubMed

Ross, A B; Savage, G P; Martin, R J; Vanhanen, L

1999-12-01

Oca (Oxalis tuberosa Mol.) or New Zealand yam, in common with other members of this genus, contains oxalate, an antinutritive factor. Twelve South American and two New Zealand cultivars of oca were analyzed for total and soluble oxalate contents of the tubers. The range of total oxalate levels was 92-221 mg/100 g of fresh weight. Levels of soluble and total oxalate extracted from the tubers were not significantly different, suggesting that no calcium oxalate is formed in the tubers. The oxalate concentrations obtained in this study for oca suggest that previously reported values are too low and that oca is a moderately high oxalate-containing food. This is the first report of a tuber crop containing moderate to high levels of soluble oxalates in the tubers and no insoluble oxalates.

Origins of domestication and polyploidy in oca (Oxalis tuberosa; Oxalidaceae). 3. AFLP data of oca and four wild, tuber-bearing taxa.

PubMed

Emshwiller, Eve; Theim, Terra; Grau, Alfredo; Nina, Victor; Terrazas, Franz

2009-10-01

Many crops are polyploids, and it can be challenging to untangle the often complicated history of their origins of domestication and origins of polyploidy. To complement other studies of the origins of polyploidy of the octoploid tuber crop oca (Oxalis tuberosa) that used DNA sequence data and phylogenetic methods, we here compared AFLP data for oca with four wild, tuber-bearing Oxalis taxa found in different regions of the central Andes. Results confirmed the divergence of two use-categories of cultivated oca that indigenous farmers use for different purposes, suggesting the possibility that they might have had separate origins of domestication. Despite previous results with nuclear-encoded, chloroplast-expressed glutamine synthetase suggesting that O. picchensis might be a progenitor of oca, AFLP data of this species, as well as different populations of wild, tuber-bearing Oxalis found in Lima Department, Peru, were relatively divergent from O. tuberosa. Results from all analytical methods suggested that the unnamed wild, tuber-bearing Oxalis found in Bolivia and O. chicligastensis in NW Argentina are the best candidates as the genome donors for polyploid O. tuberosa, but the results were somewhat equivocal about which of these two taxa is the more strongly supported as oca's progenitor.

Origins of domestication and polyploidy in oca (Oxalis tuberosa : Oxalidaceae): nrDNA ITS data.

PubMed

Emshwiller, E; Doyle, J

1998-07-01

As part of a study aimed at elucidating the origins of the octoploid tuber crop "oca," Oxalis tuberosa, DNA sequences of the internal trancribed spacer of nuclear ribosomal DNA (nrDNA ITS) were determined for oca and several wild Oxalis species, mostly from Bolivia. Phylogenetic analysis of these data supports a group of these species as being close relatives of oca, in agreement with morphology and cytology, but at odds with traditional infrageneric taxonomy. Variation in ITS sequences within this group is quite low (0-7 substitutions in the entire ITS region), contrasting with the highly divergent (unalignable in some cases) sequences within the genus overall. Some groups of morphologically differentiated species were found to have identical sequences, notably a group that includes oca, wild populations of Oxalis that bear small tubers, and several other clearly distinct species. The presence of a second, minor sequence type in at least some oca accessions suggests a possible contribution from a second genome donor, also from within this same species group. ITS data lack sufficient variation to elucidate the origins of oca precisely, but have identified a pool of candidate species and so can be used as a tool to screen yet unsampled species for possible progenitors.

Optical clearing of vaginal tissues

NASA Astrophysics Data System (ADS)

Chang, Chun-Hung; Myers, Erinn M.; Kennelly, Michael J.; Fried, Nathaniel M.

2017-02-01

Near-IR laser energy in conjunction with applied tissue cooling is being investigated for thermal remodeling of endopelvic fascia during minimally invasive treatment of female stress urinary incontinence. Previous simulations of light transport, heat transfer, and tissue thermal damage have shown that a transvaginal approach is more feasible than a transurethral approach. However, undesirable thermal insult to vaginal wall was predicted. This study explores whether an optical clearing agent (OCA) can improve optical penetration depth and completely preserve vaginal wall during subsurface treatment of endopelvic fascia. Several OCA mixtures were tested, and 100% glycerol was found to be optimal. Optical transmission studies, optical coherence tomography, reflection spectroscopy, and computer simulations of thermal damage to tissue using glycerol were performed. The OCA produced a 61% increase in optical transmission through porcine vaginal wall at 37 °C after 30 min. Monte Carlo (MC) light transport, heat transfer, and Arrhenius integral thermal damage simulations were performed. MC model showed improved energy deposition in endopelvic fascia using OCA. Without OCA, 62, 37, and 1% of energy was deposited in vaginal wall, endopelvic fascia, and urethral wall, compared with 50, 49, and 1% with OCA. Use of OCA also yielded 0.5 mm increase in treatment depth, allowing potential thermal tissue remodeling at 3 mm depth.

Bone Marrow Aspirate Concentrate versus Platelet Rich Plasma to Enhance Osseous Integration Potential for Osteochondral Allografts.

PubMed

Stoker, Aaron M; Baumann, Charles A; Stannard, James P; Cook, James L

2018-04-01

Fresh osteochondral allograft (OCA) transplantation is an attractive treatment option for symptomatic articular cartilage lesions in young, healthy patients. Since a lack of OCA bone integration can be a cause of treatment failure, methods for speeding and enhancing OCA bone integration to mitigate this potential complication are highly desirable. This study sought to determine and compare the potential of bone marrow aspirate concentrate (BMC) and leukoreduced platelet rich plasma (PRP) to repopulate the osseous portion of an OCA with cells and deliver osteogenic proteins. It was hypothesized that BMC would have significantly higher colony forming units (CFUs)/mL and seed the osseous portion of OCA with more cells than PRP. Finally, we hypothesized that the media of BMC and PRP treated OCAs would have significantly higher concentrations of osteogenic proteins compared with negative control OCAs. Cylindrical OCAs ( n  = 36) created from tissue stored for 21 days were treated with BMC ( n  = 12) or PRP ( n  = 12) obtained for 6 dogs, or left untreated as a negative control ( n  = 12). After treatment, OCAs were cultured for 7 or 14 days. Media were collected for analysis of osteogenic biomarker concentration. Samples of each BMC and PRP were tested for CFU concentration. On day 7 or 14, the grafts were assessed for cell surface adhesion and penetration using fluorescent microscopy. Significant differences in CFU and media biomarker concentration between the groups were determined using one-way analysis of variance (ANOVA) and Tukey's post-hoc test with the significance set at p  < 0.05. Only OCAs saturated with BMC had viable cells detectable on the osseous portion of the allografts at day 7 and 14 of culture. BMC samples had a significantly higher ( p  = 0.029) CFU/mL compared with PRP samples. At day 3 and/or 7 of culture, the concentration of several osteogenic proteins was significantly higher in both BMC and PRP samples. Autogenous BMC can be used to deliver both a cell population and osteogenic proteins that may improve healing of the osseous portion of the OCA clinically. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Two-stage approach for risk estimation of fetal trisomy 21 and other aneuploidies using computational intelligence systems.

PubMed

Neocleous, A C; Syngelaki, A; Nicolaides, K H; Schizas, C N

2018-04-01

To estimate the risk of fetal trisomy 21 (T21) and other chromosomal abnormalities (OCA) at 11-13 weeks' gestation using computational intelligence classification methods. As a first step, a training dataset consisting of 72 054 euploid pregnancies, 295 cases of T21 and 305 cases of OCA was used to train an artificial neural network. Then, a two-stage approach was used for stratification of risk and diagnosis of cases of aneuploidy in the blind set. In Stage 1, using four markers, pregnancies in the blind set were classified into no risk and risk. No-risk pregnancies were not examined further, whereas the risk pregnancies were forwarded to Stage 2 for further examination. In Stage 2, using seven markers, pregnancies were classified into three types of risk, namely no risk, moderate risk and high risk. Of 36 328 unknown to the system pregnancies (blind set), 17 512 euploid, two T21 and 18 OCA were classified as no risk in Stage 1. The remaining 18 796 cases were forwarded to Stage 2, of which 7895 euploid, two T21 and two OCA cases were classified as no risk, 10 464 euploid, 83 T21 and 61 OCA as moderate risk and 187 euploid, 50 T21 and 52 OCA as high risk. The sensitivity and the specificity for T21 in Stage 2 were 97.1% and 99.5%, respectively, and the false-positive rate from Stage 1 to Stage 2 was reduced from 51.4% to ∼1%, assuming that the cell-free DNA test could identify all euploid and aneuploid cases. We propose a method for early diagnosis of chromosomal abnormalities that ensures that most T21 cases are classified as high risk at any stage. At the same time, the number of euploid cases subjected to invasive or cell-free DNA examinations was minimized through a routine procedure offered in two stages. Our method is minimally invasive and of relatively low cost, highly effective at T21 identification and it performs better than do other existing statistical methods. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

76 FR 16787 - Subcommittee for Dose Reconstruction Reviews (SDRR), Advisory Board on Radiation and Worker...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-25

... Evaluation Report: OCAS- PER-012--Evaluation of Highly Insoluble Plutonium Compounds; discussion of dose reconstruction cases under review (sets 7-9); OCAS dose reconstruction quality management and assurance... 30333, Telephone (513) 533-6800, Toll Free 1 (800) CDC-INFO, E-mail ocas@cdc.gov . The Director...

Silver nanoparticles as optical clearing agent enhancers to improve caries diagnostic by optical coherence tomography

NASA Astrophysics Data System (ADS)

Carneiro, Vanda S. M.; Mota, Cláudia C. B. O.; Souza, Alex F.; da Silva, Evair J.; da Silva, Andrea F.; Gerbi, Marleny E. M. M.; Gomes, Anderson S. L.

2018-02-01

The use of silver nanoparticles as optical clearing agent (OCA) enhancers to improve caries diagnostic by optical coherence tomography (OCT) is demonstrated here. Five molars with no evident cavitation were selected. The OCAs were based on aqueous solution of silver nanoparticles (AgNP, 1.18x 1014 particles/mL, ø ≈ 10nm) and its dilution at 10% in glycerol. Teeth were placed on a platform with a micrometric screw, and after applying the OCAs, they were scanned with a Callisto SD-OCT system operating ate 930nm central wavelength. The occlusal surfaces were scanned by OCT, capturing crosssectional images with 8 mm transversal scanning, generating numerical matrices (2000x512). The OCT images had their transverse dimension preserved. AgNP-OCAs promoted image stretching due to the modification in the light optical path caused by AgNP-OCAs refractive indices close to that of the enamel. AgNP-OCAs evidenced the enamel birefringence and highlighted initial demineralization areas, that presented defined margins with higher contrast between sound and demineralized regions, with higher OCT signal intensity in those areas.

Effect of oral contraceptive agents on ascorbic acid metabolism in the rhesus monkey.

PubMed

Weininger, J; King, J C

1982-06-01

Ascorbic acid (AA) metabolism was studied in six sexually mature female rhesus monkeys with normal menstrual cycles before and during oral contraceptive administration. The animals were fed a commercial monkey stock diet (15% protein) containing no AA and given a 100 mg AA tablet daily throughout the study. After an initial adaptation period and a control period (total 8 months), combined-type oral contraceptive agents (OCAs) (50 micrograms mestranol and 1 mg norethindrone for 21 days each month) were administered to each monkey for 4 months. Serum copper and ceruloplasmin were significantly elevated during OCA treatment. There were no significant changes in plasma or leukocyte AA values during OCA use; however, urinary AA excretion decreased significantly. During the last month of the control period and the 3rd month of OCA treatment, 50 muCi of 1-14C-L-ascorbic acid were injected intravenously into each monkey. Urinary excretion of radioactivity, measured for 1 month, indicated a significantly faster AA turnover rate during the period of OCA use. These results suggest that women using OCAs may have an increased dietary requirement for AA.

Pulsed electric field processing reduces the oxalate content of oca (Oxalis tuberosa) tubers while retaining starch grains and the general structural integrity of tubers.

PubMed

Liu, Tingting; Burritt, David John; Eyres, Graham T; Oey, Indrawati

2018-04-15

The aims of this research were to investigate if pulsed electric field (PEF) treatments caused cellular/structural alterations in Oxalis tuberosa (oca) tubers and if PEF treatment could reduce tuber oxalate levels. Whole oca tubers were treated with PEF at different electric field strengths up to 1.2 kV/cm. PEF treatments above 0.5 kV/cm caused tubers to soften, but differences in the electrical properties of the tuber tissues led to an uneven PEF effect with the tuber inner cores softening more than the middle regions. Cell viability tests confirmed the unevenness of the PEF effect, however PEF caused no changes in overall tuber/tissue structure. Even at high electric field strengths the cell remained largely intact and most starch grains were retained within the cells. Despite the retention of starch, PEF treatment reduced tuber oxalate contents by almost 50% in some tissues and could potentially aid the development of low oxalate oca-based foods. Copyright © 2017 Elsevier Ltd. All rights reserved.

Real time imaging of peripheral nerve vasculature using optical coherence angiography

NASA Astrophysics Data System (ADS)

Vasudevan, Srikanth; Kumsa, Doe; Takmakov, Pavel; Welle, Cristin G.; Hammer, Daniel X.

2016-03-01

The peripheral nervous system (PNS) carries bidirectional information between the central nervous system and distal organs. PNS stimulation has been widely used in medical devices for therapeutic indications, such as bladder control and seizure cessation. Investigational uses of PNS stimulation include providing sensory feedback for improved control of prosthetic limbs. While nerve safety has been well documented for stimulation parameters used in marketed devices, novel PNS stimulation devices may require alternative stimulation paradigms to achieve maximum therapeutic benefit. Improved testing paradigms to assess the safety of stimulation will expedite the development process for novel PNS stimulation devices. The objective of this research is to assess peripheral nerve vascular changes in real-time with optical coherence angiography (OCA). A 1300-nm OCA system was used to image vasculature changes in the rat sciatic nerve in the region around a surface contacting single electrode. Nerves and vasculature were imaged without stimulation for 180 minutes to quantify resting blood vessel diameter. Walking track analysis was used to assess motor function before and 6 days following experiments. There was no significant change in vessel diameter between baseline and other time points in all animals. Motor function tests indicated the experiments did not impair functionality. We also evaluated the capabilities to image the nerve during electrical stimulation in a pilot study. Combining OCA with established nerve assessment methods can be used to study the effects of electrical stimulation safety on neural and vascular tissue in the periphery.

Heterologous expression of tyrosinase recapitulates the misprocessing and mistrafficking in oculocutaneous albinism type 2: effects of altering intracellular pH and pink-eyed dilution gene expression.

PubMed

Ni-Komatsu, Li; Orlow, Seth J

2006-03-01

The processing and trafficking of tyrosinase, a melanosomal protein essential for pigmentation, was investigated in a human epithelial 293 cell line that stably expresses the protein. The effects of the pink-eyed dilution (p) gene product, in which mutations result in oculocutaneous albinism type 2 (OCA2), on the processing and trafficking of tyrosinase in this cell line were studied. The majority of tyrosinase was retained in the endoplasmic reticulum-Golgi intermediate compartment and the early Golgi compartment in the 293 cells expressing the protein. Coexpression of p could partially correct the mistrafficking of tyrosinase in 293 cells. Tyrosinase was targeted to the late endosomal and lysosomal compartments after treatment of the cells with compounds that correct the tyrosinase mistrafficking in albino melanocytes, most likely through altering intracellular pH, while the substrate tyrosine had no effect on the processing of tyrosinase. Remarkably, this heterologous expression system recapitulates the defective processing and mistrafficking of tyrosinase observed in OCA2 albino melanocytes and certain amelanotic melanoma cells. Coexpression of other melanosomal proteins in this heterologous system may further aid our understanding of the details of normal and pathologic processing of melanosomal proteins.

Mutations of the tyrosinase gene in patients with oculocutaneous albinism from various ethnic groups in Israel

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

Gershoni-Baruch, R.; Rosenmann, A.; Droetto, S.

1994-04-01

The authors have analyzed the tyrosinase (TYR) gene in 38 unrelated patients with oculocutaneous albinism (OCA), derived from several different ethnic groups of the diverse population of Israel. They detected TYR gene mutations in 23 of the 34 patients with apparent type I (i.e., tyrosinase-deficient) OCA and in none of the patients with other clinical forms of albinism. Among Moroccan Jews with type IA (i.e., tyrosinase-negative) OCA, they detected a highly predominant mutant allele containing a missense substitution, Gly47Asp (G47D). This mutation occurs on the same haplotype as in patients from the Canary Islands and Puerto Rico, suggesting that themore » G47D mutation in these ethnically distinct populations may stem from a common origin. 28 refs., 1 fig., 2 tabs.« less

A novel missense mutation of the TYR gene in a pedigree with oculocutaneous albinism type 1 from China.

PubMed

Lin, Yu-Ying; Wei, Ai-Hua; Zhou, Zhi-Yong; Zhu, Wei; He, Xin; Lian, Shi

2011-10-01

The mutation of the tyrosinase (TYR) gene results in oculocutaneous albinism type 1 (OCA1), an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family. Genomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined. A novel missense mutation p.I151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband's wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance. This study provided new information about a novel mutation, p.I151S, in the TYR gene in a Chinese family with OCA1. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.

Evidence suggesting digenic inheritance of Waardenburg syndrome type II with ocular albinism.

PubMed

Chiang, Pei-Wen; Spector, Elaine; McGregor, Tracy L

2009-12-01

Waardenburg syndrome (WS) is a series of auditory-pigmentary disorders inherited in an autosomal dominant manner. In most patients, WS2 results from mutations in the MITF gene. MITF encodes a basic helix-loop-helix transcription factor that activates transcription of tyrosinase and other melanocyte proteins. The clinical presentation of WS is highly variable, and we believe that Tietz syndrome and WS2 with ocular albinism (OA) are likely two variations of WS2 due to the presence of modifiers. One family with a molecular diagnosis of WS2 co-segregating with OA has previously been reported. A digenic mutation mechanism including both a MITF mutation and the TYR(R402Q) hypomorphic allele was proposed to be the cause of OA in this family. Here, we present a second WS2 family with OA and provide evidence suggesting the TYR(R402Q) allele does not cause OA in this family. We hypothesize the presence of a novel OCA3 mutation together with the MITF del p.R217 mutation account for the OA phenotype in this family. Since MITF is a transcription factor for pigmentation genes, a mutation in MITF plus a heterozygous mutation in OCA3 together provide an adverse effect crossing a quantitative threshold; therefore, WS2 with OA occurs. We have hypothesized previously that the clinical spectrum and mutation mechanism of OCA depend on the pigmentation threshold of an affected individual. This unique family has provided further evidence supporting this hypothesis. We suggest that by studying OCA patients alongside WS patients with various pigmentation profiles we can facilitate further understanding of the pigmentation pathway.

FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

PubMed Central

Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A.; Trebicka, Jonel; Laleman, Wim

2016-01-01

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

Epoxy-based production of wind turbine rotor blades: occupational contact allergies.

PubMed

Pontén, Ann; Carstensen, Ole; Rasmussen, Kurt; Gruvberger, Birgitta; Isaksson, Marléne; Bruze, Magnus

2004-03-01

An industry producing rotor blades for wind turbines with an epoxy-based technology had experienced an increasing number of workers with dermatitis, among whom the frequency of occupational contact allergy (OCA) was suspected to be underestimated. To investigate the frequency of OCA by patch-testing with a specially profiled occupational patch test series. In a blinded study design, 603 workers were first interviewed and thereafter clinically examined. Based on a history of work-related skin disease, clinical findings of dermatitis, or both, 325 (53.9%) of the workers were patch-tested with an occupational patch test series and the European Standard patch test series. Of the 603 investigated workers, 10.9% had OCA and 5.6% had contact allergy to epoxy resin in the standard test series. Contact allergy to amine hardeners/catalysts was found in 4.1% of the workers. Among the workers with OCA, 48.5% reacted to work material other than epoxy resin in the European Standard patch test series. Approximately 50% of the workers with OCA would not have been detected if only the European Standard patch test series had been used.

Health properties of oca (Oxalis tuberosa) and yacon (Smallanthus sonchifolius).

PubMed

Jimenez, María Eugenia; Rossi, Analia; Sammán, Norma

2015-10-01

Andean roots and tubers are underexploited crops; many contain compounds beneficial to health, so a greater knowledge of their properties is important for encouraging their consumption. The aim of this work was to study the content of bioactive compounds of yacon and oca and their effect on intestinal health using as a model rats of the Wistar strain. Two varieties of ocas (Overa and Rosada) and yacon, which contain significant amounts of fructooligosaccharides and phenolic compounds, were chosen. Rats of the Wistar strain were fed for two months with diets containing these foods in amounts sufficient to provide 8% of fiber. A significant decrease in pH values and an increment in lactobacilli and bifidobacteria counts in the cecum of rats fed with inulin, oca Rosada and Overa were observed; there was no significant decrease in enterobacteriaceae and enterococci counts. The cecum antioxidant activity was incremented in rats fed with the experimental foods with respect to the control diets. The components of dietary fiber and phenolic compound contents in yacon and oca produce effects that contribute to the intestinal health of the experimental animals.

Barrier Requirements as the Evolutionary “Driver” of Epidermal Pigmentation in Humans

PubMed Central

ELIAS, PETER M.; MENON, GOPINATHAN; WETZEL, BRUCE K.; WILLIAMS, JOHN (JACK) W.

2011-01-01

Current explanations for the development of epidermal pigmentation during human evolution are not tenable as stand-alone hypotheses. Accordingly, we assessed instead whether xeric- and UV-B-induced stress to the epidermal permeability barrier, critical to survival in a terrestrial environment, could have “driven” the development of epidermal pigmentation. (1) Megadroughts prevailed in central Africa when hominids expanded into open savannahs [≈1.5–0.8 million years ago], resulting in sustained exposure to both extreme aridity and erythemogenic UV-B, correlating with genetic evidence that pigment developed ≈1.2 million years ago. (2) Pigmented skin is endowed with enhanced permeability barrier function, stratum corneum integrity/cohesion, and a reduced susceptibility to infections. The enhanced function of pigmented skin can be attributed to the lower pH of the outer epidermis, likely due to the persistence of (more-acidic) melanosomes into the outer epidermis, as well as the conservation of genes associated with eumelanin synthesis and melanosome acidification (e.g., TYR, OCA2 [p protein], SLC24A5, SLC45A2, MATP) in pigmented populations. Five keratinocyte-derived signals (stem cell factor⇒KIT; FOXn1⇒FGF2; IL-1α, NGF, and p53) are potential candidates to have stimulated the sequential development of epidermal pigmentation in response to stress to the barrier. We summarize evidence here that epidermal interfollicular pigmentation in early hominids likely evolved in response to stress to the permeability barrier. PMID:20209486

Comparison of 3% sorbitol vs psyllium fibre as oral contrast agents in MR enterography.

PubMed

Saini, Sidharth; Colak, Errol; Anthwal, Shalini; Vlachou, Paraskevi A; Raikhlin, Antony; Kirpalani, Anish

2014-10-01

To compare the degree of small bowel distension achieved by 3% sorbitol, a high osmolarity solution, and a psyllium-based bulk fibre as oral contrast agents (OCAs) in MR enterography (MRE). This retrospective study was approved by our institutional review board. A total of 45 consecutive normal MRE examinations (sorbitol, n = 20; psyllium, n = 25) were reviewed. The patients received either 1.5 l of 3% sorbitol or 2 l of 1.6 g kg(-1) psyllium prior to imaging. Quantitative small bowel distension measurements were taken in five segments: proximal jejunum, distal jejunum, proximal ileum, distal ileum and terminal ileum by two independent radiologists. Distension in these five segments was also qualitatively graded from 0 (very poor) to 4 (excellent) by two additional independent radiologists. Statistical analysis comparing the groups and assessing agreement included intraclass coefficients, Student's t-test and Mann-Whitney U-test. Small bowel distension was not significantly different in any of the five small bowel segments between the use of sorbitol and psyllium as OCAs in both the qualitative (p = 0.338-0.908) and quantitative assessments (p = 0.083-0.856). The mean bowel distension achieved was 20.1 ± 2.2 mm for sorbitol and 19.8 ± 2.5 mm for psyllium (p = 0.722). Visualization of the ileum was good or excellent in 65% of the examinations in both groups. Sorbitol and psyllium are not significantly different at distending the small bowel and both may be used as OCAs for MRE studies. This is the first study to directly compare the degree of distension in MRE between these two common, readily available and inexpensive OCAs.

Metal availability, soil nutrient, and enzyme activity in response to application of organic amendments in Cd-contaminated soil.

PubMed

Yang, Zhanbiao; Liu, Lixia; Lv, Yanfeng; Cheng, Zhang; Xu, Xiaoxun; Xian, Junren; Zhu, Xuemei; Yang, Yuanxiang

2018-01-01

The study investigated the effects of organic amendments: green tea amendment (GTA) and oil cake amendment (OCA) on Cd bioavailability, soil nutrients, and soil enzyme activity in Cd-contaminated soil. The amendments were added to the soil at the doses of 1, 3, and 5% and were incubated for 45 days. Then, pakchoi cabbage was planted to test the remediation effect of the above two organic amendments. The diethylenetriaminepentaacetic acid (DTPA)-extractable Cd in GTA and OCA treatments was reduced by 14.69-27.51 and 13.75-68.77%, respectively, compared to no amendment-applied treatment. The application of GTA and OCA notably decreased the proportion of exchangeable fraction of Cd, but increased the percentage of oxide and organic-bound fraction of Cd, thereby suppressing the uptake by pakchoi cabbage. Cd concentration of aboveground parts decreased by 8.21-18.05 and 7.77-35.89% in GTA and OCA treatments, respectively. Relative to the no amendment-applied treatment, both GTA and OCA had enhanced soil nutrients and enzyme activities largely. Redundancy analysis showed that organic matter, total P, available N, and DTPA-extractable Cd significantly affected the enzyme activities. Furthermore, the application of OCA at the dose of 5% was more effective in reducing bioavailable Cd, enhancing soil available nutrients and urease and catalase activities in contaminated soil. These results indicated that oil cake should be used to immobilize metal and improve fertility and quality of Cd-contaminated soil.

Optical clearing of vaginal tissues, ex vivo, for minimally invasive laser treatment of female stress urinary incontinence

NASA Astrophysics Data System (ADS)

Chang, Chun-Hung; Myers, Erinn M.; Kennelly, Michael J.; Fried, Nathaniel M.

2017-01-01

Near-infrared laser energy in conjunction with applied tissue cooling is being investigated for thermal remodeling of the endopelvic fascia during minimally invasive treatment of female stress urinary incontinence. Previous computer simulations of light transport, heat transfer, and tissue thermal damage have shown that a transvaginal approach is more feasible than a transurethral approach. However, results were suboptimal, and some undesirable thermal insult to the vaginal wall was still predicted. This study uses experiments and computer simulations to explore whether application of an optical clearing agent (OCA) can further improve optical penetration depth and completely preserve the vaginal wall during subsurface treatment of the endopelvic fascia. Several different mixtures of OCA's were tested, and 100% glycerol was found to be the optimal agent. Optical transmission studies, optical coherence tomography, reflection spectroscopy, and computer simulations [including Monte Carlo (MC) light transport, heat transfer, and Arrhenius integral model of thermal damage] using glycerol were performed. The OCA produced a 61% increase in optical transmission through porcine vaginal wall at 37°C after 30 min. The MC model showed improved energy deposition in endopelvic fascia using glycerol. Without OCA, 62%, 37%, and 1% of energy was deposited in vaginal wall, endopelvic fascia, and urethral wall, respectively, compared with 50%, 49%, and 1% using OCA. Use of OCA also resulted in 0.5-mm increase in treatment depth, allowing potential thermal tissue remodeling at a depth of 3 mm with complete preservation of the vaginal wall.

RMP Guidance for Offsite Consequence Analysis

EPA Pesticide Factsheets

Offsite consequence analysis (OCA) consists of a worst-case release scenario and alternative release scenarios. OCA is required from facilities with chemicals above threshold quantities. RMP*Comp software can be used to perform calculations described here.

Partial Oculocutaneous Albinism: Two Siblings with Features of both Hermansky Pudlak and Waardenburg's Syndrome.

PubMed

Ishaq, Mazhar; Niazi, Muhammad Khizar; Khan, Muhammad Saim; Nadeem, Yasser

2015-04-01

Albinism is an inherited abnormality of melanin synthesis with incidence of one per 20,000 births. Its clinical manifestations are related to the reduction or absence of pigmentation in the visual system and/or the skin and teguments. The clinical spectrum of Oculocutaneous Albinism (OCA) has four types ranging from OCA 1 - 4, of which OCA 1, A-1 is the most severe form. Partial cutaneous albinism which is a subtype of OCA is associated with systemic immunodeficiency disorders like Chediak Higashi (CHS), Griscelli (GS) and Hermansky-Pudlak (HPS) syndromes. A7 years boy was labeled initially as a case of Hermansky Pudlak syndrome at the age of 01 year. He as well as his 4 years old younger brother when examined in detail along with audiological investigations were diagnosed as a rare presentation of both Hermansky Pudlak and Waardenburg's syndrome.

Photodynamic therapy monitoring with optical coherence angiography

NASA Astrophysics Data System (ADS)

Sirotkina, M. A.; Matveev, L. A.; Shirmanova, M. V.; Zaitsev, V. Y.; Buyanova, N. L.; Elagin, V. V.; Gelikonov, G. V.; Kuznetsov, S. S.; Kiseleva, E. B.; Moiseev, A. A.; Gamayunov, S. V.; Zagaynova, E. V.; Feldchtein, F. I.; Vitkin, A.; Gladkova, N. D.

2017-02-01

Photodynamic therapy (PDT) is a promising modern approach for cancer therapy with low normal tissue toxicity. This study was focused on a vascular-targeting Chlorine E6 mediated PDT. A new angiographic imaging approach known as M-mode-like optical coherence angiography (MML-OCA) was able to sensitively detect PDT-induced microvascular alterations in the mouse ear tumour model CT26. Histological analysis showed that the main mechanisms of vascular PDT was thrombosis of blood vessels and hemorrhage, which agrees with angiographic imaging by MML-OCA. Relationship between MML-OCA-detected early microvascular damage post PDT (within 24 hours) and tumour regression/regrowth was confirmed by histology. The advantages of MML-OCA such as direct image acquisition, fast processing, robust and affordable system opto-electronics, and label-free high contrast 3D visualization of the microvasculature suggest attractive possibilities of this method in practical clinical monitoring of cancer therapies with microvascular involvement.

Synthesis and biomedical applications of functional poly(α-hydroxy acids) via ring-opening polymerization of O-carboxyanhydrides.

PubMed

Yin, Qian; Yin, Lichen; Wang, Hua; Cheng, Jianjun

2015-07-21

Poly(α-hydroxy acids) (PAHAs) are a class of biodegradable and biocompatible polymers that are widely used in numerous applications. One drawback of these conventional polymers, however, is their lack of side-chain functionalities, which makes it difficult to conjugate active moieties to PAHA or to fine-tune the physical and chemical properties of PAHA-derived materials through side-chain modifications. Thus, extensive efforts have been devoted to the development of methodology that allows facile preparation of PAHAs with controlled molecular weights and a variety of functionalities for widespread utilities. However, it is highly challenging to introduce functional groups into conventional PAHAs derived from ring-opening polymerization (ROP) of lactides and glycolides to yield functional PAHAs with favorable properties, such as tunable hydrophilicity/hydrophobicity, facile postpolymerization modification, and well-defined physicochemical properties. Amino acids are excellent resources for functional polymers because of their low cost, availability, and structural as well as stereochemical diversity. Nevertheless, the synthesis of functional PAHAs using amino acids as building blocks has been rarely reported because of the difficulty of preparing large-scale monomers and poor yields during the synthesis. The synthesis of functionalized PAHAs from O-carboxyanhydrides (OCAs), a class of five-membered cyclic anhydrides derived from amino acids, has proven to be one of the most promising strategies and has thus attracted tremendous interest recently. In this Account, we highlight the recent progress in our group on the synthesis of functional PAHAs via ROP of OCAs and their self-assembly and biomedical applications. New synthetic methodologies that allow the facile preparation of PAHAs with controlled molecular weights and various functionalities through ROP of OCAs are reviewed and evaluated. The in vivo stability, side-chain functionalities, and/or trigger responsiveness of several functional PAHAs are evaluated. Their biomedical applications in drug and gene delivery are also discussed. The ready availability of starting materials from renewable resources and the facile postmodification strategies such as azide-alkyne cycloaddition and the thiol-yne "click" reaction have enabled the production of a multitude of PAHAs with controlled molecular weights, narrow polydispersity, high terminal group fidelities, and structural diversities that are amenable for self-assembly and bioapplications. We anticipate that this new generation of PAHAs and their self-assembled nanosystems as biomaterials will open up exciting new opportunities and have widespread utilities for biological applications.

Identification of ERdj3 and OBF-1/BOB-1/OCA-B as direct targets of XBP-1 during plasma cell differentiation.

PubMed

Shen, Ying; Hendershot, Linda M

2007-09-01

Plasma cell differentiation is accompanied by a modified unfolded protein response (UPR), which involves activation of the Ire1 and activating transcription factor 6 branches, but not the PKR-like endoplasmic reticulum kinase branch. Ire1-mediated splicing of XBP-1 (XBP-1(S)) is required for terminal differentiation, although the direct targets of XBP-1(S) in this process have not been identified. We demonstrate that XBP-1(S) binds to the promoter of ERdj3 in plasmacytoma cells and in LPS-stimulated primary splenic B cells, which corresponds to increased expression of ERdj3 transcripts in both cases. When small hairpin RNA was used to decrease XBP-1 expression in plasmacytoma lines, ERdj3 transcripts were concomitantly reduced. The accumulation of Ig gamma H chain protein was also diminished, but unexpectedly this occurred at the transcriptional level as opposed to effects on H chain stability. The decrease in H chain transcripts correlated with a reduction in mRNA encoding the H chain transcription factor, OBF-1/BOB-1/OCA-B. Chromatin immunoprecipitation experiments revealed that XBP-1(S) binds to the OBF-1/BOB-1/OCA-B promoter in the plasmacytoma line and in primary B cells not only during plasma cell differentiation, but also in response to classical UPR activation. Gel shift assays suggest that XBP-1(S) binding occurs through a UPR element conserved in both murine and human OBF-1/BOB-1/OCA-B promoters as opposed to endoplasmic reticulum stress response elements. Our studies are the first to identify direct downstream targets of XBP-1(S) during either plasma cell differentiation or the UPR. In addition, our data further define the XBP-1(S)-binding sequence and provide yet another role for this protein as a master regulator of plasma cell differentiation.

In vitro study of the effects of ultrasound-mediated glycerol on optical attenuation of human normal and cancerous esophageal tissues with optical coherence tomography

NASA Astrophysics Data System (ADS)

Zhang, Y. Q.; Wei, H. J.; Yang, H. Q.; Guo, Z. Y.; Xie, S. S.; Gu, H. M.; Guo, X.; Zhu, Z. G.

2013-06-01

Previous studies from our group have demonstrated that glucose solution can induce optical clearing enhancement of esophageal tissues with optical coherence tomography (OCT). The aims of this study were to evaluate the optical clearing effects of ultrasound-mediated optical clearing agents (OCAs) and to find more effective methods to distinguish human normal esophageal tissues (NE) and cancerous esophageal tissues (CE). Here we used the OCT technique to investigate the optical attenuation of NE and CE in vitro after treatment with 30% glycerol alone and glycerol combined with ultrasound, respectively. Experimental results showed that the averaged attenuation coefficient of CE was significantly larger than that of NE. The maximal decreases of averaged attenuation coefficients of NE and CE were approximately 48.7% and 36.2% after treatment with 30% glycerol alone, and they were significantly lower than those treated with 30% glycerol and ultrasound (57.5% in NE and 44.8% in CE). Moreover, after treatment with 30% glycerol alone, the averaged attenuation coefficients of NE and CE reached their minima in about 80 min and 65 min, respectively. The times were much shorter in NE and CE after treatment with glycerol with ultrasound, being about 62 min and 50 min, respectively. The results suggest that there is a significant difference in the optical properties of NE and CE, and that OCT with an ultrasound-OCAs combination has the ability to distinguish CE from NE.

Optical clearing of human skin for the enhancement of optical imaging of proximal interphalangeal joints

NASA Astrophysics Data System (ADS)

Kolesnikova, Ekaterina A.; Kolesnikov, Aleksandr S.; Zabarylo, Urszula; Minet, Olaf; Genina, Elina A.; Bashkatov, Alexey N.; Tuchin, Valery V.

2014-01-01

We are proposing a new method for enhancement of optical imaging of proximal interphalangeal (PIP) joints in humans at skin using optical clearing technique. A set of illuminating laser diodes with the wavelengths 670, 820, and 904 nm were used as a light source. The laser diodes, monochromatic digital CCD camera and specific software allowed for detection of the finger joint image in a transillumination mode. The experiments were carried out in vivo with human fingers. Dehydrated glycerol and hand cream with urea (5%) were used as optical clearing agents (OCAs). The contrast of the obtained images was analyzed to determine the effect of the OCA. It was found that glycerol application to the human skin during 60 min caused the decrease of contrast in 1.4 folds for 670 nm and the increase of contrast in 1.5 and 1.7 folds for 820 nm and 904 nm, respectively. At the same time, the hand cream application to the human skin during 60 min caused the decrease of contrast in 1.1 folds for 670 nm and the increase of contrast in 1.3 and 1.1 folds for 820 nm and 904 nm, respectively. The results have shown that glycerol and the hand cream with 5% urea allow for obtaining of more distinct image of finger joint in the NIR. Obtained data can be used for development of optical diagnostic methods of rheumatoid arthritis.

75 FR 64735 - Subcommittee for Dose Reconstruction Reviews (SDRR), Advisory Board on Radiation and Worker...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-20

... cases under review (sets 7-9); OCAS dose reconstruction quality management and assurance activities. The... 30333, Telephone (513) 533-6800, Toll Free 1 (800) CDC-INFO, E- mail ocas@cdc.gov . The Director...

76 FR 17613 - Aviation Service Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-30

...) regarding audio visual warning systems (AVWS). OCAS, Inc. installs such technology under the trademark OCAS... frequencies to activate obstruction lighting and transmit audible warnings to aircraft on a potential... transmit audible warnings to pilots. We seek comment on operational, licensing, eligibility and equipment...

40 CFR 1400.7 - In general.

Code of Federal Regulations, 2013 CFR

2013-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Access to Off-Site Consequence Analysis Information by Government Officials. § 1400.7 In general. The Administrator shall provide OCA information to government officials as provided in this subpart. Any OCA...

40 CFR 1400.7 - In general.

Code of Federal Regulations, 2011 CFR

2011-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Access to Off-Site Consequence Analysis Information by Government Officials. § 1400.7 In general. The Administrator shall provide OCA information to government officials as provided in this subpart. Any OCA...

40 CFR 1400.7 - In general.

Code of Federal Regulations, 2012 CFR

2012-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Access to Off-Site Consequence Analysis Information by Government Officials. § 1400.7 In general. The Administrator shall provide OCA information to government officials as provided in this subpart. Any OCA...

40 CFR 1400.7 - In general.

Code of Federal Regulations, 2014 CFR

2014-07-01

... OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Access to Off-Site Consequence Analysis Information by Government Officials. § 1400.7 In general. The Administrator shall provide OCA information to government officials as provided in this subpart. Any OCA...

Slc45a2 and V-ATPase are regulators of melanosomal pH homeostasis in zebrafish, providing a mechanism for human pigment evolution and disease.

PubMed

Dooley, Christopher M; Schwarz, Heinz; Mueller, Kaspar P; Mongera, Alessandro; Konantz, Martina; Neuhauss, Stephan C F; Nüsslein-Volhard, Christiane; Geisler, Robert

2013-03-01

We present here the positional cloning of the Danio rerio albino mutant and show that the affected gene encodes Slc45a2. The human orthologous gene has previously been shown to be involved in human skin color variation, and mutations therein have been implicated in the disease OCA4. Through ultrastructural analysis of the melanosomes in albino alleles as well as the tyrosinase-deficient mutant sandy, we add new insights into the role of Slc45a2 in the production of melanin. To gain further understanding of the role of Slc45a2 and its possible interactions with other proteins involved in melanization, we further analyzed the role of the V-ATPase as a melanosomal acidifier. We show that it is possible to rescue the melanization potential of the albino melanosomes through genetic and chemical inhibition of V-ATPase, thereby increasing internal melanosome pH. © 2012 John Wiley & Sons A/S.

40 CFR 1400.10 - Limitation on public dissemination.

Code of Federal Regulations, 2011 CFR

2011-07-01

... SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.10 Limitation on public dissemination. Except as... officials, and qualified researchers are prohibited from disseminating OCA information and OCA rankings to...

40 CFR 1400.10 - Limitation on public dissemination.

Code of Federal Regulations, 2012 CFR

2012-07-01

... SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.10 Limitation on public dissemination. Except as... officials, and qualified researchers are prohibited from disseminating OCA information and OCA rankings to...

40 CFR 1400.10 - Limitation on public dissemination.

Code of Federal Regulations, 2014 CFR

2014-07-01

... SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.10 Limitation on public dissemination. Except as... officials, and qualified researchers are prohibited from disseminating OCA information and OCA rankings to...

40 CFR 1400.10 - Limitation on public dissemination.

Code of Federal Regulations, 2013 CFR

2013-07-01

... SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.10 Limitation on public dissemination. Except as... officials, and qualified researchers are prohibited from disseminating OCA information and OCA rankings to...

l-tyrosine induces melanocyte differentiation in novel pink-eyed dilution castaneus mouse mutant showing age-related pigmentation.

PubMed

Hirobe, Tomohisa; Ishikawa, Akira

2015-12-01

The mouse pink-eyed dilution (oculocutaneous albinism II; p/Oca2(p)) locus is known to control tyrosinase activity, melanin content, and melanosome development in melanocytes. Pink-eyed dilution castaneus (p(cas)/Oca2(p-cas)) is a novel mutant allele on mouse chromosome 7 that arose spontaneously in Indonesian wild mice, Mus musculus castaneus. Mice homozygous for Oca2(p-cas) usually exhibit pink eyes and beige-colored coat on nonagouti C57BL/6 (B6) background. Recently, a novel spontaneous mutation occurred in the progeny between this mutant and B6 mice. The eyes of this novel mutant progressively become black from pink and the coat becomes dark gray from beige with aging. The aim of this study is to clarify whatever differences exist in melanocyte proliferation and differentiation between the ordinary (pink-eyed) and novel (black-eyed) mutant using serum-free primary culture system. The characteristics of melanocyte proliferation and differentiation were investigated by serum-free primary culture system using melanocyte-proliferation medium (MDMD). The proliferation of melanoblasts in MDMD did not differ between the two mice. However, when the epidermal cell suspensions were cultured with MDMD supplemented with l-tyrosine (Tyr), the differentiation of black-eyed melanocytes was greatly induced in a concentration-dependent manner compared with pink-eyed melanocytes. Immunocytochemistry demonstrated that the expression of tyrosinase and tyrosinase-related protein-1 (Tyrp1) was greatly induced or stimulated both in pink-eyed and black-eyed melanocytes, whereas the expression of microphthalmia-associated transcription factor (Mitf) was stimulated only in black-eyed melanocytes. These results suggest that the age-related coat darkening in black-eyed mutant may be caused by the increased ability of melanocyte differentiation dependent on l-Tyr through the upregulation of tyrosinase, Tyrp1, and Mitf. This mutant mouse may be useful for animal model to clarify the mechanisms of age-related pigmentation in human skin, such as melasma and solar lentigines. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparison of 3% sorbitol vs psyllium fibre as oral contrast agents in MR enterography

PubMed Central

Saini, S; Colak, E; Anthwal, S; Vlachou, P A; Raikhlin, A

2014-01-01

Objective: To compare the degree of small bowel distension achieved by 3% sorbitol, a high osmolarity solution, and a psyllium-based bulk fibre as oral contrast agents (OCAs) in MR enterography (MRE). Methods: This retrospective study was approved by our institutional review board. A total of 45 consecutive normal MRE examinations (sorbitol, n = 20; psyllium, n = 25) were reviewed. The patients received either 1.5 l of 3% sorbitol or 2 l of 1.6 g kg−1 psyllium prior to imaging. Quantitative small bowel distension measurements were taken in five segments: proximal jejunum, distal jejunum, proximal ileum, distal ileum and terminal ileum by two independent radiologists. Distension in these five segments was also qualitatively graded from 0 (very poor) to 4 (excellent) by two additional independent radiologists. Statistical analysis comparing the groups and assessing agreement included intraclass coefficients, Student's t-test and Mann–Whitney U-test. Results: Small bowel distension was not significantly different in any of the five small bowel segments between the use of sorbitol and psyllium as OCAs in both the qualitative (p = 0.338–0.908) and quantitative assessments (p = 0.083–0.856). The mean bowel distension achieved was 20.1 ± 2.2 mm for sorbitol and 19.8 ± 2.5 mm for psyllium (p = 0.722). Visualization of the ileum was good or excellent in 65% of the examinations in both groups. Conclusion: Sorbitol and psyllium are not significantly different at distending the small bowel and both may be used as OCAs for MRE studies. Advances in knowledge: This is the first study to directly compare the degree of distension in MRE between these two common, readily available and inexpensive OCAs. PMID:25062448

40 CFR 1400.6 - Enhanced local access.

Code of Federal Regulations, 2011 CFR

2011-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Public Access § 1400.6 Enhanced local access. (a) OCA data elements. Consistent with 42 U.S.C...) OCA information. (1) LEPCs and related local government agencies are authorized and encouraged to...

40 CFR 1400.6 - Enhanced local access.

Code of Federal Regulations, 2012 CFR

2012-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Public Access § 1400.6 Enhanced local access. (a) OCA data elements. Consistent with 42 U.S.C...) OCA information. (1) LEPCs and related local government agencies are authorized and encouraged to...

40 CFR 1400.6 - Enhanced local access.

Code of Federal Regulations, 2013 CFR

2013-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Public Access § 1400.6 Enhanced local access. (a) OCA data elements. Consistent with 42 U.S.C...) OCA information. (1) LEPCs and related local government agencies are authorized and encouraged to...

40 CFR 1400.6 - Enhanced local access.

Code of Federal Regulations, 2014 CFR

2014-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Public Access § 1400.6 Enhanced local access. (a) OCA data elements. Consistent with 42 U.S.C...) OCA information. (1) LEPCs and related local government agencies are authorized and encouraged to...

Skin optical clearing potential of disaccharides

NASA Astrophysics Data System (ADS)

Feng, Wei; Shi, Rui; Ma, Ning; Tuchina, Daria K.; Tuchin, Valery V.; Zhu, Dan

2016-08-01

Skin optical clearing can significantly enhance the ability of biomedical optical imaging. Some alcohols and sugars have been selected to be optical clearing agents (OCAs). In this work, we paid attention to the optical clearing potential of disaccharides. Sucrose and maltose were chosen as typical disaccharides to compare with fructose, an excellent monosaccharide-OCA, by using molecular dynamics simulation and an ex vivo experiment. The experimental results indicated that the optical clearing efficacy of skin increases linearly with the concentration for each OCA. Both the theoretical predication and experimental results revealed that the two disaccharides exerted a better optical clearing potential than fructose at the same concentration, and sucrose is optimal. Since maltose has an extremely low saturation concentration, the other two OCAs with saturation concentrations were treated topically on rat skin in vivo, and optical coherence tomography imaging was applied to monitor the optical clearing process. The results demonstrated that sucrose could cause a more significant increase in imaging depth and signal intensity than fructose.

Collaborative effects of wavefront shaping and optical clearing agent in optical coherence tomography

NASA Astrophysics Data System (ADS)

Yu, Hyeonseung; Lee, Peter; Jo, YoungJu; Lee, KyeoReh; Tuchin, Valery V.; Jeong, Yong; Park, YongKeun

2016-12-01

We demonstrate that simultaneous application of optical clearing agents (OCAs) and complex wavefront shaping in optical coherence tomography (OCT) can provide significant enhancement of penetration depth and imaging quality. OCA reduces optical inhomogeneity of a highly scattering sample, and the wavefront shaping of illumination light controls multiple scattering, resulting in an enhancement of the penetration depth and signal-to-noise ratio. A tissue phantom study shows that concurrent applications of OCA and wavefront shaping successfully operate in OCT imaging. The penetration depth enhancement is further demonstrated for ex vivo mouse ears, revealing hidden structures inaccessible with conventional OCT imaging.

Reliability of the one-crossing approximation in describing the Mott transition

NASA Astrophysics Data System (ADS)

Vildosola, V.; Pourovskii, L. V.; Manuel, L. O.; Roura-Bas, P.

2015-12-01

We assess the reliability of the one-crossing approximation (OCA) approach in a quantitative description of the Mott transition in the framework of the dynamical mean field theory (DMFT). The OCA approach has been applied in conjunction with DMFT to a number of heavy-fermion, actinide, transition metal compounds and nanoscale systems. However, several recent studies in the framework of impurity models pointed out serious deficiencies of OCA and raised questions regarding its reliability. Here we consider a single band Hubbard model on the Bethe lattice at finite temperatures and compare the results of OCA to those of a numerically exact quantum Monte Carlo (QMC) method. The temperature-local repulsion U phase diagram for the particle-hole symmetric case obtained by OCA is in good agreement with that of QMC, with the metal-insulator transition captured very well. We find, however, that the insulator to metal transition is shifted to higher values of U and, simultaneously, correlations in the metallic phase are significantly overestimated. This counter-intuitive behaviour is due to simultaneous underestimations of the Kondo scale in the metallic phase and the size of the insulating gap. We trace the underestimation of the insulating gap to that of the second moment of the high-frequency expansion of the impurity spectral density. Calculations of the system away from the particle-hole symmetric case are also presented and discussed.

Attritional wear and abrasive surface alterations of composite resin materials in vitro.

PubMed

Göhring, T N; Besek, M J; Schmidlin, P R

2002-01-01

A laboratory study was performed with 232 specimens and 72 human enamel, 24 gold, 24 ceramic and 12 composite antagonists in 22 groups to test attritional and abrasive wear behavior of composite materials compared to wear behavior of human enamel. Belleglass HP, Concept Inlay/Onlay, Targis and Targis Upgrade 99 composite resin for lab-made restorations was tested as well as Tetric Ceram and FHC Merz light as resins for direct restorations. Natural human enamel specimens served as control. All specimens were subjected to long-term thermo-mechanical loading in a computer-controlled masticator, chemical degradation and toothbrush/toothpaste abrasion. Wear of specimen in occlusal contact area (OCA), contact-free occlusal area and wear of natural enamel cusps as well as antagonists made of gold, ceramic and composite in identical form was measured after 120,000, 240,000, 640,000 and 1200,000 load cycles. A qualitative SEM analysis was performed to support quantitative data. Belleglass HP and Targis Upgrade 99 restorative materials showed wear resistance comparable to human enamel when loaded with enamel cusps. Wear of Targis versus composite and gold antagonists was significantly higher (p<0.0001). Analysis of surface alterations showed hygroscopic expansion in all composite resins during the test. As a consequence of this study, necessity to further improve physical properties of composites for long lasting restorations was obvious. Beside of attritional wear in OCA, attention must be given to stable filler-matrix interfaces and prevention of water sorption.

Scan This Book!

ERIC Educational Resources Information Center

Albanese, Andrew Richard

2007-01-01

In this article, the author presents an interview with Brewster Kahle, leader of the Open Content Alliance (OCA). OCA book scan program is an alternative to Google's library project that aims to make books accessible online. In this interview, Kahle discusses his views on the challenges of getting books on the Web, on Google's library…

LLR data analysis and impact on lunar dynamics from recent developments at OCA LLR Station

NASA Astrophysics Data System (ADS)

Viswanathan, Vishnu; Fienga, Agnes; Courde, Clement; Torre, Jean-Marie; Exertier, Pierre; Samain, Etienne; Feraudy, Dominique; Albanese, Dominique; Aimar, Mourad; Mariey, Hervé; Viot, Hervé; Martinot-Lagarde, Gregoire

2016-04-01

Since late 2014, OCA LLR station has been able to range with infrared wavelength (1064nm). IR ranging provides both temporal and spatial improvement in the LLR observations. IR detection also permits in densification of normal points, including the L1 and L2 retroreflectors due to better signal to noise ratio. This contributes to a better modelisation of the lunar libration. The hypothesis of lunar dust and environmental effects due to the chromatic behavior noticed on returns from L2 retroreflector is discussed. In addition, data analysis shows that the effect of retroreflector tilt and the use of calibration profile for the normal point deduction algorithm, contributes to improving the precision of normal points, thereby impacting lunar dynamical models and inner physics.

Ivins talks on the Softphone OCA system from Atlantis' MDK

NASA Image and Video Library

2001-02-07

STS098-345-001 (7-20 February 2001) --- Astronaut Marsha S. Ivins, STS-98 mission specialist, places a phone call to Houston’s Mission Control Center (MCC) with the “virtual phone.” This test is designed to demonstrate communications capability of a new upgrade utilizing the existing Shuttle Orbiter Communications Adapter (OCA) infrastructure.

Borate mineral assemblages in the system Na2OCaOMgOB2O3H2O

USGS Publications Warehouse

Christ, C.L.; Truesdell, A.H.; Erd, Richard C.

1967-01-01

he significant known hydrated borate mineral assemblages (principally of the western United States) in the system Na2OCaOz.sbnd;MgOB2O3H2O are expressible in three ternary composition diagrams. Phase rule interpretation of the diagrams is consistent with observation, if the activity of H2O is generally considered to be determined by the geologic environment. The absence of conflicting tie-lines on a diagram indicates that the several mineral assemblages of the diagram were formed under relatively narrow ranges of temperature and pressure. The known structural as well as empirical formulas for the minerals are listed, and the more recent (since 1960) crystal structure findings are discussed briefly. Schematic Gibbs free energy-composition diagrams based on known solubility-temperature relations in the systems Na2B4O7-H2O and Na2B4O7-NaCl-H2O, are highly useful in the interpretation and prediction of the stability relations in these systems; in particular these diagrams indicate clearly that tincalconite, although geologically important, is everywhere a metastable phase. Crystal-chemical considerations indicate that the same thermodynamic and kinetic behavior observed in the Na2B4O7-H2O system will hold in the Ca2B6O11-H2O system. This conclusion is confirmed by the petrologic evidence. The chemical relations among the mineral assemblages of a ternary diagram are expressed by a schematic "activity-activity" diagram. These activity-activity diagrams permit the tracing-out of the paragenetic sequences as a function of changing cation and H2O activities. ?? 1967.

Effect of low zinc intake and oral contraceptive agents on nitrogen utilization and clinical findings in young women.

PubMed

Hess, F M; King, J C; Margen, S

1977-12-01

In a previous paper we reported that serum, urine and fecal zinc levels fell markedly in women taking a combination oral contraceptive agent (+OCA) and in women with normal menstrual cycles (-OCA) when they consumed a low-zinc diet (less than 0.2 mg/day) for 35 days. We evaluated other biochemical and clinical data in order to determine if depletion of accessible body zinc and/or physiologic adjustment to conserve body zinc stores had occurred. Neither low zinc intake nor oral contraceptive use appeared to influence nitrogen balance or body weight. Use of contraceptive drugs appeared to influence the response of blood parameters to zinc depletion. Serum transferrin and cholesterol declined significantly in the -OCA group, whereas alkaline phosphatase and gamma-globulin changed significantly in both groups. Clinical problems developed in all the subjects with serum zinc levels below 50 microgram/dl during the study; three of the six with serum zinc levels above 50 microgram/dl also complained of clinical symptoms. The results suggest that zinc deficiency through depletion of accessible body zinc stores developed during the 35-day study.

Return to sport after the surgical management of articular cartilage lesions in the knee: a meta-analysis.

PubMed

Krych, Aaron J; Pareek, Ayoosh; King, Alexander H; Johnson, Nick R; Stuart, Michael J; Williams, Riley J

2017-10-01

Optimal surgical treatment of chondral defects in an athletic population remains highly controversial and has yet to be determined. The purpose of this review was to (1) report data on return to sport and (2) compare activity and functional outcome measures following various cartilage restoration techniques. A comprehensive review was performed for studies with return-to-sport outcomes after microfracture (MFX), osteochondral autograft transfer (OAT), osteochondral allograft transplantation (OCA), and autologous chondrocyte implantation (ACI). All studies containing return-to-sport participation with minimum 2-year post-operative activity-based outcomes were included. A meta-analysis comparing rate of return to sport between each surgical intervention was conducted using a random-effects model. Forty-four studies met inclusion criteria (18 Level I/II, 26 Level III/IV). In total, 2549 patients were included (1756 M, 793 F) with an average age of 35 years and follow-up of 47 months. Return to sport at some level was 76 % overall, with highest rates of return after OAT (93 %), followed by OCA (88 %), ACI (82 %), and MFX (58 %). Osteochondral autograft transfer showed the fastest return to sports (5.2 ± 1.8 months) compared to 9.1 ± 2.2 months for MFX, 9.6 ± 3.0 months for OCA and 11.8 ± 3.8 months for ACI (P < 0.001). A meta-regression was conducted due to heterogeneity in preoperative factors such as patient age, lesion size, and preoperative Tegner score. None of these factors were found to be significant determinants for rate of return to sport. In conclusion, in this meta-analysis of 2549 athletes, cartilage restoration surgery had a 76 % return to sport at mid-term follow-up. Osteochondral autograft transfer offered a faster recovery and appeared to have a higher rate of return to preinjury athletics, but heterogeneity in lesion size, athlete age, and concomitant surgical procedures are important factors to consider when assessing individual athletes. This study reports on the rate of return to sport in athletes undergoing various procedures for symptomatic chondral defects. IV.

Optical clearing of vaginal tissues, ex vivo, for minimally invasive laser treatment of female stress urinary incontinence

PubMed Central

Chang, Chun-Hung; Myers, Erinn M.; Kennelly, Michael J.; Fried, Nathaniel M.

2017-01-01

Abstract. Near-infrared laser energy in conjunction with applied tissue cooling is being investigated for thermal remodeling of the endopelvic fascia during minimally invasive treatment of female stress urinary incontinence. Previous computer simulations of light transport, heat transfer, and tissue thermal damage have shown that a transvaginal approach is more feasible than a transurethral approach. However, results were suboptimal, and some undesirable thermal insult to the vaginal wall was still predicted. This study uses experiments and computer simulations to explore whether application of an optical clearing agent (OCA) can further improve optical penetration depth and completely preserve the vaginal wall during subsurface treatment of the endopelvic fascia. Several different mixtures of OCA’s were tested, and 100% glycerol was found to be the optimal agent. Optical transmission studies, optical coherence tomography, reflection spectroscopy, and computer simulations [including Monte Carlo (MC) light transport, heat transfer, and Arrhenius integral model of thermal damage] using glycerol were performed. The OCA produced a 61% increase in optical transmission through porcine vaginal wall at 37°C after 30 min. The MC model showed improved energy deposition in endopelvic fascia using glycerol. Without OCA, 62%, 37%, and 1% of energy was deposited in vaginal wall, endopelvic fascia, and urethral wall, respectively, compared with 50%, 49%, and 1% using OCA. Use of OCA also resulted in 0.5-mm increase in treatment depth, allowing potential thermal tissue remodeling at a depth of 3 mm with complete preservation of the vaginal wall. PMID:28301637

Coordination Costs for School-Located Influenza Vaccination Clinics, Maine, 2009 H1N1 Pandemic

ERIC Educational Resources Information Center

Asay, Garrett R. Beeler; Cho, Bo-Hyun; Lorick, Suchita A.; Tipton, Meredith L.; Dube, Nancy L.; Messonnier, Mark L.

2012-01-01

School nurses played a key role in Maine's school-located influenza vaccination (SLV) clinics during the 2009-2010 pandemic season. The objective of this study was to determine, from the school district perspective, the labor hours and costs associated with outside-clinic coordination activities (OCA). The authors defined OCA as labor hours spent…

Quantitative analysis of dehydration in porcine skin for assessing mechanism of optical clearing

NASA Astrophysics Data System (ADS)

Yu, Tingting; Wen, Xiang; Tuchin, Valery V.; Luo, Qingming; Zhu, Dan

2011-09-01

Dehydration induced by optical clearing agents (OCAs) can improve tissue optical transmittance; however, current studies merely gave some qualitative descriptions. We develop a model to quantitatively evaluate water content with partial least-squares method based on the measurements of near-infrared reflectance spectroscopy and weight of porcine skin. Furthermore, a commercial spectrometer with an integrating sphere is used to measure the transmittance and reflectance of skin after treatment with different OCAs, and then the water content and optical properties of sample are calculated, respectively. The results show that both the reduced scattering coefficient and dehydration of skin decrease with prolongation of action of OCAs, but the relative change in former is larger than that in latter after a 60-min treatment. The absorption coefficient at 1450 nm decreases completely coincident with dehydration of skin. Further analysis illustrates that the correlation coefficient between the relative changes in the reduced scattering coefficient and dehydration is ~1 during the 60-min treatment of agents, but there is an extremely significant difference between the two parameters for some OCAs with more hydroxyl groups, especially, glycerol or D-sorbitol, which means that the dehydration is a main mechanism of skin optical clearing, but not the only mechanism.

VizieR Online Data Catalog: GSC04778-00152 photometry and spectroscopy (Tuvikene+, 2008)

NASA Astrophysics Data System (ADS)

Tuvikene, T.; Sterken, C.; Eenmae, T.; Hinojosa-Goni, R.; Brogt, E.; Longa Pena, P.; Liimets, T.; Ahumada, M.; Troncoso, P.; Vogt, N.

2012-04-01

CCD photometry of GSC04778-00152 was carried out on 54 nights during 9 observing runs. In January 2006 the observations were made with the 41-cm Meade telescope at Observatorio Cerro Armazones (OCA), Chile, using an SBIG STL-6303E CCD camera (3072x2048 pixels, FOV 23.0'x15.4') and Johnson V filter. On 3 nights in December 2006 and on 2 nights in October 2007 we used the 2.4-m Hiltner telescope at the MDM Observatory, Arizona, USA, equipped with the 8kx8k Mosaic imager (FOV 23.6'x23.6'). In December 2006 and January 2007, we also used the 41-cm Meade telescope at OCA, using an SBIG ST-7XME CCD camera (FOV 5.9'x3.9') with no filter. Figure 3 shows all OCA light curves obtained with this configuration. At Tartu Observatory the observations were carried out in December 2006 and January 2007, using the 60-cm telescope with a SpectraSource Instruments HPC-1 camera (1024x1024 pixels, FOV 11.2'x11.2') and V filter. >From January to March 2007 the system was observed using the 1.0-m telescope at SAAO, Sutherland, South Africa with an STE4 CCD camera (1024x1024 pixels, FOV 5.3'x5.3') and UBVRI filters. Spectroscopic observations were carried out at the Tartu Observatory, Estonia, using the 1.5-m telescope with the Cassegrain spectrograph ASP-32 and an Andor Newton CCD camera. (3 data files).

Optical Chopper Assembly for the Mars Observer

NASA Technical Reports Server (NTRS)

Allen, Terry

1993-01-01

This paper describes the Honeywell-developed Optical Chopper Assembly (OCA), a component of Mars Observer spacecraft's Pressure Modulator Infrared Radiometer (PMIRR) science experiment, which will map the Martian atmosphere during 1993 to 1995. The OCA is unique because of its constant accurate rotational speed, low electrical power consumption, and long-life requirements. These strict and demanding requirements were achieved by use of a number of novel approaches.

The diffuse seismicity of the Sierra Nevada of Santa Marta, the Perijá Range, and south of the La Guajira peninsula, Colombia and Venezuela: Result of the convergence between Caribbean plate and the South American margin during the Late Neogene?

NASA Astrophysics Data System (ADS)

Chicangana, G.; Pedraza, P.; Mora-paez, H.; Ordonez Aristizabal, C. O.; Vargas-Jimenez, C. A.; Kammer, A.

2012-12-01

A diffuse low deep microseismicity located overall between the Guajira peninsula and the Sierra Nevada de Santa Marta (SNSM) was registered with the recent installation (2008 to Present) of three seismological stations in northeastern Colombia by the Colombian Seismological Network (RSNC), but mainly with the Uribia station in (the) central region of La Guajira peninsula, The microseismicity is characterized by a great population of events with 1.2 < Ml < 3.0. and few events of 3.0 < Ml < 4.0 that sporadically occur. The poor number of seismological stations in this region of Colombia impedes to locate the origin of the local seismicity; however, this seismic activity is associated to the tectonic activity of the Oca fault because with the GPS displacement analysis, neotectonics evidence found in faults traces associated to the Oca fault and the historical earthquake that affected the Colombian city of Santa Marta in 1834, lead us to conclude this. This is a big cortical fault that sets the limit between La Guajira peninsula and the SNSM. Its cortical characteristics were verified from geological data together with gravimetric and seismic exploration. The SNSM limits toward the southeast with the Cesar - Ranchería basin, and this basin in turn limits with the Perijá Range that is localized in the Colombia - Venezuela border. The SNSM, Cesar - Ranchería basin and Perijá Range limit toward the southwest with the Bucaramanga - Santa Marta fault (BSMF), the Oca fault toward the north, and Perijá - El Tigre fault toward the southeast defining a pyramidal orogenic complex. Using remote sensing images data with geological and regional geophysical information, we proposed that this orogenic complex was originated as a result of the Panama arc with the northwestern South America accretion. The final adjustment of the Caribbean plate (CP) between North America and South America during the Late Neogene produced the big cortical faults systems activation like Oca - Moron - El Pilar in Colombia and Venezuela toward the south of the Caribbean Plate (CP), and Motegua - Walton - Enriquillo - Plantain Garden toward the north of the CP. This situation was originated of a new subduction development of the Nazca - Cocos plates toward the south and the west of the Panama arc; when this happened, the evolution of the Present - day configuration of the Nazca plate and Galapagos Spreading Center started. From the Early Pliocene, the BSMF and the Oca fault were reactivated: the BSMF, with a left lateral movement, and the Oca fault with a right lateral movement. This last mobility produces the cortical diffuse seismicity that we are showing here.

Countering Air and Missile Threats

DTIC Science & Technology

2012-03-23

information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources , gathering... apportionment guidance by the JFC. Functional component commands serve to ease the burden on the theater and joint task force staffs, free the JFC to focus...action (COA) to attain the desired objectives. Counterair requires a combination of OCA and DCA operations based on the JFC’s air apportionment

The influence of health-specific social network site use on the psychological well-being of cancer-affected people.

PubMed

Erfani, Seyedezahra Shadi; Blount, Yvette; Abedin, Babak

2016-05-01

We aimed to explore and examine how and in what ways the use of social network sites (SNSs) can improve health outcomes, specifically better psychological well-being, for cancer-affected people. Qualitative semi-structured interviews were conducted with users of the Ovarian Cancer Australia Facebook page (OCA Facebook), the exemplar SNS used in this study. Twenty-five women affected by ovarian cancer who were users of OCA Facebook were interviewed. A multi-theory perspective was employed to interpret the data. Most of the study participants used OCA Facebook daily. Some users were passive and only observed created content, while other users actively posted content and communicated with other members. Analysis showed that the use of this SNS enhanced social support for users, improved the users' experiences of social connectedness, and helped users learn and develop social presence, which ultimately improved their psychological well-being. The strong theoretical underpinning of our research and empirically derived results led to a new understanding of the capacity of SNSs to improve psychological well-being. Our study provides evidence showing how the integration of these tools into existing health services can enhance patients' psychological well-being. This study also contributes to the body of knowledge on the implications of SNS use for improving the psychological well-being of cancer-affected people. This research assessed the relationship between the use of SNSs, specifically OCA Facebook, and the psychological well-being of cancer-affected people. The study confirmed that using OCA Facebook can improve psychological well-being by demonstrating the potential value of SNSs as a support service in the healthcare industry. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The development of skin immersion clearing method for increasing of laser exposure efficiency on subcutaneous objects

NASA Astrophysics Data System (ADS)

Kozina, Alexandra M.; Genina, Elina A.; Terentyuk, Georgy S.; Terentyuk, Artem G.; Bashkatov, Alexey N.; Tuchin, Valery V.; Khlebtsov, Boris N.

2012-06-01

In this paper we have studied effect of a hyperosmotic optical clearing agent (OCA), such as polyethylene glycol, on the fluorescence intensity from a target located in subcutaneous area in the model experiments. As a fluorescence agent the nanocomposite including gold nanorods with hematophorphyrin was used. The remitted fluorescent signal traveling to the tissue surface was monitored over time as the tissue was treated with the OCA. The detected fluorescent signal increased as the scattering in tissue samples was substantially reduced. The study has shown how OCA can be used to improve the detected signal at localization of subcutaneous target tissue at the photothermal or photodynamic therapy. Immersion clearing of skin can be also useful for improvement of laser exposure efficiency due to the increasing of light penetration depth.

40 CFR 1400.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PREVENTION REQUIREMENTS; RISK MANAGEMENT PROGRAMS UNDER THE CLEAN AIR ACT SECTION 112(r)(7); DISTRIBUTION OF... analysis (OCA) information means sections 2 through 5 of a risk management plan (consisting of an... through 5 of a risk management plan or any Administrator-created electronic database. (k) Off-site...

Speckle interferometry with PISCO in Merate and prospects for the future

NASA Astrophysics Data System (ADS)

Scardia, M.; Prieur, J. L.; Argyle, R. W.; Pansecchi, L.; Gili, R.; Koechlin, L.

2012-05-01

Speckle interferometry measurements of binary stars have been regularly obtained with PISCO at the 1-meter Zeiss telescope of the I.N.A.F. - Osservatorio Astronomico di Brera (Merate, Italy) since the end of 2003. We present here some recent results and some projects for extending and improving the scientific reach of our program. In particular, we plan to acquire more efficient detectors and install PISCO on a computer-controlled telescope in a better site belonging to Observatoire de la Côte d'Azur (OCA, Caussols, France). In the future, we would like to be able to operate remotely PISCO, its detector and the telescope. Finally we present PISCO2, the new speckle camera of our group that has been built for the OCA 76-cm refractor.)

Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging

PubMed Central

ISHIKAWA, Akira; SUGIYAMA, Makoto; HONDO, Eiichi; KINOSHITA, Keiji; YAMAGISHI, Yuki

2015-01-01

Oca2p-cas (oculocutaneous albinism II; pink-eyed dilution castaneus) is a coat color mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus mice. Mice homozygous for Oca2p-cas usually exhibit pink eyes and gray coat hair on the non-agouti genetic background, and this ordinary phenotype remains unchanged throughout life. During breeding of a mixed strain carrying this gene on the C57BL/6J background, we discovered a novel spontaneous mutation that causes darkening of the eyes and coat hair with aging. In this study, we developed a novel mouse model showing this unique phenotype. Gross observations revealed that the pink eyes and gray coat hair of the novel mutant young mice became progressively darker in color by approximately 3 months after birth. Light and transmission-electron microscopic observations revealed a marked increase in melanin pigmentation of coat hair shafts and choroid of the eye in the novel mice compared to that in the ordinary mice. Sequence analysis of Oca2p-cas revealed a 4.1-kb deletion involving exons 15 and 16 of its wild-type gene. However, there was no sequence difference between the two types of mutant mice. Mating experiments suggested that the novel mutant phenotype was not inherited in a simple fashion, due to incomplete penetrance. The novel spontaneous mutant mouse is the first example of progressive hair darkening animals and is an essential animal model for understanding of the regulation mechanisms of melanin biosynthesis with aging. PMID:25739360

Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging.

PubMed

Ishikawa, Akira; Sugiyama, Makoto; Hondo, Eiichi; Kinoshita, Keiji; Yamagishi, Yuki

2015-01-01

Oca2(p-cas) (oculocutaneous albinism II; pink-eyed dilution castaneus) is a coat color mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus mice. Mice homozygous for Oca2(p-cas) usually exhibit pink eyes and gray coat hair on the non-agouti genetic background, and this ordinary phenotype remains unchanged throughout life. During breeding of a mixed strain carrying this gene on the C57BL/6J background, we discovered a novel spontaneous mutation that causes darkening of the eyes and coat hair with aging. In this study, we developed a novel mouse model showing this unique phenotype. Gross observations revealed that the pink eyes and gray coat hair of the novel mutant young mice became progressively darker in color by approximately 3 months after birth. Light and transmission-electron microscopic observations revealed a marked increase in melanin pigmentation of coat hair shafts and choroid of the eye in the novel mice compared to that in the ordinary mice. Sequence analysis of Oca2(p-cas) revealed a 4.1-kb deletion involving exons 15 and 16 of its wild-type gene. However, there was no sequence difference between the two types of mutant mice. Mating experiments suggested that the novel mutant phenotype was not inherited in a simple fashion, due to incomplete penetrance. The novel spontaneous mutant mouse is the first example of progressive hair darkening animals and is an essential animal model for understanding of the regulation mechanisms of melanin biosynthesis with aging.

[Cost-effectiveness analysis of 2 strategies of Helicobacter pylori eradication: results of a prospective and randomized study in primary care].

PubMed

Gomollón, F; Valdepérez, J; Garuz, R; Fuentes, J; Barrera, F; Malo, J; Tirado, M; Simón, M A

2000-06-03

To analyze cost-effectiveness of two different strategies to treat H. pylori infection in peptic ulcer in the primary care setting. Consecutive patients with endoscopic diagnosis of peptic ulcer were randomized to one of two strategies: a) treatment during 7 days with omeprazole, tetracycline, metronidazole and bismuth subcitrate ("quadruple" therapy) and if failure second-line treatment with omeprazole, amoxycillin and clarithromycin during 7 days (OCA7), and b) initial treatment with OCA7 and if failure treatment with "quadruple therapy". End point was eradication 8 weeks after last treatment dose. Direct and indirect costs were estimated (euros, 1997) and a cost-effectiveness analysis using a decision-tree model was undertaken after real clinical data. 95% confidence intervals are given. After screening 255 patients, 97 were finally included. 48 patients were given strategy a and 49 strategy b. Eradication was obtained (intention-to-treat) in 72.9% (CI 95%: 58.2-84.7) in group a versus 91.8% (CI 95%: 80.4-97.7) (p < 0.05) in group b. Mean cost per case treated was lower in group a (237 versus 268 euros) but cost per case eradicated was lower in group b (320 versus 296 euros). The cost was primarily determined by efficacy. Treatment with OCA7 followed by rescue with "quadruple" therapy if failure is more efficient in our area that the inverse strategy. Efficiency is mostly determined by efficacy.

Molecular Dynamics Simulations of Protein-Ligand Complexes in Near Physiological Conditions

NASA Astrophysics Data System (ADS)

Wambo, Thierry Oscar

Proteins are important molecules for their key functions. However, under certain circumstances, the function of these proteins needs to be regulated to keep us healthy. Ligands are small molecules often used to modulate the function of proteins. The binding affinity is a quantitative measure of how strong the ligand will modulate the function of the protein: a strong binding affinity will highly impact the performance of the protein. It becomes clear that it is critical to have appropriate techniques to accurately compute the binding affinity. The most difficult task in computer simulations is how to efficiently sample the space spanned by the ligand during the binding process. In this work, we have developed some schemes to compute the binding affinity of a ligand to a protein, and of a metal ion to a protein. Application of these techniques to some complexes yield results in agreement with experimental values. These methods are a brute force approach and make no assumption other than that the complexes are governed by the force field used. Specifically, we computed the free energy of binding between (1) human carbonic anhydrase II and the drug acetazolamide (hcaII-AZM), (2) human carbonic anhydrase II and the zinc ion (hcaII-Zinc), and (3) beta-lactoglobulin and five fatty acids complexes (BLG-FAs). We found the following free energies of binding in unit of kcal/mol: -12.96 +/-2.44 (-15.74) for hcaII-Zinc complex, -5.76+/-0.76 (-5.57) for BLG-OCA , -4.44+/-1.08 (-5.22) for BLG-DKA,-6.89+/-1.25 (-7.24) for BLG-DAO, -8.57+/-0.82 (-8.14) for BLG-MYR, -8.99+/-0.87 (-8.72) for BLG-PLM, and -11.87+/-1.8 (-10.8) for hcaII-AZM. The values inside the parentheses are experimental results. The simulations and quantitative analysis of each system provide interesting insights into the interactions between each entity and helps us to better understand the dynamics of these systems.

STS-93 MS Hawley works with data associated with the OCA on the middeck

NASA Image and Video Library

2013-11-18

STS093-327-004 (23-27 July 1999) --- Astronaut Steven A. Hawley works with data associated with the Orbital Communications Adapter (OCA) on the middeck of the Space Shuttle Columbia. Not far away from him is the window-mounted instrument which supports the Southwest Ultraviolet Imaging System (SWUIS). SWUIS is an innovative telescope/charge-coupled device camera system designed to image planets and other solar system bodies.

Heart-rate sensitive optical coherence angiography for measuring vascular changes due to posttraumatic brain injury in mice

NASA Astrophysics Data System (ADS)

Tremoleda, Jordi L.; Alvarez, Karl; Aden, Abdirahman; Donnan, Robert; Michael-Titus, Adina T.; Tomlins, Peter H.

2017-12-01

Traumatic brain injury (TBI) results in direct vascular disruption, triggering edema, and reduction in cerebral blood flow. Therefore, understanding the pathophysiology of brain microcirculation following TBI is important for the development of effective therapies. Optical coherence angiography (OCA) is a promising tool for evaluating TBI in rodent models. We develop an approach to OCA that uses the heart-rate frequency to discriminate between static tissue and vasculature. This method operates on intensity data and is therefore not phase sensitive. Furthermore, it does not require spatial overlap of voxels and thus can be applied to pre-existing datasets for which oversampling may not have been explicitly considered. Heart-rate sensitive OCA was developed for dynamic assessment of mouse microvasculature post-TBI. Results show changes occurring at 5-min intervals within the first 50 min of injury.

Airflow-directed in situ electrospinning of a medical glue of cyanoacrylate for rapid hemostasis in liver resection

NASA Astrophysics Data System (ADS)

Jiang, Kai; Long, Yun-Ze; Chen, Zhao-Jun; Liu, Shu-Liang; Huang, Yuan-Yuan; Jiang, Xingyu; Huang, Zhi-Qiang

2014-06-01

Rapid hemostasis of solitary organs is still a big challenge in surgical procedures or after major trauma in both civilians and on the battlefield. Here, we report the first use of an airflow-directed in situ electrospinning method to precisely and homogeneously deposit a medical glue of n-octyl-2-cyanoacrylate (OCA) ultrathin fibers onto a wound surface to realize rapid hemostasis in dozens of seconds. In vivo and in vitro experiments on pig liver resection demonstrate that the self-assembled electrospun OCA membrane with high strength, good flexibility and integrity is very compact and no fluid seeping is observed even under a pressure of 147 mm Hg. A similar effect has been achieved in an in vivo experiment on pig lung resection. The results provide a very promising alternative for rapid hemostasis of solitary organs as well as other traumas, providing evidence that the postoperative drainage tube may not be always necessary for surgery in the near future.Rapid hemostasis of solitary organs is still a big challenge in surgical procedures or after major trauma in both civilians and on the battlefield. Here, we report the first use of an airflow-directed in situ electrospinning method to precisely and homogeneously deposit a medical glue of n-octyl-2-cyanoacrylate (OCA) ultrathin fibers onto a wound surface to realize rapid hemostasis in dozens of seconds. In vivo and in vitro experiments on pig liver resection demonstrate that the self-assembled electrospun OCA membrane with high strength, good flexibility and integrity is very compact and no fluid seeping is observed even under a pressure of 147 mm Hg. A similar effect has been achieved in an in vivo experiment on pig lung resection. The results provide a very promising alternative for rapid hemostasis of solitary organs as well as other traumas, providing evidence that the postoperative drainage tube may not be always necessary for surgery in the near future. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr01412j

Selected gene polymorphisms effect on skin and hair pigmentation in Polish children at the prepubertal age.

PubMed

Sitek, Aneta; Rosset, Iwona; Żądzińska, Elżbieta; Siewierska-Górska, Anna; Pietrowska, Edyta; Strapagiel, Dominik

2016-11-01

Background : Human pigmentation, similarly as many other biological features, changes in the course of post-natal ontogenesis, while in case of hair, pigmentation changes are more distinctive than in the skin or the iris. It is therefore extremely important to identify the genes, involved in the constitution of human pigmentation features at various stages of ontogenesis. Results of this type of analyses are of high practical significance in forensic study because they enable to create mathematical tools, allowing for prediction of the pigmentation phenotype, based on DNA studies. Aim : The objective of the investigation was finding out whether the genes, associated with pigmentation of adult subjects, differentiated in any way the newly forming pigmentation phenotype in Polish prepubertal children. Material and methods : The study encompassed Polish children, aged 7 to 10 years, without any abnormalities in skin or hair pigmentation. A total of 245 children were examined. Constitutive skin pigmentation according to skin melanin index (SMI) was evaluated, using a dermaspectrometer, and classified into three groups based on the reference values of 25 and 75 percentile for Polish children. Hair colors were evaluated by means of the descriptive Fischer-Saller scale and classified by a division of color variants (as accepted in that scale) (light blonde, blonde, dark blonde, brown and dark brown). In saliva samples, collected from the children, five (5) single nucleotide polymorphisms were identified: SNPs : rs1800401 ( OCA2 -15q11.2-q12), rs35264875 ( TPCN2 -11q13.3), rs16891982 ( SLC45A2 -5p13.2), rs12913832 ( HERC2 -15q13) and rs1805007 ( MC1R -16q24.3). An association between each allele of verified genotype and skin and hair color phenotypes was assessed, using the z-statistic and associated p -value. The quality of classifiers was evaluated by 10-fold stratified cross-validation and was characterized by the area under the receiver operating characteristic curve (AUC). Results : Light skin pigmentation phenotype (SMI<25 percentile) was associated with rs1805007 ( MC1R ) (allelic OR=3.95; 95% Cl:1.20-12.99; p =0.0235), while the dark shade of the skin (SMI>75 percentile) with rs16891982 ( SLC45A2 ) (allelic OR =14.37; 95% Cl: 1.78-115.88; p =0.0123). The probability of dark hair (brown and dark brown) in childhood was increased by T rs12913832 allele ( HERC2 ) (OR=3.63); 95% Cl: 2.25-5.85; p < 0.0001) and dependent on it - rs1800401 ( OCA2 ) (OR=6.31; 95% Cl: 1.74-22.91; p =0.0051). Other SNPs were not significantly associated with skin and hair color but improved prediction of these features. Conclusions : From the five gene polymorphisms analysed in Polish children the strongest correlation with hair color has the rs12913832 ( HERC2 ) and with skin color - rs16891982 ( SLC45A2 ). Therefore, the above-mentioned polymorphisms may be used as components of potential models, used to predict pigmentation features in European origin children in prepubertal age. To improve predictive value of the potential scoring model for hair color, the following should be additionally included: rs1800401 ( OCA2 ), rs35264875 ( TPCN2 ) and rs1805007 ( MC1R ), while for skin color: rs12913832 ( HERC2 ) and rs1805007 ( MC1R ).

Environment, Safety, and Health Self-Assessment Report, Fiscal Year 2008

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

Chernowski, John

2009-02-27

Lawrence Berkeley National Laboratory's Environment, Safety, and Health (ES&H) Self-Assessment Program ensures that Integrated Safety Management (ISM) is implemented institutionally and by all divisions. The Self-Assessment Program, managed by the Office of Contract Assurance (OCA), provides for an internal evaluation of all ES&H programs and systems at LBNL. The functions of the program are to ensure that work is conducted safely, and with minimal negative impact to workers, the public, and the environment. The Self-Assessment Program is also the mechanism used to institute continuous improvements to the Laboratory's ES&H programs. The program is described in LBNL/PUB 5344, Environment, Safety, andmore » Health Self-Assessment Program and is composed of four distinct assessments: the Division Self-Assessment, the Management of Environment, Safety, and Health (MESH) review, ES&H Technical Assurance, and the Appendix B Self-Assessment. The Division Self-Assessment uses the five core functions and seven guiding principles of ISM as the basis of evaluation. Metrics are created to measure performance in fulfilling ISM core functions and guiding principles, as well as promoting compliance with applicable regulations. The five core functions of ISM are as follows: (1) Define the Scope of Work; (2) Identify and Analyze Hazards; (3) Control the Hazards; (4) Perform the Work; and (5) Feedback and Improvement. The seven guiding principles of ISM are as follows: (1) Line Management Responsibility for ES&H; (2) Clear Roles and Responsibilities; (3) Competence Commensurate with Responsibilities; (4) Balanced Priorities; (5) Identification of ES&H Standards and Requirements; (6) Hazard Controls Tailored to the Work Performed; and (7) Operations Authorization. Performance indicators are developed by consensus with OCA, representatives from each division, and Environment, Health, and Safety (EH&S) Division program managers. Line management of each division performs the Division Self-Assessment annually. The primary focus of the review is workplace safety. The MESH review is an evaluation of division management of ES&H in its research and operations, focusing on implementation and effectiveness of the division's ISM plan. It is a peer review performed by members of the LBNL Safety Review Committee (SRC), with staff support from OCA. Each division receives a MESH review every two to four years, depending on the results of the previous review. The ES&H Technical Assurance Program (TAP) provides the framework for systematic reviews of ES&H programs and processes. The intent of ES&H Technical Assurance assessments is to provide assurance that ES&H programs and processes comply with their guiding regulations, are effective, and are properly implemented by LBNL divisions. The Appendix B Performance Evaluation and Measurement Plan (PEMP) requires that LBNL sustain and enhance the effectiveness of integrated safety, health, and environmental protection through a strong and well-deployed system. Information required for Appendix B is provided by EH&S Division functional managers. The annual Appendix B report is submitted at the close of the fiscal year. This assessment is the Department of Energy's (DOE) primary mechanism for evaluating LBNL's contract performance in ISM.« less

Determination of optimal glycerol concentration for optical tissue clearing

NASA Astrophysics Data System (ADS)

Youn, Eungjun; Son, Taeyoon; Kim, Han-Sung; Jung, Byungjo

2012-02-01

The laser scattering in tissue is significant in diagnostic and therapeutic purposes of laser. Many studies have been conducted to minimize laser scattering in tissue and therefore, to maximize the clinical efficacy by enhancing photon density. Optical clearing agents (OCAs) have been employed for optical tissue clearing (OTC). This study was aimed to investigate the optimal concentration of an OCA, glycerol, in topical application,, so that it can be utilized for clinical diagnosis and therapy in dermatology. Glycerol was topically applied to avoid possible edema caused by dermal injection. The effect of OTC was quantitatively evaluated as a function of the concentration of glycerol with various methods. Optical methods such as optical coherence tomography (OCT) and an integrating sphere were used to assess the enhancement of light penetration depth and refractive index matching. In addition, a non-optical method, ultrasound scanner, was utilized to evaluate quantitatively collagen dissociation. The results revealed that 70 % glycerol was the optimal concentration of OTC for topical application. This study may provide a guideline regarding to the use of glycerol for optimal diagnostic and therapeutic effects in dermatology.

[From the asylums to the community: the reform process of National Colony "Dr. Manuel A. Montes de Oca"].

PubMed

Rossetto, Jorge

2009-01-01

Since 2004, a profound transformation of the asylum care model, characterized by overcrowding, lack of discharge and absence of rehabilitation programs, and social reinsertion, has been developed at National Colony "Dr. Manuel A. Montes de Oca". During this period, a plan that contemplates several programs and projects aimed at restoring the rights of institutionalized people with mental disabilities and promoting opportunities for social inclusion has been implemented.

What Comes after Ursodeoxycholic Acid in Primary Biliary Cholangitis?

PubMed

Wong, Lin Lee; Hegade, Vinod S; Jones, David E J

2017-01-01

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by chronic cholestasis. Treatment with the accepted primary therapy ursodeoxycholic acid (UDCA) has been shown to be associated with delayed disease progression probably through reduced impact of cholestatic injury on the target biliary epithelial cells. Patients with inadequate response to UDCA (which can be identified through validated biochemical criteria) are at increased risk of disease progression, need for liver transplantation, and death. Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second-line therapy in PBC and has been recently licensed by the Food and Drug Administration and European Medicines Agency for use in patients showing an inadequate response to UDCA or who are unable to tolerate it. Although evidence for biochemical improvement by OCA is compelling, there is, as yet, no evidence that OCA improves hard clinical outcomes or quality of life. In addition, OCA may not be suitable for PBC patients with pruritus as it can worsen the symptom. Other novel agents currently in clinical development may have better side-effect profile. Fibrates have the potential but currently lack high quality evidence to support their routine clinical use in PBC. Symptom management of PBC is challenging and ASBT inhibitors and rituximab are being evaluated for pruritus and fatigue, respectively. © 2017 S. Karger AG, Basel.

A UHF RFID system with on-chip-antenna tag for short range communication

NASA Astrophysics Data System (ADS)

Qi, Peng; Chun, Zhang; Xijin, Zhao; Zhihua, Wang

2015-05-01

A UHF RF identification system based on the 0.18 μm CMOS process has been developed for short range and harsh size requirement applications, which is composed of a fully integrated tag and a special reader. The whole tag chip with the antenna takes up an area of 0.36 mm2, which is smaller than other reported tags with an on-chip antenna (OCA) using the standard CMOS process. A self-defined protocol is proposed to reduce the power consumption, and minimize the size of the tag. The specialized SOC reader system consists of the RF transceiver, digital baseband, MCU and host interface. Its power consumption is about 500 mW. Measurement results show that the system's reading range is 2 mm with 20 dBm reader output power. With an inductive antenna printed on a paper substrate around the OCA tag, the reading range can be extended from several centimeters to meters, depending on the shape and size of the inductive antenna.

The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate.

PubMed

Lee, Sung-Eun; Choi, Soo Young; Bang, Ju-Hee; Kim, Soo-Hyun; Jang, Eun-Jung; Byeun, Ji-Young; Park, Jin Eok; Jeon, Hye-Rim; Oh, Yun Jeong; Kim, Myungshin; Kim, Dong-Wook

2012-11-01

The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy. Copyright © 2012 Elsevier Inc. All rights reserved.

Investigation of multiple optical and biometric properties of optic nerve head (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hong, Young-Joo; Chan, Aaron C.; Kasaragod, Deepa K.; Makita, Shuichi; Miura, Masahiro; Yasuno, Yoshiaki

2017-02-01

Glaucoma is a group of eye diseases which results in optic nerve damage and vision loss. Optical coherence tomography (OCT) has been widely used to investigate geometric risk factor of glaucoma. However, material properties of ONH are also important to understand intra-ocular pressure related stress. We developed Jones-matrix based multifunctional posterior eye OCT (JM-OCT), which uses 1-μm band swept-source with a 100-kHz A-line rate. It provides three different optical properties, attenuation coefficient (AC), local birefringence (LB), and optical coherence angiography (OCA). We investigated the utility those properties for the investigation of normal ONH cases. 3 mm x 3 mm area around ONH was scanned for each eye, and biometric parameters were measured in hospital. Statistical analyses were performed with the mean values of above parameters at the regions of prelamina, lamina cribrosa, peripapillary sclera, and peripapillary nerve fiber layer, and biometric parameters of age, axial eye length, refractive error, and intraocular pressure. In qualitative observation, the lamina cribrosa generally shows more hyper signals in AC, LB, and OCA than prelamina. In t-test, AC, LB, and OCA showed significant difference (p < 0.05) between prelamina and lamina cribrosa, while conventional OCT did not. In correlation test, axial eye length is positively correlated with LB and AC in lamina cribrosa. And these LB and AC are also negatively correlated with the refractive error. Age was found to be negatively correlated with OCA in lamina cribrosa.

Further evidence for population specific differences in the effect of DNA markers and gender on eye colour prediction in forensics.

PubMed

Pośpiech, Ewelina; Karłowska-Pik, Joanna; Ziemkiewicz, Bartosz; Kukla, Magdalena; Skowron, Małgorzata; Wojas-Pelc, Anna; Branicki, Wojciech

2016-07-01

The genetics of eye colour has been extensively studied over the past few years, and the identified polymorphisms have been applied with marked success in the field of Forensic DNA Phenotyping. A picture that arises from evaluation of the currently available eye colour prediction markers shows that only the analysis of HERC2-OCA2 complex has similar effectiveness in different populations, while the predictive potential of other loci may vary significantly. Moreover, the role of gender in the explanation of human eye colour variation should not be neglected in some populations. In the present study, we re-investigated the data for 1020 Polish individuals and using neural networks and logistic regression methods explored predictive capacity of IrisPlex SNPs and gender in this population sample. In general, neural networks provided higher prediction accuracy comparing to logistic regression (AUC increase by 0.02-0.06). Four out of six IrisPlex SNPs were associated with eye colour in the studied population. HERC2 rs12913832, OCA2 rs1800407 and SLC24A4 rs12896399 were found to be the most important eye colour predictors (p < 0.007) while the effect of rs16891982 in SLC45A2 was less significant. Gender was found to be significantly associated with eye colour with males having ~1.5 higher odds for blue eye colour comparing to females (p = 0.002) and was ranked as the third most important factor in blue/non-blue eye colour determination. However, the implementation of gender into the developed prediction models had marginal and ambiguous impact on the overall accuracy of prediction confirming that the effect of gender on eye colour in this population is small. Our study indicated the advantage of neural networks in prediction modeling in forensics and provided additional evidence for population specific differences in the predictive importance of the IrisPlex SNPs and gender.

Ploidy levels among species in the 'Oxalis tuberosa alliance' as inferred by flow cytometry.

PubMed

Emshwiller, Eve

2002-06-01

The 'Oxalis tuberosa alliance' is a group of Andean Oxalis species allied to the Andean tuber crop O. tuberosa Molina (Oxalidaceae), commonly known as 'oca'. As part of a larger project studying the origins of polyploidy and domestication of cultivated oca, flow cytometry was used to survey DNA ploidy levels among Bolivian and Peruvian accessions of alliance members. In addition, this study provided a first assessment of C-values in the alliance by estimating nuclear DNA contents of these accessions using chicken erythrocytes as internal standard. Ten Bolivian accessions of cultivated O. tuberosa were confirmed to be octoploid, with a mean nuclear DNA content of approx. 3.6 pg/2C. Two Peruvian wild Oxalis species, O. phaeotricha and O. picchensis, were inferred to be tetraploid (both with approx. 1.67 pg/2C), the latter being one of the putative progenitors of O. tuberosa identified by chloroplast-expressed glutamine synthetase data in prior work. The remaining accessions (from 78 populations provisionally identified as 35 species) were DNA diploid, with nuclear DNA contents varying from 0.79 to 1.34 pg/2C.

Heterodyne Interferometry in InfraRed at OCA-Calern Observatory in the seventies

NASA Astrophysics Data System (ADS)

Gay, J.; Rabbia, Y.

2014-04-01

We report on various works carried four decades ago, so as to develop Heterodyne Interferometry in InfraRed (10 μm) at Calern Observatory (OCA, France), by building an experiment, whose the acronym "SOIRDETE" means "Synthese d'Ouverture en InfraRouge par Detection hETErodyne". Scientific and technical contexts by this time are recalled, as well as basic principles of heterodyne interferometry. The preliminary works and the SOIRDETE experiment are briefly described. Short comments are given in conclusion regarding the difficulties which have prevented the full success of the SOIRDETE experiment.

Improved osteochondral allograft preservation using serum-free media at body temperature.

PubMed

Garrity, Joseph T; Stoker, Aaron M; Sims, Hannah J; Cook, James L

2012-11-01

Osteochondral allografts (OCAs) are currently preserved at 4°C and used within 28 days of donor harvest. The window of opportunity for implantation is limited to 14 days due to a 2-week disease testing protocol. Osteochondral allograft tissues stored at 37°C will have significantly higher chondrocyte viability, as well as superior biochemical and biomechanical properties, than those stored at 4°C. Controlled laboratory study. Osteochondral allografts from 15 adult canine cadavers were aseptically harvested within 4 hours of death. Medial and lateral femoral condyles were stored in Media 1, similar to the current standard, or Media 2, an anti-inflammatory and chondrogenic media containing dexamethasone and transforming growth factor-β3, at 4°C or 37°C for up to 56 days. Chondrocyte viability, glycosaminoglycan (GAG) and collagen (hydroxyproline [HP]) content, biomechanical properties, and collagen II and aggrecan content were assessed at days 28 and 56. Five femoral condyles were stored overnight and assessed the next day to serve as controls. Storage in Media 1 at 37°C maintained chondrocyte viability at significantly higher levels than in any other media-temperature combination and at levels not significantly different from controls. Osteochondral allografts stored in either media at 4°C showed a significant decrease in chondrocyte viability throughout storage. Glycosaminoglycan and HP content were maintained through 56 days of storage in OCAs in Media 1 at 37°C. There were no significant differences in elastic or dynamic moduli among groups at day 56. Qualitative immunohistochemistry demonstrated the presence of collagen II and aggrecan throughout all layers of cartilage. Osteochondral allograft viability, matrix content and composition, and biomechanical properties were maintained at "fresh" levels through 56 days of storage in Media 1 at 37°C. Osteochondral allografts stored at 4°C were unable to maintain viability or matrix integrity through 28 days of storage. These findings suggest that storage of OCAs in a defined media at 37°C is superior to current protocols (4°C) for tissue preservation prior to transplantation. Storage of OCAs in serum-free chemically defined media at 37°C can increase the "window of opportunity" for implantation of optimal tissue from 14 days to 42 days after disease testing clearance.

Spread of X-chromosome inactivation into chromosome 15 is associated with Prader-Willi syndrome phenotype in a boy with a t(X;15)(p21.1;q11.2) translocation.

PubMed

Sakazume, Satoru; Ohashi, Hirofumi; Sasaki, Yuki; Harada, Naoki; Nakanishi, Katsumi; Sato, Hidenori; Emi, Mitsuru; Endoh, Kazushi; Sohma, Ryoichi; Kido, Yasuhiro; Nagai, Toshiro; Kubota, Takeo

2012-01-01

X-chromosome inactivation (XCI) is an essential mechanism in females that compensates for the genome imbalance between females and males. It is known that XCI can spread into an autosome of patients with X;autosome translocations. The subject was a 5-year-old boy with Prader-Willi syndrome (PWS)-like features including hypotonia, hypo-genitalism, hypo-pigmentation, and developmental delay. G-banding, fluorescent in situ hybridization, BrdU-incorporated replication, human androgen receptor gene locus assay, SNP microarrays, ChIP-on-chip assay, bisulfite sequencing, and real-time RT-PCR were performed. Cytogenetic analyses revealed that the karyotype was 46,XY,der(X)t(X;15)(p21.1;q11.2),-15. In the derivative chromosome, the X and half of the chromosome 15 segments showed late replication. The X segment was maternal, and the chromosome 15 region was paternal, indicating its post-zygotic origin. The two chromosome 15s had a biparental origin. The DNA methylation level was relatively high in the region proximal from the breakpoint, and the level decreased toward the middle of the chromosome 15 region; however, scattered areas of hypermethylation were found in the distal region. The promoter regions of the imprinted SNRPN and the non-imprinted OCA2 genes were completely and half methylated, respectively. However, no methylation was found in the adjacent imprinted gene UBE3A, which contained a lower density of LINE1 repeats. Our findings suggest that XCI spread into the paternal chromosome 15 led to the aberrant hypermethylation of SNRPN and OCA2 and their decreased expression, which contributes to the PWS-like features and hypo-pigmentation of the patient. To our knowledge, this is the first chromosome-wide methylation study in which the DNA methylation level is demonstrated in an autosome subject to XCI.

Midterm results of osteochondral allograft transplantation to the humeral head.

PubMed

Riff, Andrew J; Yanke, Adam B; Shin, Jason J; Romeo, Anthony A; Cole, Brian J

2017-07-01

This study evaluated clinical outcomes of osteochondral allograft (OCA) transplantation for humeral head osteochondral defects. We hypothesized that patients with isolated humeral head disease would achieve favorable results and that patients with bipolar disease would experience inferior outcomes. We identified patients who underwent humeral head OCA transplantation. Subjective questionnaire data were obtained preoperatively and at a minimum of 2 years postoperatively. Radiographs were evaluated for graft incorporation. Failure was defined by conversion to shoulder arthroplasty, American Shoulder and Elbow Surgeons score <50, or dissatisfaction with the surgical result. Twenty patients (65% male) met inclusion criteria. Patients were an average age of 24.8 ± 8.1 years. Eleven patients underwent concomitant glenoid surgery (microfracture or meniscal allograft resurfacing). Follow-up was available for 18 patients (90%) at mean of 67 months. All grafts incorporated except 2. Four patients underwent shoulder arthroplasty at mean of 25 months postoperatively (all after pain pump chondrolysis). Eleven of the 20 patients were satisfied (all dissatisfied patients underwent glenoid surgery). Significant improvements (P < .001) were seen for the visual analog scale (from 6.1 to 1.5), Simple Shoulder Test (from 32 to 73), American Shoulder and Elbow Surgeons score (from 39 to 76), and the physical component of the 12-Item Short Form Survey (from 38 to 48). Pain pump patients who did not progress to arthroplasty experienced inferior satisfaction (40% vs. 87.5%, P = .04) and a trend toward inferior outcomes compared with the rest of the cohort. OCA transplantation is a viable option for young patients with isolated humeral chondral injury. Patients with bipolar disease or a history of intra-articular pain pump have increased failure and decreased subjective outcomes. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Assessment of boric acid and borax using the IEHR evaluative process for assessing human developmental and reproductive toxicity of agents

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

Moore, J.A.

This document presents an evaluation of the reproductive and developmental effects of boric acid, H3BO3 (CAS Registry No. 10043-35-3) and disodium tetraborate decahydrate or borax, Na2B4O2O(CAS Registry No. 1303-96-4). The element, boron, does not exist naturally. In dilute aqueous solution and at physiological pH (7.4), the predominant species in undissociated boric acid (greater than 98%), irrespective of whether the initial material was boric acid of borax. Therefore, it is both useful and correct to compare exposures and dosages to boric acid and borax in terms of `boron equivalents`, since both materials form equivalent species in dilute aqueous solution with similarmore » systemic effects. In order to be clear in this document, the term `boron` will refer to `boron equivalents` or percent boron in boric acid and borax.« less

Optical clearing of skin enhanced with hyaluronic acid for increased contrast of optoacoustic imaging

NASA Astrophysics Data System (ADS)

Liopo, Anton; Su, Richard; Tsyboulski, Dmitri A.; Oraevsky, Alexander A.

2016-08-01

Enhanced delivery of optical clearing agents (OCA) through skin may improve sensitivity of optical and optoacoustic (OA) methods of imaging, sensing, and monitoring. This report describes a two-step method for enhancement of light penetration through skin. Here, we demonstrate that topical application of hyaluronic acid (HA) improves skin penetration of hydrophilic and lipophilic OCA and thus enhances their performance. We examined the OC effect of 100% polyethylene and polypropylene glycols (PPGs) and their mixture after pretreatment by HA, and demonstrated significant increase in efficiency of light penetration through skin. Increased light transmission resulted in a significant increase of OA image contrast in vitro. Topical pretreatment of skin for about 30 min with 0.5% HA in aqueous solution offers effective delivery of low molecular weight OCA such as a mixture of PPG-425 and polyethylene glycol (PEG)-400. The developed approach of pretreatment by HA prior to application of clearing agents (PEG and PPG) resulted in a ˜47-fold increase in transmission of red and near-infrared light and significantly enhanced contrast of OA images.

LASSO, two-way, and GPS time comparisons: A (very) preliminary status report

NASA Technical Reports Server (NTRS)

Veillet, Christian J. L.; Feraudy, D.; Torre, J. M.; Mangin, J. F.; Grudler, P.; Baumont, Francoise S.; Gaignebet, Jean C.; Hatat, J. L.; Hanson, Wayne; Clements, A.

1990-01-01

The first results are presented on the time transfer experiments between TUG (Graz, Austria) and OCA (Grasse, France) using common view Global Positioning System (GPS) and two-way stations at both sites. The present data, providing arms of the clock offsets of 2 to 3 nanoseconds for a three month period, have to be further analyzed before any conclusions on the respective precision and accuracy of these techniques can be drawn. Two years after its start, the Laser Synchronization from Stationary Orbit (LASSO) experiment is finally giving its first results at TUG and OCA. The first analysis of three common sessions permitted researchers to conclude that the LASSO package on board Meteosat P2 is working satisfactorily, and that time transfer using this method should provide clock offsets at better than 1 nanosecond precision, and clock rates at better than 10(exp -12) s/s in a 5 to 10 minutes session. A new method for extracting this information from the raw data sent by LASSO should enhance the performances of this experiment, exploiting the stability of the on-board oscillator.

Genetic modulation of the iris transillumination defect: a systems genetics analysis using the expanded family of BXD glaucoma strains

PubMed Central

Swaminathan, Shankar; Lu, Hong; Williams, Robert W; Lu, Lu; Jablonski, Monica M

2013-01-01

We investigated the contributions of Tyrp1 and Gpnmb to the iris transillumination defect (TID) in five age cohorts of BXD mice. Using systems genetics, we also evaluated the role of other known pigmentation genes (PGs). Mapping studies indicate that Tyrp1 contributes to the phenotype at all ages, yet the TID maps to Gpnmb only in the oldest cohort. Composite interval mapping reveals secondary loci viz. Oca2, Myo5a, Prkcz, and Zbtb20 that modulate the phenotype in the age groups up to 10–13 months. The contributions of Tyrp1 and Gpnmb were highly significant in all age cohorts. Moreover, in young mice, all six gene candidates had substantial interactions in our model. Our model accounted for 71–88% of the explained variance of the TID phenotype across the age bins. These results demonstrate that along with Tyrp1 and Gpnmb, Oca2, Myo5a, Prkcz, and Zbtb20 modulate the TID in an age-dependent manner. PMID:23582180

LASSO observations at McDonald and OCA/CERGA: A preliminary analysis

NASA Technical Reports Server (NTRS)

Veillet, CH.; Fridelance, P.; Feraudy, D.; Boudon, Y.; Shelus, P. J.; Ricklefs, R. L.; Wiant, J. R.

1993-01-01

The Laser Synchronization from Synchronous Orbit (LASSO) observations between USA and Europe were made possible with the move of Meteosat 3/P2 toward 50 deg W. Two Lunar Laser Ranging stations participated into the observations: the MLRS at McDonald Observatory (Texas, USA) and OCA/CERGA (Grasse, France). Common sessions were performed since 30 Apr. 1992, and will be continued up to the next Meteosat 3/P2 move further West (planned for January 1993). The preliminary analysis made with the data already collected by the end of Nov. 1992 shows that the precision which can be obtained from LASSO is better than 100 ps, the accuracy depending on how well the stations maintain their time metrology, as well as on the quality of the calibration (still to be made.) For extracting such a precision from the data, the processing has been drastically changed compared to the initial LASSO data analysis. It takes into account all the measurements made, timings on board, and echoes at each station. This complete use of the data increased dramatically the confidence into the synchronization results.

METEOSPACE, solar monitoring and space weather at Calern observatory

NASA Astrophysics Data System (ADS)

Corbard, T.; Malherbe, J.-M.; Crussaire, D.; Morand, F.; Ruty, F.; Biree, L.; Aboudarham, J.; Fuller, N.; Renaud, C.; Meftah, M.

2016-12-01

METEOSPACE is a new partnership project between the Paris Observatory (OP), the Observatoire de la Côte d'Azur (OCA), the French Air Force and a service company (LUNA technology) for the development and operation of a set of small telescopes Hα / Ca II K / Ca II H / G band to be installed at on the Calern plateau (OCA). The objective is to monitor solar activity for both research and its applications in space weather through continuous optical observations of the dynamic phenomena that are visible in the chromosphere: eruptions, destabilization of the filaments triggering coronal mass ejections and associated Moreton waves.

A Comparison of the Effect of Two Power Toothbrushes on the Gingival Health and Plaque Status of Subjects with Moderate Gingivitis.

PubMed

Starke, Michelle; Delaurenti, Marcia; Ward, Marilyn; Souza, Sonia; Milleman, Kimberly R; Milleman, Jeffery L

2017-03-01

To compare the effect of the Philips Sonicare DiamondClean plus Premium plaque control brush head with the Oral-B 7000 plus CrossAction brush head on gingivitis and supragingival plaque reduction following a 42-day period of home use. This was a randomized, parallel, examiner-blind, prospective clinical trial conducted on generally healthy subjects. Eligible subjects met the following eligibility criteria: age 18-65, non-smoker, routine manual toothbrush user, ≥ 50 sites of gingival bleeding per the Gingival Bleeding Index (GBI), and ≥ 1.8 plaque score per the Modified Plaque Index (MPI), assessed three to six hours following the last oral hygiene procedure. Eligible subjects were enrolled in the study and randomly assigned to use either a Philips Sonicare DiamondClean with Premium plaque control brush head power toothbrush (SPC) or an Oral-B® 7000 with CrossAction™ brush head power toothbrush (OCA), for twice daily home use over a period of 42 days. All subjects were dispensed a standard fluoride-containing dentifrice and both toothbrushes were to be used in their respective Deep Clean modes. Safety and efficacy evaluations were performed at 14 and 42 days following Baseline. Two-hundred eighty-four subjects completed this trial (142 subjects per treatment group). Least squares mean (95% CI) estimates for reduction and percent reduction of gingivitis per Modified Gingival Index (MGI) following 42 days of product use for the SPC group were 1.17 (1.10, 1.24) and 45.68% (42.95%, 48.40%); for the OCA group they were 0.69 (0.62, 0.76) and 26.83% (24.10%, 29.56%). The mean difference (95% CI) between the two treatment groups was 0.48 (0.38, 0.58) and 18.85% (14.99%, 22.70%) for reduction and percent reduction, respectively. The lower limit of the 95% CI for the difference in Overall score between the two treatment groups was greater than the predefined non-inferiority margin (i.e., -0.10 or -5%); therefore SPC was declared non-inferior to OCA. In addition, since the 95% CI for the difference did not include zero, SPC was declared superior to OCA in the reduction of gingivitis per MGI at Day 42 (p-value < 0.0001). Similarly, for MGI at Day 14 and for GBI and MPI at Day 14 and Day 42, significantly larger reductions were observed for SPC compared to OCA (p-value < 0.0001). Philips Sonicare DiamondClean with Premium plaque control brush head (SPC) was statistically superior to the Oral-B 7000 with CrossAction brush head (OCA) in reducing gingival inflammation, gingival bleeding, and supragingival plaque following 14 and 42 days of home use. Both products were safe for use.

Water and oil wettability of anodized 6016 aluminum alloy surface

NASA Astrophysics Data System (ADS)

Rodrigues, S. P.; Alves, C. F. Almeida; Cavaleiro, A.; Carvalho, S.

2017-11-01

This paper reports on the control of wettability behaviour of a 6000 series aluminum (Al) alloy surface (Al6016-T4), which is widely used in the automotive and aerospace industries. In order to induce the surface micro-nanostructuring of the surface, a combination of prior mechanical polishing steps followed by anodization process with different conditions was used. The surface polishing with sandpaper grit size 1000 promoted aligned grooves on the surface leading to static water contact angle (WCA) of 91° and oil (α-bromonaphthalene) contact angle (OCA) of 32°, indicating a slightly hydrophobic and oleophilic character. H2SO4 and H3PO4 acid electrolytes were used to grow aluminum oxide layers (Al2O3) by anodization, working at 15 V/18° C and 100 V/0 °C, respectively, in one or two-steps configuration. Overall, the anodization results showed that the structured Al surfaces were hydrophilic and oleophilic-like with both WCA and OCA below 90°. The one-step configuration led to a dimple-shaped Al alloy surface with small diameter of around 31 nm, in case of H2SO4, and with larger diameters of around 223 nm in case of H3PO4. The larger dimples achieved with H3PO4 electrolyte allowed to reach a slight hydrophobic surface. The thicker porous Al oxide layers, produced by anodization in two-step configuration, revealed that the liquids can penetrate easily inside the non-ordered porous structures and, thus, the surface wettability tended to superhydrophilic and superoleophilic character (CA < 10°). These results indicate that the capillary-pressure balance model, described for wettability mechanisms of porous structures, was broken. Moreover, thicker oxide layers with narrow pores of about 29 nm diameter allowed to achieve WCA < OCA. This inversion in favour of the hydrophilic-oleophobic surface behaviour is of great interest either for lubrication of mechanical components or in water-oil separation process.

pH-Manipulated Underwater-Oil Adhesion Wettability Behavior on the Micro/Nanoscale Semicircular Structure and Related Thermodynamic Analysis.

PubMed

Tie, Lu; Guo, Zhiguang; Liu, Weimin

2015-05-20

Controlling oil of wettability behavior in response to the underwater out stimulation has shown promising applications in understanding and designing novel micro- or nanofluidic devices. In this article, the pH-manipulated underwater-oil adhesion wetting phenomenon and superoleophobicity on the micro- and nanotexture copper mesh films (CMF) were investigated. It should be noted that the surface exhibits underwater superoleophobicity under different pH values of the solution; however, the underwater-oil adhesion behavior on the surface is dramatically influenced by the pH value of the solution. On the basis of the thermodynamic analysis, a plausible mechanism to explain the pH-controllable underwater-oil adhesion and superoleophobic wetting behavior observed on a micro- and nanoscale semicircular structure has been revealed. Furthermore, variation of chemistry (intrinsic oil contact angle (OCA)) of the responsive surface that due to the carboxylic acid groups is protonated or deprotonated by the acidic or basic solution on free energy (FE) with its barrier (FEB) and equilibrium oil contact angle (EOCA) with it hysteresis (OCAH) are discussed. The result shows that a critical intrinsic OCA on the micro- and nano- semicircular texture is necessary for conversion from the oil Cassie impregnating to oil Cassie wetting state. In a water/oil/solid system, the mechanism reveals that the differences between the underwater OCA and oil adhesive force of the responsive copper mesh film under different pH values of solution are ascribed to the different oil wetting state that results from combining the changing intrinsic OCA and micro-/nanosemicircular structures. These results are well in agreement with the experiment.

VizieR Online Data Catalog: Cerro Armazones spectroscopy of F dwarfs (Pribulla+, 2014)

NASA Astrophysics Data System (ADS)

Pribulla, T.; Sebastian, D.; Ammler-von Eiff, M.; Stahl, O.; Berndt, A.; Chini, R.; Hoffmeister, V.; Mugrauer, M.; Neuhauser, R.; Vanko, M.

2015-04-01

Optical spectroscopy at the OCA was secured using the BESO spectrograph fibre-fed from the focus of the 1.5m Hexapod telescope (see Fuhrmann et al. 2011). 409 spectra of 187 dwarfs were obtained between 2009 April 10 and 2010 March 29. Exposure times ranged between 300 and 1800s. (2 data files).

Computational analysis of histidine mutations on the structural stability of human tyrosinases leading to albinism insurgence.

PubMed

Hassan, Mubashir; Abbas, Qamar; Raza, Hussain; Moustafa, Ahmed A; Seo, Sung-Yum

2017-07-25

Misfolding and structural alteration in proteins lead to serious malfunctions and cause various diseases in humans. Mutations at the active binding site in tyrosinase impair structural stability and cause lethal albinism by abolishing copper binding. To evaluate the histidine mutational effect, all mutated structures were built using homology modelling. The protein sequence was retrieved from the UniProt database, and 3D models of original and mutated human tyrosinase sequences were predicted by changing the residual positions within the target sequence separately. Structural and mutational analyses were performed to interpret the significance of mutated residues (N 180 , R 202 , Q 202 , R 211 , Y 363 , R 367 , Y 367 and D 390 ) at the active binding site of tyrosinases. CSpritz analysis depicted that 23.25% residues actively participate in the instability of tyrosinase. The accuracy of predicted models was confirmed through online servers ProSA-web, ERRAT score and VERIFY 3D values. The theoretical pI and GRAVY generated results also showed the accuracy of the predicted models. The CCA negative correlation results depicted that the replacement of mutated residues at His within the active binding site disturbs the structural stability of tyrosinases. The predicted CCA scores of Tyr 367 (-0.079) and Q/R 202 (0.032) revealed that both mutations have more potential to disturb the structural stability. MD simulation analyses of all predicted models justified that Gln 202 , Arg 202 , Tyr 367 and D 390 replacement made the protein structures more susceptible to destabilization. Mutational results showed that the replacement of His with Q/R 202 and Y/R 363 has a lethal effect and may cause melanin associated diseases such as OCA1. Taken together, our computational analysis depicts that the mutated residues such as Q/R 202 and Y/R 363 actively participate in instability and misfolding of tyrosinases, which may govern OCA1 through disturbing the melanin biosynthetic pathway.

Identification and Mapping of Mechanically Exfoliated 1H-MoS2 Flakes for Field-Effect Transistors

DTIC Science & Technology

2014-08-01

structures directly onto 1H- and 2H-MoS2. A methyl methacrylate (MMA) and polymethyl methacrylate ( PMMA ) bilayer resist process will be used for all...the fiscal year. 9 5. References 1. Novoselov KS, Geim AK, Morozov SV, Jiang D, Zhang Y, Dubonos SV, Grigorieva IV, Firsov AA . Electric...photoluminescence PMMA polymethyl methacrylate TMDs transition metal dichalcogenides 12 1 DEFENSE TECH INFO CTR (PDF) ATTN DTIC OCA (PDF) 2

The effects of epidermal debridement of partial-thickness burns on infection and reepithelialization in swine.

PubMed

Singer, A J; Thode, H C; McClain, S A

2000-02-01

Early postburn debridement of burn blisters is controversial. This study was conducted to compare rates of infection and reepithelialization in debrided vs nondebrided second-degree burns in swine. This was a prospective, blinded, controlled, experimental trial using isoflurane-anesthetized swine. Standardized partial-thickness burns were inflicted by applying an aluminum bar preheated to 80 degrees C to the backs and flanks of two young pigs for 20 seconds. In half of the burns the necrotic epidermis was manually debrided. All burns were randomly treated with octylcyanoacrylate spray (OCA) or dry gauze (C). Full-thickness biopsies were taken at 7, 10, and 14 days for blinded histopathologic evaluation. The primary outcomes were the proportions of infected burns at days 7 and 10 and the proportion of completely reepithelialized burns at day 14. Burns were considered infected in the presence of intradermal neutrophils containing bacteria (intraobserver agreement, K = 1.00). A secondary outcome was the proportion of burns with the presence of scar tissue (abnormal collagen under polarized light; intraobserver correlation, K = 0.93). Chi-square tests were used for group comparisons. This study had 90% power to detect a 40-percentage-point difference in infection rates (alpha = 0.05). A total of 126 biopsies from 42 burns were available for review. Infection rates were higher in the debrided burns both at day 7 (55% vs 4.5%, p < 0.001) and at day 10 (65% vs 9%, p < 0.001) after injury. The proportion of nondebrided burns that were completely reepithelialized was higher at days 10 (68% vs 0%, p < 0.001) and 14 (100% vs 65%, p = 0.003). The presence of scar tissue was more common in debrided burns (75% vs 4.5%, p < 0.001). Burns treated with OCA had fewer infections than controls (4% vs 55%, p < 0.001). Fewer OCA-treated debrided burns were reepithelialized at 14 days than those that were not debrided (30% vs 100%, p = 0.001). Under the current study conditions, early postburn epidermal debridement of second-degree burns resulted in more infections and slower reepithelialization rates in swine. The effects of early postburn epidermal debridement in humans should be explored.

Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults.

PubMed

Lee, Jennifer; Zhang, Wenhui; Moy, Selina; Kowalski, Donna; Kerbusch, Virginie; van Gelderen, Marcel; Sawamoto, Taiji; Grunenberg, Nicole; Keirns, James

2013-03-01

Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. In this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0-∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. Thirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0-∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%-125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%-68.6%]) and AUC0-∞, by 17% (GMR, 83.2% [90% CI, 74.2%-93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0-∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%-78.7%]) and 18% (82.4% [72.6%-93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%-31.3%]) and AUC0-∞ by 51% (48.7% [43.3%-54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%-46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%-60.5%]) for AUC0-∞. The fed/fasted ratios for mirabegron Cmax and AUC0-∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5-2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. Mirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757. Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

T2L2 on JASON-2: First Evaluation of the Flying Model

DTIC Science & Technology

2007-01-01

Para, J.-M. Torre R&D Metrology CNRS/GEMINI Observatoire de la Côte d’Azur Caussol, France E-mail: philippe.guillemot@cnes.fr Abstract...Laser Link” experiment T2L2 [1], under development at OCA (Observatoire de la Côte d’Azur) and CNES (Centre National d’Etudes Spatiales), France, will be...Experimental Astronomy, 7, 191-207. [2] P. Fridelance and C. Veillet, 1995, “Operation and data analysis in the LASSO experiment,” Metrologia

Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians

PubMed Central

Nan, Hongmei; Kraft, Peter; Hunter, David J.; Han, Jiali

2009-01-01

Human pigmentation is a polygenic quantitative trait with high heritability. Although a large number of single nucleotide polymorphisms (SNPs) have been identified in pigmentation genes, very few SNPs have been examined in relation to human pigmentary phenotypes and skin cancer risk. We evaluated the associations between fifteen SNPs in eight candidate pigmentation genes (TYR, TYRP1, OCA2, SLC24A5, SLC45A2, POMC, ASIP, and ATRN) and both pigmentary phenotypes (hair color, skin color, and tanning ability) and skin cancer risk in a nested case-control study of Caucasians within the Nurses’ Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 common controls. We found that the TYR Arg402Gln variant was significantly associated with skin color (p-value =7.7×10−4) and tanning ability (p-value =7.3×10−4); the SLC45A2 Phe374Leu variant was significantly associated with hair color (black to blonde) (p-value =2.4×10−7), skin color (p-value =1.1×10−7), and tanning ability (p-value =2.5×10−4). These associations remained significant after controlling for MC1R variants. No significant associations were found between these polymorphisms and the risk of skin cancer. We observed that the TYRP1 rs1408799 and SLC45A2 -1721 C>G were associated with melanoma risk (OR, 0.77; 95% CI, 0.60–0.98 and OR, 0.75; 95% CI, 0.60–0.95, respectively). The TYR Ser192Tyr was associated with SCC risk (OR, 1.23; 95% CI, 1.00–1.50). The TYR haplotype carrying only the Arg402Gln variant allele was significantly associated with SCC risk (OR, 1.35; 95% CI, 1.04–1.74). The OCA2 Arg419Gln and ASIP g.8818 A>G were associated with BCC risk (OR, 1.50; 95% CI, 1.06–2.13 and OR, 0.73; 95% CI, 0.53–1.00, respectively). The haplotype near ASIP (rs4911414[T] and rs1015362[G]) was significantly associated with fair skin color (OR, 2.28; 95% CI, 1.46–3.57) as well as the risks of melanoma (OR, 1.68; 95% CI, 1.18–2.39) and SCC (OR, 1.54; 95% CI, 1.08–2.19). These associations remained similar after adjusting for pigmentary phenotypes and MC1R variants. The statistical power of this study was modest and additional studies are warranted to confirm the associations observed in the present study. This study provides evidence for the contribution of pigmentation genetic variants, in addition to the MC1R variants, to variation in human pigmentary phenotypes and possibly the development of skin cancer. PMID:19384953

Optical coherence microscopy of mouse cortical vasculature surrounding implanted electrodes

NASA Astrophysics Data System (ADS)

Hammer, Daniel X.; Lozzi, Andrea; Abliz, Erkinay; Greenbaum, Noah; Turner, Kevin P.; Pfefer, T. Joshua; Agrawal, Anant; Krauthamer, Victor; Welle, Cristin G.

2014-03-01

Optical coherence microscopy (OCM) provides real-time, in-vivo, three-dimensional, isotropic micron-resolution structural and functional characterization of tissue, cells, and other biological targets. Optical coherence angiography (OCA) also provides visualization and quantification of vascular flow via speckle-based or phase-resolved techniques. Performance assessment of neuroprosthetic systems, which allow direct thought control of limb prostheses, may be aided by OCA. In particular, there is a need to examine the underlying mechanisms of chronic functional degradation of implanted electrodes. Angiogenesis, capillary network remodeling, and changes in flow velocity are potential indicators of tissue changes that may be associated with waning electrode performance. The overall goal of this investigation is to quantify longitudinal changes in vascular morphology and capillary flow around neural electrodes chronically implanted in mice. We built a 1315-nm OCM system to image vessels in neocortical tissue in a cohort of mice. An optical window was implanted on the skull over the primary motor cortex above a penetrating shank-style microelectrode array. The mice were imaged bi-weekly to generate vascular maps of the region surrounding the implanted microelectrode array. Acute effects of window and electrode implantation included vessel dilation and profusion of vessels in the superficial layer of the cortex (0-200 μm). In deeper layers surrounding the electrode, no qualitative differences were seen in this early phase. These measurements establish a baseline vascular tissue response from the cortical window preparation and lay the ground work for future longitudinal studies to test the hypothesis that vascular changes will be associated with chronic electrode degradation.

The Convergent Evolution of Blue Iris Pigmentation in Primates Took Distinct Molecular Paths

PubMed Central

Meyer, Wynn K; Zhang, Sidi; Hayakawa, Sachiko; Imai, Hiroo; Przeworski, Molly

2013-01-01

How many distinct molecular paths lead to the same phenotype? One approach to this question has been to examine the genetic basis of convergent traits, which likely evolved repeatedly under a shared selective pressure. We investigated the convergent phenotype of blue iris pigmentation, which has arisen independently in four primate lineages: humans, blue-eyed black lemurs, Japanese macaques, and spider monkeys. Characterizing the phenotype across these species, we found that the variation within the blue-eyed subsets of each species occupies strongly overlapping regions of CIE L*a*b* color space. Yet whereas Japanese macaques and humans display continuous variation, the phenotypes of blue-eyed black lemurs and their sister species (whose irises are brown) occupy more clustered subspaces. Variation in an enhancer of OCA2 is primarily responsible for the phenotypic difference between humans with blue and brown irises. In the orthologous region, we found no variant that distinguishes the two lemur species or associates with quantitative phenotypic variation in Japanese macaques. Given the high similarity between the blue iris phenotypes in these species and that in humans, this finding implies that evolution has used different molecular paths to reach the same end. Am J Phys Anthropol 151:398–407, 2013.© 2013 Wiley Periodicals, Inc. PMID:23640739

Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits

PubMed Central

Eriksson, Nicholas; Macpherson, J. Michael; Tung, Joyce Y.; Hon, Lawrence S.; Naughton, Brian; Saxonov, Serge; Avey, Linda; Wojcicki, Anne; Pe'er, Itsik; Mountain, Joanna

2010-01-01

Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here we report initial results from a participant-driven study of 22 traits. Replications of associations (in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, TYR, TYRP1, ASIP, and MC1R) for hair color, eye color, and freckling validate the Web-based, self-reporting paradigm. The identification of novel associations for hair morphology (rs17646946, near TCHH; rs7349332, near WNT10A; and rs1556547, near OFCC1), freckling (rs2153271, in BNC2), the ability to smell the methanethiol produced after eating asparagus (rs4481887, near OR2M7), and photic sneeze reflex (rs10427255, near ZEB2, and rs11856995, near NR2F2) illustrates the power of the approach. PMID:20585627

Determination of Benzo[α]pyrene in Edible Oil Using Tetraoxocalix[2]arene[2]triazine Bonded Silica SPE Sorbent.

PubMed

Guo, Yun; Zhao, Wen-Jie; Deng, Zhi-Fen; Hongbo, Wang; Peng, Bin; Ma, Xue; Lan, Chen; Zhang, Shu-Sheng

2018-06-01

Benzo[α]pyrene (BaP) is a well-known carcinogen in edible oil. In this study, a method combined solid-phase extraction (SPE) with fluorescent detection was developed using tetraoxocalix[2]arene[2]triazine sorbent (SiO 2 -OCA) for the clean-up and enrichment of BaP. The interaction between SiO 2 -OCA and BaP involves a donor-acceptor complex mechanism. The experimental procedure was as follows: BaP was extracted from edible oil with DMF/H 2 O (9:1, v/v). Then, the ratio of DMF/H 2 O was adjusted to 1:2 prior to SPE. The final concentrate was analyzed using a fluorescence detector at excitation and emission wavelengths of 255 and 420 nm. The method was fully validated. The linearity was in the range of 0.1-100 μg kg -1 with a coefficient of 0.999. The limits of detection and quantification were 0.03 and 0.1 μg kg -1 , respectively. The average recoveries were in the range of 88.0-122.3%. The intraday and interday precisions were 6.8% and 9.2%, respectively. Compared with other methods, the method reported in this article shows a good detection limit, high reproducibility and recovery, and linearity over a broad concentration range. This established method was also applied to evaluate real samples. The concentration of six tested samples was below 5 μg kg -1 .

Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family.

PubMed

Yahalom, Claudia; Sharon, Dror; Dalia, Eli; Simhon, Shiran Ben; Shemesh, Efrat; Blumenfeld, Anat

2015-06-01

To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling.

Switchable skin window induced by optical clearing method for dermal blood flow imaging

NASA Astrophysics Data System (ADS)

Wang, Jing; Shi, Rui; Zhu, Dan

2013-06-01

Optical imaging techniques have shown tremendous potential for assessing cutaneous microcirculation, but the imaging depth and contrast is limited by the strong scattering of skin. Current skin windows have to be fulfilled by surgical operation and suffer from some side effects. In this study, a switchable skin window was developed by topical application of an optical clearing agent (OCA) and saline on rat skin in vivo. The validity of the skin window was evaluated by the laser speckle contrast imaging technique, and the safety of OCA to the body was tested through histologic examinations. The results indicated that administration of OCA or saline on rat skin in vivo can open or close the window of skin repeatedly for three days. With the repair effect of hyaluronic acid and Vaseline, it is able to repeatedly visualize the dermal blood vessels and flow distribution. Long-term observation shows that there is no abnormal reflection in micro-structure, body weight, organ coefficients, histopathologic lesions, or toxic reactions compared with a control group. This switchable window will provide an effective tool not only for cutaneous microcirculation with laser speckle contrast imaging, but also for diagnosis and treatment of peripheral vascular diseases, including tumor research with various optical imaging techniques.

Fabrication of a novel superhydrophobic and superoleophilic surface by one-step electrodeposition method for continuous oil/water separation

NASA Astrophysics Data System (ADS)

Xiang, Meisu; Jiang, Meihuizi; Zhang, Yanzong; Liu, Yan; Shen, Fei; Yang, Gang; He, Yan; Wang, Lilin; Zhang, Xiaohong; Deng, Shihuai

2018-03-01

A novel superhydrophobic and superoleophilic surface was fabricated by one-step electrodeposition on stainless steel meshes, and the durability and oil/water separation properties were assessed. Field emission scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), fourier transform infrared spectroscopy (FT-IR) and optical contact angle measurements were used to characterize surface morphologies, chemical compositions, and wettabilities, respectively. The results indicated that the as-prepared mesh preformed excellent superhydrophobicity and superoleophilicity with a high water contact angle (WCA) of 162 ± 1° and oil contact angle of (OCA) 0°. Meanwhile, the as-prepared mesh also exhibited continuous separation capacity of many kinds of oil/water mixtures, and the separation efficiency for lubrication oil/water mixture was about 98.6%. In addition, after 10 separation cycles, the as-prepared mesh possessed the WCAs of 155 ± 2°, the OCAs of 0° and the separation efficiency of 97.8% for lubrication oil/water mixtures. The as-prepared mesh also retained superhydrophobic and superoleophilic properties after abrading, immersing in salt solutions and different pH solutions.

Pleiotropic effects of coat colour-associated mutations in humans, mice and other mammals.

PubMed

Reissmann, Monika; Ludwig, Arne

2013-01-01

The characterisation of the pleiotropic effects of coat colour-associated mutations in mammals illustrates that sensory organs and nerves are particularly affected by disorders because of the shared origin of melanocytes and neurocytes in the neural crest; e.g. the eye-colour is a valuable indicator of disorders in pigment production and eye dysfunctions. Disorders related to coat colour-associated alleles also occur in the skin (melanoma), reproductive tract and immune system. Additionally, the coat colour phenotype of an individual influences its general behaviour and fitness. Mutations in the same genes often produce similar coat colours and pleiotropic effects in different species (e.g., KIT [reproductive disorders, lethality], EDNRB [megacolon] and LYST [CHS]). Whereas similar disorders and similar-looking coat colour phenotypes sometimes have a different genetic background (e.g., deafness [EDN3/EDNRB, MITF, PAX and SNAI2] and visual diseases [OCA2, RAB38, SLC24A5, SLC45A2, TRPM1 and TYR]). The human predilection for fancy phenotypes that ignore disorders and genetic defects is a major driving force for the increase of pleiotropic effects in domestic species and laboratory subjects since domestication has commenced approximately 18,000 years ago. Copyright © 2013 Elsevier Ltd. All rights reserved.

Exploring methods for comparing the real-world effectiveness of treatments for osteoporosis: adjusted direct comparisons versus using patients as their own control.

PubMed

Karlsson, Linda; Mesterton, Johan; Tepie, Maurille Feudjo; Intorcia, Michele; Overbeek, Jetty; Ström, Oskar

2017-09-21

Using Swedish and Dutch registry data for women initiating bisphosphonates, we evaluated two methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for differences in patient baseline characteristics. Each method has advantages and disadvantages; both are potential complements to clinical trial analyses. We evaluated methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for both observed and unobserved confounding. Swedish and Dutch registry data for women initiating zoledronate or oral bisphosphonates (OBPs; alendronate/risedronate) were used; the primary outcome was fracture. In adjusted direct comparisons (ADCs), regression and matching techniques were used to account for baseline differences in known risk factors for fracture (e.g., age, previous fracture, comorbidities). In an own-control analysis (OCA), for each treatment, fracture incidence in the first 90 days following treatment initiation (the baseline risk period) was compared with fracture incidence in the 1-year period starting 91 days after treatment initiation (the treatment exposure period). In total, 1196 and 149 women initiating zoledronate and 14,764 and 25,058 initiating OBPs were eligible in the Swedish and Dutch registries, respectively. Owing to the small Dutch zoledronate sample, only the Swedish data were used to compare fracture incidences between treatment groups. ADCs showed a numerically higher fracture incidence in the zoledronate than in the OBPs group (hazard ratio 1.09-1.21; not statistically significant, p > 0.05). For both treatment groups, OCA showed a higher fracture incidence in the baseline risk period than in the treatment exposure period, indicating a treatment effect. OCA showed a similar or greater effect in the zoledronate group compared with the OBPs group. ADC and OCA each possesses advantages and disadvantages. Combining both methods may provide an estimate of real-world treatment efficacy that could potentially complement clinical trial findings.

Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry

PubMed Central

2013-01-01

Background Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima’s D, Fay and Wu’s H and Fu and Li’s D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution. Results Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies. Conclusions We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation. PMID:23848512

Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry.

PubMed

Hider, Jessica L; Gittelman, Rachel M; Shah, Tapan; Edwards, Melissa; Rosenbloom, Arnold; Akey, Joshua M; Parra, Esteban J

2013-07-12

Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution. Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies. We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation.

Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a caucasian family

PubMed Central

Tommasi, Stefania; Strippoli, Sabino; Pellegrini, Cristina; Concetta Fargnoli, Maria; Pilato, Brunella; Natalicchio, Iole; Guida, Gabriella; Pinto, Rosamaria

2017-01-01

Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology. To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes. In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree. From the analysis of the pedigree, we were able to identify a “protective” haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model. PMID:27776349

Oxygen Compatibility Assessment of Components and Systems

NASA Technical Reports Server (NTRS)

Stoltzfus, Joel; Sparks, Kyle

2010-01-01

Fire hazards are inherent in oxygen systems and a storied history of fires in rocket engine propulsion components exists. To detect and mitigate these fire hazards requires careful, detailed, and thorough analyses applied during the design process. The oxygen compatibility assessment (OCA) process designed by NASA Johnson Space Center (JSC) White Sands Test Facility (WSTF) can be used to determine the presence of fire hazards in oxygen systems and the likelihood of a fire. This process may be used as both a design guide and during the approval process to ensure proper design features and material selection. The procedure for performing an OCA is a structured step-by-step process to determine the most severe operating conditions; assess the flammability of the system materials at the use conditions; evaluate the presence and efficacy of ignition mechanisms; assess the potential for a fire to breach the system; and determine the reaction effect (the potential loss of life, mission, and system functionality as the result of a fire). This process should be performed for each component in a system. The results of each component assessment, and the overall system assessment, should be recorded in a report that can be used in the short term to communicate hazards and their mitigation and to aid in system/component development and, in the long term, to solve anomalies that occur during engine testing and operation.

Albinism and lung fibrosis in a young man - the first case of adult Hermansky-Pudlak Syndrome reported in Malaysia.

PubMed

Liza, A F; Aziah, A M

2012-12-01

A young gentleman of Indian descent with oculacutaneous albinism (OCA) was found to have severe pulmonary fibrosis at first presentation. Following investigations, he was diagnosed with Hermansky-Pudlak Syndrome (HPS). It is a genetic condition characterised by albinism, bleeding diathesis and multisystem disorder observed in individuals of particular descents. Although there is no curative treatment apart from lung transplantation, preventive measures to minimise pulmonary insult may change the natural history of the disease. Therefore HPS should be actively sought, monitored and risk factors addressed in individuals with OCA and bleeding diathesis particularly those of Indian descent as they may develop serious complications such as pulmonary fibrosis in the future.

Elucidating the Role of cAb1 and the Abi-Family of cAB1 Target Proteins in Cancer Development and Progression

DTIC Science & Technology

2000-07-01

1996;87:2252. members. J Biol Chem. 1996;271:31,704. SH2 regulatory domain in a non-phosphotyro- 36. DiNoto R, LoRardo C, Schiavone EM, et al. Stem 11...Information Center (DTIC-OCA), 8725 John J. Kingman Road, Fort Belvoir, VA 22060-6218 SUBJECT: Request Change in Distribution Statement 1. The U.S. Army

Checkpoint Pathways Activated by Re-Replication in Breast Cancer Cells

DTIC Science & Technology

2011-05-01

107- 13. 9. Zhu W DA. An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G2/M Checkpoint and DNA Damage Repair upon...re-replication. J Biol Chem 2007;282:30357-62. 25. Montes de Oca R, Andreassen PR, Margossian SP, et al. Regulated interaction of the Fanconi anemia ...protein, FANCD2, with chromatin. Blood 2005;105:1003-9. 26. Zhu W DA. An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating

Microencapsulation of 2-octylcyanoacrylate tissue adhesive for self-healing acrylic bone cement.

PubMed

Brochu, Alice B W; Chyan, William J; Reichert, William M

2012-10-01

Here, we report the first phase of developing self-healing acrylic bone cement: the preparation and characterization of polyurethane (PUR) microcapsules containing a medical cyanoacrylate tissue adhesive. Capsules were prepared by interfacial polymerization of a toluene-2,4-diisocyanate-based polyurethane prepolymer with 1,4-butanediol to encapsulate 2-octylcyanoacrylate (OCA). Various capsule characteristics, including: resultant morphology, average size and size distribution, shell thickness, content and reactivity of encapsulated agent, and shelf life are investigated and their reliance on solvent type and amount, surfactant type and amount, temperature, pH, agitation rate, reaction time, and mode of addition of the oil phase to the aqueous phase are presented. Capsules had average diameters ranging from 74 to 222 μm and average shell thicknesses ranging from 1.5 to 6 μm. The capsule content was determined via thermogravimetric analysis and subsequent analysis of the capsules following up to 8 weeks storage revealed minimal loss of core contents. Mechanical testing of OCA-containing capsules showed individual capsules withstood compressive forces up to a few tenths of Newtons, and the contents released from crushed capsules generated tensile adhesive forces of a few Newtons. Capsules were successfully mixed into the poly(methyl methacrylate) bone cement, surviving the mixing process, exposure to methyl methacrylate monomer, and the resulting exothermic matrix curing. Copyright © 2012 Wiley Periodicals, Inc.

Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor–Negative Breast Cancer Survival

PubMed Central

Tyrer, Jonathan; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Schulz-Wendtland, Rüdiger; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Milne, Roger L.; Arias, José Ignacio; Menéndez, Primitiva; Benítez, Javier; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia; Couch, Fergus J.; Olson, Janet E.; Fredericksen, Zachary S.; Wang, Xianshu; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Southey, Melissa C.; Devilee, Peter; Tollenaar, Rob A. E. M.; Seynaeve, Caroline; García-Closas, Montserrat; Lissowska, Jolanta; Sherman, Mark E.; Bolton, Kelly L.; Hall, Per; Czene, Kamila; Cox, Angela; Brock, Ian W.; Elliott, Graeme C.; Reed, Malcolm W. R.; Greenberg, David; Anton-Culver, Hoda; Ziogas, Argyrios; Humphreys, Manjeet; Easton, Douglas F.; Caporaso, Neil E.; Pharoah, Paul D. P.

2010-01-01

Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. Methods We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case–control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. Results In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor–negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10−5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10−4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor–negative breast cancer. PMID:20308648

Liquid chromatography-mass spectrometry identification of anthocyanins of isla oca (Oxalis tuberosa, Mol.) tubers.

PubMed

Alcalde-Eon, Cristina; Saavedra, Gloria; de Pascual-Teresa, Sonia; Rivas-Gonzalo, Julián C

2004-10-29

High-performance liquid chromatography (HPLC)-diode array detection (DAD)-mass spectrometry (MS) techniques have been successfully employed in the identification of the anthocyanins of the coloured tubers of isla oca (Oxalis tuberosa), the second most cultivated tuber in the Andean region. Tubers underwent a pre-treatment step in order to inhibit enzymatic reactions and to obtain a stable powder or "concentrate". This concentrate was dissolved, purified and then analysed. Eight different compounds were found. The major peaks were malvidin glucosides (malvidin 3-O-glucoside and 3,5-O-diglucoside). The rest of the peaks were 3,5-O-diglucosides of petunidin and peonidin, and 3-O-glucosides of delphinidin, petunidin and peonidin. Only malvidin 3-O-acetylglucoside-5-O-glucoside was found as an acylated anthocyanin.

Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2

PubMed Central

Hodson, Daniel J.; Shaffer, Arthur L.; Xiao, Wenming; Wright, George W.; Schmitz, Roland; Phelan, James D.; Yang, Yandan; Webster, Daniel E.; Rui, Lixin; Kohlhammer, Holger; Nakagawa, Masao; Waldmann, Thomas A.; Staudt, Louis M.

2016-01-01

The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2–OCA-B interface, we reveal a requirement for this protein–protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell–restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity. PMID:26993806

Disposal and Reuse of Bergstrom Air Force Base, Texas. Final Environmental Impact Statement.

DTIC Science & Technology

1993-07-01

Scavenger species detected in the landfill area include the opossum (Didelphis marsupialis) and northern raccoon (Procyon lotor). House mice ( Mus musculus ...a, ~ a, CC CU 00 .C UC CC CU m oca Em - ~< 0 EE mU CCJ -a)UCE c:E .0 , 2 48~ C In CC 0 0~ 0 m CU .2~ z. CaU. (C 0U CU CU E C) C- 7E m CU o C E C z E...Disturbed By Phase - Proposed Action ............................ 2-11 2.2-4 Projected Flight Operations - Proposed Action

Adaptation of Dunn Solar Telescope for Jovian Doppler spectro imaging

NASA Astrophysics Data System (ADS)

Underwood, Thomas A.; Voelz, David; Schmider, François-Xavier; Jackiewicz, Jason; Dejonghe, Julien; Bresson, Yves; Hull, Robert; Goncalves, Ivan; Gualme, Patrick; Morand, Frédéric; Preis, Olivier

2017-09-01

This paper describes instrumentation used to adapt the Dunn Solar Telescope (DST) located on Sacramento Peak in Sunspot, NM for observations using the Doppler Spectro Imager (DSI). The DSI is based on a Mach-Zehnder interferometer and measures the Doppler shift of solar lines allowing for the study of atmospheric dynamics of giant planets and the detection of their acoustic oscillations. The instrumentation is being designed and built through a collaborative effort between a French team from the Observatoire de la Cote d'Azur (OCA) that designed the DSI and a US team at New Mexico State University (NMSU). There are four major components that couple the DSI to the DST: a guider/tracker, fast steering mirror (FSM), pupil stabilizer and transfer optics. The guider/tracker processes digital video to centroid-track the planet and outputs voltages to the DST's heliostat controls. The FSM removes wavefront tip/tilt components primarily due to turbulence and the pupil stabilizer removes any slow pupil "wander" introduced by the telescope's heliostat/turret arrangement. The light received at a science port of the DST is sent through the correction and stabilization components and into the DSI. The FSM and transfer optics designs are being provided by the OCA team and serve much the same functions as they do for other telescopes at which DSI observations have been conducted. The pupil stabilization and guider are new and are required to address characteristics of the DST.

Installation Restoration Program. Phase 2 - Confirmation/ Quantification. Stage 2 for McChord Air Force Base, Washington

DTIC Science & Technology

1986-04-30

Si 35 Areas E and J Waste Disposal Sites and IRP Phase II Monitoring Well Locations ^ 36 Areas F and H Waste Disposal Sites and IRP Phase II...4 oMe c hy 1 - 2 - Pen eeaocie lephchelene 1.2- Trene Dlchloroechyle 1,1,1-Trlchloroechene Toluene Tinyl Acftcete H.P-Xylene 0-Xylene ACIDS AW) OTMEKS...4) a. > n k. Q 41 ^ 0 oca Li »I 4) M 41 X C (B w < G a. v 1 m M ! Si 118 swe Table 16 TOTAL AND SOLUBLE HEAVY

Genetic diversity of the Andean tuber-bearing species, oca (Oxalis tuberosa Mol.), investigated by inter-simple sequence repeats.

PubMed

Pissard, A; Ghislain, M; Bertin, P

2006-01-01

The Andean tuber-bearing species, Oxalis tuberosa Mol., is a vegetatively propagated crop cultivated in the uplands of the Andes. Its genetic diversity was investigated in the present study using the inter-simple sequence repeat (ISSR) technique. Thirty-two accessions originating from South America (Argentina, Bolivia, Chile, and Peru) and maintained in vitro were chosen to represent the ecogeographic diversity of its cultivation area. Twenty-two primers were tested and 9 were selected according to fingerprinting quality and reproducibility. Genetic diversity analysis was performed with 90 markers. Jaccard's genetic distance between accessions ranged from 0 to 0.49 with an average of 0.28 +/- 0.08 (mean +/- SD). Dendrogram (UPGMA (unweighted pair-group method with arithmetic averaging)) and factorial correspondence analysis (FCA) showed that the genetic structure was influenced by the collection site. The two most distant clusters contained all of the Peruvian accessions, one from Bolivia, none from Argentina or Chile. Analysis by country revealed that Peru presented the greatest genetic distances from the other countries and possessed the highest intra-country genetic distance (0.30 +/- 0.08). This suggests that the Peruvian oca accessions form a distinct genetic group. The relatively low level of genetic diversity in the oca species may be related to its predominating reproduction strategy, i.e., vegetative propagation. The extent and structure of the genetic diversity of the species detailed here should help the establishment of conservation strategies.

UCM Meteor and Fireball Research group: Results 2012--2014

NASA Astrophysics Data System (ADS)

Ocaña, F.; Sánchez de Miguel, A.; Zamorano, J.; Izquierdo, J.; Pascual, S.; Palos, M. F.; Oré, S.; Rodríguez-Coira, G.; Zamora, S.; Lorenzo, C.; San Juan, R.; Muñoz-Ibáñez, B.; Vázquez, C.; Alonso-Moragón, A.; Gallego, J.; Trigo-Rodríguez, J. M.; Madiedo, J. M.

2015-05-01

Most of the activity of the group is based on the Fireball Detection Station located at the Observatorio UCM, a system consisting of 6 high-sensitivity videocameras covering the whole sky with wide-angle lenses during nighttime. Another 15 cameras have been placed by the researchers between 10 and 200 km away from Madrid for multiple station observations. It works as a node in the SPanish Meteor and Fireball Network (SPMN), a network of similar stations covering the atmosphere over Spain. Besides the continuous monitoring, the group has worked on the recording and analysis of some meteor showers. Most of the attention was focused on the Draconids 2011 campaign at Observatorio de Sierra Nevada (Trigo-Rodríguez, J. M., Madiedo, J. M., Williams, I. P., et al. 2013, MNRAS, 433, 560; Ocaña, F., Palos, M. F., Zamorano, J., et al. 2013, Proceedings of the International Meteor Conference, 31st IMC, La Palma, Canary Islands, Spain, 2012, 70), and the 2012 Geminids balloon-borne mission over Spain (Sánchez de Miguel, A., Ocaña, F., Madiedo, J. M., et al. 2013, Lunar and Planetary Science Conference, 44, 2202). The products of the station have been used for undergraduate thesis projects at the Physics Faculty (Ocaña, F., 2011, UCM e-prints, 13292) and other undergraduate projects. In 2013 the station received new equipment thanks to the Certamen Arquímedes award, complementing the detection with spectroscopic and frame-integrating devices.

The Role of Second Phase Intermetallic Particles on the Spall Failure of 5083 Aluminum

DTIC Science & Technology

2016-12-01

of mechanically processed 5083 aluminum (i.e., cold and hot rolled, extruded , etc.) has been previously studied by several researchers [1–4]. Results...Velocity Interferometry System for Any Reflector (VISAR) [6]. In addition, four end-state (ex situ spall recovery) experiments were conducted to augment all... extruded AMX602 Mg alloy (unpublished) J. dynamic behavior mater. (2016) 2:476–483 483 123 9 1 DEFENSE TECHNICAL (PDF) INFORMATION CTR DTIC OCA

Qualitative breakdown of the noncrossing approximation for the symmetric one-channel Anderson impurity model at all temperatures

NASA Astrophysics Data System (ADS)

Sposetti, C. N.; Manuel, L. O.; Roura-Bas, P.

2016-08-01

The Anderson impurity model is studied by means of the self-consistent hybridization expansions in its noncrossing (NCA) and one-crossing (OCA) approximations. We have found that for the one-channel spin-1 /2 particle-hole symmetric Anderson model, the NCA results are qualitatively wrong for any temperature, even when the approximation gives the exact threshold exponents of the ionic states. Actually, the NCA solution describes an overscreened Kondo effect, because it is the same as for the two-channel infinite-U single-level Anderson model. We explicitly show that the NCA is unable to distinguish between these two very different physical systems, independently of temperature. Using the impurity entropy as an example, we show that the low-temperature values of the NCA entropy for the symmetric case yield the limit Simp(T =0 ) →ln√{2 }, which corresponds to the zero temperature entropy of the overscreened Kondo model. Similar pathologies are predicted for any other thermodynamic property. On the other hand, we have found that the OCA approach lifts the artificial mapping between the models and restores correct properties of the ground state, for instance, a vanishing entropy at low enough temperatures Simp(T =0 ) →0 . Our results indicate that the very well known NCA should be used with caution close to the symmetric point of the Anderson model.

RMP Guidance for Warehouses - Chapter 4: Offsite Consequence Analysis

EPA Pesticide Factsheets

Offsite consequence analysis (OCA) informs government and the public about potential consequences of an accidental toxic or flammable chemical release at your facility, and consists of a worst-case release scenario and alternative release scenarios.

RMP Guidance for Chemical Distributors - Chapter 4: Offsite Consequence Analysis

EPA Pesticide Factsheets

How to perform the OCA for regulated substances, informing the government and the public about potential consequences of an accidental chemical release at your facility. Includes calculations for worst-case scenario, alternative scenarios, and endpoints.

Double-lumen balloon for Onyx® embolization via extracranial arteries in transverse sigmoid dural arteriovenous fistulas: initial experience.

PubMed

Clarençon, Frédéric; Di Maria, Federico; Gabrieli, Joseph; Carpentier, Alexandre; Pistochi, Silvia; Bartolini, Bruno; Zeghal, Chiheb; Chiras, Jacques; Sourour, Nader-Antoine

2016-10-01

Transverse-sigmoid dural arteriovenous fistulas (TS DAVFs) can be challenging to treat by endovascular means. Indeed, a total cure of the fistula can only be achieved when complete occlusion of the fistulous point(s) is obtained by penetration of the embolic agent. However, in some cases, especially for transosseous branches from extracranial arteries like the occipital artery (OcA) or the superficial temporal artery (STA), such penetration is usually poor, leading to major proximal reflux and incomplete fistula obliteration. We present three cases of embolization in two patients with TS DAVF through the OcA and/or the STA with Onyx® using a double-lumen balloon (Microvention, Tustin, CA, USA). This technique allows the penetration of the embolic agent in the transosseous branches by forming a counter-pressure with the inflated balloon. This technique may be useful to achieve complete occlusion of TS DAVFs by endovascular means.

Comparison of two-way satellite time transfer and GPS common-view time transfer between OCA and TUG

NASA Technical Reports Server (NTRS)

Kirchner, Dieter; Thyr, U.; Ressler, H.; Robnik, R.; Grudler, P.; Baumont, Francoise S.; Veillet, Christian; Lewandowski, Wlodzimierz W.; Hanson, W.; Clements, A.

1992-01-01

For about one year the time scales UTC(OCA) and UTC(TUG) were compared by means of GPS and two-way satellite time transfer. At the end of the experiment both links were independently 'calibrated' by measuring the differential delays of the GPS receivers and of the satellite earth stations by transportation of a GPS receiver and of one of the satellite terminals. The results obtained by both methods differ by about 3 ns, but reveal a seasonal variation of about 8 ns peak-to-peak which is likely the result of a temperature-dependence of the delays of the GPS receivers used. For the comparison of both methods the stabilities of the timescales are of great importance. Unfortunately, during the last three months of the experiment a less stable clock had to be used for the generation of UTC(TUG).

Speckle Interferometry with the OCA Kuhn 22" Telescope

NASA Astrophysics Data System (ADS)

Wasson, Rick

2018-04-01

Speckle interferometry measurements of double stars were made in 2015 and 2016, using the Kuhn 22-inch classical Cassegrain telescope of the Orange County Astronomers, a Point Grey Blackfly CMOS camera, and three interference filters. 272 observations are reported for 177 systems, with separations ranging from 0.29" to 2.9". Data reduction was by means of the REDUC and Speckle Tool Box programs. Equipment, observing procedures, calibration, data reduction, and analysis are described, and unusual results for 11 stars are discussed in detail.

National Dam Inspection Program. Ilion Reservoir Number 2 Dam (NY 00185), Mohawk River Basin, Town of German Flatts, Herkimer County, New York. Phase I Inspection Report,

DTIC Science & Technology

1981-09-01

OCA/TACT p£ oPc £ /K) f/A^Aft-P A^gA G>r (pQifiJC, &ÖQ& To t>oo£. OTHER — ofGtXTtoto -*- KA-I^TYCJA^C^. PtoceooߣS €?. o...cast iron pipe contemplated for this wojk, including the furnishing of all special castings, de- livered at Ilion, N. Y., together with all material

The Effect of a Flare Pack on the High Speed Performance of the Jindivik Mk203B Target Aircraft,

DTIC Science & Technology

1980-09-01

8217.SA. 6ME5 bAP C I- 4A ft 06 V1WY .4 V000 1P V4 405,s *4,40 WM M ft Op a~ BmE anf e.- -’ X.WOM 13.1,0 %0000 vmv400 %500 1~wO . 0 00 4111,S a 4!o~ca cocoa...Defence Scientist 2 Superintendent, Science and Technology Programs 3 Australian Defence Scientific and Technical Representative (UK) Counsellor, Defence

The effect of gravity on liquid plug propagation in a two-dimensional channel

NASA Astrophysics Data System (ADS)

Suresh, V.; Grotberg, J. B.

2005-03-01

The effect of plug propagation speed and gravity on the quasisteady motion of a liquid plug in a two-dimensional liquid-lined channel oriented at an angle α with respect to gravity is studied. The problem is motivated by the transport of liquid plugs instilled into pulmonary airways in medical treatments such as surfactant replacement therapy, drug delivery, and liquid ventilation. The capillary number Ca is assumed to be small, while the Bond number Bo is arbitrary. Using matched asymptotic expansions and lubrication theory, expressions are obtained for the thickness of the trailing films left behind by the plug and the pressure drop across it as functions of Ca, Bo, α and the thickness of the precursor films. When the Bond number is small it is found that the trailing film thickness and the flow contribution to the pressure drop scale as Ca2/3 at leading order with coefficients that depend on Bo and α. The first correction to the film thickness is found to occur at O(Ca) compared to O(Ca4/3) in the Bo=0 case. Asymmetry in the liquid distribution is quantified by calculating the ratio of liquid volumes above and below the centerline of the channel, VR ˙. VR=1 at Bo=0, indicating a symmetric distribution, and decreases with Bo and Ca, but increases with the plug length Lp. The decrease of VR with Ca suggests that higher propagation speeds in small airways may result in less homogenous liquid distribution, which is in contrast to the expected effect in large airways. For given values of the other parameters, a maximum capillary number Cac is identified above which the plug will eventually rupture. When the Bond number becomes equal to an orientation-dependent critical value Boc, it is found that the scaling of the film thickness and pressure drop change to Ca1/2 and Ca1/6, respectively. It is shown that this scaling is valid for small increments of the Bond number over its critical value, Bo=Boc+BCa1/6, but for higher Bond numbers the asymptotic approach breaks down.

Sunlight exposure, pigmentation, and incident age-related macular degeneration.

PubMed

Klein, Barbara E K; Howard, Kerri P; Iyengar, Sudha K; Sivakumaran, Theru A; Meyers, Kristin J; Cruickshanks, Karen J; Klein, Ronald

2014-08-14

Examine potential effects of sunlight exposure, hair color, eye color, and selected gene single-nucleotide polymorphisms (SNPs) on incidence of AMD. Subjects participated in up to five examinations over a 20-year period. Eye color, self-reported hair color as a teenager, and sunlight exposure were ascertained at the baseline examination. Presence and severity of AMD and its lesions were determined via fundus photographs. Genetic data were available on a subset of participants. The SNPs CFH Y402H rs1061170 and ARMS2 A69S rs10490924 were used to analyze genetic risk of AMD; OCA2 rs4778241 and HERC2 rs12913832 represented genetic determinants of eye color. Incidence of early AMD was higher in blond/red-haired persons compared with brown/black-haired persons (hazard ratio [HR] 1.25, P = 0.02) and in persons with high sun exposure in their thirties (HR 1.41, P = 0.02). However, neither was significant after adjustment for multiple comparisons. Eye (HR 1.36, P = 0.006) and hair color (HR 1.42, P = 0.003) were associated with incidence of any retinal pigmentary abnormalities (RPAs). Both remained significant after adjustment for multiple comparisons. Neither presence of alleles for light-colored eyes nor those associated with high risk of late AMD altered the association of eye or hair color with early AMD. None of the characteristics studied were significantly associated with late AMD. Modest associations of eye color, hair color, and HERC2 genotype with any RPAs were found. Genes for AMD did not affect these associations. Eye color phenotype was more strongly associated with outcomes than HERC2 or OCA2 genotype. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

General RMP Guidance - Chapter 4: Offsite Consequence Analysis

EPA Pesticide Factsheets

This chapter provides basic compliance information, not modeling methodologies, for people who plan to do their own air dispersion modeling. OCA is a required part of the risk management program, and involves worst-case and alternative release scenarios.

40 CFR 1400.12 - Qualified researchers.

Code of Federal Regulations, 2012 CFR

2012-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.12 Qualified researchers. The Administrator is authorized to provide OCA information, including facility identification, to qualified researchers pursuant to a system developed and...

40 CFR 1400.12 - Qualified researchers.

Code of Federal Regulations, 2013 CFR

2013-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.12 Qualified researchers. The Administrator is authorized to provide OCA information, including facility identification, to qualified researchers pursuant to a system developed and...

40 CFR 1400.12 - Qualified researchers.

Code of Federal Regulations, 2011 CFR

2011-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.12 Qualified researchers. The Administrator is authorized to provide OCA information, including facility identification, to qualified researchers pursuant to a system developed and...

40 CFR 1400.12 - Qualified researchers.

Code of Federal Regulations, 2014 CFR

2014-07-01

...); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.12 Qualified researchers. The Administrator is authorized to provide OCA information, including facility identification, to qualified researchers pursuant to a system developed and...

Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity

PubMed Central

Bin, Bum-Ho; Bhin, Jinhyuk; Yang, Seung Ha; Shin, Misun; Nam, Yeon-Ju; Choi, Dong-Hwa; Shin, Dong Wook; Lee, Ai-Young; Hwang, Daehee; Cho, Eun-Gyung; Lee, Tae Ryong

2015-01-01

The SLC45A2 gene encodes a Membrane-Associated Transporter Protein (MATP). Mutations of this gene cause oculocutaneous albinism type 4 (OCA4). However, the molecular mechanism of its action in melanogenesis has not been elucidated. Here, we discuss the role of MATP in melanin production. The SLC45A2 gene is highly enriched in human melanocytes and melanoma cell lines, and its protein, MATP, is located in melanosomes. The knockdown of MATP using siRNAs reduced melanin content and tyrosinase activity without any morphological change in melanosomes or the expression of melanogenesis-related proteins. Interestingly, the knockdown of MATP significantly lowered the melanosomal pH, as verified through DAMP analysis, suggesting that MATP regulates melanosomal pH and therefore affects tyrosinase activity. Finally, we found that the reduction of tyrosinase activity associated with the knockdown of MATP was readily recovered by copper treatment in the in vitro L-DOPA oxidase activity assay of tyrosinase. Considering that copper is an important element for tyrosinase activity and that its binding to tyrosinase depends on melanosomal pH, MATP may play an important role in regulating tyrosinase activity via controlling melanosomal pH. PMID:26057890

Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes

PubMed Central

Barón, Anna E.; Asdigian, Nancy L.; Gonzalez, Victoria; Aalborg, Jenny; Terzian, Tamara; Stiegmann, Regan A.; C.Torchia, Enrique; Berwick, Marianne; Dellavalle, Robert P.; G.Morelli, Joseph; Mokrohisky, Stefan T.; Crane, Lori A.; Box, Neil F.

2014-01-01

Background Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar ultraviolet (UV) light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed. Methods We conducted a longitudinal study from ages 6 through 10 in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams. MC1R and HERC2/OCA2 rs12913832 were genotyped and linear mixed models were used to identify main and interaction effects. Results All measures of sun exposure (chronic, sunburns and waterside vacations) contributed to total nevus counts, and cumulative chronic exposure acted as the major driver of nevus development. Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair color variants. Sunburns increased numbers of larger nevi (≥2 mm) in subjects with certain MC1R and rs12913832 genotypes. Conclusions Complex interactions between different UV exposure profiles and genotype combinations determine nevus numbers and size, and the degree of facial freckling. Impact Our findings emphasize the importance of implementing sun-protective behavior in childhood regardless of genetic make-up; although children with particular genetic variants may benefit from specifically targeted preventive measures to counteract their inherent risk of melanoma. Moreover, we demonstrate, for the first time, that longitudinal studies are a highly powered tool to uncover new gene-environment interactions that increase cancer risk. PMID:25410285

Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes.

PubMed

Barón, Anna E; Asdigian, Nancy L; Gonzalez, Victoria; Aalborg, Jenny; Terzian, Tamara; Stiegmann, Regan A; Torchia, Enrique C; Berwick, Marianne; Dellavalle, Robert P; Morelli, Joseph G; Mokrohisky, Stefan T; Crane, Lori A; Box, Neil F

2014-12-01

Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed. We conducted a longitudinal study from ages 6 through 10 years in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams. MC1R and HERC2/OCA2 rs12913832 were genotyped and linear mixed models were used to identify main and interaction effects. All measures of sun exposure (chronic, sunburns, and waterside vacations) contributed to total nevus counts, and cumulative chronic exposure acted as the major driver of nevus development. Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair color variants. Sunburns increased the numbers of larger nevi (≥2 mm) in subjects with certain MC1R and rs12913832 genotypes. Complex interactions between different UV exposure profiles and genotype combinations determine nevus numbers and size, and the degree of facial freckling. Our findings emphasize the importance of implementing sun-protective behavior in childhood regardless of genetic make-up, although children with particular genetic variants may benefit from specifically targeted preventive measures to counteract their inherent risk of melanoma. Moreover, we demonstrate, for the first time, that longitudinal studies are a highly powered tool to uncover new gene-environment interactions that increase cancer risk. ©2014 American Association for Cancer Research.

Theoretical study on the reaction mechanism of CH 4 with CaO

NASA Astrophysics Data System (ADS)

Yang, Hua-Qing; Hu, Chang-Wei; Qin, Song

2006-11-01

The reaction pathways and energetics for the reaction of methane with CaO are discussed on the singlet spin state potential energy surface at the B3LYP/6-311+G(2df,2p) and QCISD/6-311++G(3df,3pd)//B3LYP/6-311+G(2df,2p) levels of theory. The reaction of methane with CaO is proposed to proceed in the following reaction pathways: CaO + CH 4 → CaOCH 4 → [TS] → CaOH + CH 3, CaO + CH 4 → OCaCH 4 → [TS] → HOCaCH 3 → CaOH + CH 3 or [TS] → CaCH 3OH → Ca + CH 3OH, and OCaCH 4 → [TS] → HCaOCH 3 → CaOCH 3 + H or [TS] → CaCH 3OH → Ca + CH 3OH. The gas-phase methane-methanol conversion by CaO is suggested to proceed via two kinds of important reaction intermediates, HOCaCH 3 and HCaOCH 3, and the reaction pathway via the hydroxy intermediate (HOCaCH 3) is energetically more favorable than the other one via the methoxy intermediate (HCaOCH 3). The hydroxy intermediate HOCaCH 3 is predicted to be the energetically most preferred configuration in the reaction of CaO + CH 4. Meanwhile, these three product channels (CaOH + CH 3, CaOCH 3 + H and Ca + CH 3OH) are expected to compete with each other, and the formation of methyl radical is the most preferable pathway energetically. On the other hand, the intermediates HCaOCH 3 and HOCaCH 3 are predicted to be the energetically preferred configuration in the reaction of Ca + CH 3OH, which is precisely the reverse reaction of methane hydroxylation.

The OCA CCD Camera Controller

DTIC Science & Technology

1996-01-01

multi CCD arrays for wide field telescopes with an array of 8x8 1K CCDs in use at Las Campanas Observatory in Chile . The same group is also involved...Verify key EPROM -292H VIH . VIH Program security bitl 1 29AH . VPP Program security’ bit 2 *. .298H -Vpp Verify security bits - 9HVIH ViI NOTE: 1...Pulsed from V.. to VIL and returned to VIH . EPROM PROGRAMMING AND VERIFICATION ..t= 21’C to-+27 ’rC:-VCC= 5V ±10%VS3 = OV. SYMBOL I .-- PARAMETER MIN MAX

OCaPPI-Db: an oligonucleotide probe database for pathogen identification through hybridization capture.

PubMed

Gasc, Cyrielle; Constantin, Antony; Jaziri, Faouzi; Peyret, Pierre

2017-01-01

The detection and identification of bacterial pathogens involved in acts of bio- and agroterrorism are essential to avoid pathogen dispersal in the environment and propagation within the population. Conventional molecular methods, such as PCR amplification, DNA microarrays or shotgun sequencing, are subject to various limitations when assessing environmental samples, which can lead to inaccurate findings. We developed a hybridization capture strategy that uses a set of oligonucleotide probes to target and enrich biomarkers of interest in environmental samples. Here, we present Oligonucleotide Capture Probes for Pathogen Identification Database (OCaPPI-Db), an online capture probe database containing a set of 1,685 oligonucleotide probes allowing for the detection and identification of 30 biothreat agents up to the species level. This probe set can be used in its entirety as a comprehensive diagnostic tool or can be restricted to a set of probes targeting a specific pathogen or virulence factor according to the user's needs. : http://ocappidb.uca.works. © The Author(s) 2017. Published by Oxford University Press.

Laser Induced Fluorescence Spectroscopy of Jet-Cooled CaOCa

NASA Astrophysics Data System (ADS)

Sullivan, Michael N.; Frohman, Daniel J.; Heaven, Michael; Fawzy, Wafaa M.

2016-06-01

The group IIA metals have stable hypermetallic oxides of the general form MOM. Theoretical interest in these species is associated with the multi-reference character of the ground states. It is now established that the ground states can be formally assigned to the M+O^{2-M+} configuration, which leaves two electrons in orbitals that are primarily metal-centered ns orbitals. Hence the MOM species are diradicals with very small energy spacings between the lowest energy singlet and triplet states. Previously, we have characterized the lowest energy singlet transition (1Σ^{+u← X1Σ+g}) of BeOBe. In this study we obtained the first electronic spectrum of CaOCa. Jet-cooled laser induced fluorescence spectra were recorded for multiple bands that occured within the 14,800 - 15,900 cm-1 region. Most of the bands exhibited simple P/R branch rotational line patterns that were blue-shaded. Only even rotational levels were observed, consistent with the expected X 1Σ^{+g} symmetry of the ground state (40Ca has zero nuclear spin). A progression of excited bending modes was evident in the spectrum, indicating that the transition is to an upper state that has a bent equilibrium geometry. Molecular constants were extracted from the rovibronic bands using PGOPHER. The experimental results and interpretation of the spectrum, which was guided by the predictions of electronic structure calculation, will be presented.

Transmembrane Na+ and Ca2+ electrochemical gradients in cardiac muscle and their relationship to force development

PubMed Central

1982-01-01

Na+- and CA2+-sensitive microelectrodes were used to measure intracellular Na+ and Ca2+ activities (alpha iCa) of sheep ventricular muscle and Purkinje strands to study the interrelationship between Na+ and Ca2+ electrochemical gradients (delta muNa and delta muCa) under various conditions. In ventricular muscle, alpha iNa was 6.4 +/- 1.2 mM and alpha iCa was 87 +/- 20 nM ([Ca/+] = 272 nM). A graded decrease of external Na+ activity (alpha oNa) resulted in decrease of alpha iNa, and increase of alpha iCa. There was increase of twitch tension in low- alpha oNa solutions, and occasional increase of resting tension in 40% alpha oNa. Increase of external Ca2+ (alpha oCa) resulted in increase of alpha iCa and decrease of alpha iNa. Decrease of alpha oCa resulted in decrease of alpha iCa and increase of alpha iNa. The apparent resting Na-Ca energy ratio (delta muCa/delta muNa) was between 2.43 and 2.63. When the membrane potential (Vm) was depolarized by 50 mM K+ in ventricular muscle, Vm depolarized by 50 mV, alpha iNa decreased, and alpha iCa increased, with the development of a contracture. The apparent energy coupling ratio did not change with depolarization. 5 x 10(-6) M ouabain induced a large increase in alpha iNa ad alpha iCa, accompanied by an increase in twitch and resting tension. Under the conditions we have studied, delta muNa and delta muCa appeared to be coupled and n was nearly constant at 2.5, as would be expected if the Na-Ca exchange system was able to set the steady level of alpha iCa. Tension threshold was about 230 nM alpha iCa. The magnitude of twitch tension was directly related to alpha iCa. PMID:6292328

Challenges for present and future estimates of anthropogenic carbon in the Indian Ocean

NASA Astrophysics Data System (ADS)

Goyet, C.; Touratier, F.

One of the main challenges we face today is to determine the evolution of the penetration of anthropogenic CO2 into the Indian Ocean and its impacts on marine and human life. Anthropogenic CO2 reaches the ocean via air-sea interactions as well as riverine inputs. It is then stored in the ocean and follows the oceanic circulation. As the carbon dioxide from the atmosphere penetrates into the sea, it reacts with water and acidifies the ocean. Consequently, the whole marine ecosystem is perturbed, thus potentially affecting the food web, which has, in turn, a direct impact on seafood supply for humans. Naturally, this will mainly affect the growing number of people living in coastal areas. Although anthropogenic CO2 in the ocean is identical with natural CO2 and therefore cannot be detected alone, many approaches are available today to estimate it. Since most of the results of these methods are globally in agreement, here we chose one of these methods, the tracer using oxygen, total inorganic carbon, and total alkalinity (TrOCA) approach, to compute the 3-D distribution of the anthropogenic CO2 concentrations throughout the Indian Ocean. The results of this distribution clearly illustrate the contrast between the Arabian Sea and the Bay of Bengal. They further show the importance of the southern part of this ocean that carries some anthropogenic CO2 at great depths. In order to determine the future anthropogenic impacts on the Indian Ocean, it is urgent and necessary to understand the present state. As the seawater temperature increases, how and how fast will the ocean circulation change? What will the impacts on seawater properties be? Many people are living on the bordering coasts, how will they be affected?

Molecular and Clinical Characterization of Albinism in a Large Cohort of Italian Patients

PubMed Central

Gargiulo, Annagiusi; Testa, Francesco; Rossi, Settimio; Di Iorio, Valentina; Fecarotta, Simona; de Berardinis, Teresa; Iovine, Antonello; Magli, Adriano; Signorini, Sabrina; Fazzi, Elisa; Galantuomo, Maria Silvana; Fossarello, Maurizio; Montefusco, Sandro; Ciccodicola, Alfredo; Neri, Alberto; Macaluso, Claudio; Simonelli, Francesca; Surace, Enrico Maria

2011-01-01

Purpose. The purpose of this study was to identify the molecular basis of albinism in a large cohort of Italian patients showing typical ocular landmarks of the disease and to provide a full characterization of the clinical ophthalmic manifestations. Methods. DNA samples from 45 patients with ocular manifestations of albinism were analyzed by direct sequencing analysis of five genes responsible for albinism: TYR, P, TYRP1, SLC45A2 (MATP), and OA1. All patients studied showed a variable degree of skin and hair hypopigmentation. Eighteen patients with distinct mutations in each gene associated with OCA were evaluated by detailed ophthalmic analysis, optical coherence tomography (OCT), and fundus autofluorescence. Results. Disease-causing mutations were identified in more than 95% of analyzed patients with OCA (28/45 [62.2%] cases with two or more mutations; 15/45 [33.3%] cases with one mutation). Thirty-five different mutant alleles were identified of which 15 were novel. Mutations in TYR were the most frequent (73.3%), whereas mutations in P occurred more rarely (13.3%) than previously reported. Novel mutations were also identified in rare loci such as TYRP1 and MATP. Mutations in the OA1 gene were not detected. Clinical assessment revealed that patients with iris and macular pigmentation had significantly higher visual acuity than did severe hypopigmented phenotypes. Conclusions. TYR gene mutations represent a relevant cause of oculocutaneous albinism in Italy, whereas mutations in P present a lower frequency than that found in other populations. Clinical analysis revealed that the severity of the ocular manifestations depends on the degree of retinal pigmentation. PMID:20861488

Laser ranging with the MéO telescope to improve orbital accuracy of space debris

NASA Astrophysics Data System (ADS)

Hennegrave, L.; Pyanet, M.; Haag, H.; Blanchet, G.; Esmiller, B.; Vial, S.; Samain, E.; Paris, J.; Albanese, D.

2013-05-01

Improving orbital accuracy of space debris is one of the major prerequisite to performing reliable collision prediction in low earth orbit. The objective is to avoid false alarms and useless maneuvers for operational satellites. This paper shows how laser ranging on debris can improve the accuracy of orbit determination. In March 2012 a joint OCA-Astrium team had the first laser echoes from space debris using the MéO (Métrologie Optique) telescope of the Observatoire de la Côte d'Azur (OCA), upgraded with a nanosecond pulsed laser. The experiment was conducted in full compliance with the procedures dictated by the French Civil Aviation Authorities. To perform laser ranging measurement on space debris, the laser link budget needed to be improved. Related technical developments were supported by implementation of a 2J pulsed laser purchased by ASTRIUM and an adapted photo detection. To achieve acquisition of the target from low accuracy orbital data such as Two Lines Elements, a 2.3-degree field of view telescope was coupled to the original MéO telescope 3-arcmin narrow field of view. The wide field of view telescope aimed at pointing, adjusting and acquiring images of the space debris for astrometry measurement. The achieved set-up allowed performing laser ranging and angular measurements in parallel, on several rocket stages from past launches. After a brief description of the set-up, development issues and campaigns, the paper discusses added-value of laser ranging measurement when combined to angular measurement for accurate orbit determination. Comparison between different sets of experimental results as well as simulation results is given.

Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype.

PubMed

Fernandez, Bridget A; Green, Jane S; Bursey, Ford; Barrett, Brendan; MacMillan, Andrée; McColl, Sarah; Fernandez, Sara; Rahman, Proton; Mahoney, Krista; Pereira, Sergio L; Scherer, Stephen W; Boycott, Kym M; Woods, Michael O

2012-11-21

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. The siblings' phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with "partial OCA" in childhood. This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

Chemical Safety Information, Site Security and Fuels Regulatory Relief Act: Public Distribution of Off-Site Consequence Analysis Information Fact Sheet

EPA Pesticide Factsheets

Based on assessments of increased risk of terrorist/criminal activity, EPA and DOJ have issued a rule that allows public access to OCA information in ways that are designed to minimize likelihood of chemical accidents and public harm.

Assessment of the Incentives Created by Public Disclosure of Off-Site Consequence Analysis Information for Reduction in the Risk of Accidental Releases

EPA Pesticide Factsheets

The off-site consequence analysis (OCA) evaluates the potential for worst-case and alternative accidental release scenarios to harm the public and environment around the facility. Public disclosure would likely reduce the number/severity of incidents.

Second Generation Weather Impacts Decision Aid User’s Manual

DTIC Science & Technology

2013-09-01

from the pulldown Base Reference Time menu. Most models start at times based on Coordinated Universal Time (UTC) or Zulu time (Z) with the selections...Effects Matrix Z Zulu time 31 No. of Copies Organization 1 DEFENSE TECHNICAL (PDF) INFORMATION CTR DTIC OCA 1 DIRECTOR (PDF) US

Mass Digitization of Books

ERIC Educational Resources Information Center

Coyle, Karen

2006-01-01

Mass digitization of the bound volumes that we generally call "books" has begun, and, thanks to the interest in Google and all that it does, it is getting widespread media attention. The Open Content Alliance (OCA), a library initiative formed after Google announced its library book digitization project, has brought library digitization projects…

40 CFR 1400.11 - Limitation on dissemination to State and local government officials.

Code of Federal Regulations, 2014 CFR

2014-07-01

... PROGRAMS UNDER THE CLEAN AIR ACT SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.11 Limitation on... prohibited from disseminating OCA information to State and local government officials. Violation of this...

40 CFR 1400.11 - Limitation on dissemination to State and local government officials.

Code of Federal Regulations, 2013 CFR

2013-07-01

... PROGRAMS UNDER THE CLEAN AIR ACT SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.11 Limitation on... prohibited from disseminating OCA information to State and local government officials. Violation of this...

40 CFR 1400.11 - Limitation on dissemination to State and local government officials.

Code of Federal Regulations, 2012 CFR

2012-07-01

... PROGRAMS UNDER THE CLEAN AIR ACT SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.11 Limitation on... prohibited from disseminating OCA information to State and local government officials. Violation of this...

40 CFR 1400.11 - Limitation on dissemination to State and local government officials.

Code of Federal Regulations, 2011 CFR

2011-07-01

... PROGRAMS UNDER THE CLEAN AIR ACT SECTION 112(r)(7); DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION DISTRIBUTION OF OFF-SITE CONSEQUENCE ANALYSIS INFORMATION Other Provisions § 1400.11 Limitation on... prohibited from disseminating OCA information to State and local government officials. Violation of this...

Security Notice To Federal, State and Local Officials Receiving Access to the Risk Management Program’s Off-site Consequence Analysis Information

EPA Pesticide Factsheets

Based on the Chemical Safety Information, Site Security and Fuels Regulatory Relief Act (CSISSFRRA), this notice states that while you may share with the public data from OCA sections, it is illegal to disclose/distribute the sections themselves.

T2L2/Jason-2, first year of processing activities

NASA Astrophysics Data System (ADS)

Exertier, P.

2009-11-01

The T2L2 (Time Transfer by Laser Link) project, developed by CNES and OCA will permit the synchronization of remote ultra stable clocks and the determination of their performances over intercontinental distances. The principle is derived from laser telemetry technology with a dedicated space equipment designed to record arrival time of laser pulses at the satellite. T2L2 was accepted in 2005 to be on board the Jason-2 altimetry satellite. It has been successfully launched from Vandenberg (CA, US) in June 2008. T2L2 acquired the first laser pulses a few days after the launch. First analysis permitted to validate some important characteristics of the instrument such as sensitivity, noise, dynamic, event timer precision and ground to space time stability.

SED16 autonomous star tracker night sky testing

NASA Astrophysics Data System (ADS)

Foisneau, Thierry; Piriou, Véronique; Perrimon, Nicolas; Jacob, Philippe; Blarre, Ludovic; Vilaire, Didier

2017-11-01

The SED16 is an autonomous multi-missions star tracker which delivers three axis satellite attitude in an inertial reference frame and the satellite angular velocity with no prior information. The qualification process of this star sensor includes five validation steps using optical star simulator, digitized image simulator and a night sky tests setup. The night sky testing was the final step of the qualification process during which all the functions of the star tracker were used in almost nominal conditions : Autonomous Acquisition of the attitude, Autonomous Tracking of ten stars. These tests were performed in Calern in the premises of the OCA (Observatoire de la Cote d'Azur). The test set-up and the test results are described after a brief review of the sensor main characteristics and qualification process.

Amphiphobic Polytetrafluoroethylene Membranes for Efficient Organic Aerosol Removal.

PubMed

Feng, Shasha; Zhong, Zhaoxiang; Zhang, Feng; Wang, Yong; Xing, Weihong

2016-04-06

Polytetrafluoroethylene (PTFE) membrane is an extensively used air filter, but its oleophilicity leads to severe fouling of the membrane surface due to organic aerosol deposition. Herein, we report the fabrication of a new amphiphobic 1H,1H,2H,2H-perfluorodecyl acrylate (PFDAE)-grafted ZnO@PTFE membrane with enhanced antifouling functionality and high removal efficiency. We use atomic-layer deposition (ALD) to uniformly coat a layer of nanosized ZnO particles onto porous PTFE matrix to increase surface area and then subsequently graft PFDAE with plasma. Consequently, the membrane surface showed both superhydrophobicity and oleophobicity with a water contact angle (WCA) and an oil contact angle (OCA) of 150° and 125°, respectively. The membrane air permeation rate of 513 (m(3) m(-2) h(-1) kPa(-1)) was lower than the pristine membrane rate of 550 (m(3) m(-2) h(-1) kPa(-1)), which indicates the surface modification slightly decreased the membrane air permeation. Significantly, the filtration resistance of this amphiphobic membrane to the oil aerosol system was much lower than the initial one. Moreover, the filter exhibited exceptional organic aerosol removal efficiencies that were greater than 99.5%. These results make the amphiphobic PTFE membranes very promising for organic aerosol-laden air-filtration applications.

PERSEE: a nulling interferometer with dynamic correction of external perturbations

NASA Astrophysics Data System (ADS)

Jacquinod, S.; Houairi, K.; Le Duigou, J.-M.; Barillot, M.; Cassaing, F.; Réess, J.-M.; Hénault, F.; Sorrente, B.; Morinaud, G.; Amans, J.-P.; Coudé du Foresto, V.; Ollivier, M.

2017-11-01

Nulling interferometry is one of the direct detection methods assessed to find and characterize extrasolar planets and particularly telluric ones. Several projects such as Darwin [1;2], TPF-I [3;4], PEGASE [5;6] or FKSI [7], are currently considered. One of the main issues is the feasibility of a stable polychromatic null despite the presence of significant disturbances, induced by vibrations, atmospheric turbulence on the ground or satellite drift. Satisfying all these requirements is a great challenge and a key issue of these missions. In the context of the PEGASE mission, it was decided (in 2006), to build a laboratory demonstrator named PERSEE. It is the first laboratory setup which couples deep nulling interferometry with a free flying GNC simulator [8]. It is developed by a consortium composed of CNES, IAS, LESIA, OCA, ONERA, and TAS. In this paper, we detail the main objectives, the set-up and the function of the bench. We describe all the subsystems and we focus particularly on two key points of PERSEE: the beam combiner and the Fringe tracker.

Hazardous Materials Management System. A Guide for Local Emergency Managers.

DTIC Science & Technology

1981-07-01

UDE OIL OCA EM~GENY ~A~iGRS𔄀. PERFORMING ORG. REPORT NUMBER F O . . . S . C O N T R A T l C R .Y N U BE R ) (i MYRAJ/LEE a&PENELOPE G./ROE *OCP41-79...out of, through, and within the area. Estimate the frequencies of shipments and the types and quanti ti es of ma teri al s i nvol ved. F (NOTE: Rer...reactions 4. Double- replacement reactions S . Oxidation- reduction reactions - Page 44 - B. Rate of Chemical Reactions I. Nature of material 2. Subdivision of

Environmental Report on the Northwest Pacific for the Marine Seismic System (MSS)

DTIC Science & Technology

1980-12-01

Kuroshio Cur rent is I oca t ed. F. Surface Currents Surface current circulation in the Northwest Pacific consists of the eastward-flowing warm water...overlying surface waters back to early late Miocene time. Prior to this, and through the Oligocene , the seamount was buried beneath a nearly equally

Developing Communication Confidence and Professional Identity in Chemistry through International Online Collaborative Learning

ERIC Educational Resources Information Center

Skagen, Darlene; McCollum, Brett; Morsch, Layne; Shokoples, Brandon

2018-01-01

The use of online collaborative assignments (OCAs) between two flipped organic chemistry classrooms, one in Canada and the other in the United States, was examined for impact on learners. The intervention was designed to support content mastery, aid in increasing students' communication skills through chemistry drawing and verbalization,…

75 FR 3911 - Advisory Board on Radiation and Worker Health (ABRWH or Advisory Board), National Institute for...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-25

...: The Advisory Board was established under the Energy Employees Occupational Illness Compensation... employees at any Department of Energy facility who were exposed to radiation but for whom it is not feasible... Labor (DOL) Program Update; Department of Energy (DOE) Program Update; OCAS Science Update; Special...

Miniature wide field-of-view star trackers for spacecraft attitude sensing and navigation

NASA Technical Reports Server (NTRS)

Mccarty, William; Curtis, Eric; Hull, Anthony; Morgan, William

1993-01-01

Introducing a family of miniature, wide field-of-view star trackers for low cost, high performance spacecraft attitude determination and navigation applications. These devices, derivative of the WFOV Star Tracker Camera developed cooperatively by OCA Applied Optics and the Lawrence Livermore National Laboratory for the Brilliant Pebbles program, offer a suite of options addressing a wide range of spacecraft attitude measurement and control requirements. These sensors employ much wider fields than are customary (ranging between 20 and 60 degrees) to assure enough bright stars for quick and accurate attitude determinations without long integration intervals. The key benefit of this approach are light weight, low power, reduced data processing loads and high information carrier rates for wide ACS bandwidths. Devices described range from the proven OCA/LLNL WFOV Star Tracker Camera (a low-cost, space-qualified star-field imager utilizing the spacecraft's own computer and centroiding and position-finding), to a new autonomous subsystem design featuring dual-redundant cameras and completely self-contained star-field data processing with output quaternion solutions accurate to 100 micro-rad, 3 sigma, for stand-alone applications.

Accident epidemiology and the U.S. chemical industry: accident history and worst-case data from RMP*Info.

PubMed

Kleindorfer, Paul R; Belke, James C; Elliott, Michael R; Lee, Kiwan; Lowe, Robert A; Feldman, Harold I

2003-10-01

This article reports on the data collected on one of the most ambitious government-sponsored environmental data acquisition projects of all time, the Risk Management Plan (RMP) data collected under section 112(r) of the Clean Air Act Amendments of 1990. This RMP Rule 112(r) was triggered by the Bhopal accident in 1984 and led to the requirement that each qualifying facility develop and file with the U.S. Environmental Protection Agency a Risk Management Plan (RMP) as well as accident history data for the five-year period preceding the filing of the RMP. These data were collected in 1999-2001 on more than 15,000 facilities in the United States that store or use listed toxic or flammable chemicals believed to be a hazard to the environment or to human health of facility employees or off-site residents of host communities. The resulting database, RMP*Info, has become a key resource for regulators and researchers concerned with the frequency and severity of accidents, and the underlying facility-specific factors that are statistically associated with accident and injury rates. This article analyzes which facilities actually filed under the Rule and presents results on accident frequencies and severities available from the RMP*Info database. This article also presents summaries of related results from RMP*Info on Offsite Consequence Analysis (OCA), an analytical estimate of the potential consequences of hypothetical worst-case and alternative accidental releases on the public and environment around the facility. The OCA data have become a key input in the evaluation of site security assessment and mitigation policies for both government planners as well as facility managers and their insurers. Following the survey of the RMP*Info data, we discuss the rich set of policy decisions that may be informed by research based on these data.

Characterization using XRD of puzzolanic materials from residual sludge from water treatment

NASA Astrophysics Data System (ADS)

Barón, G.; Montaño, A. M.; González, C. P.

2017-12-01

The goal of this work is to do mechanical and chemical characterization of puzzolanic materials using compressive strength measurements and X-Ray Diffraction (XRD). These materials are composed of red clay and aluminous sludge produced by the treatment of potable water at Planta Algodonal, Ocaña, Norte de Santander, Colombia. Ceramic bricks were sintered to 1100°C and ten were characterized in their physically, mechanically and chemically properties. The results showed that the relationships with which the Colombian standards according to NTC 4017 (100KGF/cm2) for non-structural bricks are maintained for those containing 10% (105Kgf/cm2) and 20% (102.9Kgf/cm2) of sludge with respect to clay.

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice.

PubMed

Jouihan, Hani; Will, Sarah; Guionaud, Silvia; Boland, Michelle L; Oldham, Stephanie; Ravn, Peter; Celeste, Anthony; Trevaskis, James L

2017-11-01

Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. OCA and IP118 alone and in combination were sub-chronically administered to Lep ob /Lep ob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lep ob /Lep ob mice was graded using a customized integrated scoring system. OCA reduced liver weight and lipid in NASH mice (both by -17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (-21%), liver lipid (-15%), ALT (-29%), and AST (-27%). The combination of OCA + IP118 further reduced liver weight (-29%), liver lipid (-22%), ALT (-39%), and AST (-36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (-4.3% and -3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (-25.3%) to a greater degree than IP118 alone (-12.5%) and further improved glucose tolerance and reduced hepatic lipid. Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Long-term kinetics of Salmonella Typhimurium ATCC 14028 survival on peanuts and peanut confectionery products

PubMed Central

Carminati, Joyce A.; Morishita, Karen N.; Amorim Neto, Dionísio P.; Pinheiro, Hildete P.; Maia, Rafael P.

2018-01-01

Due to recent large outbreaks, peanuts have been considered a product of potential risk for Salmonella. Usually, peanut products show a low water activity (aw) and high fat content, which contribute to increasing the thermal resistance and survival of Salmonella. This study evaluated the long-term kinetics of Salmonella survival on different peanut products under storage at 28°C for 420 days. Samples of raw in-shell peanuts (aw = 0.29), roasted peanuts (aw = 0.39), unblanched peanut kernel (aw = 0.54), peanut brittle (aw = 0.30), paçoca (aw = 0.40) and pé-de-moça (aw = 0.68) were inoculated with Salmonella Typhimurium ATCC 14028 at two inoculum levels (3 and 6 log cfu/ g). The Salmonella behavior was influenced (p<0.05) by aw, lipid, carbohydrate and protein content. In most cases for both inoculum levels, the greatest reductions were seen after the first two weeks of storage, followed by a slower decline phase. The lowest reductions were verified in paçoca and roasted peanuts, with counts of 1.01 and 0.87 log cfu/ g at low inoculum level and 2.53 and 3.82 log cfu/ g at high inoculum level at the end of the storage time. The highest loss of viability was observed in pé-de-moça, with absence of Salmonella in 10-g after 180 days at low inoculum level. The Weibull model provided a suitable fit to the data (R2≥0.81), with δ value ranging from 0.06 to 49.75 days. Therefore, the results demonstrated that Salmonella survives longer in peanut products, beyond the shelf life (>420 days), especially in products with aw around 0.40. PMID:29401480

The classical pink-eyed dilution mutation affects angiogenic responsiveness.

PubMed

Rogers, Michael S; Boyartchuk, Victor; Rohan, Richard M; Birsner, Amy E; Dietrich, William F; D'Amato, Robert J

2012-01-01

Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis.

Effects of Proud Large Osteochondral Plugs on Contact Forces and Knee Kinematics: A Robotic Study.

PubMed

Du, Peter Z; Markolf, Keith L; Boguszewski, Daniel V; Yamaguchi, Kent T; Lama, Christopher J; McAllister, David R; Jones, Kristofer J

2018-05-01

Osteochondral allograft (OCA) transplantation is used to treat large focal femoral condylar articular cartilage defects. A proud plug could affect graft survival by altering contact forces (CFs) and knee kinematics. A proud OCA plug will significantly increase CF and significantly alter knee kinematics throughout controlled knee flexion. Controlled laboratory study. Human cadaver knees had miniature load cells, each with a 20-mm-diameter cylinder of native bone/cartilage attached at its exact anatomic position, installed in both femoral condyles at standardized locations representative of clinical defects. Spacers were inserted to create proud plug conditions of +0.5, +1.0, and +1.5 mm. CFs and knee kinematics were recorded as a robot flexed the knee continuously from 0° to 50° under 1000 N of tibiofemoral compression. CFs were increased significantly (vs flush) for all proudness conditions between 0° and 45° of flexion (medial) and 0° to 50° of flexion (lateral). At 20°, the average increases in medial CF for +0.5-mm, +1-mm, and +1.5-mm proudness were +80 N (+36%), +155 N (+70%), and +193 N (+87%), respectively. Corresponding increases with proud lateral plugs were +44 N (+14%), +90 N (+29%), and +118 N (+38%). CF increases for medial plugs at 20° of flexion were significantly greater than those for lateral plugs at all proudness conditions. At 50°, a 1-mm proud lateral plug significantly decreased internal tibial rotation by 15.4° and decreased valgus rotation by 2.5°. A proud medial or lateral plug significantly increased CF between 0° and 45° of flexion. Our results suggest that a medial plug at 20° may be more sensitive to graft incongruity than a lateral plug. The changes in rotational kinematics with proud lateral plugs were attributed to earlier contact between the proud plug's surface and the lateral meniscus, leading to rim impingement with decreased tibial rotation. Increased CF and altered knee kinematics from a proud femoral plug could affect graft viability. Plug proudness of only 0.5 mm produced significant changes in CF and knee kinematics, and the clinically accepted 1-mm tolerance may need to be reexamined in view of our findings.

Aircraft Hydraulic Systems Dynamic Analysis. Volume 8. Transient Thermal Analysis (HYTTHA). Computer Program Technical Description

DTIC Science & Technology

1977-02-01

8217P(V, .’f\\,, OCA A, 4 6), V"D(S4, 3LL) X , )lq , 5)\\8, 1( 5) , + ITP ,V0L.L,ACVI;’ D ’k-11AY VA[.IL11:3 + , ’AV./24,/, PLAC/25/,r~ f/26/ ,’A/27/, ITP /28...8217) DT(TFA2)=D( ITF) DT( rPN) =D( irF) DT(’TVF1)=D( ITF) iT(TrVF2) =D( I’rF) L1=L( 1) L2=L( 2) TF( Ll)D( ITP ) TF( L,2)=D( IT F) TC ( L1) =D( ITC) TC( L2)=D...34Gas Dynamics", McGraw Hill, 1958 7. Report GH20-0205-4 "System/360 Scientific Subroutine Package - Version III, Programmer’s Manual," IBM Corp., August

The common occurrence of epistasis in the determination of human pigmentation and its impact on DNA-based pigmentation phenotype prediction.

PubMed

Pośpiech, Ewelina; Wojas-Pelc, Anna; Walsh, Susan; Liu, Fan; Maeda, Hitoshi; Ishikawa, Takaki; Skowron, Małgorzata; Kayser, Manfred; Branicki, Wojciech

2014-07-01

The role of epistatic effects in the determination of complex traits is often underlined but its significance in the prediction of pigmentation phenotypes has not been evaluated so far. The prediction of pigmentation from genetic data can be useful in forensic science to describe the physical appearance of an unknown offender, victim, or missing person who cannot be identified via conventional DNA profiling. Available forensic DNA prediction systems enable the reliable prediction of several eye and hair colour categories. However, there is still space for improvement. Here we verified the association of 38 candidate DNA polymorphisms from 13 genes and explored the extent to which interactions between them may be involved in human pigmentation and their impact on forensic DNA prediction in particular. The model-building set included 718 Polish samples and the model-verification set included 307 independent Polish samples and additional 72 samples from Japan. In total, 29 significant SNP-SNP interactions were found with 5 of them showing an effect on phenotype prediction. For predicting green eye colour, interactions between HERC2 rs12913832 and OCA2 rs1800407 as well as TYRP1 rs1408799 raised the prediction accuracy expressed by AUC from 0.667 to 0.697 and increased the prediction sensitivity by >3%. Interaction between MC1R 'R' variants and VDR rs731236 increased the sensitivity for light skin by >1% and by almost 3% for dark skin colour prediction. Interactions between VDR rs1544410 and TYR rs1042602 as well as between MC1R 'R' variants and HERC2 rs12913832 provided an increase in red/non-red hair prediction accuracy from an AUC of 0.902-0.930. Our results thus underline epistasis as a common phenomenon in human pigmentation genetics and demonstrate that considering SNP-SNP interactions in forensic DNA phenotyping has little impact on eye, hair and skin colour prediction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Turbulence Spectral Widths View Angle Independence as Observed by Doppler Radar

DTIC Science & Technology

1989-10-01

t, 1*+ 0 1T t+ ( 10) 2.+ 1I+. 3 3 1 9 Z1 9 1 1 21 S I 10 30 .. 1 11 30 49 3 D. 10 33 !’~3 . 02 2. F6 ’ -36 6 3 6 5 so 6 6 31 If., 68r t+.+ I’. . . .I... ACCA . .. AbA Co. CA•,A~ ... . ... C . .* CC~ CC C .... AC ... C . AC... CC CC . . . .. AAA C A 52CCC.CCCC A C AC. 51. CC 37. A. CACC C Cb...coeCcients b t e. and CCC ’l C. ..... .. o. oCA . .... °AACAA CC * C ... C 12.)0 35. 39. ’.. ’.5. A.. 37. 51 . 18. A• ACCA CCCCCCCCCCCCCCCCCCCCCC

U.S. EPA, Pesticide Product Label, RANGE CATTLE LIVESTOCK & SHEEP DIP CONCENTRATE, 03/02/1984

EPA Pesticide Factsheets

2011-04-21

... CiSDc~e of in a ~an,tdr.f ~arCf1:1 )r lnc~'1erd~~cn, crt 1~ d~~owe~:'/ sta~e ~nc :oca1 aLJt~ori~ies. ~~ :urp~~c. :; Jur··~~, s:a, :~~ ~f ;~~~e. ...

Early Communication System (ECOMM) for ISS

NASA Technical Reports Server (NTRS)

Gaylor, Kent; Tu, Kwei

1999-01-01

The International Space Station (ISS) Early Communications System (ECOMM) was a Johnson Space Center (JSC) Avionic Systems Division (ASD) in-house developed communication system to provide early communications between the ISS and the Mission Control Center-Houston (MCC-H). This system allows for low rate commands (link rate of 6 kbps) to be transmitted through the Tracking and Data Relay Satellite System (TDRSS) from MCC-H to the ISS using TDRSS's S-band Single Access Forward (SSA/) link service. This system also allows for low rate telemetry (link rate of 20.48 kbps) to be transmitted from ISS to MCC-H through the TDRSS using TDRSS's S-band Single Access Return (SSAR) link service. In addition this system supports a JSC developed Onboard Communications Adapter (OCA) that allows for a two-way data exchange of 128 kbps between MCC-H and the ISS through TDRSS. This OCA data can be digital video/audio (two-way videoconference), and/or file transfers, and/or "white board". The key components of the system, the data formats used by the system to insure compatibility with the future ISS S-Band System, as well as how other vehicles may be able to use this system for their needs are discussed in this paper.

Prime Contract Awards Alphabetically by Contractor, by State or Country, and Place, FY83, Part 10 (Universal Aircraft Parts Inc-Zytron Corp).

DTIC Science & Technology

1983-01-01

FIELDS & ALI 33-88 B C B 5 2 2 J070 000 A7 MAINT-REPAIR OF EQ/ADP EQUIP 3 6 4 1 1 K OCAO 0029 DAC , 33-88 B C A 5 3 2 W070 000 $1 LEASE-RENTAL OF EQ...D OCW63 0071 DAC 83-C0414 B C Z 5 3 2 S206 000 SI GUARD SERVICES 7 9 3 5 L 06 1 B J 2 D 83-C0450 B C Z 5 3 2 S206 000 Si GUARD SERVICES 7 9 7 5 L 06...C2470 J085 N62’ CONTRACTOR TOTAL 9 1,541 WALLER TODD & SADLI LA JUNTA COLORADO 040309 1520 06 1 C OCA65 0055 DAC 0-82-D4446 E C B 5 3 2 9140 000 A8A

Monitoring the growth of polyoxomolybdate nanoparticles in suspension by flow field-flow fractionation.

PubMed

Chen, Bailin; Jiang, Huijian; Zhu, Yan; Cammers, Arthur; Selegue, John P

2005-03-30

We follow the evolution of polyoxomolybdate nanoparticles in suspensions derived from the keplerate (NH4)42[MoVI72MoV60O372(CH3CO2)30(H2O)72].ca..300H2O.ca..10CH3CO2NH4 ({Mo132}) by flow field-flow fractionation (FlFFF) to monitor the particle-size distribution in situ, atomic force and high-resolution transmission electron microscopy (AFM, SEM, and HRTEM) to confirm particle sizes, inductively coupled plasma-optical emission spectrometry (ICP-OES) to determine the Mo content of the FlFFF-separated fractions, and UV/visible spectroscopy to confirm the identity of the species in suspension. We observe the formation of 3-75-nm polyoxomolybdate particles in suspension and the dynamic growth of {Mo132} crystals.

The AMBRE Project: Stellar parameterisation of the ESO:FEROS archived spectra

NASA Astrophysics Data System (ADS)

Worley, C. C.; de Laverny, P.; Recio-Blanco, A.; Hill, V.; Bijaoui, A.; Ordenovic, C.

2012-06-01

Context. The AMBRE Project is a collaboration between the European Southern Observatory (ESO) and the Observatoire de la Côte d'Azur (OCA) that has been established in order to carry out the determination of stellar atmospheric parameters for the archived spectra of four ESO spectrographs. Aims: The analysis of the FEROS archived spectra for their stellar parameters (effective temperatures, surface gravities, global metallicities, alpha element to iron ratios and radial velocities) has been completed in the first phase of the AMBRE Project. From the complete ESO:FEROS archive dataset that was received, a total of 21 551 scientific spectra have been identified, covering the period 2005 to 2010. These spectra correspond to 6285 stars. Methods: The determination of the stellar parameters was carried out using the stellar parameterisation algorithm, MATISSE (MATrix Inversion for Spectral SynthEsis), which has been developed at OCA to be used in the analysis of large scale spectroscopic studies in galactic archaeology. An analysis pipeline has been constructed that integrates spectral normalisation, cleaning and radial velocity correction procedures in order that the FEROS spectra could be analysed automatically with MATISSE to obtain the stellar parameters. The synthetic grid against which the MATISSE analysis is carried out is currently constrained to parameters of FGKM stars only. Results: Stellar atmospheric parameters, effective temperature, surface gravity, metallicity and alpha element abundances, were determined for 6508 (30.2%) of the FEROS archived spectra (~3087 stars). Radial velocities were determined for 11 963 (56%) of the archived spectra. 2370 (11%) spectra could not be analysed within the pipeline due to very low signal-to-noise ratios or missing spectral orders. 12 673 spectra (58.8%) were analysed in the pipeline but their parameters were discarded based on quality criteria and error analysis determined within the automated process. The majority of these rejected spectra were found to have broad spectral features, as probed both by the direct measurement of the features and cross-correlation function breadths, indicating that they may be hot and/or fast rotating stars, which are not considered within the adopted reference synthetic spectra grid. The current configuration of the synthetic spectra grid is devoted to slow-rotating FGKM stars. Hence non-standard spectra (binaries, chemically peculiar stars etc.) that could not be identified may pollute the analysis.

A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder.

PubMed

Abdel-Salam, Ghada M H; Miyake, Noriko; Eid, Maha M; Abdel-Hamid, Mohamed S; Hassan, Nihal A; Eid, Ola M; Effat, Laila K; El-Badry, Tarek H; El-Kamah, Ghada Y; El-Darouti, Mohamed; Matsumoto, Naomichi

2011-11-01

The designation microcephalic osteodysplastic primordial dwarfism (MOPD) refers to a group of autosomal recessive disorders, comprising microcephaly, growth retardation, and a skeletal dysplasia. The different types of MOPD have been delineated on the basis of clinical, radiological, and genetic criteria. We describe two brothers, born to healthy, consanguineous parents, with intrauterine and postnatal growth retardation, microcephaly with abnormal gyral pattern and partial agenesis of corpus callosum, and skeletal anomalies reminiscent of those described in MOPD type I. This was confirmed by the identification of the homozygous g.55G > A mutation of RNU4ATAC encoding U4atac snRNA. The sibs had yellowish-gray hair, fair skin, and deficient retinal pigmentation. Skin biopsy showed abnormal melanin function but OCA genes were normal. The older sib had an intracranial hemorrhage at 1 week after birth, the younger developed chilblains-like lesions at the age 2½ years old but analysis of the SAMHD1 and TREX1 genes did not show any mutations. To the best of our knowledge, vasculopathy and pigmentary disorders have not been reported in MOPD I. Copyright © 2011 Wiley Periodicals, Inc.

[Mg2+]o/[Ca2+]o determines Ca2+ response at fertilization: tuning of adult phenotype?

PubMed

Ozil, Jean-Pierre; Sainte-Beuve, Thierry; Banrezes, Bernadette

2017-11-01

Alteration of the postnatal phenotype has sparked great concern about the developmental impact of culture media used at fertilization. However, the mechanisms and compounds involved are yet to be determined. Here, we used the Ca 2+ responses from mouse eggs fertilized by ICSI as a dynamic and quantitative marker to understand the role of compounds in egg functioning and establish possible correlations with adult phenotypes. We computed 134 Ca 2+ responses from the first to the last oscillation in media with specific formulations. Analyses demonstrate that eggs generated two times as many Ca 2+ oscillations in KSOM as in M16 media (18.8 ± 7.0 vs 9.2 ± 2.5). Moreover, the time increment of the delay between two consecutive oscillations, named TIbO, is the most sensitive coefficient characterizing the mechanism that paces Ca 2+ oscillations once the egg has been fertilized. Neither doubling external free Ca 2+ nor dispermic fertilization increased significantly the total number of Ca 2+ oscillations. In contrast, removing Mg 2+ from the M16 boosted Ca 2+ oscillations to 54.0 ± 35.2. Hence, [Mg 2+ ] o /[Ca 2+ ] o appears to determine the number, duration and frequency of the Ca 2+ oscillations. These changes were correlated with long-term effects. The rate of female's growth was impacted with the 'KSOM' females having only half the fat deposit of 'M16' females. Moreover, adult animals issued from M16 had significantly smaller brain weight vs 'KSOM' and 'control' animals. TIbO is a new Ca 2+ coefficient that gauges the very early functional impact of culture media. It offers the possibility of establishing correlations with postnatal consequences according to IVF medium formulation.Free French abstract: A French translation of this abstract is freely available at http://www.reproduction-online.org/content/154/5/675/suppl/DC2. © 2017 Society for Reproduction and Fertility.

Imaging of the human choroid with a 1.7 MHz A-scan rate FDML swept source OCT system

NASA Astrophysics Data System (ADS)

Gorczynska, I.; Migacz, J. V.; Jonnal, R.; Zawadzki, R. J.; Poddar, R.; Werner, J. S.

2017-02-01

We demonstrate OCT angiography (OCTA) and Doppler OCT imaging of the choroid in the eyes of two healthy volunteers and in a geographic atrophy case. We show that visualization of specific choroidal layers requires selection of appropriate OCTA methods. We investigate how imaging speed, B-scan averaging and scanning density influence visualization of various choroidal vessels. We introduce spatial power spectrum analysis of OCT en face angiographic projections as a method of quantitative analysis of choroicapillaris morphology. We explore the possibility of Doppler OCT imaging to provide information about directionality of blood flow in choroidal vessels. To achieve these goals, we have developed OCT systems utilizing an FDML laser operating at 1.7 MHz sweep rate, at 1060 nm center wavelength, and with 7.5 μm axial imaging resolution. A correlation mapping OCA method was implemented for visualization of the vessels. Joint Spectral and Time domain OCT (STdOCT) technique was used for Doppler OCT imaging.

Sequences associated with human iris pigmentation.

PubMed Central

Frudakis, Tony; Thomas, Matthew; Gaskin, Zach; Venkateswarlu, K; Chandra, K Suresh; Ginjupalli, Siva; Gunturi, Sitaram; Natrajan, Sivamani; Ponnuswamy, Viswanathan K; Ponnuswamy, K N

2003-01-01

To determine whether and how common polymorphisms are associated with natural distributions of iris colors, we surveyed 851 individuals of mainly European descent at 335 SNP loci in 13 pigmentation genes and 419 other SNPs distributed throughout the genome and known or thought to be informative for certain elements of population structure. We identified numerous SNPs, haplotypes, and diplotypes (diploid pairs of haplotypes) within the OCA2, MYO5A, TYRP1, AIM, DCT, and TYR genes and the CYP1A2-15q22-ter, CYP1B1-2p21, CYP2C8-10q23, CYP2C9-10q24, and MAOA-Xp11.4 regions as significantly associated with iris colors. Half of the associated SNPs were located on chromosome 15, which corresponds with results that others have previously obtained from linkage analysis. We identified 5 additional genes (ASIP, MC1R, POMC, and SILV) and one additional region (GSTT2-22q11.23) with haplotype and/or diplotypes, but not individual SNP alleles associated with iris colors. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. Diplotypes for these genes explain 15% of iris color variation. Apart from representing the first comprehensive candidate gene study for variable iris pigmentation and constituting a first step toward developing a classification model for the inference of iris color from DNA, our results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers. PMID:14704187

Pharmacoeconomic comparison of Helicobacter pylori eradication regimens.

PubMed

Sancar, Mesut; Izzettin, Fikret Vehbi; Apikoglu-Rabus, Sule; Besisik, Fatih; Tozun, Nurdan; Dulger, Gul

2006-08-01

Helicobacter pylori is the most important etiologic agent for development of peptic ulcer, chronic gastritis and gastric carcinomas. It is now well established that H. pylori eradication treatment is more cost-effective than acid suppressing therapies alone for the treatment of peptic ulcer disease. However, the comparative cost-effectiveness of various H. pylori eradication regimens is still not clear. This study was designed to make a pharmacoeconomic comparison of different H. pylori eradication regimens in patients with peptic ulcer disease or chronic gastritis, using real-world cost and effectiveness data. Istanbul University Hospital and Marmara University Hospital. A total of 75 patients diagnosed as H. pylori (+) by endoscopy were randomized to receive one of the seven H. pylori treatment protocols. These protocols were as follows: (LAC) = 'lansoprazole 30 mg bid + amoxicillin 1 g bid + clarithromycin 500 mg bid' for 7 days and (OCM) = 'omeprazole 20 mg bid + clarithromycin 250 mg bid + metronidazole 500 mg bid'; (OAM) = 'omeprazole 40 mg qd + amoxicillin 500 mg tid + metronidazole 500 mg tid'; (MARB) = 'metronidazole 250 mg tid + amoxicillin 500 mg qid + ranitidine 300 mg hs + bismuth 300 mg qid'; (OAC) = omeprazole 20 mg bid + amoxicillin 1 g bid + clarithromycin 500 mg bid'; (OCA) = omeprazole 40 mg bid + clarithromycin 500 mg bid + amoxicillin 1 g bid'; (OAB) = 'omeprazole 20 mg bid + amoxicillin 500 mg tid + bismuth 300 mg qid' each for 14 days. Only direct costs were included in the analysis. Effectiveness was measured in terms of "successful eradication". The cost-effectiveness ratios of the regimens were calculated using these effectiveness and cost data. The perspective of the study was assumed as the Government's perspective. Cost-effectiveness ratios of eradication regimens. MARB and OCA regimens were found to be more cost-effective than the other treatment regimens. The eradication rates and cost-effectiveness ratios calculated for these protocols were 90% (158.7 euros) for MARB and 90% (195.8 euros) for OCA regimen. This study confirms the importance of using local pharmacoeconomic data. Analyses such as this give decision-makers the tools to choose a better treatment option which is both highly effective yet and has a low cost.

Study of the epidermis ablation effect on the efficiency of optical clearing of skin in vivo

NASA Astrophysics Data System (ADS)

Genina, E. A.; Ksenofontova, N. S.; Bashkatov, A. N.; Terentyuk, G. S.; Tuchin, V. V.

2017-06-01

We present the results of a comparative analysis of optical immersion clearing of skin in laboratory animals in vivo with and without preliminary ablation of epidermis. Laser ablation is implemented using a setup based on a pulsed erbium laser (λ = 2940 nm). The size of the damaged region amounted to 6 × 6 mm, the depth being smaller than 50 μm. As an optical clearing agent (OCA), use is made of polyethylene glycol (PEG-300). Based on optical coherence tomography, we use the single scattering model to estimate the scattering coefficient in the process of optical clearing in 2 regions at depths of 50-170 μm and 150-400 μm. The results show that skin surface ablation leads to the local oedema of the affected region that increases the scattering coefficient. However, the intense evaporation of water from the ablation zone facilitates the optical clearing at the expense of tissue dehydration, particularly in the upper layers. The assessment of the optical clearing efficiency shows that the efficiency exceeding 30% can be achieved at a depth from 50 to 170 μm in 120 min after ablation, as well as after the same ablation with subsequent application of PEG-300, which increases the efficiency of the immersion method by almost 1.8 times. At a depth from 150 to 400 μm, dehydration of upper layers cannot completely compensate for an increase in light scattering by dermis after epidermis ablation. The additional effect of OCA enhances the optical clearing of skin at the expense of improving the refractive index matching between dermis components, but the maximal efficiency of optical clearing in 120 min does not exceed 6%.

Mechanism of Action of Presynaptic Neurotoxins

DTIC Science & Technology

1985-09-01

Asialoglycoproteins in Cultured Hepatocytes . Ches. =7, 3191-3197. Harford, J., Klausner, R. D., and Ashwell, G. (1984) Inhibition of the Endocytic Pathway...valid marker for neurons in the CNS and neuronal cells when grown in culture ( Mirsky et al., 1978). Recently, the binding interactions have been...Gangliosides in Nervous Tissue Cultures and Binding of I-Labelled Tetanus Toxin, a Neuronal Marker . L. f ocA . 12, 329-334. Dimpfel, V., and

Review of reactor pressure vessel evaluation report for Yankee Rowe Nuclear Power Station (YAEC No. 1735)

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

Cheverton, R.D.; Dickson, T.L.; Merkle, J.G.

1992-03-01

The Yankee Atomic Electric Company has performed an Integrated Pressurized Thermal Shock (IPTS)-type evaluation of the Yankee Rowe reactor pressure vessel in accordance with the PTS Rule (10 CFR 50. 61) and a US Regulatory Guide 1.154. The Oak Ridge National Laboratory (ORNL) reviewed the YAEC document and performed an independent probabilistic fracture-mechnics analysis. The review included a comparison of the Pacific Northwest Laboratory (PNL) and the ORNL probabilistic fracture-mechanics codes (VISA-II and OCA-P, respectively). The review identified minor errors and one significant difference in philosophy. Also, the two codes have a few dissimilar peripheral features. Aside from these differences,more » VISA-II and OCA-P are very similar and with errors corrected and when adjusted for the difference in the treatment of fracture toughness distribution through the wall, yield essentially the same value of the conditional probability of failure. The ORNL independent evaluation indicated RT{sub NDT} values considerably greater than those corresponding to the PTS-Rule screening criteria and a frequency of failure substantially greater than that corresponding to the primary acceptance criterion'' in US Regulatory Guide 1.154. Time constraints, however, prevented as rigorous a treatment as the situation deserves. Thus, these results are very preliminary.« less

Review of reactor pressure vessel evaluation report for Yankee Rowe Nuclear Power Station (YAEC No. 1735)

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

Cheverton, R.D.; Dickson, T.L.; Merkle, J.G.

1992-03-01

The Yankee Atomic Electric Company has performed an Integrated Pressurized Thermal Shock (IPTS)-type evaluation of the Yankee Rowe reactor pressure vessel in accordance with the PTS Rule (10 CFR 50. 61) and a US Regulatory Guide 1.154. The Oak Ridge National Laboratory (ORNL) reviewed the YAEC document and performed an independent probabilistic fracture-mechnics analysis. The review included a comparison of the Pacific Northwest Laboratory (PNL) and the ORNL probabilistic fracture-mechanics codes (VISA-II and OCA-P, respectively). The review identified minor errors and one significant difference in philosophy. Also, the two codes have a few dissimilar peripheral features. Aside from these differences,more » VISA-II and OCA-P are very similar and with errors corrected and when adjusted for the difference in the treatment of fracture toughness distribution through the wall, yield essentially the same value of the conditional probability of failure. The ORNL independent evaluation indicated RT{sub NDT} values considerably greater than those corresponding to the PTS-Rule screening criteria and a frequency of failure substantially greater than that corresponding to the ``primary acceptance criterion`` in US Regulatory Guide 1.154. Time constraints, however, prevented as rigorous a treatment as the situation deserves. Thus, these results are very preliminary.« less

Stable Imaging for Astronomy (SIA)

NASA Astrophysics Data System (ADS)

Beaulieu, Mathilde; Ottogalli, Sebastien; Preis, Olivier; Bresson, Yves; Rivet, Jean-Pierre; Abe, Lyu; Vakili, Farrokh

2014-07-01

One of the most challenging fields of astronomical instrumentation is probably high-contrast imaging since it ultimately combines ultra-high sensitivity at low flux and the ability to cope with photon flux contrasts of several hundreds of millions or even more. These two aspects implicitly require that high-contrast instruments should be highly stable in the sense of the reproducibility of their measurements at different times, but also, continuously stable over time. In most high contrast instruments or experiments, their sensitivity is broken after at most tens of minutes of operation due to uncontrolled and unknown behaviour of the whole experiment regarding the environmental conditions. In this paper, we introduce a general approach of an exhaustive stability study for high-contrast imaging that has been initiated at Lagrange Laboratory, Observatoire de la Côte d'Azur (OCA). On a practical ground, one of the fundamental issues of this study is the metrology, which is the basis of all reproducible measurements. We describe a small experiment designed to understand the behaviour of one of our ultra-precise metrology tools (a commercial sub-nanometric 3-way interferometer) and derive the conditions under which its operation delivers reliable results. The approach will apply to the high-contrast imaging test-bench SPEED, under development at OCA.

Direct-writing lithography using laser diode beam focused with single elliptical microlens

NASA Astrophysics Data System (ADS)

Hasan, Md. Nazmul; Haque, Muttahid-Ull; Trisno, Jonathan; Lee, Yung-Chun

2015-10-01

A lithography method is proposed for arbitrary patterning using an elliptically diverging laser diode beam focused with a single planoconvex elliptical microlens. Simulations are performed to model the propagation properties of the laser beam and to design the elliptical microlens, which has two different profiles in the x- and y-axis directions. The microlens is fabricated using an excimer laser dragging method and is then attached to the laser diode using double-sided optically cleared adhesive (OCA) tape. Notably, the use of OCA tape removes the need for a complicated alignment procedure and thus significantly reduces the assembly cost. The minimum focused spot of the laser diode beam is investigated by performing single-shot exposure tests on a photoresist (PR) layer. Finally, the practical feasibility of this lithography technique to generate an arbitrary pattern is demonstrated by dotted and continuous features through thin chromium layer deposition on PR and a metal lift-off process. The results show that the minimum feature size for the dotted patterns is around 6.23 μm, while the minimum linewidths for continuous patterns is 6.44 μm. In other words, the proposed focusing technique has significant potential for writing any arbitrary high-resolution pattern for applications like printed circuit board fabrication.

Prenatal molecular diagnosis of oculocutaneous albinism (OCA) in a large cohort of Israeli families.

PubMed

Rosenmann, Ada; Bejarano-Achache, Idit; Eli, Dalia; Maftsir, Genia; Mizrahi-Meissonnier, Liliana; Blumenfeld, Anat

2009-10-01

To present our accumulated data on prenatal molecular diagnosis of oculocutaneous albinism (OCA) in a large cohort of Israeli albino families. Albinism consists of variable phenotypes, but only families with predicted severely handicapped albino offspring, who declared their wish to terminate a pregnancy of such a fetus, are eligible for prenatal testing. Prenatal testing is not offered otherwise. Following detailed genetic investigation and counseling, molecular prenatal testing was performed using the combination of mutation screening, direct sequencing, and haplotype analysis. A total of 55 prenatal tests were performed in 37 families; in 26 families the propositus was the child, and in 11, a parent or a close relative. In 32 families tyrosinase (TYR) mutations were diagnosed. In 5 families a P gene mutation was detected. Twelve albino fetuses were diagnosed. Following further genetic counseling, all couples elected to terminate the pregnancy. Three additional pregnancies were terminated for other reasons. Families with increased risk for an albino child with severe visual handicap, seek premarital and prenatal genetic counseling and testing, for the prevention of affected offspring. Our combined methods of molecular genetic testing enable a nationwide approach for prevention of albinism. The same paradigm can be applied to other populations affected with albinism.

Genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry.

PubMed

Rawofi, Lida; Edwards, Melissa; Krithika, S; Le, Phuong; Cha, David; Yang, Zhaohui; Ma, Yanyun; Wang, Jiucun; Su, Bing; Jin, Li; Norton, Heather L; Parra, Esteban J

2017-01-01

Currently, there is limited knowledge about the genetics underlying pigmentary traits in East Asian populations. Here, we report the results of the first genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry. We obtained quantitative skin pigmentation measures (M-index) in the inner upper arm of the participants using a portable reflectometer ( N  = 305). Quantitative measures of iris color (expressed as L*, a* and b* CIELab coordinates) were extracted from high-resolution iris pictures ( N  = 342). We also measured the color differences between the pupillary and ciliary regions of the iris (e.g., iris heterochromia). DNA samples were genotyped with Illumina's Infinium Multi-Ethnic Global Array (MEGA) and imputed using the 1000 Genomes Phase 3 samples as reference haplotypes. For skin pigmentation, we did not observe any genome-wide significant signal. We followed-up in three independent Chinese samples the lead SNPs of five regions showing multiple common markers (minor allele frequency ≥ 5%) with good imputation scores and suggestive evidence of association ( p -values < 10 -5 ). One of these markers, rs2373391, which is located in an intron of the ZNF804B gene on chromosome 7, was replicated in one of the Chinese samples ( p  = 0.003). For iris color, we observed genome-wide signals in the OCA2 region on chromosome 15. This signal is driven by the non-synonymous rs1800414 variant, which explains 11.9%, 10.4% and 6% of the variation observed in the b*, a* and L* coordinates in our sample, respectively. However, the OCA2 region was not associated with iris heterochromia. Additional genome-wide association studies in East Asian samples will be necessary to further disentangle the genetic architecture of pigmentary traits in East Asian populations.

Genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry

PubMed Central

Rawofi, Lida; Edwards, Melissa; Krithika, S; Le, Phuong; Cha, David; Yang, Zhaohui; Ma, Yanyun; Wang, Jiucun; Su, Bing; Jin, Li; Norton, Heather L.

2017-01-01

Background Currently, there is limited knowledge about the genetics underlying pigmentary traits in East Asian populations. Here, we report the results of the first genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry. Methods We obtained quantitative skin pigmentation measures (M-index) in the inner upper arm of the participants using a portable reflectometer (N = 305). Quantitative measures of iris color (expressed as L*, a* and b* CIELab coordinates) were extracted from high-resolution iris pictures (N = 342). We also measured the color differences between the pupillary and ciliary regions of the iris (e.g., iris heterochromia). DNA samples were genotyped with Illumina’s Infinium Multi-Ethnic Global Array (MEGA) and imputed using the 1000 Genomes Phase 3 samples as reference haplotypes. Results For skin pigmentation, we did not observe any genome-wide significant signal. We followed-up in three independent Chinese samples the lead SNPs of five regions showing multiple common markers (minor allele frequency ≥ 5%) with good imputation scores and suggestive evidence of association (p-values < 10−5). One of these markers, rs2373391, which is located in an intron of the ZNF804B gene on chromosome 7, was replicated in one of the Chinese samples (p = 0.003). For iris color, we observed genome-wide signals in the OCA2 region on chromosome 15. This signal is driven by the non-synonymous rs1800414 variant, which explains 11.9%, 10.4% and 6% of the variation observed in the b*, a* and L* coordinates in our sample, respectively. However, the OCA2 region was not associated with iris heterochromia. Discussion Additional genome-wide association studies in East Asian samples will be necessary to further disentangle the genetic architecture of pigmentary traits in East Asian populations. PMID:29109912

VizieR Online Data Catalog: BVIc light curves of 57 Cepheids (Berdnikov+,

NASA Astrophysics Data System (ADS)

Berdnikov, L. N.; Kniazev, A. Yu.; Sefako, R.; Kravtsov, V. V.; Zhujko, S. V.

2014-04-01

In 2008-2013, we obtained 11333 CCD BV Ic frames for 57 Cepheids from the General Catalogue of Variable Stars. We performed our observations with the 76-cm telescope of the South AfricanAstronomicalObservatory (SAAO, South Africa) and the 40-cm telescope of the Cerro Armazones Astronomical Observatory of the Universidad Catolica del Norte (OCA, Chile) using the SBIG ST-10XME CCD camera. The tables of observations, the plots of light curves, and the current light elements are presented. Comparison of our light curves with those constructed from photoelectric observations shows that the differences between their mean magnitudes exceed 0.05mag in 20% of the cases. This suggests the necessity of performing CCD observations for all Cepheids. (2 data files).

Mission Accomplishment through Outsourcing

DTIC Science & Technology

2006-02-07

salary only and does not include associated benefits. According to the U.S. 7 Chamber of Commerce , employee benefit costs represent 37.6 percent of...articles/ glossary.html#o. 10 Office of Personnel Management, U.S. Government, http://www.opm.gov/oca/06tables/html/dcb.asp. 11 U.S. Chamber of Commerce , http...employee% 20turnover. U.S. Chamber of Commerce . http://www.uschamber.com/press/ releases/2005/january//05-13.htm. USGA. “Employee Turnover

A Preliminary Study of the Application of Probabilistic Risk Assessment Techniques to High-Energy Laser Safety

DTIC Science & Technology

2001-12-01

32. Maxwell , J . R., & Beard, J . (1973). Bi-directional reflectance model validation and utilization. Tehnical Report AFAL-TR-73-303. Michigan... CECILIA MONTES DE OCA, Ist Lt, USAF Contract Monitor RICHARD L. MILLER, PhD Chief, Directed Energy Bioeffects Division Form Approved REPORT... J .. . a •. . . ......... ..... ... a.. •. l • • , 0.3 0.1 .. . .. . .. . . .. . . ......... ....... .. , 0.0 1 10 100 l000 Kinetic Energy, ft-ibf

Management of obstructive calcular anuria with acute renal failure in children less than 4 years in age: a protocol for initial urinary drainage in relation to planned definitive stone management.

PubMed

ElSheemy, Mohammed S; Shoukry, Ahmed I; Shouman, Ahmed M; ElShenoufy, Ahmed; Aboulela, Waseem; Daw, Kareem; Hussein, Ahmed A; Morsi, Hany A

2014-12-01

To describe and evaluate our protocol for management of children≤4years old with obstructive calcular anuria (OCA) and acute renal failure (ARF) to improve selection of initial urinary drainage (ID) method and to facilitate subsequent definitive stone management (DSM) as studies discussing this special group of patients are still few. Patients with a contraindication to any method of ID were excluded. Decision (percutaneous nephrostomy (PCN) or double J (JJ) stent) was based on degree of hydronephrosis and planned DSM. We used 4.8-5Fr JJ or 6-8Fr PCN under general anesthesia and fluoroscopic guidance. According to our protocol, JJ is inserted for hydronephrosis≤grade 1. When the hydronephrosis is >grade 1, patients with radiolucent stones were treated by JJ whatever the site of the stone. When the stones were radiopaque, PCN was reserved for stones in a solitary functioning kidney and bilateral ureteric stones prepared for subsequent bilateral ureterolithotomy (or stone prepared for ureterolithotomy in a solitary kidney). After normalization of renal functions, DSM was staged attacking only one side before discharge. Both sides were cleared at the same session in cases with bilateral ureterolithotomy. Renal or ureteric stones suitable for SWL in a solitary kidney were treated with percutaneous nephrolithotripsy (PNL) or ureteroscopy. This was followed also in patients with bilateral stones suitable for SWL by clearing one side using ureteroscopy or PNL before discharge. Open surgery (OS) was reserved for cases with failed ureteroscopy or PNL, for ureteric stones>2.5 cm in size or very large volume complex renal stones. Stone free rate (SFR) was evaluated by CT. Our protocol was evaluated as regard recovery of renal functions, complications, and number of interventions to clear stones. This study included 62 boys and 22 girls presented with anuria for 1-4 days. JJ and PCN were inserted in 105 and 30 ureterorenal units (URU), respectively. Creatinine returns normal within 72 h. JJ insertion formed a part of DSM in 78/159 (49%) URU (stones prepared for extracorporeal shockwave lithotripsy or oral chemolytic dissolution therapy). PCN was the ideal tract for subsequent PNL in 11/159 (6.9%) URU. Accordingly, ID participated by 55.97% in DSM. Both operative and imaging times were slightly longer with PCN than JJ. There was no statistically significant difference in the insertion success or mean period to return to normal chemistry. Complications of both methods were mild and without any significant difference. Endourologic procedures constituted the majority of our interventions. Open surgical and endoscopic interventions for clearance of stones (including ID, treatment conversion and 2ry procedures) were done once for 25 patients, twice for 43 patients while it was needed three times for 16 patients. Total number of interventions was 149 procedures. SFR was 94%. Our protocol ensures adequate ID with minimal complications when using our selection criteria in children≤4 years in age with OCA and ARF. It also minimizes number of subsequent procedures to clear stones. Complications and success in insertion and drainage were equivalent in PCN and JJ groups. Copyright © 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Cross-Cultural Consumer Acceptability and Purchase Intent of Forage-Finished Rib-Eye Steaks.

PubMed

Torrico, Damir Dennis; Wardy, Wisdom; Pujols, Kairy Dharali; Carabante, Kennet Mariano; Jirangrat, Wannita; Scaglia, Guillermo; Janes, Marlene E; Prinyawiwatkul, Witoon

2015-10-01

Rib-eye steaks, from 3 forage-finished systems (S1, S2, and S3) and 1 commercial steak (C), either cooked by 1-sided-grilling or 2-sided-grilling, were evaluated for sensory acceptability [overall appearance (ORA) and overall appearance of fat (OAF) for raw steaks; overall appearance (OCA), overall beef aroma (OBA), overall beef flavor (OBF), juiciness, tenderness and overall liking (OL) for cooked steaks] and purchase intent by Hispanic, Asian and U.S. consumers. They also indicated preferred degree of doneness and cooking methods. Cross-cultural differences in preferences and consumer acceptability of rib-eye steaks were observed. Grilling was the most preferred cooking method. Hispanics and Asians preferred medium and/or medium well, while U.S. consumers preferred medium and/or medium rare. For cooked steaks, the population effect was significant for all sensory attributes; Asians generally scored lower than did Hispanics and U.S. consumers. C and S3 generally had higher scores for all sensory attributes across 3 populations. Purchase intent for all forage-finished steaks was higher for Hispanics and U.S. consumers compared to Asians (50.0% to 77.8% compared with 43.2% to 65.9%). Attributes influencing purchase intent of forage-finished steaks differed among populations: tenderness (odds ratio = 1.4) for Hispanics, OCA (odds ratio = 1.5) for Asians, and OBF (odds ratio = 1.3) for U.S. consumers. Overall, this study demonstrated that the type of forage-finished system and ethnic differences influenced sensory acceptability and purchase intent of forage-finished rib-eye steaks. Demand for forage-finished beef has increased worldwide due to its potential health benefits. Little is known regarding the cross-cultural effects on the consumer acceptance of forage-finished beef. We evaluated sensory acceptance and purchase intent of raw and cooked forage-finished rib-eye steaks using Hispanic, Asian, and U.S. (White and African American) populations. This study demonstrated that consumer acceptability and purchase intent of forage-finished rib-eye steaks differed among Hispanic, Asian, and U.S. populations. This information can be used to guide development and marketing strategies for beef products. © 2015 Institute of Food Technologists®

MATISSE: alignment, integration, and test phase first results

NASA Astrophysics Data System (ADS)

Allouche, F.; Robbe-Dubois, S.; Lagarde, S.; Cruzalèbes, P.; Antonelli, P.; Bresson, Y.; Fantei-Caujolle, Y.; Marcotto, A.; Morel, S.; Beckmann, U.; Bettonvil, F.; Berio, Ph.; Heininger, M.; Lehmitz, M.; Agocs, T.; Brast, R.; Elswijk, E.; Ives, D.; Meixner, K.; Laun, W.; Mellein, M.; Neumann, U.; Bailet, C.; Clausse, J.-M.; Matter, A.; Meilland, A.; Millour, F.; Petrov, R. G.; Accardo, M.; Bristow, P.; Frahm, R.; Glindemann, A.; Gonzáles Herrera, J.-C.; Lizon, J.-L.; Schöller, M.; Graser, U.; Jaffe, W.; Lopez, B.

2016-08-01

MATISSE (Multi AperTure mid-Infrared SpectroScopic Experiment) is the spectro-interferometer for the VLTI of the European Southern Observatory, operating in near and mid-infrared, and combining up to four beams from the unit or the auxiliary telescopes. MATISSE will offer new breakthroughs in the study of circumstellar environments by allowing the multispectral mapping of the material distribution, the gas and essentially the dust. The instrument consists in a warm optical system (WOP) accepting four optical beams and relaying them after a dichroic splitting (for the L and M- and N- spectral bands) to cold optical benches (COB) located in two separate cryostats. The Observatoire de la Côte d'Azur is in charge of the WOP providing the spectral band separation, optical path equalization and modulation, pupil positioning, beam anamorphosis, beam commutation, and calibration. NOVA-ASTRON is in charge of the COB providing the functions of beam selection, reduction of thermal background emission, spatial filtering, pupil transfer, photometry and interferometry splitting, additional beam anamorphosis, spectral filtering, polarization selection, image dispersion, and image combination. The Max Planck Institut für Radio Astronomie is in charge of the operation and performance validation of the two detectors, a HAWAII-2RG from Teledyne for the L- and M- bands and a Raytheon AQUARIUS for the N-band. Both detectors are provided by ESO. The Max Planck Institut für Astronomie is in charge of the electronics and the cryostats for which the requirements on space limitations and vibration stability resulted on very specific and stringent decisions on the design. The integration and test of the COB: the two cryogenic systems, including the cold benches and the detectors, have been conducted at MPIA in parallel with the integration of the WOP at OCA. At the end of 2014, the complete instrument was integrated at OCA. Following this integration, a period of interface and alignment between the COB and the WOP took place resulting in the first interference fringes in the L-band during summer 2015 and the first interference fringes in the N-ban in March 2016. After a period of optimization of both the instrument reliability and the environmental working conditions, the test plan is presently being conducted in order to evaluate the complete performance of the instrument and its compliance with the high-level requirements. The present paper gives the first results of the alignment, integration and test phase of the MATISSE instrument.

A Finite Difference Approximation for a Coupled System of Nonlinear Size-Structured Populations

DTIC Science & Technology

2000-01-01

are available. For a classical Lotka - Volterra competition model which is represented by a system of N di erential equations, conditions on the growth...Methods Appl. Sci., 9 (1999), 1379-1391. [5] S. Ahmed, Extinction of Species in Nonautonomous Lotka - Volterra Systems, Proc. Amer. Math. Soc., 127 (1999...Walter DeGruyter, Berlin, 1995. [7] S. Ahmed and F. Montes de Oca, Extinction in Nonautonomous T -periodic Lotka - Volterra System, Appl. Math. Comput

First Trimester Noninvasive Prenatal Diagnosis: A Computational Intelligence Approach.

PubMed

Neocleous, Andreas C; Nicolaides, Kypros H; Schizas, Christos N

2016-09-01

The objective of this study is to examine the potential value of using machine learning techniques such as artificial neural network (ANN) schemes for the noninvasive estimation, at 11-13 weeks of gestation, the risk for euploidy, trisomy 21 (T21), and other chromosomal aneuploidies (O.C.A.), from suitable sonographic, biochemical markers, and other relevant data. A database(1) (1)The dataset can become available for academic purposes by communicating directly with the authors.

[Community residential devices associated with Psychiatric Hospital "Dr. Manuel A. Montes De Oca" in the Province of Buenos Aires, Argentina].

PubMed

Keena, Cecilia; Rossetto, Jorge; Somoza, Matías; De Lellis, Martín

2017-01-01

The psychiatric hospital "Dr. Manuel A. Montes de Oca" has developed a Program for the Reform of the Model of Attention and Integral Rehabilitation that includes the implantation of community residential devices in the area of influence of the Institution. This program, which aims at the progressive replacement of asylum beds, has been the subject of an evaluative investigation that has included almost all the devices through a transversal and descriptive design, with instruments of survey created by the equipment and in agreement with the References of the Institution. The present article proposes to initiate a set of evaluative works in different dimensions concerning the institutional reform process, describing the antecedents, the objectives and the methodology and development of the study to achieve the general characterization of the devices. The main results of the study are summarized below on a set of aspects that we consider most signifcant for the characterization of the devices: a) Type of users served; B) Coverage of Care; C) Method of approach; D) Use of social and health services; E) Expenses and returns to the Institution; E) Main barriers encountered in the implementation of such devices. The work concludes with a series of proposals that are based on the survey carried out tending to promote the greatest possible sustainability in the implementation of the selected community devices.

Confocal Raman microscopy supported by optical clearing treatment of the skin—influence on collagen hydration

NASA Astrophysics Data System (ADS)

Sdobnov, Anton Yu; Tuchin, Valery V.; Lademann, Juergen; E Darvin, Maxim

2017-07-01

Confocal Raman microscopy (CRM) is employed to study the skin physiology, drug permeation and skin disease monitoring. In order to increase the depth of investigations, the effect of optical clearing was observed on porcine ear skin ex vivo. The optical clearing agents (OCAs) glycerol and iohexol (Omnipaque™) were applied to the porcine ear skin and investigated by CRM after 30 and 60 min of treatment. The extent of optical clearing by utilizing concentrations of 70% glycerol and 100% Omnipaque™ was evaluated. The intensity of the skin-related Raman peaks significantly increased starting from the depth 160 µm for Omnipaque™ and 40 µm for glycerol (p  ⩽  0.05) after 60 min of treatment. The OCAs’ influence on the collagen hydration in the deep-located dermis was investigated. Both OCAs induce skin dehydration, but the effect of glycerol treatment (30 min and 60 min) is stronger. The obtained results demonstrate that with increasing the treatment time, both glycerol and Omnipaque™ solutions improve the optical clearing of porcine skin making the deep-located dermal regions able for investigations. At the used concentrations and time intervals, glycerol is more effective than Omnipaque™. However, Omnipaque™ is more promising than glycerol for future in vivo applications as it is an already approved pharmaceutic substance without any known impact on the skin structure.

Sensitivity Analysis of Weather Variables on Offsite Consequence Analysis Tools in South Korea and the United States.

PubMed

Kim, Min-Uk; Moon, Kyong Whan; Sohn, Jong-Ryeul; Byeon, Sang-Hoon

2018-05-18

We studied sensitive weather variables for consequence analysis, in the case of chemical leaks on the user side of offsite consequence analysis (OCA) tools. We used OCA tools Korea Offsite Risk Assessment (KORA) and Areal Location of Hazardous Atmospheres (ALOHA) in South Korea and the United States, respectively. The chemicals used for this analysis were 28% ammonia (NH₃), 35% hydrogen chloride (HCl), 50% hydrofluoric acid (HF), and 69% nitric acid (HNO₃). The accident scenarios were based on leakage accidents in storage tanks. The weather variables were air temperature, wind speed, humidity, and atmospheric stability. Sensitivity analysis was performed using the Statistical Package for the Social Sciences (SPSS) program for dummy regression analysis. Sensitivity analysis showed that impact distance was not sensitive to humidity. Impact distance was most sensitive to atmospheric stability, and was also more sensitive to air temperature than wind speed, according to both the KORA and ALOHA tools. Moreover, the weather variables were more sensitive in rural conditions than in urban conditions, with the ALOHA tool being more influenced by weather variables than the KORA tool. Therefore, if using the ALOHA tool instead of the KORA tool in rural conditions, users should be careful not to cause any differences in impact distance due to input errors of weather variables, with the most sensitive one being atmospheric stability.

Optical clearing of melanoma in vivo: characterization by diffuse reflectance spectroscopy and optical coherence tomography

NASA Astrophysics Data System (ADS)

Pires, Layla; Demidov, Valentin; Vitkin, I. Alex; Bagnato, Vanderlei; Kurachi, Cristina; Wilson, Brian C.

2016-08-01

Melanoma is the most aggressive type of skin cancer, with significant risk of fatality. Due to its pigmentation, light-based imaging and treatment techniques are limited to near the tumor surface, which is inadequate, for example, to evaluate the microvascular density that is associated with prognosis. White-light diffuse reflectance spectroscopy (DRS) and near-infrared optical coherence tomography (OCT) were used to evaluate the effect of a topically applied optical clearing agent (OCA) in melanoma in vivo and to image the microvascular network. DRS was performed using a contact fiber optic probe in the range from 450 to 650 nm. OCT imaging was performed using a swept-source system at 1310 nm. The OCT image data were processed using speckle variance and depth-encoded algorithms. Diffuse reflectance signals decreased with clearing, dropping by ˜90% after 45 min. OCT was able to image the microvasculature in the pigmented melanoma tissue with good spatial resolution up to a depth of ˜300 μm without the use of OCA; improved contrast resolution was achieved with optical clearing to a depth of ˜750 μm in tumor. These findings are relevant to potential clinical applications in melanoma, such as assessing prognosis and treatment responses. Optical clearing may also facilitate the use of light-based treatments such as photodynamic therapy.

Heart rate sensitive optical coherence angiography

NASA Astrophysics Data System (ADS)

Alvarez, Karl; Lopez-Tremoleda, Jordi; Donnan, Rob; Michael-Titus, Adina T.; Tomlins, Peter H.

2018-02-01

Optical coherence angiography (OCA) enables visualisation of three-dimensional micro-vasculature from optical coherence tomography data volumes. Typically, various statistical methods are used to discriminate static tissue from blood flow within vessels. In this paper, we introduce a new method that relies upon the beating heart frequency to isolate blood vessels from the surrounding tissue. Vascular blood flow is assumed to be more strongly modulated by the heart-beat compared to surrounding tissue and therefore short-time Fourier transform of sequential measurements can discriminate the two. Furthermore, it is demonstrated that adjacent B-Scans within an OCT data volume can provide the required sampling frequency. As such, the technique can be considered to be a spatially mapped variation of photoplethysmography (PPG), whereby each image voxel operates as a PPG detector. This principle is demonstrated using both a model system and in vivo for monitoring the vascular changes effected by traumatic brain injury in mice. In vivo measurements were acquired at an A-Scan rate of 10kHz to form a 500x500x512 (lateral x lateral x axial) pixel volume, enabling sequential sampling of the mouse heart rate in an expected range of 300-600 bpm. One of the advantages of this new OCA processing method is that it can be used in conjunction with existing algorithms as an additional filter for signal to noise enhancement.

Coordination and structure of Ca(II)-acetate complexes in aqueous solution studied by a combination of Raman and XAFS spectroscopies

NASA Astrophysics Data System (ADS)

Muñoz Noval, Álvaro; Nishio, Daisuke; Kuruma, Takuya; Hayakawa, Shinjiro

2018-06-01

The determination of the structure of Ca(II)-acetate in aqueous solution has been addressed by combining Raman and X-ray absorption fine structure spectroscopies. The pH-dependent speciation of the acetate/Ca(II) system has been studied observing modifications in specific Raman bands of the carboxyl group. The current results evidence the Ca(II)-acetate above acetate pKa forms a bidentate complex and presents a coordination 6, in which the Ca-O shell radius decrease of about 0.1 Å with respect the hydrated Ca2+ with coordination 8. The experimental results show the OCO angle of the carboxyl in the complex is close to 124°, being the OCaO angle about 60°.

Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.

PubMed

Chahal, Harvind S; Lin, Yuan; Ransohoff, Katherine J; Hinds, David A; Wu, Wenting; Dai, Hong-Ji; Qureshi, Abrar A; Li, Wen-Qing; Kraft, Peter; Tang, Jean Y; Han, Jiali; Sarin, Kavita Y

2016-07-18

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.

Proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type Ia.

PubMed

Peralta, Rosario; Sabban, Emilia Cohen; Friedman, Paula; Marcucci, Carolina; Bollea Garlatti, Luis A; Galimberti, Gastón; Cabo, Horacio

2017-01-01

Albino patients are at great risk for developing cutaneous neoplasms, including melanomas. In this paper we describe the dermatoscopic findings of nevi in two patients with oculocutaneous albinism type Ia (OCA-Ia) highlighting that they manifest a vascular pattern similar to that described for amelanotic melanoma. We propose managing these patients with dermoscopy, using the comparative approach, digital follow up (DFU), and reflectance confocal microscopy as a complementary tool for difficult cases.

Computational methods for fracture analysis of heavy-section steel technology (HSST) pressure vessel experiments

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

Bass, B.R.; Bryan, R.H.; Bryson, J.W.

This paper summarizes the capabilities and applications of the general-purpose and special-purpose computer programs that have been developed for use in fracture mechanics analyses of HSST pressure vessel experiments. Emphasis is placed on the OCA/USA code, which is designed for analysis of pressurized-thermal-shock (PTS) conditions, and on the ORMGEN/ADINA/ORVIRT system which is used for more general analysis. Fundamental features of these programs are discussed, along with applications to pressure vessel experiments.

Annual Report to Congress, Fiscal Year 1997. A Report by the Scientific Advisory Board of the Strategic Environmental Research and Development Program.

DTIC Science & Technology

1998-03-01

Environmental Research June 18, 1998 Ms. Joyce Chiras Defense Technical Information Center DTIC/OCA Suite 0944 8725 John J. Kingman Road Ft. Belvoir, VA 22060...6218 Re: Strategic Environmental Research and Development Program (SERDP) Annual Reports to Congress - FY 1997 Dear Ms. Chiras : Enclosed are copies of...Achievement in Water Science and Technology, National Water Research Institute, 1996; The Gordon Maskew Fair Award, American Academy of Environmental

Carrier Aviation and Hybrid Conflict: The Future of the Strike Fighter

DTIC Science & Technology

2011-05-01

MDTC NTA NTSIR OCA OEF OIF PGM. ROE SACT SAM SAR· SEAD SFARP SFTI SFWT .STW T& R TST UAS UCAS-D ULT Acronyms Anti Air Warfare...34tance ’ \\ ’ ’ of air-to-air training, or suggest a change to the training and readiness matrix (T& R ) or IDRC, but rather examine the mission...illustrate another example of the emphasis on air-to~air. In 2008, the new T & R matrix for the USMC F/ A-18 eliminated the Air Combat Tactics

Multi-objective optimization in the development of oil and water repellent cellulose fabric based on response surface methodology and the desirability function

NASA Astrophysics Data System (ADS)

Ahmad, Naseer; Kamal, Shahid; Raza, Zulfiqar Ali; Hussain, Tanveer

2017-03-01

The present study investigated multi-response optimization of certain input parameters viz. concentrations of oil and water repellent finish (Oleophobol CP-C®), dimethylol dihydroxy ethylene urea based cross linking agent (Knittex FEL) and curing temperature on some mechanical, (i.e. tear and tensile strengths), functional (i.e., water contact angle ‘WCA’, oil contact angle ‘OCA’) and comfort (i.e. crease recovery angle ‘CRA’, air permeability ‘AP’, and stiffness) properties of an oleo-hydrophobic finished fabric under response surface methodology and the desirability function. The results have been examined using analysis of variance (ANOVA) and desirability function for the identification of optimum levels of input variables. The ANOVA was employed also to identify the percentage contribution of process factors. Under the optimized conditions, which were obtained with a total desirability value of 0.7769, the experimental values of Oleophobol CP-C® (O-CPC), Knittex FEL (K-FEL) and curing temperature (C-Temp) agreed closely with the predicted values. The optimized process parameters for maximum WCA (135°), OCA (129°), AP (290 m s-1), CRA (214°), tear (1492 gf) and tensile (764 N) strengths and minimum stiffness (3.2928 cm) were found to be: concentration of OCP-C as 44.44 g l-1, concentration of cross linker K-FEL as 32.07 g l-1 and C-Temp as 161.81 °C.

The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein.

PubMed

Utzeri, V J; Bertolini, F; Ribani, A; Schiavo, G; Dall'Olio, S; Fontanesi, L

2016-02-01

A feral donkey population (Equus asinus), living in the Asinara National Park (an island north-west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper-binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across-population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E-18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource. © 2015 Stichting International Foundation for Animal Genetics.

Impact of Myopia on Corneal Biomechanics in Glaucoma and Nonglaucoma Patients.

PubMed

Chansangpetch, Sunee; Panpruk, Rawiphan; Manassakorn, Anita; Tantisevi, Visanee; Rojanapongpun, Prin; Hurst, Cameron P; Lin, Shan C

2017-10-01

We evaluated the impact of myopia on corneal biomechanical properties in primary open-angle glaucoma (POAG) and nonglaucoma patients, and the effect of modification of glaucoma on myopic eyes. This cross-sectional study included 66 POAG eyes (33 myopia, 33 nonmyopia) and 66 normal eyes (33 myopia, 33 nonmyopia). Seven corneal biomechanical parameters were measured by ultra-high-speed Scheimpflug imaging, including corneal deformation amplitude (CDA), inward/outward corneal applanation length (ICA, OCA), inward/outward corneal velocity (ICV, OCV), radius, and peak distance (PD). Mean age (SD) of the 65 male (49%) and 67 female (51%) patients was 59 (9.82) years. Myopia was associated with significantly higher CDA (adjusted effect = 0.104, P = 0.001) and lower OCV (adjusted effect = -0.105, P < 0.001) in the POAG group. Within the nonglaucoma group, myopic eyes had a significantly lower OCV (adjusted effect = -0.086, P < 0.001) and higher CDA (adjusted effect = 0.079, P = 0.001). All parameters except PD suggested that glaucoma modified the effect of myopia on corneal biomechanics. Percentage differences in the adjusted myopic effect between POAG and nonglaucoma patients was 31.65, 27.27, 31.65, 50.00, 22.09, and 60.49 for CDA, ICA, OCA, ICV, OCV, and radius, respectively. Myopia had a significant impact on corneal biomechanical properties in the POAG and nonglaucoma groups. The differences in corneal biomechanical parameters suggest that myopia is correlated with significantly lower ocular rigidity. POAG may enhance the effects of myopia on most of these parameters.

New records of helminths of Sceloporus pyrocephalus Cope (Squamata, Phrynosomatidae) from Guerrero and Michoacán, Mexico, with the description of a new species of Thubunaea Seurat, 1914 (Nematoda, Physalopteridae)

PubMed Central

de Oca, Edgar Uriel Garduño-Montes; López-Caballero, Jorge D.; Mata-López, Rosario

2017-01-01

Abstract A total of 61 specimens of the Red-headed Spiny Lizard Sceloporus pyrocephalus Cope (Phrynosomatidae) collected during the breeding season (June/July 2003, 2004 and 2005) from Western Mexico were examined for helminths. The morphological characterization of the helminths found was made through light microscopy and scanning electron microscopy. Nine taxa of helminths were identified, two cestodes: Mesocestoides sp. and Oochoristica sp., and seven nematodes: Parapharyngodon ayotzinapaensis Garduño-Montes de Oca, Mata-López & León-Règagnon, 2016, Parapharyngodon tikuinii Garduño-Montes de Oca, Mata-López & León-Règagnon, 2016, Parapharyngodon sp., Physalopterinae gen. sp., Skrjabinoptera scelopori Caballero-Rodríguez, 1971, Strongyluris similis Caballero, 1938 and a new species of Thubunaea Seurat, 1914. Larvae of Mesocestoides sp. and Physalopterinae gen. sp. were found in the body cavity and digestive tract, respectively. Excluding the species of Parapharyngodon Chatterji, 1933, S. pyrocephalus is recorded for the first time as a host of the remaining seven taxa of helminths. Additionally, Thubunaea leonregagnonae sp. n. is described and illustrated as a new nematode species, parasite of S. pyrocephalus from Mexico. This new species can be differentiated from the majority of its congeners by the absence of spicules, the particular pattern of caudal papillae in males and the small ratio of oesophagus length:male total body length (0.1–0.16). PMID:29290707

New records of helminths of Sceloporus pyrocephalus Cope (Squamata, Phrynosomatidae) from Guerrero and Michoacán, Mexico, with the description of a new species of Thubunaea Seurat, 1914 (Nematoda, Physalopteridae).

PubMed

de Oca, Edgar Uriel Garduño-Montes; López-Caballero, Jorge D; Mata-López, Rosario

2017-01-01

A total of 61 specimens of the Red-headed Spiny Lizard Sceloporus pyrocephalus Cope (Phrynosomatidae) collected during the breeding season (June/July 2003, 2004 and 2005) from Western Mexico were examined for helminths. The morphological characterization of the helminths found was made through light microscopy and scanning electron microscopy. Nine taxa of helminths were identified, two cestodes: Mesocestoides sp. and Oochoristica sp., and seven nematodes: Parapharyngodon ayotzinapaensis Garduño-Montes de Oca, Mata-López & León-Règagnon, 2016, Parapharyngodon tikuinii Garduño-Montes de Oca, Mata-López & León-Règagnon, 2016, Parapharyngodon sp., Physalopterinae gen. sp., Skrjabinoptera scelopori Caballero-Rodríguez, 1971, Strongyluris similis Caballero, 1938 and a new species of Thubunaea Seurat, 1914. Larvae of Mesocestoides sp. and Physalopterinae gen. sp. were found in the body cavity and digestive tract, respectively. Excluding the species of Parapharyngodon Chatterji, 1933, S. pyrocephalus is recorded for the first time as a host of the remaining seven taxa of helminths. Additionally, Thubunaea leonregagnonae sp. n. is described and illustrated as a new nematode species, parasite of S. pyrocephalus from Mexico. This new species can be differentiated from the majority of its congeners by the absence of spicules, the particular pattern of caudal papillae in males and the small ratio of oesophagus length:male total body length (0.1-0.16).

Improved eye- and skin-color prediction based on 8 SNPs.

PubMed

Hart, Katie L; Kimura, Shey L; Mushailov, Vladimir; Budimlija, Zoran M; Prinz, Mechthild; Wurmbach, Elisa

2013-06-01

To improve the 7-plex system to predict eye and skin color by increasing precision and detailed phenotypic descriptions. Analysis of an eighth single nucleotide polymorphism (SNP), rs12896399 (SLC24A4), showed a statistically significant association with human eye color (P=0.007) but a rather poor strength of agreement (κ=0.063). This SNP was added to the 7-plex system (rs12913832 at HERC2, rs1545397 at OCA2, rs16891982 at SLC45A2, rs1426654 at SLC24A5, rs885479 at MC1R, rs6119471 at ASIP, and rs12203592 at IRF4). Further, the instruction guidelines on the interpretation of genotypes were changed to create a new 8-plex system. This was based on the analysis of an 803-sample training set of various populations. The newly developed 8-plex system can predict the eye colors brown, green, and blue, and skin colors light, not dark, and not light. It is superior to the 7-plex system with its additional ability to predict blue eye and light skin color. The 8-plex system was tested on an additional 212 samples, the test set. Analysis showed that the number of positive descriptions for eye colors as being brown, green, or blue increased significantly (P=6.98e-15, z-score: -7.786). The error rate for eye-color prediction was low, at approximately 5%, while the skin color prediction showed no error in the test set (1% in training set). We can conclude that the new 8-plex system for the prediction of eye and skin color substantially enhances its former version.

Acute changes associated with electrode insertion measured with optical coherence microscopy

NASA Astrophysics Data System (ADS)

Hammer, Daniel X.; Lozzi, Andrea; Boretsky, Adam; Agrawal, Anant; Welle, Cristin G.

2016-03-01

Despite advances in functional neural imaging, penetrating microelectrodes provide the most direct interface for the extraction of neural signals from the nervous system and are a critical component of many high degree-of-freedom braincomputer interface devices. Electrode insertion is a traumatic event that elicits a complex neuroinflammatory response. In this investigation we applied optical coherence microscopy (OCM), particularly optical coherence angiography (OCA), to characterize the immediate tissue response during microelectrode insertion. Microelectrodes of varying dimension and footprint (one-, two-, and four-shank) were inserted into mouse motor cortex beneath a window after craniotomy surgery. The microelectrodes were inserted in 3-4 steps at 15-20°, with approximately 250 μm linear insertion distance for each step. Before insertion and between each step, OCM datasets were collected, including for quantitative capillary velocimetry. A cohort of control animals without microelectrode insertion was also imaged over a similar time period (2-3 hours). Mechanical tissue deformation was observed in all the experimental animals. The quantitative angiography results varied across animals, and were not correlated with device dimensions. In some cases, localized flow drop-out was observed in a small region surrounding the electrode, while in other instances a global disruption in flow occurred, perhaps as a result of large vessel compression caused by mechanical pressure. OCM is a tool that can be used in various neurophotonics applications, including quantification of the neuroinflammatory response to penetrating electrode insertion.

Hematopoietic Colony Formation from Human Growth Factor-Dependent TF1 Cells and Human Cord Blood Myeloid Progenitor Cells Depends on SHP2 Phosphatase Function

PubMed Central

Etienne-Julan, Maryse; Gotoh, Akihiko; Braun, Stephen E.; Lu, Li; Cooper, Scott; Feng, Gen-Sheng; Li, Xing Jun

2013-01-01

The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity. PMID:23082805

Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on SHP2 phosphatase function.

PubMed

Broxmeyer, Hal E; Etienne-Julan, Maryse; Gotoh, Akihiko; Braun, Stephen E; Lu, Li; Cooper, Scott; Feng, Gen-Sheng; Li, Xing Jun; Chan, Rebecca J

2013-03-15

The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity.

Oral Historical, Documentary, and Archaeological Investigations of Colbert, Barton, and Vinton, Mississippi: An Interim Report on Phase I of the Tombigbee Historic Townsites Project. Volume II.

DTIC Science & Technology

1982-05-01

newcomer to the area. most of his infor- mation was secondhand . However, person and nlace names h nroi.ied zuiced the initial research for this proiect...written many books on Mississinni -ilstrx.. . imrortance his interview to the project is his concise sv-nopis ,: oca1 li t ,r . ! was most familiar... Books of Insane Hospital, 1371-19&0 (Lowndes and Monroe counties) Business Letters (Insurance Companies) IF72-78, 1375-76, :373 (Clay. Lowndes, and

VLSI (Very Large Scale Integration) Design Tools, Reference Manual, Release 3.0.

DTIC Science & Technology

1985-08-01

generators/mult prior to running mult. The generated layout is output in directory 1ca in caesar cells with names of the form "caesarame*oca. Mut is a cft ...vlsa) spice(1.vlsi), User’s Guide to AML VLSI Dodgen Tools Reference Manual, UW/NW VLSI Consortium, University of Washington, (Christopher Terman, MIT...of the form ’caesarname..ca. Muls is a cft -based program and therefore also produces *.bd fiIls ’Caesaramew may not begin with the string mule. The

A Catalog of Eclipsing Binaries and Variable Stars Observed with ASTEP 400 from Dome C, Antarctica

NASA Astrophysics Data System (ADS)

Chapellier, E.; Mékarnia, D.; Abe, L.; Guillot, T.; Agabi, K.; Rivet, J.-P.; Schmider, F.-X.; Crouzet, N.; Aristidi, E.

2016-10-01

We used the large photometric database of the ASTEP program, whose primary goal was to detect exoplanets in the southern hemisphere from Antarctica, to search for eclipsing binaries (EcBs) and variable stars. 673 EcBs and 1166 variable stars were detected, including 31 previously known stars. The resulting online catalogs give the identification, the classification, the period, and the depth or semi-amplitude of each star. Data and light curves for each object are available at http://astep-vo.oca.eu.

Software structure for Vega/Chara instrument

NASA Astrophysics Data System (ADS)

Clausse, J.-M.

2008-07-01

VEGA (Visible spEctroGraph and polArimeter) is one of the focal instruments of the CHARA array at Mount Wilson near Los Angeles. Its control system is based on techniques developed on the GI2T interferometer (Grand Interferometre a 2 Telescopes) and on the SIRIUS fibered hyper telescope testbed at OCA (Observatoire de la Cote d'Azur). This article describes the software and electronics architecture of the instrument. It is based on local network architecture and uses also Virtual Private Network connections. The server part is based on Windows XP (VC++). The control software is on Linux (C, GTK). For the control of the science detector and the fringe tracking systems, distributed API use real-time techniques. The control software gathers all the necessary informations of the instrument. It allows an automatic management of the instrument by using an original task scheduler. This architecture intends to drive the instrument from remote sites, such as our institute in South of France.

Corsica: A Multi-Mission Absolute Calibration Site

NASA Astrophysics Data System (ADS)

Bonnefond, P.; Exertier, P.; Laurain, O.; Guinle, T.; Femenias, P.

2013-09-01

In collaboration with the CNES and NASA oceanographic projects (TOPEX/Poseidon and Jason), the OCA (Observatoire de la Côte d'Azur) developed a verification site in Corsica since 1996, operational since 1998. CALibration/VALidation embraces a wide variety of activities, ranging from the interpretation of information from internal-calibration modes of the sensors to validation of the fully corrected estimates of the reflector heights using in situ data. Now, Corsica is, like the Harvest platform (NASA side) [14], an operating calibration site able to support a continuous monitoring with a high level of accuracy: a 'point calibration' which yields instantaneous bias estimates with a 10-day repeatability of 30 mm (standard deviation) and mean errors of 4 mm (standard error). For a 35-day repeatability (ERS, Envisat), due to a smaller time series, the standard error is about the double ( 7 mm).In this paper, we will present updated results of the absolute Sea Surface Height (SSH) biases for TOPEX/Poseidon (T/P), Jason-1, Jason-2, ERS-2 and Envisat.

Impact of Myopia on Corneal Biomechanics in Glaucoma and Nonglaucoma Patients

PubMed Central

Panpruk, Rawiphan; Manassakorn, Anita; Tantisevi, Visanee; Rojanapongpun, Prin; Hurst, Cameron P.; Lin, Shan C.

2017-01-01

Purpose We evaluated the impact of myopia on corneal biomechanical properties in primary open-angle glaucoma (POAG) and nonglaucoma patients, and the effect of modification of glaucoma on myopic eyes. Methods This cross-sectional study included 66 POAG eyes (33 myopia, 33 nonmyopia) and 66 normal eyes (33 myopia, 33 nonmyopia). Seven corneal biomechanical parameters were measured by ultra-high-speed Scheimpflug imaging, including corneal deformation amplitude (CDA), inward/outward corneal applanation length (ICA, OCA), inward/outward corneal velocity (ICV, OCV), radius, and peak distance (PD). Results Mean age (SD) of the 65 male (49%) and 67 female (51%) patients was 59 (9.82) years. Myopia was associated with significantly higher CDA (adjusted effect = 0.104, P = 0.001) and lower OCV (adjusted effect = −0.105, P < 0.001) in the POAG group. Within the nonglaucoma group, myopic eyes had a significantly lower OCV (adjusted effect = −0.086, P < 0.001) and higher CDA (adjusted effect = 0.079, P = 0.001). All parameters except PD suggested that glaucoma modified the effect of myopia on corneal biomechanics. Percentage differences in the adjusted myopic effect between POAG and nonglaucoma patients was 31.65, 27.27, 31.65, 50.00, 22.09, and 60.49 for CDA, ICA, OCA, ICV, OCV, and radius, respectively. Conclusions Myopia had a significant impact on corneal biomechanical properties in the POAG and nonglaucoma groups. The differences in corneal biomechanical parameters suggest that myopia is correlated with significantly lower ocular rigidity. POAG may enhance the effects of myopia on most of these parameters. PMID:28979996

Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities.

PubMed

Gege, Christian; Kinzel, Olaf; Steeneck, Christoph; Schulz, Andreas; Kremoser, Claus

2014-01-01

The Farnesoid X Receptor (FXR) was recently validated in clinical studies using the bile acid analogue Obeticholic Acid (OCA) as an attractive drug target for liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). OCA, however, turned out to induce cholesterol- related side effects upon prolonged treatment and it shows bile acid like pharmacokinetics. The quest for synthetic non-steroidal FXR agonists with general drug likeliness and improved pharmacokinetic and - dynamic properties has started more than a decade ago: The first non-steroidal and selective FXR agonist with decent submicromolar potency, GW4064, was patented in 1998 and published in 2000. Since then, many pharmaceutical companies have taken GW4064 as a structural template for their efforts in identifying novel patentable FXR agonists with the GW-derived trisubstituted isoxazole general structure. However, so far only one compound out of these different series has made it into the early stages of clinical development: The Px-102/Px-104 from Phenex is currently tested in a phase IIa study in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). In this review we try to summarize from the patent and scientific literature the attempts to improve the GW4064 structure into different directions. Furthermore, we suggest directions for further improvements of this special class of synthetic FXR agonists which all display the typical "hammerhead"-conformation in the FXR ligand binding pocket that provides the basis for their impressive in vitro and in vivo potencies.

The Impact of Organization Culture on Satisfaction of Engineers in Technology

NASA Technical Reports Server (NTRS)

Westbrook, Jerry W.; Takada, Pamela W.; Roth, Axel (Technical Monitor)

2001-01-01

In today's technological workplace with the shortage of qualified knowledge workers, the factors that lead to job satisfaction have increasing importance. Several past studies have indicated that knowledge worker job satisfaction increases when Herzberg motivators are present. Other research has indicated that job satisfaction improves as the degree of organic organizational culture increases. After examining the factors that led to knowledge worker job satisfaction, the current study was undertaken. Knowledge workers in varying organizational cultures were surveyed in an effort to determine if there is a relationship between the degree of knowledge worker job satisfaction and the measure of organic organization culture. Two survey instruments, the Organizational Cultural Assessment (OCA) developed by Riegle, and the Minnesota Satisfaction Questionnaire (MSQ), were utilized. The OCA delineates degree of organic culture present whereas the MSQ measures job satisfaction. Results of both surveys were statistically analyzed to determine if knowledge workers experience higher satisfaction levels in organic organizational cultures. Once data was analyzed and the hypothesis proven, this could lead companies to move toward an organic culture with emphasis on motivators in an effort to make their organizational culture more conducive to higher employee retention. Through understanding the factors that lead to increased job satisfaction, corporate resources could more efficiently utilized. A total of eight high technology workplaces were surveyed. Five of the eight workplaces yielded statistically significant positive correlation between a positive organizational culture and increased job satisfaction. These initial results indicate the connection between culture and job satisfaction. The relationship will be further analyzed through future surveys of numerous high technology workplaces.

Novel Genetic Loci Associated with Retinal Microvascular Diameter

PubMed Central

Jensen, Richard A.; Sim, Xueling; Smith, Albert Vernon; Li, Xiaohui; Jakobsdóttir, Jóhanna; Cheng, Ching-Yu; Brody, Jennifer A.; Cotch, Mary Frances; Mcknight, Barbara; Klein, Ronald; Wang, Jie Jin; Kifley, Annette; Harris, Tamara B.; Launer, Lenore J.; Taylor, Kent D.; Klein, Barbara E.K.; Raffel, Leslie J.; Li, Xiang; Ikram, M. Arfan; Klaver, Caroline C.; van der Lee, Sven J.; Mutlu, Unal; Hofman, Albert; Uitterlinden, Andre G.; Liu, Chunyu; Kraja, Aldi T.; Mitchell, Paul; Gudnason, Vilmundur; Rotter, Jerome I.; Boerwinkle, Eric; van Duijn, Cornelia M.; Psaty, Bruce M.; Wong, Tien Y.

2015-01-01

Background There is increasing evidence that retinal microvascular diameters are associated with cardio- and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size. Methods and Results This study extends previous genome-wide association study results using 24,000+ multi-ethnic participants from 7 discovery and 5,000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single nucleotide polymorphisms (SNPs) and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent (CRVE) and the central retinal arteriole equivalent (CRAE). We report 4 new loci associated with CRVE, one of which is also associated with CRAE. The 4 SNPs are rs7926971 in TEAD1 (p=3.1×10−11, minor allele frequency (MAF)=0.43), rs201259422 in TSPAN10 (p=4.4×10−9, MAF=0.27), rs5442 in GNB3 (p=7.0×10−10, MAF=0.05) and rs1800407 in OCA2 (p=3.4×10−8, MAF=0.05). The latter SNP, rs1800407, was also associated with CRAE (p=6.5×10−12). Results from the gene-based burden tests were null. In phenotype look-ups, SNP rs201255422 was associated with both systolic (p=0.001) and diastolic blood pressure (p=8.3×10−04). Conclusions Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease. PMID:26567291

Atmospheric Sciences Meet Astronomy: Mutual Benefits from two Different Approaches

NASA Astrophysics Data System (ADS)

Kausch, Wolfgang; Noll, Stefan; Kimeswenger, Stefan; Kondrak, Matthias; Unterguggenberger, Stefanie; Przybilla, Norbert; Lakićević, Maša; Zeilinger, Werner

2016-04-01

Light from astronomical targets has to pass the Earth's atmosphere when being observed by ground-based telescope facilities. The signal detected by modern astronomical spectrographs is significantly influenced by molecular absorption and airglow emission. The first mainly arises from various species in the lower, thus denser atmosphere, whereas the latter is caused by chemiluminescence in the mesopause region and above. As ground-based astronomical spectrographs are optimised from the near-UV to the mid-infrared regime (0.3....25μm), a number of absorption features from numerous species are directly visible (e.g. H2O, CO2, CH4, O2, O3,...). The same is true for the airglow emission arising e.g. from the hydroxyl radical and oxygen. The high resolution provided by some spectrographs and their frequent usage allows a detailed investigation of atmospheric lines. Usually being a source of noise for astronomers, which needs to be corrected for, this influence can be used to precisely analyse the composition and the state of the Earth's atmosphere above an observatory. On the other hand, a good knowledge of this allows astronomers to better correct for this influence. Thus, both, atmospheric and astronomical sciences highly benefit from a good understanding of the atmospheric state above an observatory. During the past years we conducted several studies to link astronomical and atmospheric data. For this purpose we use data taken with the Very Large Telescope (VLT) operated by the European Southern Observatory, and the Cerro Armazones Observatory (OCA, University of Bochum, Germany; Universidad Católica del Norte, Chile), both located in the Chilean Atacama desert. The three spectrographs used in our studies are X-Shooter@VLT (resolving power R˜3300...18000, wavelength range λ=0.3...2.5μm), UVES@VLT (R˜20.000....110.000, λ=0.3....1.1μm), and BESO@OCA (R=50000@Hα=0.656μm, λ=0.38 - 0.84μm). In addition, we use atmospheric data obtained with the satellites ENVISAT (MIPAS instrument), Aura (MLS), and TIMED (SABER), and modelled data from the Global Data Assimilation System (GDAS), and the ERA/MACC reanalysis from the European Centre for Medium-Range Weather Forecasts (ECMWF). In this presentation we give an overview on our methods to link these various data, the impact/application of these data on atmospheric sciences and observations with classical and future astro-particle Cherenkov telescopes, and present recent results.

VizieR Online Data Catalog: Periods of 4-10 Myr old T Tauri members of Orion OB1 (Karim+, 2016)

NASA Astrophysics Data System (ADS)

Karim, M. T.; Stassun, K. G.; Briceno, C.; Vivas, A. K.; Raetz, S.; Mateu, C.; Downes, J. J.; Calvet, N.; Hernandez, J.; Neuhauser, R.; Mugrauer, M.; Takahashi, H.; Tachihara, K.; Chini, R.; Cruz-Dias, G. A.; Aarnio, A.; James, D. J.; Hackstein, M.

2017-02-01

The Astronomia Variability Survey of Orion (CVSO) was carried out at the Llano del Hato National Astronomical Observatory in Venezuela, with the QUEST CCD mosaic camera (8000*8000pixels) on the 1m (clear aperture) Schmidt telescope, with a plate scale of 1.02''/pixel and field of view of 5.4 deg2. This V-, RC-, and IC-band multi-epoch survey, covering ~180deg2 of the Orion OB1 association, spans a time baseline of 12yr, from 1998 December to 2011 February. The 25 Ori cluster was observed by the 0.6/0.9m Schmidt-type telescope at Jena Observatory (Germany), the two 5.9'' telescopes at Observatorio Cerro Armazones (OCA, Chile), and the 1.5m reflector at the Gunma Astronomical Observatory in Japan, over four observing campaigns during the years 2010-2013. The Jena Schmidt-type telescope was equipped with the optical Schmidt Telescope Camera (STK), with an e2v 42-10 2048*2048 detector, yielding a plate scale of 1.55''/pixel and a field of view of 53'*53', thus encompassing most of the cluster. The Jena 50s exposures, all taken through the R filter, were centered on 25 Ori. A total of 8506 individual exposures were obtained in 108 nights. The Gunma 1.5m reflector observations were carried out by obtaining 60s integrations in R with the Gunma Low-resolution Spectrograph and Imager (GLOWS), which has an e2v CCD55-30 1250*1152 pixel detector with a 0.6''/pixel scale, covering a field of view of 12.5'*11.5'. Observations were obtained during four nights in year 2010. The Observatorio Cerro Armazones observations were done in the R band using the RoBoTT (Robotic Bochum TWin Telescope), which consists of twin Takahashi 150mm aperture apochromatic astrographs, each equipped with an Apogee U16M camera with a KAF-16803 4096*4096 pixel CCD, providing a 2.7°*2.7° field of view with 2.37''/pixel scale. The 60s exposures were centered on 25 Ori, spanning an area much larger than the cluster. OCA data were obtained during all YETI seasons. During the nights of 2006 January 8-15, we used the 0.9m telescope with the 8000*8000 pixel MOSAIC imager at the Kitt Peak National Observatory (KPNO), Arizona, USA, to obtain IC-band time-series observations of several regions in the Orion OB1 association, including the 25 Ori cluster in the OB1a subassociation, and fields in the OB1b subassociation, under NOAO program 2005B-0529. (1 data file).

Evaluation of Low Melting Halide Systems for Battery Applications.

DTIC Science & Technology

1983-04-01

prominent peak at 95 cm-1 . The spectrum of the other sample exhibits 124 -4 ,4 -4 -44 .. t - CD - 0o - N. 0 uN C)(j QCD oca CD u C 125. the same peaks... lattice with 6-fold coordination about in this region can be drawn. However. his isotherms have aluminum and melts at 192.4 ’C with a AH° of 35.3 kJ the...temperature in the composition of SbC.AICI is favored by the relatively large direction of increasing aluminum bromide content. just as lattice energy of

Programs and Perspectives of Visible Long Baseline Interferometry VEGA/CHARA

NASA Astrophysics Data System (ADS)

Mourard, D.; Nardetto, N.; Ligi, R.; Perraut, K.

VEGA/CHARA is a visible spectro-interferometer installed on the CHARA Array at Mount Wilson Observatory. Combining high spectral resolution (6,000 or 30,000) and high angular resolution (0.3 mas), VEGA/CHARA opens a wide class of astrophysical topics in the stellar physics domain. Circumstellar environments and fundamental parameters with a high precision could be studied. We will present a review of recent results and discuss the programs currently engaged in the field of pulsating stars and more generally for the fundamental stellar parameters. Details could be found at http://www-n.oca.eu/vega/en/publications/index.htm.

VizieR Online Data Catalog: AMBRE project. FEROS archived spectra (Worley+, 2012)

NASA Astrophysics Data System (ADS)

Worley, C. C.; de Laverny, P.; Recio-Blanco, A.; Hill, V.; Bijaoui, A.; Ordenovic, C.

2017-11-01

This first release concerns the FEROS data collected from 2005, October to 2009, December. The spectra were reduced by ESO with the corresponding automatic pipeline and then sent to the Observatoire de la Cote d'Azur (OCA, Nice) for ingestion into a dedicated pipeline (see paper). All FEROS spectra cover the domain 350nm-920nm at a resolution of about 48000. Before their ingestion into MATISSE, these spectra have been convolved at a lower resolution (Δλ=0.33Å), sliced and resampled (total number of pixels = 11890). (1 data file).

Induction of homologous recombination following in utero exposure to DNA-damaging agents.

PubMed

Karia, Bijal; Martinez, Jo Ann; Bishop, Alexander J R

2013-11-01

Much of our understanding of homologous recombination, as well as the development of the working models for these processes, has been derived from extensive work in model organisms, such as yeast and fruit flies, and mammalian systems by studying the repair of induced double strand breaks or repair following exposure to genotoxic agents in vitro. We therefore set out to expand this in vitro work to ask whether DNA-damaging agents with varying modes of action could induce somatic change in an in vivo mouse model of homologous recombination. We exposed pregnant dams to DNA-damaging agents, conferring a variety of lesions at a specific time in embryo development. To monitor homologous recombination frequency, we used the well-established retinal pigment epithelium pink-eyed unstable assay. Homologous recombination resulting in the deletion of a duplicated 70 kb fragment in the coding region of the Oca2 gene renders this gene functional and can be visualized as a pigmented eyespot in the retinal pigment epithelium. We observed an increased frequency of pigmented eyespots in resultant litters following exposure to cisplatin, methyl methanesulfonate, ethyl methanesulfonate, 3-aminobenzamide, bleomycin, and etoposide with a contrasting decrease in the frequency of detectable reversion events following camptothecin and hydroxyurea exposure. The somatic genomic rearrangements that result from such a wide variety of differently acting damaging agents implies long-term potential effects from even short-term in utero exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

Laser, GPS and absolute gravimetry vertical positioning time series comparison at the OCA observatory, France

NASA Astrophysics Data System (ADS)

Nicolas, J.; Nocquet, J.; van Camp, M.; Coulot, D.

2003-12-01

Time-dependent displacements of stations usually have magnitude close to the accuracy of each individual technique, and it still remains difficult to separate the true geophysical motion from possible artifacts inherent to each space geodetic technique. The Observatoire de la C“te d'Azur (OCA), located at Grasse, France benefits from the collocation of several geodetic instruments and techniques (3 laser ranging stations, and a permanent GPS) what allows us to do a direct comparison of the time series. Moreover, absolute gravimetry measurement campaigns have also been regularly performed since 1997, first by the "Ecole et Observatoire des Sciences de la Terre (EOST) of Strasbourg, France, and more recently by the Royal Observatory of Belgium. This study presents a comparison between the positioning time series of the vertical component derived from the SLR and GPS analysis with the gravimetric results from 1997 to 2003. The laser station coordinates are based on a LAGEOS -1 and -2 combined solution using reference 10-day arc orbits, the ITRF2000 reference frame, and the IERS96 conventions. Different GPS weekly global solutions provided from several IGS are combined and compared to the SLR results. The absolute gravimetry measurements are converted into vertical displacements with a classical gradient. The laser time series indicate a strong annual signal at the level of about 3-4 cm peak to peak amplitude on the vertical component. Absolute gravimetry data agrees with the SLR results. GPS positioning solutions also indicate a significant annual term, but with a magnitude of only 50% of the one shown by the SLR solution and by the gravimetry measurements. Similar annual terms are also observed on other SLR sites we processed, but usually with! lower and various amplitudes. These annual signals are also compared to vertical positioning variations corresponding to an atmospheric loading model. We present the level of agreement between the different techniques and we discuss possible explanations for the discrepancy noted between the signals. At last, we expose explanations for the large annual term at Grasse: These annual variations could be partly due to an hydrological loading effect on the karstic massif on which the observatory is located.

Classes Azur Astro Espace International Hands-on Space Experience

NASA Astrophysics Data System (ADS)

Jung, P.

2002-01-01

Created in 1994 in the wake of the closure of the Space Camp of Patrick Baudry in Cannes, Classes Azur Astro Espace (AAE) provide a world's unique combination of space and astronomy courses, as given by active and retired professionals of two of the best space and astronomical facilities extant: Alcatel Space in Cannes and Observatoire de la Côte d'Azur (OCA) in Nice, Grasse and Caussols. Fifteen space modules, of 30 to 60 minutes each, have been established, giving simple and clear explanations on launchers, satellites, their applications, their development, together with an historical background. Basic experiments are included, such as an unique small catapult to explain gravity, or more classical water rockets. The basic AAE sojourn extends over 3 days: one day for space (including a visit of Alcatel Space, the biggest satellite manufacturer outside the US and Russia), one day for astronomy (including a visit of the biggest observatory in Europe) and one day à-la-carte (Côte d'Azur offers much, such as the Oceanographic Museum in Monaco). More and more groups are adding a fourth day, with a visit to the nice old village of Perinaldo in Italy, where famous astronomer Cassini was born. Lycée de Cachan, near Paris, even takes 12-day sojourns every year. The public has been extremely wide, from age 5 to 70, from students to enthusiasts. Coming initially all over from France, participants now include since 2001 German and Italian pupils and teachers. In 2001 also, ESA came in the shape of a Space Camp. ISU's Master of Space Studies participates to a shortened version of AAE every even-year. Up to the end of 2001, 62 classes with 2,025 participants from 20 countries had thus come to enjoy space education on Côte d'Azur. Such success is due in no small part to the very attractive price and flexibility of these activities, notably thanks to the support of ESA, CNES, Rectorat d'Académie de Nice, Conseil Général des Alpes-Maritimes, Ville de Cannes, AAAF, TDF, Alcatel Space and OCA.

Sulfur isotope change across the Early Mississippian K-O (Kinderhookian-Osagean) δ13C excursion

NASA Astrophysics Data System (ADS)

Maharjan, Dev; Jiang, Ganqing; Peng, Yongbo; Nicholl, Michael J.

2018-07-01

Paired carbonate associate sulfate (CAS) sulfur isotopes (δ34SCAS), pyrite sulfur isotopes (δ34SPY) and CAS oxygen isotopes (δ18OCAS) across the Early Mississippian K-O δ13C excursion are documented from two sections of a west-dipping carbonate ramp in the southern Great Basin, western U.S.A. A 4-6‰ positive δ34SCAS anomaly, accompanied by negative shifts in δ34SPY and δ18OCAS, is found within the K-O δ13C excursion. In the section with a broader δ13C excursion, Δ34S (Δ34 S =δ34SCAS-δ34SPY) increases from 15‰ to 45‰ and δ13Ccarb drops from 7‰ to 4‰ at the same stratigraphic interval. If this δ34SCAS anomaly represents a global phenomenon, the large magnitude (4-6‰) and short duration (shorter than that of δ13C) suggest an unusual pyrite burial event that expanded from sediments to the ocean water column. In this scenario, the areal and volumetric expansion of sulfate reduction and pyrite burial was likely triggered by abundantly available organic matter near the peak of the K-O δ13C excursion, during which organic carbon production and burial may have reached a maximum, thus substantially expanding the oxygen minimum zone (OMZ). Numerical simulations suggest that pyrite burial rates 2.5-5 times higher than that of the modern ocean followed by sulfide oxidation are required to produce the observed δ34SCAS anomaly in a sulfate-rich ([SO4] ≥28 mM) Early Mississippian ocean. Alternatively, the sulfur and CAS oxygen isotope anomalies may record local sulfur cycling in a foreland basin where changes in weathering input and bottom-water redox conditions in response to sea-level fall and cooling resulted in isotope changes. In both scenarios (either local or global), the integrated carbon, sulfur, and CAS-oxygen isotope data suggest a much more dynamic sulfur cycle across the K-O δ13C excursion than has been previously suggested.

An in situ polymerization approach for the synthesis of superhydrophobic and superoleophilic nanofibrous membranes for oil-water separation

NASA Astrophysics Data System (ADS)

Shang, Yanwei; Si, Yang; Raza, Aikifa; Yang, Liping; Mao, Xue; Ding, Bin; Yu, Jianyong

2012-11-01

Superhydrophobic and superoleophilic nanofibrous membranes exhibiting robust oil-water separation performance were prepared by a facile combination of electrospun cellulose acetate (CA) nanofibers and a novel in situ polymerized fluorinated polybenzoxazine (F-PBZ) functional layer that incorporated silica nanoparticles (SiO2 NPs). By employing the F-PBZ/SiO2 NPs modification, the pristine hydrophilic CA nanofibrous membranes were endowed with a superhydrophobicity with the water contact angle of 161° and a superoleophilicity with the oil contact angle of 3°. Surface morphological studies have indicated that the wettability of resultant membranes could be manipulated by tuning the surface composition as well as the hierarchical structures. The quantitative hierarchical roughness analysis using the N2 adsorption method has confirmed the major contribution of SiO2 NPs on enhancing the porous structure, and a detailed correlation between roughness and solid-liquid interface pinning is proposed. Furthermore, the as-prepared membranes exhibited fast and efficient separation for oil-water mixtures and excellent stability over a wide range of pH conditions, which would make them a good candidate in industrial oil-polluted water treatments and oil spill cleanup, and also provided a new insight into the design and development of functional nanofibrous membranes through F-PBZ modification.Superhydrophobic and superoleophilic nanofibrous membranes exhibiting robust oil-water separation performance were prepared by a facile combination of electrospun cellulose acetate (CA) nanofibers and a novel in situ polymerized fluorinated polybenzoxazine (F-PBZ) functional layer that incorporated silica nanoparticles (SiO2 NPs). By employing the F-PBZ/SiO2 NPs modification, the pristine hydrophilic CA nanofibrous membranes were endowed with a superhydrophobicity with the water contact angle of 161° and a superoleophilicity with the oil contact angle of 3°. Surface morphological studies have indicated that the wettability of resultant membranes could be manipulated by tuning the surface composition as well as the hierarchical structures. The quantitative hierarchical roughness analysis using the N2 adsorption method has confirmed the major contribution of SiO2 NPs on enhancing the porous structure, and a detailed correlation between roughness and solid-liquid interface pinning is proposed. Furthermore, the as-prepared membranes exhibited fast and efficient separation for oil-water mixtures and excellent stability over a wide range of pH conditions, which would make them a good candidate in industrial oil-polluted water treatments and oil spill cleanup, and also provided a new insight into the design and development of functional nanofibrous membranes through F-PBZ modification. Electronic supplementary information (ESI) available: Detailed synthesis and structural confirmation of BAF-tfa, FT-IR results, OCA results and Movie S1. See DOI: 10.1039/c2nr33063f

Cholestenoic acids regulate motor neuron survival via liver X receptors

PubMed Central

Theofilopoulos, Spyridon; Griffiths, William J.; Crick, Peter J.; Yang, Shanzheng; Meljon, Anna; Ogundare, Michael; Kitambi, Satish Srinivas; Lockhart, Andrew; Tuschl, Karin; Clayton, Peter T.; Morris, Andrew A.; Martinez, Adelaida; Reddy, M. Ashwin; Martinuzzi, Andrea; Bassi, Maria T.; Honda, Akira; Mizuochi, Tatsuki; Kimura, Akihiko; Nittono, Hiroshi; De Michele, Giuseppe; Carbone, Rosa; Criscuolo, Chiara; Yau, Joyce L.; Seckl, Jonathan R.; Schüle, Rebecca; Schöls, Ludger; Sailer, Andreas W.; Kuhle, Jens; Fraidakis, Matthew J.; Gustafsson, Jan-Åke; Steffensen, Knut R.; Björkhem, Ingemar; Ernfors, Patrik; Sjövall, Jan; Arenas, Ernest; Wang, Yuqin

2014-01-01

Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death. PMID:25271621

Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats.

PubMed

Yang, Jing; Sun, Lixin; Wang, Lu; Hassan, Hozeifa M; Wang, Xuan; Hylemon, Phillip B; Wang, Tao; Zhou, Huiping; Zhang, Luyong; Jiang, Zhenzhou

2017-01-01

Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 μg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7α-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo . The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro . The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity.

(T2L2) Time Transfer by Laser Link

NASA Technical Reports Server (NTRS)

Veillet, Christian; Fridelance, Patricia

1995-01-01

T2L2 (Time Transfer by Laser Link) is a new generation time transfer experiment based on the principles of LASSO (Laser Synchronization from Synchronous Orbit) and used with an operational procedure developed at OCA (Observatoire de la Cote d'Azur) during the active intercontinental phase of LASSO. The hardware improvements could lead to a precision better than 10 ps for time transfer (flying clock monitoring or ground based clock comparison). Such a package could fly on any spacecraft with a stable clock. It has been developed in France in the frame of the PHARAO project (cooled atom clock in orbit) involving CNES and different laboratories. But T2L2 could fly on any spacecraft carrying a stable oscillator. A GPS satellite would be a good candidate, as T2L2 could allow to link the flying clock directly to ground clocks using light, aiming to important accuracy checks, both for time and for geodesy. Radioastron (a flying VLBI antenna with a H-maser) is also envisioned, waiting for a PHARAO flight. The ultimate goal of T2L2 is to be part of more ambitious missions, as SORT (Solar Orbit Relativity Test), aiming to examine aspects of the gravitation in the vicinity of the Sun.

In situ polymerized superhydrophobic and superoleophilic nanofibrous membranes for gravity driven oil-water separation

NASA Astrophysics Data System (ADS)

Tang, Xiaomin; Si, Yang; Ge, Jianlong; Ding, Bin; Liu, Lifang; Zheng, Gang; Luo, Wenjing; Yu, Jianyong

2013-11-01

Creating an efficient, cost-effective method that can provide simple, practical and high-throughput separation of oil-water mixtures has proved extremely challenging. This work responds to these challenges by designing, fabricating and evaluating a novel fluorinated polybenzoxazine (F-PBZ) modified nanofibrous membrane optimized to achieve gravity driven oil-water separation. The membrane design is then realized by a facile combination of electrospun poly(m-phenylene isophthalamide) (PMIA) nanofibers and an in situ polymerized F-PBZ functional layer incorporating SiO2 nanoparticles (SiO2 NPs). By employing the F-PBZ/SiO2 NP modification, the pristine hydrophilic PMIA nanofibrous membranes are endowed with promising superhydrophobicity with a water contact angle of 161° and superoleophilicity with an oil contact angle of 0°. This new membrane shows high thermal stability (350 °C) and good repellency to hot water (80 °C), and achieves an excellent mechanical strength of 40.8 MPa. Furthermore, the as-prepared membranes exhibited fast and efficient separation of oil-water mixtures by a solely gravity driven process, which makes them good candidates for industrial oil-polluted water treatments and oil spill cleanup, and also provided new insights into the design and development of functional nanofibrous membranes through F-PBZ modification.Creating an efficient, cost-effective method that can provide simple, practical and high-throughput separation of oil-water mixtures has proved extremely challenging. This work responds to these challenges by designing, fabricating and evaluating a novel fluorinated polybenzoxazine (F-PBZ) modified nanofibrous membrane optimized to achieve gravity driven oil-water separation. The membrane design is then realized by a facile combination of electrospun poly(m-phenylene isophthalamide) (PMIA) nanofibers and an in situ polymerized F-PBZ functional layer incorporating SiO2 nanoparticles (SiO2 NPs). By employing the F-PBZ/SiO2 NP modification, the pristine hydrophilic PMIA nanofibrous membranes are endowed with promising superhydrophobicity with a water contact angle of 161° and superoleophilicity with an oil contact angle of 0°. This new membrane shows high thermal stability (350 °C) and good repellency to hot water (80 °C), and achieves an excellent mechanical strength of 40.8 MPa. Furthermore, the as-prepared membranes exhibited fast and efficient separation of oil-water mixtures by a solely gravity driven process, which makes them good candidates for industrial oil-polluted water treatments and oil spill cleanup, and also provided new insights into the design and development of functional nanofibrous membranes through F-PBZ modification. Electronic supplementary information (ESI) available: Detailed synthesis and structural confirmation of BAF-oda, OCA results, Raman spectrum and Movies S1 and S2. See DOI: 10.1039/c3nr03937d

Ureteric stents vs percutaneous nephrostomy for initial urinary drainage in children with obstructive anuria and acute renal failure due to ureteric calculi: a prospective, randomised study.

PubMed

ElSheemy, Mohammed S; Shouman, Ahmed M; Shoukry, Ahmed I; ElShenoufy, Ahmed; Aboulela, Waseem; Daw, Kareem; Hussein, Ahmed A; Morsi, Hany A; Badawy, Hesham

2015-03-01

To compare percutaneous nephrostomy (PCN) tube vs JJ ureteric stenting as the initial urinary drainage method in children with obstructive calcular anuria (OCA) and post-renal acute renal failure (ARF) due to bilateral ureteric calculi, to identify the selection criteria for the initial urinary drainage method that will improve urinary drainage, decrease complications and facilitate the subsequent definitive clearance of stones, as this comparison is lacking in the literature. A series of 90 children aged ≤12 years presenting with OCA and ARF due to bilateral ureteric calculi were included from March 2011 to September 2013 at Cairo University Pediatric Hospital in this randomised comparative study. Patients with grade 0-1 hydronephrosis, fever or pyonephrosis were excluded. No patient had any contraindication for either method of drainage. Stable patients (or patients stabilised by dialysis) were randomised (non-blinded, block randomisation, sealed envelope method) into PCN-tube or bilateral JJ-stent groups (45 patients for each group). Initial urinary drainage was performed under general anaesthesia and fluoroscopic guidance. We used 4.8-6 F JJ stents or 6-8 F PCN tubes. The primary outcomes were the safety and efficacy of both groups for the recovery of renal functions. Both groups were compared for operative and imaging times, complications, and the period required for a return to normal serum creatinine levels. The secondary outcomes included the number of subsequent interventions needed for clearance of stones. Additional analysis was done for factors affecting outcome within each group. All presented patients completed the study with intention-to-treat analysis. There was no significant difference between the PCN-tube and JJ-stent groups for the operative and imaging times, period for return to a normal creatinine level and failure of insertion. There were significantly more complications in the PCN-tube group. The stone size (>2 cm) was the only factor affecting the rates of mucosal complications, operative time and failure of insertion in the JJ-stent group. The degree of hydronephrosis significantly affected the operative time for PCN-tube insertion. Grade 2 hydronephrosis was associated with all cases of insertion failure in the PCN-tube group. The total number of subsequent interventions needed to clear stones was significantly higher in the PCN-tube group, especially in patients with bilateral stones destined for chemolytic dissolution (alkalinisation) or extracorporeal shockwave lithotripsy (ESWL). We recommend the use of JJ stents for initial urinary drainage for stones that will be subsequently treated with chemolytic dissolution or ESWL, as this will lower the total number of subsequent interventions needed to clear the stones. This is also true for stones destined for ureteroscopy (URS), as JJ-stent insertion will facilitate subsequent URS due to previous ureteric stenting. Mild hydronephrosis will prolong the operative time for PCN-tube insertion and may increase the incidence of insertion failure. We recommend the use of PCN tube if the stone size is >2 cm, as there was a greater risk of possible iatrogenic ureteric injury during stenting with these larger ureteric stones in addition to prolongation of operative time with an increased incidence of failure. © 2014 The Authors. BJU International © 2014 BJU International.

ACS (Alma Common Software) operating a set of robotic telescopes

NASA Astrophysics Data System (ADS)

Westhues, C.; Ramolla, M.; Lemke, R.; Haas, M.; Drass, H.; Chini, R.

2014-07-01

We use the ALMA Common Software (ACS) to establish a unified middleware for robotic observations with the 40cm Optical, 80cm Infrared and 1.5m Hexapod telescopes located at OCA (Observatorio Cerro Armazones) and the ESO 1-m located at La Silla. ACS permits to hide from the observer the technical specifications, like mount-type or camera-model. Furthermore ACS provides a uniform interface to the different telescopes, allowing us to run the same planning program for each telescope. Observations are carried out for long-term monitoring campaigns to study the variability of stars and AGN. We present here the specific implementation to the different telescopes.

MICROSCOPE mission: drag-free and attitude control system expertise activities toward the scientific team

NASA Astrophysics Data System (ADS)

Delavault, Stéphanie; Prieur, Pascal; Liénart, Thomas; Robert, Alain; Guidotti, Pierre-Yves

2018-04-01

Microscope is a CNES-ESA-ONERA-CNRS-OCA-DLR-ZARM mission dedicated to the test of the Equivalence Principle with an improved accuracy of 10-15. The 300 kg drag-free microsatellite was launched on April 25th 2016 into a 710 km dawndusk sun-synchronous orbit for a 2-year mission. To comply with stringent requirements, the drag-free and attitude control system (DFACS) involves the scientific accelerometer as main sensor and a set of 8 cold gas proportional thrusters. Once in mission mode, within the CNES drag-free expertise center (CECT) the DFACS team provides several services to the system and to the scientific mission center: cold gas monitoring and management, `Attitude' ancillary data, DFACS expertise ancillary data. For this purpose, expertise tools have been implemented in the CECT, using the flexibility and efficiency of Matlab™ utilities. This paper presents the role of the CECT within the mission and details the expertise activities of the DFACS team illustrated with some typical in flight results.

Network topology for the formation of solvated electrons in binary CaO-Al2O3 composition glasses.

PubMed

Akola, Jaakko; Kohara, Shinji; Ohara, Koji; Fujiwara, Akihiko; Watanabe, Yasuhiro; Masuno, Atsunobu; Usuki, Takeshi; Kubo, Takashi; Nakahira, Atsushi; Nitta, Kiyofumi; Uruga, Tomoya; Weber, J K Richard; Benmore, Chris J

2013-06-18

Glass formation in the CaO-Al2O3 system represents an important phenomenon because it does not contain typical network-forming cations. We have produced structural models of CaO-Al2O3 glasses using combined density functional theory-reverse Monte Carlo simulations and obtained structures that reproduce experiments (X-ray and neutron diffraction, extended X-ray absorption fine structure) and result in cohesive energies close to the crystalline ground states. The O-Ca and O-Al coordination numbers are similar in the eutectic 64 mol % CaO (64CaO) glass [comparable to 12CaO·7Al2O3 (C12A7)], and the glass structure comprises a topologically disordered cage network with large-sized rings. This topologically disordered network is the signature of the high glass-forming ability of 64CaO glass and high viscosity in the melt. Analysis of the electronic structure reveals that the atomic charges for Al are comparable to those for Ca, and the bond strength of Al-O is stronger than that of Ca-O, indicating that oxygen is more weakly bound by cations in CaO-rich glass. The analysis shows that the lowest unoccupied molecular orbitals occurs in cavity sites, suggesting that the C12A7 electride glass [Kim SW, Shimoyama T, Hosono H (2011) Science 333(6038):71-74] synthesized from a strongly reduced high-temperature melt can host solvated electrons and bipolarons. Calculations of 64CaO glass structures with few subtracted oxygen atoms (additional electrons) confirm this observation. The comparable atomic charges and coordination of the cations promote more efficient elemental mixing, and this is the origin of the extended cage structure and hosted solvated (trapped) electrons in the C12A7 glass.

Ploidy Levels among Species in the ‘Oxalis tuberosa Alliance’ as Inferred by Flow Cytometry

PubMed Central

EMSHWILLER, EVE

2002-01-01

The ‘Oxalis tuberosa alliance’ is a group of Andean Oxalis species allied to the Andean tuber crop O. tuberosa Molina (Oxalidaceae), commonly known as ‘oca’. As part of a larger project studying the origins of polyploidy and domestication of cultivated oca, flow cytometry was used to survey DNA ploidy levels among Bolivian and Peruvian accessions of alliance members. In addition, this study provided a first assessment of C‐values in the alliance by estimating nuclear DNA contents of these accessions using chicken erythrocytes as internal standard. Ten Bolivian accessions of cultivated O. tuberosa were confirmed to be octoploid, with a mean nuclear DNA content of approx. 3·6 pg/2C. Two Peruvian wild Oxalis species, O. phaeotricha and O. picchensis, were inferred to be tetraploid (both with approx. 1·67 pg/2C), the latter being one of the putative progenitors of O. tuberosa identified by chloroplast‐expressed glutamine synthetase data in prior work. The remaining accessions (from 78 populations provisionally identified as 35 species) were DNA diploid, with nuclear DNA contents varying from 0·79 to 1·34 pg/2C. PMID:12102530

Interoperability Between Coastal Web Atlases Using Semantic Mediation: A Case Study of the International Coastal Atlas Network (ICAN)

NASA Astrophysics Data System (ADS)

Wright, D. J.; Lassoued, Y.; Dwyer, N.; Haddad, T.; Bermudez, L. E.; Dunne, D.

2009-12-01

Coastal mapping plays an important role in informing marine spatial planning, resource management, maritime safety, hazard assessment and even national sovereignty. As such, there is now a plethora of data/metadata catalogs, pre-made maps, tabular and text information on resource availability and exploitation, and decision-making tools. A recent trend has been to encapsulate these in a special class of web-enabled geographic information systems called a coastal web atlas (CWA). While multiple benefits are derived from tailor-made atlases, there is great value added from the integration of disparate CWAs. CWAs linked to one another can query more successfully to optimize planning and decision-making. If a dataset is missing in one atlas, it may be immediately located in another. Similar datasets in two atlases may be combined to enhance study in either region. *But how best to achieve semantic interoperability to mitigate vague data queries, concepts or natural language semantics when retrieving and integrating data and information?* We report on the development of a new prototype seeking to interoperate between two initial CWAs: the Marine Irish Digital Atlas (MIDA) and the Oregon Coastal Atlas (OCA). These two mature atlases are used as a testbed for more regional connections, with the intent for the OCA to use lessons learned to develop a regional network of CWAs along the west coast, and for MIDA to do the same in building and strengthening atlas networks with the UK, Belgium, and other parts of Europe. Our prototype uses semantic interoperability via services harmonization and ontology mediation, allowing local atlases to use their own data structures, and vocabularies (ontologies). We use standard technologies such as OGC Web Map Services (WMS) for delivering maps, and OGC Catalogue Service for the Web (CSW) for delivering and querying ISO-19139 metadata. The metadata records of a given CWA use a given ontology of terms called local ontology. Human or machine users formulate their requests using a common ontology of metadata terms, called global ontology. A CSW mediator rewrites the user’s request into CSW requests over local CSWs using their own (local) ontologies, collects the results and sends them back to the user. To extend the system, we have recently added global maritime boundaries and are also considering nearshore ocean observing system data. Ongoing work includes adding WFS, error management, and exception handling, enabling Smart Searches, and writing full documentation. This prototype is a central research project of the new International Coastal Atlas Network (ICAN), a group of 30+ organizations from 14 nations (and growing) dedicated to seeking interoperability approaches to CWAs in support of coastal zone management and the translation of coastal science to coastal decision-making.

Phosphorylation and cellular function of the human Rpa2 N-terminus in the budding yeast Saccharomyces cerevisiae.

PubMed

Ghospurkar, Padmaja L; Wilson, Timothy M; Liu, Shengqin; Herauf, Anna; Steffes, Jenna; Mueller, Erica N; Oakley, Gregory G; Haring, Stuart J

2015-02-01

Maintenance of genome integrity is critical for proper cell growth. This occurs through accurate DNA replication and repair of DNA lesions. A key factor involved in both DNA replication and the DNA damage response is the heterotrimeric single-stranded DNA (ssDNA) binding complex Replication Protein A (RPA). Although the RPA complex appears to be structurally conserved throughout eukaryotes, the primary amino acid sequence of each subunit can vary considerably. Examination of sequence differences along with the functional interchangeability of orthologous RPA subunits or regions could provide insight into important regions and their functions. This might also allow for study in simpler systems. We determined that substitution of yeast Replication Factor A (RFA) with human RPA does not support yeast cell viability. Exchange of a single yeast RFA subunit with the corresponding human RPA subunit does not function due to lack of inter-species subunit interactions. Substitution of yeast Rfa2 with domains/regions of human Rpa2 important for Rpa2 function (i.e., the N-terminus and the loop 3-4 region) supports viability in yeast cells, and hybrid proteins containing human Rpa2 N-terminal phospho-mutations result in similar DNA damage phenotypes to analogous yeast Rfa2 N-terminal phospho-mutants. Finally, the human Rpa2 N-terminus (NT) fused to yeast Rfa2 is phosphorylated in a manner similar to human Rpa2 in human cells, indicating that conserved kinases recognize the human domain in yeast. The implication is that budding yeast represents a potential model system for studying not only human Rpa2 N-terminal phosphorylation, but also phosphorylation of Rpa2 N-termini from other eukaryotic organisms. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Laser Ranging for Effective and Accurate Tracking of Space Debris in Low Earth Orbits

NASA Astrophysics Data System (ADS)

Blanchet, Guillaume; Haag, Herve; Hennegrave, Laurent; Assemat, Francois; Vial, Sophie; Samain, Etienne

2013-08-01

The paper presents the results of preliminary design options for an operational laser ranging system adapted to the measurement of the distance of space debris. Thorough analysis of the operational parameters is provided with identification of performance drivers and assessment of enabling design options. Results from performance simulation demonstrate how the range measurement enables improvement of the orbit determination when combined with astrometry. Besides, experimental results on rocket-stage class debris in LEO were obtained by Astrium beginning of 2012, in collaboration with the Observatoire de la Côte d'Azur (OCA), by operating an experimental laser ranging system supported by the MéO (Métrologie Optique) telescope.

Hydrogenated amorphous silicon coatings may modulate gingival cell response

NASA Astrophysics Data System (ADS)

Mussano, F.; Genova, T.; Laurenti, M.; Munaron, L.; Pirri, C. F.; Rivolo, P.; Carossa, S.; Mandracci, P.

2018-04-01

Silicon-based materials present a high potential for dental implant applications, since silicon has been proven necessary for the correct bone formation in animals and humans. Notably, the addition of silicon is effective to enhance the bioactivity of hydroxyapatite and other biomaterials. The present work aims to expand the knowledge of the role exerted by hydrogen in the biological interaction of silicon-based materials, comparing two hydrogenated amorphous silicon coatings, with different hydrogen content, as means to enhance soft tissue cell adhesion. To accomplish this task, the films were produced by plasma enhanced chemical vapor deposition (PECVD) on titanium substrates and their surface composition and hydrogen content were analyzed by means of X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectrophotometry (FTIR) respectively. The surface energy and roughness were measured through optical contact angle analysis (OCA) and high-resolution mechanical profilometry respectively. Coated surfaces showed a slightly lower roughness, compared to bare titanium samples, regardless of the hydrogen content. The early cell responses of human keratinocytes and fibroblasts were tested on the above mentioned surface modifications, in terms of cell adhesion, viability and morphometrical assessment. Films with lower hydrogen content were endowed with a surface energy comparable to the titanium surfaces. Films with higher hydrogen incorporation displayed a lower surface oxidation and a considerably lower surface energy, compared to the less hydrogenated samples. As regards mean cell area and focal adhesion density, both a-Si coatings influenced fibroblasts, but had no significant effects on keratinocytes. On the contrary, hydrogen-rich films increased manifolds the adhesion and viability of keratinocytes, but not of fibroblasts, suggesting a selective biological effect on these cells.

Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations

PubMed Central

Candille, Sophie I.; Absher, Devin M.; Beleza, Sandra; Bauchet, Marc; McEvoy, Brian; Garrison, Nanibaa’ A.; Li, Jun Z.; Myers, Richard M.; Barsh, Gregory S.; Tang, Hua; Shriver, Mark D.

2012-01-01

Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world. PMID:23118974

Facile way in fabricating a cotton fabric membrane for switchable oil/water separation and water purification

NASA Astrophysics Data System (ADS)

Li, Yubin; Feng, Ziliang; He, Yi; Fan, Yi; Ma, Jing; Yin, Xiangying

2018-05-01

With dopamine and NiFe2O4 particles, a novel modified cotton fabric (PDA-NiFe2O4@CF) was prepared by one-pot method. Surface morphology, composition of the PDA-NiFe2O4@CF were investigated with SEM, EDX, XRD and FT-IR, respectively. According to the results, the cotton fiber surface was well coated with NiFe2O4 particles. Subsequently, wetting behavior of the modified cotton fabric was determined. The PDA-NiFe2O4@CF is superamphiphilic in air, and a dual lyophobic behavior was indicated with an oil contact angle (OCA) of 153° under water and a water contact angle (WCA) of 145° under oil. The rough micro-nano scale surface structure and high-surface-energy compositions of the PDA-NiFe2O4@CF makes the surface to be easily covered by one medium and enables it to repel other unmixable medium simultaneously. Therefore, water-oil mixtures can be separated on demand. Besides, with the unusual dual lyophobic surface of PDA-NiFe2O4@CF, both two types of emulsions were separated by gravity driven. On the other hand, it was also found that the as-prepared PDA-NiFe2O4@CF had good adsorption performance for methylene blue.

The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity.

PubMed

Campbell, Clinton J V; Lee, Jung Bok; Levadoux-Martin, Marilyne; Wynder, Tracy; Xenocostas, Anargyros; Leber, Brian; Bhatia, Mickie

2010-09-02

The molecular basis for the unique proliferative and self-renewal properties that hierarchically distinguish human stem cells from progenitors and terminally differentiated cells remains largely unknown. We report a role for the Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) as an indispensable regulator of self-renewal in human stem cells and show that a functional dependence on Mcl-1 defines the human stem cell hierarchy. In vivo pharmacologic targeting of the Bcl-2 family members in human hematopoietic stem cells (HSCs) and human leukemic stem cells reduced stem cell regenerative and self-renewal function. Subsequent protein expression studies showed that, among the Bcl-2 family members, only Mcl-1 was up-regulated exclusively in the human HSC fraction on in vivo regeneration of hematopoiesis. Short hairpin RNA-knockdown of Mcl-1 in human cord blood cells did not affect survival in the HSC or hematopoietic progenitor cell fractions in vitro but specifically reduced the in vivo self-renewal function of human HSCs. Moreover, knockdown of Mcl-1 in ontogenetically primitive human pluripotent stem cells resulted in almost complete ablation of stem cell self-renewal function. Our findings show that Mcl-1 is an essential regulator of stem cell self-renewal in humans and therefore represents an axis for therapeutic interventions.

P2Y12 expression and function in alternatively activated human microglia

PubMed Central

Ase, Ariel R.; Kinsara, Angham; Rao, Vijayaraghava T.S.; Michell-Robinson, Mackenzie; Leong, Soo Yuen; Butovsky, Oleg; Ludwin, Samuel K.; Séguéla, Philippe; Bar-Or, Amit; Antel, Jack P.

2015-01-01

Objective: To investigate and measure the functional significance of altered P2Y12 expression in the context of human microglia activation. Methods: We performed in vitro and in situ experiments to measure how P2Y12 expression can influence disease-relevant functional properties of classically activated (M1) and alternatively activated (M2) human microglia in the inflamed brain. Results: We demonstrated that compared to resting and classically activated (M1) human microglia, P2Y12 expression is increased under alternatively activated (M2) conditions. In response to ADP, the endogenous ligand of P2Y12, M2 microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism. P2Y12 antagonism was also shown to decrease migratory and inflammatory responses in human microglia upon exposure to nucleotides that are released during CNS injury; no effects were observed in human monocytes or macrophages. In situ experiments confirm that P2Y12 is selectively expressed on human microglia and elevated under neuropathologic conditions that promote Th2 responses, such as parasitic CNS infection. Conclusion: These findings provide insight into the roles of M2 microglia in the context of neuroinflammation and suggest a mechanism to selectively target a functionally unique population of myeloid cells in the CNS. PMID:25821842

Prime Contractors with Awards Over $25,000 by Name, Location, and Contract Number, Fiscal Year 1992 (McKendree W I Co., Inc.-Photon Dynamics, Inc.)

DTIC Science & Technology

1993-01-01

4 0 04l0 O 0(JoCQcj ~ (, j C E ~ ~ ~ ~ ~ ~ ~ ~ c  0 00 44~~4 00eO,. 0zfOt E cm, L44(4𔃾 C0.m04000o0C4.> 4) ,, C, ,0C *4I 0) U IL L05 c=I - Voz ...000 000-40 D .0 0 ~ o0a I0: 0 -K <pap aý 0P0I’a.a’..) Pa~la~al~aa~al (J~a2a~ a .00 PaC~r~Paa~aO~a-’O Pa 4~ ~~~ ~~ w0 IP -I - Oca~f a (P 10 a( 0I’ ’P...5,II 41 a Id 0. 0. EDa DOM12 m 00I0 Qm- Oa 0. i 0 00 mI 00 4 01 NO4 m cu 0-1 C0 C!! 200 I.. 4IOO : N IP , 2 ’ (U)0 4 r1211 a 4444 Im m 0 0 1OZZOO~~i

Local morphologic scale: application to segmenting tumor infiltrating lymphocytes in ovarian cancer TMAs

NASA Astrophysics Data System (ADS)

Janowczyk, Andrew; Chandran, Sharat; Feldman, Michael; Madabhushi, Anant

2011-03-01

In this paper we present the concept and associated methodological framework for a novel locally adaptive scale notion called local morphological scale (LMS). Broadly speaking, the LMS at every spatial location is defined as the set of spatial locations, with associated morphological descriptors, which characterize the local structure or heterogeneity for the location under consideration. More specifically, the LMS is obtained as the union of all pixels in the polygon obtained by linking the final location of trajectories of particles emanating from the location under consideration, where the path traveled by originating particles is a function of the local gradients and heterogeneity that they encounter along the way. As these particles proceed on their trajectory away from the location under consideration, the velocity of each particle (i.e. do the particles stop, slow down, or simply continue around the object) is modeled using a physics based system. At some time point the particle velocity goes to zero (potentially on account of encountering (a) repeated obstructions, (b) an insurmountable image gradient, or (c) timing out) and comes to a halt. By using a Monte-Carlo sampling technique, LMS is efficiently determined through parallelized computations. LMS is different from previous local scale related formulations in that it is (a) not a locally connected sets of pixels satisfying some pre-defined intensity homogeneity criterion (generalized-scale), nor is it (b) constrained by any prior shape criterion (ball-scale, tensor-scale). Shape descriptors quantifying the morphology of the particle paths are used to define a tensor LMS signature associated with every spatial image location. These features include the number of object collisions per particle, average velocity of a particle, and the length of the individual particle paths. These features can be used in conjunction with a supervised classifier to correctly differentiate between two different object classes based on local structural properties. In this paper, we apply LMS to the specific problem of classifying regions of interest in Ovarian Cancer (OCa) histology images as either tumor or stroma. This approach is used to classify lymphocytes as either tumor infiltrating lymphocytes (TILs) or non-TILs; the presence of TILs having been identified as an important prognostic indicator for disease outcome in patients with OCa. We present preliminary results on the tumor/stroma classification of 11,000 randomly selected locations of interest, across 11 images obtained from 6 patient studies. Using a Probabilistic Boosting Tree (PBT), our supervised classifier yielded an area under the receiver operation characteristic curve (AUC) of 0.8341 +/-0.0059 over 5 runs of randomized cross validation. The average LMS computation time at every spatial location for an image patch comprising 2000 pixels with 24 particles at every location was only 18s.

Mental disorder prevalence and associated risk factors in three prisons of Spain.

PubMed

Zabala-Baños, M C; Segura, A; Maestre-Miquel, C; Martínez-Lorca, M; Rodríguez-Martín, B; Romero, D; Rodríguez, M

2016-01-01

To determine the lifetime and monthly prevalence of people with mental disorders and its association with sociodemographic factors and criminal risk in three Spanish prisons (Ocaña, Madrid I, II and VI). Cross-sectional epidemiological study of a sample of 184 inmates. Socio-demographic and criminal data were collected by an ad hoc interview. Mental disorders were assessed with the clinical version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders Axis I Disorders (SCID-I). Life prevalence of mental disorders was 90.2%. The most common mental disorders and substance abuse or dependence was 72.3%, followed by mood disorder (38.5%) and psychotic disorders (34.2%). Moreover, the prevalence of any mental disorder in the last month was 52.2%. The main psychotic disorder (20.7%) was followed by substance abuse or dependence (18.5%), and mood disorder state (13%). A socio-demographic profile as a risk for each disorder was found. The prevalence of people with mental disorders is very high in Spanish prisons, and is associated with a distinct demographic profile. It is essential to continue researching this reality, translating the results into therapeutic and preventive action adapted to the status of inmates to reduce social inequalities in this high priority public health situation.

Phase I, open-cycle absorption solar cooling. Part IV. Executive summary analysis and resolution of critical issues and recommendations for Phase II. Final report

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

Wood, B.D.

The objective of this project is to advance lower cost solar cooling technology with the feasibility analysis, design and evaluation of proof-of-concept open cycle solar cooling concepts. The work is divided into three phases, with planned completion of each phase before proceeding with the following phase: Phase I - performance/economic/environmental related analysis and exploratory studies; Phase II - design and construction of an experimental system, including evaluative testing; Phase III - extended system testing during operation and engineering modifications as required. For Phase I, analysis and resolution of critical issues were completed with the objective of developing design specifications formore » an improved prototype OCA system.« less

The application of probabilistic fracture analysis to residual life evaluation of embrittled reactor vessels

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

Dickson, T.L.; Simonen, F.A.

1992-05-01

Probabilistic fracture mechanics analysis is a major element of comprehensive probabilistic methodology on which current NRC regulatory requirements for pressurized water reactor vessel integrity evaluation are based. Computer codes such as OCA-P and VISA-II perform probabilistic fracture analyses to estimate the increase in vessel failure probability that occurs as the vessel material accumulates radiation damage over the operating life of the vessel. The results of such analyses, when compared with limits of acceptable failure probabilities, provide an estimation of the residual life of a vessel. Such codes can be applied to evaluate the potential benefits of plant-specific mitigating actions designedmore » to reduce the probability of failure of a reactor vessel. 10 refs.« less

The application of probabilistic fracture analysis to residual life evaluation of embrittled reactor vessels

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

Dickson, T.L.; Simonen, F.A.

1992-01-01

Probabilistic fracture mechanics analysis is a major element of comprehensive probabilistic methodology on which current NRC regulatory requirements for pressurized water reactor vessel integrity evaluation are based. Computer codes such as OCA-P and VISA-II perform probabilistic fracture analyses to estimate the increase in vessel failure probability that occurs as the vessel material accumulates radiation damage over the operating life of the vessel. The results of such analyses, when compared with limits of acceptable failure probabilities, provide an estimation of the residual life of a vessel. Such codes can be applied to evaluate the potential benefits of plant-specific mitigating actions designedmore » to reduce the probability of failure of a reactor vessel. 10 refs.« less

CCD BVI c observations of Cepheids

NASA Astrophysics Data System (ADS)

Berdnikov, L. N.; Kniazev, A. Yu.; Sefako, R.; Kravtsov, V. V.; Zhujko, S. V.

2014-02-01

In 2008-2013, we obtained 11333 CCD BVI c frames for 57 Cepheids from the General Catalogue of Variable Stars. We performed our observations with the 76-cm telescope of the South African Astronomical Observatory (SAAO, South Africa) and the 40-cm telescope of the Cerro Armazones Astronomical Observatory of the Universidad Católica del Norte (OCA, Chile) using the SBIG ST-10XME CCD camera. The tables of observations, the plots of light curves, and the current light elements are presented. Comparison of our light curves with those constructed from photoelectric observations shows that the differences between their mean magnitudes exceed 0ṃ05 in 20% of the cases. This suggests the necessity of performing CCD observations for all Cepheids.

Nulling Stabilization in the Presence of Perturbation

NASA Astrophysics Data System (ADS)

Houairi, K.; Cassaing, F.; Le Duigou, J. M.; Barillot, M.; Coudé du Foresto, V.; Hénault, F.; Jacquinod, S.; Ollivier, M.; Reess, J.-M.; Sorrente, B.

2007-07-01

Nulling interferometry is one of the most promising methods to study habitable extrasolar systems. In this context, several projects have been proposed such as ALADDIN on ground or DARWIN and PEGASE in space. A first step towards these missions will be performed with a laboratory breadboard, named PERSEE, built by a consortium including CNES, IAS, LESIA, OCA, ONERA and TAS. Its main goals are the demonstration of a polychromatic null with a 10-4 rejection rate and a 10-5 stability despite the introduction of realistic perturbations, the study of the interfaces with the formation-flying spacecrafts and the joint operation of the cophasing system with the nuller. The broadboard integration should end in 2009, then PERSEE will be open to proposals from the scientific community.

Computational Identification of the Paralogs and Orthologs of Human Cytochrome P450 Superfamily and the Implication in Drug Discovery

PubMed Central

Pan, Shu-Ting; Xue, Danfeng; Li, Zhi-Ling; Zhou, Zhi-Wei; He, Zhi-Xu; Yang, Yinxue; Yang, Tianxin; Qiu, Jia-Xuan; Zhou, Shu-Feng

2016-01-01

The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs. The functional implications and implications in drug discovery and evolutionary biology were then discussed. GeneCards and Ensembl were used to identify the paralogs of human CYPs. We have used a panel of online databases to identify the orthologs of human CYP genes: NCBI, Ensembl Compara, GeneCards, OMA (“Orthologous MAtrix”) Browser, PATHER, TreeFam, EggNOG, and Roundup. The results show that each human CYP has various numbers of paralogs and orthologs using GeneCards and Ensembl. For example, the paralogs of CYP2A6 include CYP2A7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 2R1, 2S1, 2U1, and 2W1; CYP11A1 has 6 paralogs including CYP11B1, 11B2, 24A1, 27A1, 27B1, and 27C1; CYP51A1 has only three paralogs: CYP26A1, 26B1, and 26C1; while CYP20A1 has no paralog. The majority of human CYPs are well conserved from plants, amphibians, fishes, or mammals to humans due to their important functions in physiology and xenobiotic disposition. The data from different approaches are also cross-validated and validated when experimental data are available. These findings facilitate our understanding of the evolutionary relationships and functional implications of the human CYP superfamily in drug discovery. PMID:27367670

Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies.

PubMed

Kanaan, Georges N; Ichim, Bianca; Gharibeh, Lara; Maharsy, Wael; Patten, David A; Xuan, Jian Ying; Reunov, Arkadiy; Marshall, Philip; Veinot, John; Menzies, Keir; Nemer, Mona; Harper, Mary-Ellen

2018-04-01

Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT-related proteins from all kingdoms of life

PubMed Central

2011-01-01

Background The inorganic (Pi) phosphate transporter (PiT) family comprises known and putative Na+- or H+-dependent Pi-transporting proteins with representatives from all kingdoms. The mammalian members are placed in the outer cell membranes and suggested to supply cells with Pi to maintain house-keeping functions. Alignment of protein sequences representing PiT family members from all kingdoms reveals the presence of conserved amino acids and that bacterial phosphate permeases and putative phosphate permeases from archaea lack substantial parts of the protein sequence when compared to the mammalian PiT family members. Besides being Na+-dependent Pi (NaPi) transporters, the mammalian PiT paralogs, PiT1 and PiT2, also are receptors for gamma-retroviruses. We have here exploited the dual-function of PiT1 and PiT2 to study the structure-function relationship of PiT proteins. Results We show that the human PiT2 histidine, H502, and the human PiT1 glutamate, E70, - both conserved in eukaryotic PiT family members - are critical for Pi transport function. Noticeably, human PiT2 H502 is located in the C-terminal PiT family signature sequence, and human PiT1 E70 is located in ProDom domains characteristic for all PiT family members. A human PiT2 truncation mutant, which consists of the predicted 10 transmembrane (TM) domain backbone without a large intracellular domain (human PiT2ΔR254-V483), was found to be a fully functional Pi transporter. Further truncation of the human PiT2 protein by additional removal of two predicted TM domains together with the large intracellular domain created a mutant that resembles a bacterial phosphate permease and an archaeal putative phosphate permease. This human PiT2 truncation mutant (human PiT2ΔL183-V483) did also support Pi transport albeit at very low levels. Conclusions The results suggest that the overall structure of the Pi-transporting unit of the PiT family proteins has remained unchanged during evolution. Moreover, in combination, our studies of the gene structure of the human PiT1 and PiT2 genes (SLC20A1 and SLC20A2, respectively) and alignment of protein sequences of PiT family members from all kingdoms, along with the studies of the dual functions of the human PiT paralogs show that these proteins are excellent as models for studying the evolution of a protein's structure-function relationship. PMID:21586110

Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT-related proteins from all kingdoms of life.

PubMed

Bøttger, Pernille; Pedersen, Lene

2011-05-17

The inorganic (Pi) phosphate transporter (PiT) family comprises known and putative Na(+)- or H(+)-dependent Pi-transporting proteins with representatives from all kingdoms. The mammalian members are placed in the outer cell membranes and suggested to supply cells with Pi to maintain house-keeping functions. Alignment of protein sequences representing PiT family members from all kingdoms reveals the presence of conserved amino acids and that bacterial phosphate permeases and putative phosphate permeases from archaea lack substantial parts of the protein sequence when compared to the mammalian PiT family members. Besides being Na(+)-dependent P(i) (NaP(i)) transporters, the mammalian PiT paralogs, PiT1 and PiT2, also are receptors for gamma-retroviruses. We have here exploited the dual-function of PiT1 and PiT2 to study the structure-function relationship of PiT proteins. We show that the human PiT2 histidine, H(502), and the human PiT1 glutamate, E(70),--both conserved in eukaryotic PiT family members--are critical for P(i) transport function. Noticeably, human PiT2 H(502) is located in the C-terminal PiT family signature sequence, and human PiT1 E(70) is located in ProDom domains characteristic for all PiT family members.A human PiT2 truncation mutant, which consists of the predicted 10 transmembrane (TM) domain backbone without a large intracellular domain (human PiT2ΔR(254)-V(483)), was found to be a fully functional P(i) transporter. Further truncation of the human PiT2 protein by additional removal of two predicted TM domains together with the large intracellular domain created a mutant that resembles a bacterial phosphate permease and an archaeal putative phosphate permease. This human PiT2 truncation mutant (human PiT2ΔL(183)-V(483)) did also support P(i) transport albeit at very low levels. The results suggest that the overall structure of the P(i)-transporting unit of the PiT family proteins has remained unchanged during evolution. Moreover, in combination, our studies of the gene structure of the human PiT1 and PiT2 genes (SLC20A1 and SLC20A2, respectively) and alignment of protein sequences of PiT family members from all kingdoms, along with the studies of the dual functions of the human PiT paralogs show that these proteins are excellent as models for studying the evolution of a protein's structure-function relationship. © 2011 Bøttger and Pedersen; licensee BioMed Central Ltd.

Preparation of anticoagulant PyC biomaterials with super-hydrophobic surface.

PubMed

Ze, Wang; Wen-Sheng, Tan; Ye-Xia; Ming, Zhang; Xiao-Ping, Li; Jian-Guo, Qiu; Xiao-Hong, Yang

2018-01-01

Pyrolytic carbon (PyC) is a kind of biomaterial which is chemically inert and has excellent biocompatibility. In order to obtain a super-hydrophobic PyC surface to improve anticoagulation and inhibit thrombus, this study prepares grating pair structure, microhole array structure, helix structure on PyC surface by nanoseconds laser etching. Rod-like ZnO film and ball-like ZnO film are prepared on the PyC surface by the hydrothermal method; polyvinyl pyrrolidone (PVP) nanofiber film and PVP/TiO 2 complex nanofiber film are prepared on the PyC surface by the electrospinning method; the PyC surface is silanized. Finally, surface microstructure and surface energy are characterized by scanning electron microscopy and contact angle meter (OCA20, German DataPhysics Co.). The periodical microstructures are formed respectively by nanoseconds laser etching. The surface roughness is increased by the hydrothermal and electrospinning method. Through infiltration experiment on rough and smooth PyC surfaces, rough PyC surface with microstructure is super-hydrophobic and has greater than 150° contact angle, which decreases blood flow resistance and inhibits thrombus.

Cryopreservation of in vitro shoot apices of Oxalis tuberosa Mol.

PubMed

Gonzalez-Benito, M E; Mendoza-Condori, V H; Molina-Garcia, A D

2007-01-01

Oca (Oxalis tuberosa Mol.) is an under-utilized tuber crop from the Andean region. Cryopreservation would allow the safe and long-term preservation of the genetic resources of this crop. A protocol for the cryopreservation of in vitro grown shoots has been developed using the vitrification solution PVS2. Two genotypes were studied (G1 and G27). Nodal segments were cultured on MS medium and incubated at 10 degree C with 16 h photoperiod and 10 mol per square meter per second irradiance, for two weeks. Apices were then excised and cultured on MS+0.15 M sucrose for 3 days at 5 degree C in darkness. Subsequently, apices were immersed in a loading solution (liquid MS medium+2 M glycerol+0.4 M sucrose), and then treated with the vitrification solution PVS2 for 0 to 40 minutes. Cryovials were then immersed in liquid nitrogen. Four weeks after rewarming and culture on recovery medium, genotype G1 showed approximately 60 percent recovery (normal growth) with 20 min PVS2 treatment. Genotype G27 showed lower recovery (30 percent). Differential scanning calorimetry yielded a Tg midpoint for PSV2 solution of ca. -120 degree C. Calorimetric studies on apices at different stages of the cryopreservation protocol showed a change in calorimetric parameters consistent with a decrease in the amount of frozen water as the protocol advanced.

Blockade of human P2X7 receptor function with a monoclonal antibody.

PubMed

Buell, G; Chessell, I P; Michel, A D; Collo, G; Salazzo, M; Herren, S; Gretener, D; Grahames, C; Kaur, R; Kosco-Vilbois, M H; Humphrey, P P

1998-11-15

A monoclonal antibody (MoAb) specific for the human P2X7 receptor was generated in mice. As assessed by flow cytometry, the MoAb labeled human blood-derived macrophage cells natively expressing P2X7 receptors and cells transfected with human P2X7 but not other P2X receptor types. The MoAb was used to immunoprecipitate the human P2X7 receptor protein, and in immunohistochemical studies on human lymphoid tissue, P2X7 receptor labeling was observed within discrete areas of the marginal zone of human tonsil sections. The antibody also acted as a selective antagonist of human P2X7 receptors in several functional studies. Thus, whole cell currents, elicited by the brief application of 2',3'-(4-benzoyl)-benzoyl-ATP in cells expressing human P2X7, were reduced in amplitude by the presence of the MoAb. Furthermore, preincubation of human monocytic THP-1 cells with the MoAb antagonized the ability of P2X7 agonists to induce the release of interleukin-1beta.

Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle.

PubMed

Hristov, Kiril L; Chen, Muyan; Afeli, Serge A Y; Cheng, Qiuping; Rovner, Eric S; Petkov, Georgi V

2012-06-01

The functional role of the voltage-gated K(+) (K(V)) channels in human detrusor smooth muscle (DSM) is largely unexplored. Here, we provide molecular, electrophysiological, and functional evidence for the expression of K(V)2.1, K(V)2.2, and the electrically silent K(V)9.3 subunits in human DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of K(V)2.1, K(V)2.2, and K(V)4.2 homotetrameric channels and of K(V)2.1/9.3 heterotetrameric channels, was used to examine the role of these channels in human DSM function. Human DSM tissues were obtained during open bladder surgeries from patients without a history of overactive bladder. Freshly isolated human DSM cells were studied using RT-PCR, immunocytochemistry, live-cell Ca(2+) imaging, and the perforated whole cell patch-clamp technique. Isometric DSM tension recordings of human DSM isolated strips were conducted using tissue baths. RT-PCR experiments showed mRNA expression of K(V)2.1, K(V)2.2, and K(V)9.3 (but not K(V)4.2) channel subunits in human isolated DSM cells. K(V)2.1 and K(V)2.2 protein expression was confirmed by Western blot analysis and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the voltage step-induced K(V) current in freshly isolated human DSM cells. ScTx1 (100 nM) significantly increased the intracellular Ca(2+) level in DSM cells. In human DSM isolated strips, ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude and muscle force, and enhanced the amplitude of the electrical field stimulation-induced contractions within the range of 3.5-30 Hz stimulation frequencies. These findings reveal that ScTx1-sensitive K(V)2-containing channels are key regulators of human DSM excitability and contractility and may represent new targets for pharmacological or genetic intervention for bladder dysfunction.

Functional Cus1p Is Found with Hsh155p in a Multiprotein Splicing Factor Associated with U2 snRNA

PubMed Central

Pauling, Michelle Haynes; McPheeters, David S.; Ares, Manuel

2000-01-01

To explore the dynamics of snRNP structure and function, we have studied Cus1p, identified as a suppressor of U2 snRNA mutations in budding yeast. Cus1p is homologous to human SAP145, a protein present in the 17S form of the human U2 snRNP. Here, we define the Cus1p amino acids required for function in yeast. The segment of Cus1p required for binding to Hsh49p, a homolog of human SAP49, is contained within an essential region of Cus1p. Antibodies against Cus1p coimmunoprecipitate U2 snRNA, as well as Hsh155p, a protein homologous to human SAP155. Biochemical fractionation of splicing extracts and reconstitution of heat-inactivated splicing extracts from strains carrying a temperature-sensitive allele of CUS1 indicate that Cus1p and Hsh155p reside in a functional, high-salt-stable complex that is salt-dissociable from U2 snRNA. We propose that Cus1p, Hsh49p, and Hsh155p exist in a stable protein complex which can exchange with a core U2 snRNP and which is necessary for U2 snRNP function in prespliceosome assembly. The Cus1p complex shares functional as well as structural similarities with human SF3b. PMID:10688664

Effect of aberrations in human eye on contrast sensitivity function

NASA Astrophysics Data System (ADS)

Quan, Wei; Wang, Feng-lin; Wang, Zhao-qi

2011-06-01

The quantitative analysis of the effect of aberrations in human eye on vision has important clinical value in the correction of aberrations. The wave-front aberrations of human eyes were measured with the Hartmann-Shack wave-front sensor and modulation transfer function (MTF) was computed from the wave-front aberrations. Contrast sensitivity function (CSF) was obtained from MTF and the retinal aerial image modulation (AIM). It is shown that the 2nd, 3rd, 4th, 5th, 6th Zernike aberrations deteriorate contrast sensitivity function. When the 2nd, 3rd, 4th, 5th, 6th Zernike aberrations are corrected high contrast sensitivity function can be obtained.

Understanding of gas phase deposition of reactive magnetron sputtered TiO2 thin films and its correlation with bactericidal efficiency

NASA Astrophysics Data System (ADS)

Panda, A. B.; Mahapatra, S. K.; Barhai, P. K.; Das, A. K.; Banerjee, I.

2012-10-01

Nanostructured TiO2 thin films were deposited using RF reactive magnetron sputtering at different O2 flow rates (20, 30, 50 and 60 sccm) and constant RF power of 200 W. In situ investigation of the nucleation and growth of the films was made by Optical Emission Spectroscopy (OES). The nano amorphous nature as revealed from X-ray diffraction (XRD) of the as deposited films and abundance of the Ti3+ surface oxidation states and surface hydroxyl group (OH-) in the films deposited at 50 sccm as determined from X-ray photo electron spectroscopy (XPS) was explained on the basis of emission spectra studies. The increase in band gap and decrease in particle size with O2 flow rate was observed from transmission spectra of UV-vis spectroscopy. Photoinduced hydrophilicity has been studied using Optical Contact Angle (OCA) measurement. The post irradiated films showed improved hydrophilicity. The bactericidal efficiency of these films was investigated taking Escherichia coli as model bacteria. The films deposited at 50 sccm shows better bactericidal activity as revealed from the optical density (OD) measurement. The qualitative analysis of the bactericidal efficiency was depicted from Scanning Electron Microscope images. A correlation between bactericidal efficiency and the deposited film has been established and explained on the basis of nucleation growth, band gap and hydrophilicity of the films.

Causal Evidence from Humans for the Role of Mediodorsal Nucleus of the Thalamus in Working Memory.

PubMed

Peräkylä, Jari; Sun, Lihua; Lehtimäki, Kai; Peltola, Jukka; Öhman, Juha; Möttönen, Timo; Ogawa, Keith H; Hartikainen, Kaisa M

2017-12-01

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general ( OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors ( OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. "Total errors" is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.

Expression of HLA Class II Molecules in Humanized NOD.Rag1KO.IL2RgcKO Mice Is Critical for Development and Function of Human T and B Cells

PubMed Central

Danner, Rebecca; Chaudhari, Snehal N.; Rosenberger, John; Surls, Jacqueline; Richie, Thomas L.; Brumeanu, Teodor-Doru; Casares, Sofia

2011-01-01

Background Humanized mice able to reconstitute a surrogate human immune system (HIS) can be used for studies on human immunology and may provide a predictive preclinical model for human vaccines prior to clinical trials. However, current humanized mouse models show sub-optimal human T cell reconstitution and limited ability to support immunoglobulin class switching by human B cells. This limitation has been attributed to the lack of expression of Human Leukocyte Antigens (HLA) molecules in mouse lymphoid organs. Recently, humanized mice expressing HLA class I molecules have been generated but showed little improvement in human T cell reconstitution and function of T and B cells. Methods We have generated NOD.Rag1KO.IL2RγcKO mice expressing HLA class II (HLA-DR4) molecules under the I-Ed promoter that were infused as adults with HLA-DR-matched human hematopoietic stem cells (HSC). Littermates lacking expression of HLA-DR4 molecules were used as control. Results HSC-infused HLA-DR4.NOD.Rag1KO.IL-2RγcKO mice developed a very high reconstitution rate (>90%) with long-lived and functional human T and B cells. Unlike previous humanized mouse models reported in the literature and our control mice, the HLA-DR4 expressing mice reconstituted serum levels (natural antibodies) of human IgM, IgG (all four subclasses), IgA, and IgE comparable to humans, and elicited high titers of specific human IgG antibodies upon tetanus toxoid vaccination. Conclusions Our study demonstrates the critical role of HLA class II molecules for development of functional human T cells able to support immunoglobulin class switching and efficiently respond to vaccination. PMID:21611197

The human RHOX gene cluster: target genes and functional analysis of gene variants in infertile men.

PubMed

Borgmann, Jennifer; Tüttelmann, Frank; Dworniczak, Bernd; Röpke, Albrecht; Song, Hye-Won; Kliesch, Sabine; Wilkinson, Miles F; Laurentino, Sandra; Gromoll, Jörg

2016-11-15

The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode proteins involved in processes relevant to spermatogenesis; e.g. stress protection and cell survival. One of the target genes of RHOXF2/2B is RHOXF1, suggesting cross-regulation to enhance transcriptional responses. The potential role of RHOX in human infertility was addressed by sequencing all RHOX exons in a group of 250 patients with severe oligozoospermia. This revealed two mutations in RHOXF1 (c.515G > A and c.522C > T) and four in RHOXF2/2B (-73C > G, c.202G > A, c.411C > T and c.679G > A), of which only one (c.202G > A) was found in a control group of men with normal sperm concentration. Functional analysis demonstrated that c.202G > A and c.679G > A significantly impaired the ability of RHOXF2/2B to regulate downstream genes. Molecular modelling suggested that these mutations alter RHOXF2/F2B protein conformation. By combining clinical data with in vitro functional analysis, we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility.

EDC IMPACT: Chemical UV filters can affect human sperm function in a progesterone-like manner

PubMed Central

Rehfeld, A; Egeberg, D L; Almstrup, K; Petersen, J H; Dissing, S

2018-01-01

Human sperm cell function must be precisely regulated to achieve natural fertilization. Progesterone released by the cumulus cells surrounding the egg induces a Ca2+ influx into human sperm cells via the CatSper Ca2+-channel and thereby controls sperm function. Multiple chemical UV filters have been shown to induce a Ca2+ influx through CatSper, thus mimicking the effect of progesterone on Ca2+ signaling. We hypothesized that these UV filters could also mimic the effect of progesterone on sperm function. We examined 29 UV filters allowed in sunscreens in the US and/or EU for their ability to affect acrosome reaction, penetration, hyperactivation and viability in human sperm cells. We found that, similar to progesterone, the UV filters 4-MBC, 3-BC, Meradimate, Octisalate, BCSA, HMS and OD-PABA induced acrosome reaction and 3-BC increased sperm penetration into a viscous medium. The capacity of the UV filters to induce acrosome reaction and increase sperm penetration was positively associated with the ability of the UV filters to induce a Ca2+ influx. None of the UV filters induced significant changes in the proportion of hyperactivated cells. In conclusion, chemical UV filters that mimic the effect of progesterone on Ca2+ signaling in human sperm cells can similarly mimic the effect of progesterone on acrosome reaction and sperm penetration. Human exposure to these chemical UV filters may impair fertility by interfering with sperm function, e.g. through induction of premature acrosome reaction. Further studies are needed to confirm the results in vivo. PMID:28874401

EDC IMPACT: Chemical UV filters can affect human sperm function in a progesterone-like manner.

PubMed

Rehfeld, A; Egeberg, D L; Almstrup, K; Petersen, J H; Dissing, S; Skakkebæk, N E

2018-01-01

Human sperm cell function must be precisely regulated to achieve natural fertilization. Progesterone released by the cumulus cells surrounding the egg induces a Ca 2+ influx into human sperm cells via the CatSper Ca 2+ -channel and thereby controls sperm function. Multiple chemical UV filters have been shown to induce a Ca 2+ influx through CatSper, thus mimicking the effect of progesterone on Ca 2+ signaling. We hypothesized that these UV filters could also mimic the effect of progesterone on sperm function. We examined 29 UV filters allowed in sunscreens in the US and/or EU for their ability to affect acrosome reaction, penetration, hyperactivation and viability in human sperm cells. We found that, similar to progesterone, the UV filters 4-MBC, 3-BC, Meradimate, Octisalate, BCSA, HMS and OD-PABA induced acrosome reaction and 3-BC increased sperm penetration into a viscous medium. The capacity of the UV filters to induce acrosome reaction and increase sperm penetration was positively associated with the ability of the UV filters to induce a Ca 2+ influx. None of the UV filters induced significant changes in the proportion of hyperactivated cells. In conclusion, chemical UV filters that mimic the effect of progesterone on Ca 2+ signaling in human sperm cells can similarly mimic the effect of progesterone on acrosome reaction and sperm penetration. Human exposure to these chemical UV filters may impair fertility by interfering with sperm function, e.g. through induction of premature acrosome reaction. Further studies are needed to confirm the results in vivo . © 2018 The authors.

Transgenic Mice Carrying GLUD2 as a Tool for Studying the Expressional and the Functional Adaptation of this Positive Selected Gene in Human Brain Evolution.

PubMed

Plaitakis, Andreas; Kotzamani, Dimitra; Petraki, Zoe; Delidaki, Maria; Rinotas, Vagelis; Zaganas, Ioannis; Douni, Eleni; Sidiropoulou, Kyriaki; Spanaki, Cleanthe

2018-05-18

Human evolution is characterized by brain expansion and up-regulation of genes involved in energy metabolism and synaptic transmission, including the glutamate signaling pathway. Glutamate is the excitatory transmitter of neural circuits sub-serving cognitive functions, with glutamate-modulation of synaptic plasticity being central to learning and memory. GLUD2 is a novel positively-selected human gene involved in glutamatergic transmission and energy metabolism that underwent rapid evolutionary adaptation concomitantly with prefrontal cortex enlargement. Two evolutionary replacements (Gly456Ala and Arg443Ser) made hGDH2 resistant to GTP inhibition and allowed distinct regulation, enabling enhanced enzyme function under high glutamatergic system demands. GLUD2 adaptation may have contributed to unique human traits, but evidence for this is lacking. GLUD2 arose through retro-positioning of a processed GLUD1 mRNA to the X chromosome, a DNA replication mechanism that typically generates pseudogenes. However, by finding a suitable promoter, GLUD2 is thought to have gained expression in nerve and other tissues, where it adapted to their particular needs. Here we generated GLUD2 transgenic (Tg) mice by inserting in their genome a segment of the human X chromosome, containing the GLUD2 gene and its putative promoter. Double IF studies of Tg mouse brain revealed that the human gene is expressed in the host mouse brain in a pattern similar to that observed in human brain, thus providing credence to the above hypothesis. This expressional adaptation may have conferred novel role(s) on GLUD2 in human brain. Previous observations, also in GLUD2 Tg mice, generated and studied independently, showed that the non-redundant function of hGDH2 is markedly activated during early post-natal brain development, contributing to developmental changes in prefrontal cortex similar to those attributed to human divergence. Hence, GLUD2 adaptation may have influenced the evolutionary course taken by the human brain, but understanding the mechanism(s) involved remains challenging.

Molecular cloning and functional characterization of the promoter region of the human uncoupling protein-2 gene.

PubMed

Tu, N; Chen, H; Winnikes, U; Reinert, I; Marmann, G; Pirke, K M; Lentes, K U

1999-11-19

As a member of the uncoupling protein family, UCP2 is ubiquitously expressed in rodents and humans, implicating a major role in thermogenesis. To analyze promoter function and regulatory motifs involved in the transcriptional regulation of UCP2 gene expression, 3.3 kb of 5'-flanking region of the human UCP2 (hUCP2) gene have been cloned. Sequence analysis showed that the promoter region of hUCP2 lacks a classical TATA or CAAT box, however, appeared GC-rich resulting in the presence of several Sp-1 motifs and Ap-1/-2 binding sites near the transcription initiation site. Functional characterization of human UCP2 promoter-CAT fusion constructs in transient expression assays showed that minimal promoter activity was observed within 65 bp upstream of the transcriptional start site (+1). 75 bp further upstream (from nt -141 to -66) a strong cis-acting regulatory element (or enhancer) was identified, which significantly enhanced basal promoter activity. The regulation of human UCP2 gene expression involves complex interactions among positive and negative regulatory elements distributed over a minimum of 3.3 kb of the promoter region. Copyright 1999 Academic Press.

CUS2, a Yeast Homolog of Human Tat-SF1, Rescues Function of Misfolded U2 through an Unusual RNA Recognition Motif

PubMed Central

Yan, Dong; Perriman, Rhonda; Igel, Haller; Howe, Kenneth J.; Neville, Megan; Ares, Manuel

1998-01-01

A screen for suppressors of a U2 snRNA mutation identified CUS2, an atypical member of the RNA recognition motif (RRM) family of RNA binding proteins. CUS2 protein is associated with U2 RNA in splicing extracts and interacts with PRP11, a subunit of the conserved splicing factor SF3a. Absence of CUS2 renders certain U2 RNA folding mutants lethal, arguing that a normal activity of CUS2 is to help refold U2 into a structure favorable for its binding to SF3b and SF3a prior to spliceosome assembly. Both CUS2 function in vivo and the in vitro RNA binding activity of CUS2 are disrupted by mutation of the first RRM, suggesting that rescue of misfolded U2 involves the direct binding of CUS2. Human Tat-SF1, reported to stimulate Tat-specific, transactivating region-dependent human immunodeficiency virus transcription in vitro, is structurally similar to CUS2. Anti-Tat-SF1 antibodies coimmunoprecipitate SF3a66 (SAP62), the human homolog of PRP11, suggesting that Tat-SF1 has a parallel function in splicing in human cells. PMID:9710584

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

PubMed Central

Coffee, R. Lane; Tessier, Charles R.; Woodruff, Elvin A.; Broadie, Kendal

2010-01-01

SUMMARY Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity. PMID:20442204

Photo-crosslinkable cyanoacrylate bioadhesive: shrinkage kinetics, dynamic mechanical properties, and biocompatibility of adhesives containing TMPTMA and POSS nanostructures as crosslinking agents.

PubMed

Ghasaban, S; Atai, M; Imani, M; Zandi, M; Shokrgozar, M-A

2011-11-01

The study investigates the photo-polymerization shrinkage behavior, dynamic mechanical properties, and biocompatibility of cyanoacrylate bioadhesives containing POSS nanostructures and TMPTMA as crosslinking agents. Adhesives containing 2-octyl cyanoacrylate (2-OCA) and different percentages of POSS nanostructures and TMPTMA as crosslinking agents were prepared. The 1-phenyl-1, 2-propanedione (PPD) was incorporated as photo-initiator into the adhesive in 1.5, 3, and 4 wt %. The shrinkage strain of the specimens was measured using bonded-disk technique. Shrinkage strain, shrinkage strain rate, maximum and time at maximum shrinkage strain rate were measured and compared. Mechanical properties of the adhesives were also studied using dynamic mechanical thermal analysis (DMTA). Biocompatibility of the adhesives was examined by MTT method. The results showed that shrinkage strain increased with increasing the initiator concentration up to 3 wt % in POSS-containing and 1.5 wt % in TMPTMA-containing specimens and plateaued out at higher concentrations. By increasing the crosslinking agent, shrinkage strain, and shrinkage strain rate increased and the time at maximum shrinkage strain rate decreased. The study indicates that the incorporation of crosslinking agents into the cyanoacrylate adhesives resulted in improved mechanical properties. Preliminary MTT studies also revealed better biocompatibility profile for the adhesives containing crosslinking agents comparing to the neat specimens. Copyright © 2011 Wiley Periodicals, Inc.

The AMBRE project: Parameterisation of FGK-type stars from the ESO:HARPS archived spectra

NASA Astrophysics Data System (ADS)

De Pascale, M.; Worley, C. C.; de Laverny, P.; Recio-Blanco, A.; Hill, V.; Bijaoui, A.

2014-10-01

Context. The AMBRE project is a collaboration between the European Southern Observatory (ESO) and the Observatoire de la Côte d'Azur (OCA). It has been established to determine the stellar atmospheric parameters of the archived spectra of four ESO spectrographs. Aims: The analysis of the ESO:HARPS archived spectra for the determination of their atmospheric parameters (effective temperature, surface gravity, global metallicities, and abundance of α-elements over iron) is presented. The sample being analysed (AMBRE:HARPS) covers the period from 2003 to 2010 and is comprised of 126 688 scientific spectra corresponding to ~17 218 different stars. Methods: For the analysis of the AMBRE:HARPS spectral sample, the automated pipeline developed for the analysis of the AMBRE:FEROS archived spectra has been adapted to the characteristics of the HARPS spectra. Within the pipeline, the stellar parameters are determined by the MATISSE algorithm, which has been developed at OCA for the analysis of large samples of stellar spectra in the framework of galactic archaeology. In the present application, MATISSE uses the AMBRE grid of synthetic spectra, which covers FGKM-type stars for a range of gravities and metallicities. Results: We first determined the radial velocity and its associated error for the ~15% of the AMBRE:HARPS spectra, for which this velocity had not been derived by the ESO:HARPS reduction pipeline. The stellar atmospheric parameters and the associated chemical index [α/Fe] with their associated errors have then been estimated for all the spectra of the AMBRE:HARPS archived sample. Based on key quality criteria, we accepted and delivered the parameterisation of 93 116 (74% of the total sample) spectra to ESO. These spectra correspond to ~10 706 stars; each are observed between one and several hundred times. This automatic parameterisation of the AMBRE:HARPS spectra shows that the large majority of these stars are cool main-sequence dwarfs with metallicities greater than -0.5 dex (as expected, given that HARPS has been extensively used for planet searches around GK-stars).

Production of functional human insulin-like growth factor binding proteins (IGFBPs) using recombinant expression in HEK293 cells.

PubMed

Wanscher, Anne Sofie Molsted; Williamson, Michael; Ebersole, Tasja Wainani; Streicher, Werner; Wikström, Mats; Cazzamali, Giuseppe

2015-04-01

Insulin-like growth factor binding proteins (IGFBPs) display many functions in humans including regulation of the insulin-like growth factor (IGF) signaling pathway. The various roles of human IGFBPs make them attractive protein candidates in drug discovery. Structural and functional knowledge on human proteins with therapeutic relevance is needed to design and process the next generation of protein therapeutics. In order to conduct structural and functional investigations large quantities of recombinant proteins are needed. However, finding a suitable recombinant production system for proteins such as full-length human IGFBPs, still remains a challenge. Here we present a mammalian HEK293 expression method suitable for over-expression of secretory full-length human IGFBP-1 to -7. Protein purification of full-length human IGFBP-1, -2, -3 and -5 was conducted using a two-step chromatography procedure and the final protein yields were between 1 and 12mg protein per liter culture media. The recombinant IGFBPs contained PTMs and exhibited high-affinity interactions with their natural ligands IGF-1 and IGF-2. Copyright © 2014 Elsevier Inc. All rights reserved.

Function and regulation of AUTS2, a gene implicated in autism and human evolution.

PubMed

Oksenberg, Nir; Stevison, Laurie; Wall, Jeffrey D; Ahituv, Nadav

2013-01-01

Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD-associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.

39 CFR 221.6 - Field organization.

Code of Federal Regulations, 2010 CFR

2010-07-01

... functional units responsible for finance, human resources, marketing, and operations support. (2) Reporting... support, finance, human resources, information technology, administrative support, and marketing. (2... assigned, Headquarters field units are responsible for legal services, corporate relations, human resources...

Demonstration of GTG as an endogenous initiation codon for a human mRNA transcript revealed by molecular cloning of the serpin endopin 2B.

PubMed

Hwang, Shin-Rong; Garza, Christina Z; Wegrzyn, Jill; Hook, Vivian Y H

2004-08-16

This study demonstrates utilization of the novel GTG initiation codon for translation of a human mRNA transcript that encodes the serpin endopin 2B, a protease inhibitor. Molecular cloning revealed the nucleotide sequence of the human endopin 2B cDNA. Its deduced primary sequence shows high homology to bovine endopin 2A that possesses cross-class protease inhibition of elastase and papain. Notably, the human endopin 2B cDNA sequence revealed GTG as the predicted translation initiation codon; the predicted translation product of 46 kDa endopin 2B was produced by in vitro translation of 35S-endopin 2B with mammalian (rabbit) protein translation components. Importantly, bioinformatic studies demonstrated the presence of the entire human endopin 2B cDNA sequence with GTG as initiation codon within the human genome on chromosome 14. Further evidence for GTG as a functional initiation codon was illustrated by GTG-mediated in vitro translation of the heterologous protein EGFP, and by GTG-mediated expression of EGFP in mammalian PC12 cells. Mutagenesis of GTG to GTC resulted in the absence of EGFP expression in PC12 cells, indicating the function of GTG as an initiation codon. In addition, it was apparent that the GTG initiation codon produces lower levels of translated protein compared to ATG as initiation codon. Significantly, GTG-mediated translation of endopin 2B demonstrates a functional human gene product not previously predicted from initial analyses of the human genome. Further analyses based on GTG as an alternative initiation codon may predict new candidate genes of the human genome.

49 CFR 382.303 - Post-accident testing.

Code of Federal Regulations, 2010 CFR

2010-10-01

... functions with respect to the vehicle, if the accident involved the loss of human life; or (2) Who receives... performing safety-sensitive functions with respect to the vehicle, if the accident involved the loss of human life; or (2) Who receives a citation within thirty-two hours of the occurrence under State or local law...

Manufacturing, integration, and test results of the MATISSE cold optics bench

NASA Astrophysics Data System (ADS)

Bettonvil, Felix C. M.; Kroes, G.; Agoćs, T.; van Duin, A.; Elswijk, E.; de Haan, M.; ter Horst, R.; Kragt, J.; Kuindersma, J.; Navarro, R.; Roelfsema, R.; Schuil, M.; Tromp, T.; Venema, L.; van Kessel, F.; Jaskó, A.

2014-07-01

MATISSE is the second-generation mid-infrared interferometric spectrograph and imager for ESO's Very Large Telescope Interferometer (VLTI). NOVA-ASTRON is responsible for the Cold Optics Bench (COB), representing the last part of the optics train where the four beams are re-arranged, spectrally dispersed and combined. The COB consist of two sister units, one for the LM-band, one for the N-band, which were successively completed at NOVA-ASTRON in autumn 2013 and spring 2014. The LM-band COB is under cryogenic test in its cryostat at MPIA/Heidelberg; the N-band COB finished cryogenic tests and has been installed at OCA/Nice for integration together with the Warm Optics. This paper focuses on the manufacturing, integration and test results of the COBs, and gives an overview of the current status.

Choroidal imaging by one-micrometer dual-beam Doppler optical coherence angiography with adjustable velocity range

NASA Astrophysics Data System (ADS)

Jaillon, Franck; Makita, Shuichi; Yasuno, Yoshiaki

2012-03-01

Ability of a new version of one-micrometer dual-beam optical coherence angiography (OCA) based on Doppler optical coherence tomography (OCT), is demonstrated for choroidal vasculature imaging. A particular feature of this system is the adjustable time delay between two probe beams. This allows changing the measurable velocity range of moving constituents such as blood without alteration of the scanning protocol. Since choroidal vasculature is made of vessels having blood flows with different velocities, this technique provides a way of discriminating vessels according to the velocity range of their inner flow. An example of choroid imaging of a normal emmetropic eye is here given. It is shown that combining images acquired with different velocity ranges provides an enhanced vasculature representation. This method may be then useful for pathological choroid characterization.

FoxP2 regulates neurogenesis during embryonic cortical development.

PubMed

Tsui, David; Vessey, John P; Tomita, Hideaki; Kaplan, David R; Miller, Freda D

2013-01-02

The transcription factor FoxP2 has been associated with the development of human speech but the underlying cellular function of FoxP2 is still unclear. Here we provide evidence that FoxP2 regulates genesis of some intermediate progenitors and neurons in the mammalian cortex, one of the key centers for human speech. Specifically, knockdown of FoxP2 in embryonic cortical precursors inhibits neurogenesis, at least in part by inhibiting the transition from radial glial precursors to neurogenic intermediate progenitors. Moreover, overexpression of human, but not mouse, FoxP2 enhances the genesis of intermediate progenitors and neurons. In contrast, expression of a human FoxP2 mutant that causes vocalization deficits decreases neurogenesis, suggesting that in the murine system human FoxP2 acts as a gain-of-function protein, while a human FoxP2 mutant acts as a dominant-inhibitory protein. These results support the idea that FoxP2 regulates the transition from neural precursors to transit-amplifying progenitors and ultimately neurons, and shed light upon the molecular changes that might contribute to evolution of the mammalian cortex.

Functional Characterization of the Human Mariner Transposon Hsmar2

PubMed Central

Gil, Estel; Bosch, Assumpcio; Lampe, David; Lizcano, Jose M.; Perales, Jose C.; Danos, Olivier; Chillon, Miguel

2013-01-01

DNA transposons are mobile elements with the ability to mobilize and transport genetic information between different chromosomal loci. Unfortunately, most transposons copies are currently inactivated, little is known about mariner elements in humans despite their role in the evolution of the human genome, even though the Hsmar2 transposon is associated to hotspots for homologous recombination involved in human genetic disorders as Charcot–Marie–Tooth, Prader-Willi/Angelman, and Williams syndromes. This manuscript describes the functional characterization of the human HSMAR2 transposase generated from fossil sequences and shows that the native HSMAR2 is active in human cells, but also in bacteria, with an efficiency similar to other mariner elements. We observe that the sub-cellular localization of HSMAR2 is dependent on the host cell type, and is cytotoxic when overexpressed in HeLa cells. Finally, we also demonstrate that the binding of HSMAR2 to its own ITRs is specific, and that the excision reaction leaves non-canonical footprints both in bacteria and eukaryotic cells. PMID:24039890

Optically stimulated luminescence dating of Holocene alluvial fans, East Anatolian Fault System, Turkey

NASA Astrophysics Data System (ADS)

Dogan, Tamer; Cetin, Hasan; Yegingil, Zehra; Topaksu, Mustafa; Yüksel, Mehmet; Duygun, Fırat; Nur, Necmettin; Yegingil, İlhami

2015-07-01

In this study, the optically stimulated luminescence dating technique was used to determine the time of deposition of alluvial sediment samples from the Türkoğlu-Antakya segment of the East Anatolian Fault System (EAFS) in Turkey. The double-single aliquot regenerative dose protocol on fine grain samples was used to estimate equivalent doses (De). Annual dose rate was computed using elemental concentration of uranium (U) and thorium (Th) determined by using thick-source alpha counting and potassium (K) concentrations using X-ray fluorescence and/or atomic absorption spectroscopy. The environmental dose was measured in situ using α-Al2O3:C chips inside plastic tubes for a year. The two different bulk sediment samples collected from the Islahiye trench yielded ages of 4.54 ± 0.28 and 2.91 ± 0.23 ka. We also obtained a 2.60 ± 0.18 ka age for the alluvial deposit in the Kıranyurdu trench and 2.31 ± 0.14 ka age for an excavation area called Malzeme Ocağı. These ages were consistent with the corresponding calibrated Carbon-14 (14C) ages of the region. The differences between the determined ages were insufficient to clearly distinguish the disturbance event from the effects of bioturbation, biological mixing, or other sources of De variation in the region. They provide a record of alluvial aggradation in the region and may determine undocumented historical earthquake events.

Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking.

PubMed

Budayeva, Hanna G; Cristea, Ileana M

2016-10-01

Human sirtuin 2 (SIRT2) is an NAD + -dependent deacetylase that primarily functions in the cytoplasm, where it can regulate α-tubulin acetylation levels. SIRT2 is linked to cancer progression, neurodegeneration, and infection with bacteria or viruses. However, the current knowledge about its interactions and the means through which it exerts its functions has remained limited. Here, we aimed to gain a better understanding of its cellular functions by characterizing SIRT2 subcellular localization, the identity and relative stability of its protein interactions, and its impact on the proteome of primary human fibroblasts. To assess the relative stability of SIRT2 interactions, we used immunoaffinity purification in conjunction with both label-free and metabolic labeling quantitative mass spectrometry. In addition to the expected associations with cytoskeleton proteins, including its known substrate TUBA1A, our results reveal that SIRT2 specifically interacts with proteins functioning in membrane trafficking, secretory processes, and transcriptional regulation. By quantifying their relative stability, we found most interactions to be transient, indicating a dynamic SIRT2 environment. We discover that SIRT2 localizes to the ER-Golgi intermediate compartment (ERGIC), and that this recruitment requires an intact ER-Golgi trafficking pathway. Further expanding these findings, we used microscopy and interaction assays to establish the interaction and coregulation of SIRT2 with liprin-β1 scaffolding protein (PPFiBP1), a protein with roles in focal adhesions disassembly. As SIRT2 functions may be accomplished via interactions, enzymatic activity, and transcriptional regulation, we next assessed the impact of SIRT2 levels on the cellular proteome. SIRT2 knockdown led to changes in the levels of proteins functioning in membrane trafficking, including some of its interaction partners. Altogether, our study expands the knowledge of SIRT2 cytoplasmic functions to define a previously unrecognized involvement in intracellular trafficking pathways, which may contribute to its roles in cellular homeostasis and human diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking*

PubMed Central

Budayeva, Hanna G.; Cristea, Ileana M.

2016-01-01

Human sirtuin 2 (SIRT2) is an NAD+-dependent deacetylase that primarily functions in the cytoplasm, where it can regulate α-tubulin acetylation levels. SIRT2 is linked to cancer progression, neurodegeneration, and infection with bacteria or viruses. However, the current knowledge about its interactions and the means through which it exerts its functions has remained limited. Here, we aimed to gain a better understanding of its cellular functions by characterizing SIRT2 subcellular localization, the identity and relative stability of its protein interactions, and its impact on the proteome of primary human fibroblasts. To assess the relative stability of SIRT2 interactions, we used immunoaffinity purification in conjunction with both label-free and metabolic labeling quantitative mass spectrometry. In addition to the expected associations with cytoskeleton proteins, including its known substrate TUBA1A, our results reveal that SIRT2 specifically interacts with proteins functioning in membrane trafficking, secretory processes, and transcriptional regulation. By quantifying their relative stability, we found most interactions to be transient, indicating a dynamic SIRT2 environment. We discover that SIRT2 localizes to the ER-Golgi intermediate compartment (ERGIC), and that this recruitment requires an intact ER-Golgi trafficking pathway. Further expanding these findings, we used microscopy and interaction assays to establish the interaction and coregulation of SIRT2 with liprin-β1 scaffolding protein (PPFiBP1), a protein with roles in focal adhesions disassembly. As SIRT2 functions may be accomplished via interactions, enzymatic activity, and transcriptional regulation, we next assessed the impact of SIRT2 levels on the cellular proteome. SIRT2 knockdown led to changes in the levels of proteins functioning in membrane trafficking, including some of its interaction partners. Altogether, our study expands the knowledge of SIRT2 cytoplasmic functions to define a previously unrecognized involvement in intracellular trafficking pathways, which may contribute to its roles in cellular homeostasis and human diseases. PMID:27503897

Predictive value of plasma β2-microglobulin on human body function and senescence.

PubMed

Dong, X-M; Cai, R; Yang, F; Zhang, Y-Y; Wang, X-G; Fu, S-L; Zhang, J-R

2016-06-01

To explore the correlation between plasma β2-microglobulin (β2-MG) as senescence factor with age, heart, liver and kidney function as well as the predictive value of β2-MG in human metabolism function and senescence. 387 cases of healthy people of different ages were selected and the automatic biochemical analyzer was used to test β2-MG in plasma based on immunoturbidimetry and also all biochemical indexes. The correlation between β2-MG and age, gender and all biochemical indexes was analyzed. β2-MG was positively correlated to age, r = 0.373; and the difference was of statistical significance (p < 0.010). It was significantly negative correlated to HDL-C but positively correlated to LP (a), BUN, CREA, UA, CYS-C, LDH, CK-MB, HBDH, AST, GLB and HCY. β2-MG was closely correlated to age, heart, kidney and liver biochemical indexes, which can be taken as an important biomarker for human body function and anti-senescence and have significant basic research and clinical guidance values.

CRISPR-mediated HDAC2 disruption identifies two distinct classes of target genes in human cells.

PubMed

Somanath, Priyanka; Herndon Klein, Rachel; Knoepfler, Paul S

2017-01-01

The transcriptional functions of the class I histone deacetylases (HDACs) HDAC1 and HDAC2 are mainly viewed as both repressive and redundant based on murine knockout studies, but they may have additional independent roles and their physiological functions in human cells are not as clearly defined. To address the individual epigenomic functions of HDAC2, here we utilized CRISPR-Cas9 to disrupt HDAC2 in human cells. We find that while HDAC2 null cells exhibited signs of cross-regulation between HDAC1 and HDAC2, specific epigenomic phenotypes were still apparent using RNA-seq and ChIP assays. We identified specific targets of HDAC2 repression, and defined a novel class of genes that are actively expressed in a partially HDAC2-dependent manner. While HDAC2 was required for the recruitment of HDAC1 to repressed HDAC2-gene targets, HDAC2 was dispensable for HDAC1 binding to HDAC2-activated targets, supporting the notion of distinct classes of targets. Both active and repressed classes of gene targets demonstrated enhanced histone acetylation and methylation in HDAC2-null cells. Binding of the HDAC1/2-associated SIN3A corepressor was altered at most HDAC2-targets, but without a clear pattern. Overall, our study defines two classes of HDAC2 targets in human cells, with a dependence of HDAC1 on HDAC2 at one class of targets, and distinguishes unique functions for HDAC2.

Dual Roles of RNF2 in Melanoma Progression | Office of Cancer Genomics

Cancer.gov

Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and prometastatic.

ARF6-dependent regulation of P2Y receptor traffic and function in human platelets.

PubMed

Kanamarlapudi, Venkateswarlu; Owens, Sian E; Saha, Keya; Pope, Robert J; Mundell, Stuart J

2012-01-01

Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors, the P2Y(1) and P2Y(12) purinoceptors. Recently, we demonstrated that P2Y(1) and P2Y(12) purinoceptor activities are rapidly and reversibly modulated in human platelets, revealing that the underlying mechanism requires receptor internalization and subsequent trafficking as an essential part of this process. In this study we investigated the role of the small GTP-binding protein ADP ribosylation factor 6 (ARF6) in the internalization and function of P2Y(1) and P2Y(12) purinoceptors in human platelets. ARF6 has been implicated in the internalization of a number of GPCRs, although its precise molecular mechanism in this process remains unclear. In this study we show that activation of either P2Y(1) or P2Y(12) purinoceptors can stimulate ARF6 activity. Further blockade of ARF6 function either in cell lines or human platelets blocks P2Y purinoceptor internalization. This blockade of receptor internalization attenuates receptor resensitization. Furthermore, we demonstrate that Nm23-H1, a nucleoside diphosphate (NDP) kinase regulated by ARF6 which facilitates dynamin-dependent fission of coated vesicles during endocytosis, is also required for P2Y purinoceptor internalization. These data describe a novel function of ARF6 in the internalization of P2Y purinoceptors and demonstrate the integral importance of this small GTPase upon platelet ADP receptor function.

Evaluation of stereoscopic display with visual function and interview

NASA Astrophysics Data System (ADS)

Okuyama, Fumio

1999-05-01

The influence of binocular stereoscopic (3D) television display on the human eye were compared with one of a 2D display, using human visual function testing and interviews. A 40- inch double lenticular display was used for 2D/3D comparison experiments. Subjects observed the display for 30 minutes at a distance 1.0 m, with a combination of 2D material and one of 3D material. The participants were twelve young adults. Main optometric test with visual function measured were visual acuity, refraction, phoria, near vision point, accommodation etc. The interview consisted of 17 questions. Testing procedures were performed just before watching, just after watching, and forty-five minutes after watching. Changes in visual function are characterized as prolongation of near vision point, decrease of accommodation and increase in phoria. 3D viewing interview results show much more visual fatigue in comparison with 2D results. The conclusions are: 1) change in visual function is larger and visual fatigue is more intense when viewing 3D images. 2) The evaluation method with visual function and interview proved to be very satisfactory for analyzing the influence of stereoscopic display on human eye.

Cognitive neuroscience 2.0: building a cumulative science of human brain function

PubMed Central

Yarkoni, Tal; Poldrack, Russell A.; Van Essen, David C.; Wager, Tor D.

2010-01-01

Cognitive neuroscientists increasingly recognize that continued progress in understanding human brain function will require not only the acquisition of new data, but also the synthesis and integration of data across studies and laboratories. Here we review ongoing efforts to develop a more cumulative science of human brain function. We discuss the rationale for an increased focus on formal synthesis of the cognitive neuroscience literature, provide an overview of recently developed tools and platforms designed to facilitate the sharing and integration of neuroimaging data, and conclude with a discussion of several emerging developments that hold even greater promise in advancing the study of human brain function. PMID:20884276

Functionalized Ni@SiO2 core/shell magnetic nanoparticles as a chemosensor and adsorbent for Cu2+ ion in drinking water and human blood.

PubMed

Park, Minsung; Seo, Sungmin; Lee, Soo Jin; Jung, Jong Hwa

2010-11-01

Fluorogenic based nitrobenzofuran-functionalized Ni@SiO(2) core/shell magnetic nanoparticles have been prepared by sol-gel grafting reaction. Their ability to detect and remove metal ions was evaluated by fluorophotometry. The nanoparticles exhibited a high affinity and selectivity for Cu(2+) over competing metal ions. Furthermore, the nanoparticles efficiently removed Cu(2+) in drinking water and human blood.

Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis

PubMed Central

Rady, Brian; Chen, Yanmei; Vaca, Pilar; Wang, Qian; Wang, Yong; Salmon, Patrick; Oberholzer, José

2013-01-01

The mechanisms that control proliferation, or lack thereof, in adult human β cells are poorly understood. Controlled induction of proliferation could dramatically expand the clinical application of islet cell transplantation and represents an important component of regenerative approaches to a functional cure of diabetes. Adult human β cells are particularly resistant to common proliferative targets and often dedifferentiate during proliferation. Here we show that expression of the transcription factor E2F3 has a role in regulating β-cell quiescence and proliferation. We found human islets have virtually no expression of the pro-proliferative G1/S transcription factors E2F1–3, but an abundance of inhibitory E2Fs 4–6. In proliferative human insulinomas, inhibitory E2Fs were absent, while E2F3 is expressed. Using this pattern as a “roadmap” for proliferation, we demonstrated that ectopic expression of nuclear E2F3 induced significant expansion of insulin-positive cells in both rat and human islets. These cells did not undergo apoptosis and retained their glucose-responsive insulin secretion, showing the ability to reverse diabetes in mice. Our results suggest that E2F4–6 may help maintain quiescence in human β cells and identify E2F3 as a novel target to induce proliferation of functional β cells. Refinement of this approach may increase the islets available for cell-based therapies and research and could provide important cues for understanding in vivo proliferation of β cells. PMID:23907129

Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease

PubMed Central

Jones, Melanie A.; Amr, Sami; Ferebee, Aerial; Huynh, Phung; Rosenfeld, Jill A.; Miles, Michael F.; Davies, Andrew G.; Korey, Christopher A.; Warrick, John M.; Shiang, Rita; Elsea, Sarah H.; Girirajan, Santhosh; Grotewiel, Mike

2014-01-01

ABSTRACT Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay. PMID:24705017

The human Piwi protein Hiwi2 associates with tRNA-derived piRNAs in somatic cells

PubMed Central

Keam, Simon P.; Young, Paul E.; McCorkindale, Alexandra L.; Dang, Thurston H.Y.; Clancy, Jennifer L.; Humphreys, David T.; Preiss, Thomas; Hutvagner, Gyorgy; Martin, David I.K.; Cropley, Jennifer E.; Suter, Catherine M.

2014-01-01

The Piwi-piRNA pathway is active in animal germ cells where its functions are required for germ cell maintenance and gamete differentiation. Piwi proteins and piRNAs have been detected outside germline tissue in multiple phyla, but activity of the pathway in mammalian somatic cells has been little explored. In particular, Piwi expression has been observed in cancer cells, but nothing is known about the piRNA partners or the function of the system in these cells. We have surveyed the expression of the three human Piwi genes, Hiwi, Hili and Hiwi2, in multiple normal tissues and cancer cell lines. We find that Hiwi2 is ubiquitously expressed; in cancer cells the protein is largely restricted to the cytoplasm and is associated with translating ribosomes. Immunoprecipitation of Hiwi2 from MDAMB231 cancer cells enriches for piRNAs that are predominantly derived from processed tRNAs and expressed genes, species which can also be found in adult human testis. Our studies indicate that a Piwi-piRNA pathway is present in human somatic cells, with an uncharacterised function linked to translation. Taking this evidence together with evidence from primitive organisms, we propose that this somatic function of the pathway predates the germline functions of the pathway in modern animals. PMID:25038252

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

PubMed Central

Liévin-Le Moal, Vanessa

2013-01-01

SUMMARY Hosts are protected from attack by potentially harmful enteric microorganisms, viruses, and parasites by the polarized fully differentiated epithelial cells that make up the epithelium, providing a physical and functional barrier. Enterovirulent bacteria interact with the epithelial polarized cells lining the intestinal barrier, and some invade the cells. A better understanding of the cross talk between enterovirulent bacteria and the polarized intestinal cells has resulted in the identification of essential enterovirulent bacterial structures and virulence gene products playing pivotal roles in pathogenesis. Cultured animal cell lines and cultured human nonintestinal, undifferentiated epithelial cells have been extensively used for understanding the mechanisms by which some human enterovirulent bacteria induce intestinal disorders. Human colon carcinoma cell lines which are able to express in culture the functional and structural characteristics of mature enterocytes and goblet cells have been established, mimicking structurally and functionally an intestinal epithelial barrier. Moreover, Caco-2-derived M-like cells have been established, mimicking the bacterial capture property of M cells of Peyer's patches. This review intends to analyze the cellular and molecular mechanisms of pathogenesis of human enterovirulent bacteria observed in infected cultured human colon carcinoma enterocyte-like HT-29 subpopulations, enterocyte-like Caco-2 and clone cells, the colonic T84 cell line, HT-29 mucus-secreting cell subpopulations, and Caco-2-derived M-like cells, including cell association, cell entry, intracellular lifestyle, structural lesions at the brush border, functional lesions in enterocytes and goblet cells, functional and structural lesions at the junctional domain, and host cellular defense responses. PMID:24006470

Stomatin-Like Protein 2 Binds Cardiolipin and Regulates Mitochondrial Biogenesis and Function▿

PubMed Central

Christie, Darah A.; Lemke, Caitlin D.; Elias, Isaac M.; Chau, Luan A.; Kirchhof, Mark G.; Li, Bo; Ball, Eric H.; Dunn, Stanley D.; Hatch, Grant M.; Madrenas, Joaquín

2011-01-01

Stomatin-like protein 2 (SLP-2) is a widely expressed mitochondrial inner membrane protein of unknown function. Here we show that human SLP-2 interacts with prohibitin-1 and -2 and binds to the mitochondrial membrane phospholipid cardiolipin. Upregulation of SLP-2 expression increases cardiolipin content and the formation of metabolically active mitochondrial membranes and induces mitochondrial biogenesis. In human T lymphocytes, these events correlate with increased complex I and II activities, increased intracellular ATP stores, and increased resistance to apoptosis through the intrinsic pathway, ultimately enhancing cellular responses. We propose that the function of SLP-2 is to recruit prohibitins to cardiolipin to form cardiolipin-enriched microdomains in which electron transport complexes are optimally assembled. Likely through the prohibitin functional interactome, SLP-2 then regulates mitochondrial biogenesis and function. PMID:21746876

Repeated high-intensity exercise modulates Ca(2+) sensitivity of human skeletal muscle fibers.

PubMed

Gejl, K D; Hvid, L G; Willis, S J; Andersson, E; Holmberg, H-C; Jensen, R; Frandsen, U; Hansen, J; Plomgaard, P; Ørtenblad, N

2016-05-01

The effects of short-term high-intensity exercise on single fiber contractile function in humans are unknown. Therefore, the purposes of this study were: (a) to access the acute effects of repeated high-intensity exercise on human single muscle fiber contractile function; and (b) to examine whether contractile function was affected by alterations in the redox balance. Eleven elite cross-country skiers performed four maximal bouts of 1300 m treadmill skiing with 45 min recovery. Contractile function of chemically skinned single fibers from triceps brachii was examined before the first and following the fourth sprint with respect to Ca(2+) sensitivity and maximal Ca(2+) -activated force. To investigate the oxidative effects of exercise on single fiber contractile function, a subset of fibers was incubated with dithiothreitol (DTT) before analysis. Ca(2+) sensitivity was enhanced by exercise in both MHC I (17%, P < 0.05) and MHC II (15%, P < 0.05) fibers. This potentiation was not present after incubation of fibers with DTT. Specific force of both MHC I and MHC II fibers was unaffected by exercise. In conclusion, repeated high-intensity exercise increased Ca(2+) sensitivity in both MHC I and MHC II fibers. This effect was not observed in a reducing environment indicative of an exercise-induced oxidation of the human contractile apparatus. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region.

PubMed

Fu, Lijuan; Shi, Zhimin; Luo, Guanzheng; Tu, Weihong; Wang, XiuJie; Fang, Zhide; Li, XiaoChing

2014-10-01

Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3' untranslated region (3' UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3' UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed. Our results reveal novel regulatory functions of the human FOXP2 3' UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network.

Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses

PubMed Central

Boesch, Austin W.; Osei-Owusu, Nana Yaw; Crowley, Andrew R.; Chu, Thach H.; Chan, Ying N.; Weiner, Joshua A.; Bharadwaj, Pranay; Hards, Rufus; Adamo, Mark E.; Gerber, Scott A.; Cocklin, Sarah L.; Schmitz, Joern E.; Miles, Adam R.; Eckman, Joshua W.; Belli, Aaron J.; Reimann, Keith A.; Ackerman, Margaret E.

2016-01-01

Antibodies raised in Indian rhesus macaques [Macaca mulatta (MM)] in many preclinical vaccine studies are often evaluated in vitro for titer, antigen-recognition breadth, neutralization potency, and/or effector function, and in vivo for potential associations with protection. However, despite reliance on this key animal model in translation of promising candidate vaccines for evaluation in first in man studies, little is known about the properties of MM immunoglobulin G (IgG) subclasses and how they may compare to human IgG subclasses. Here, we evaluate the binding of MM IgG1, IgG2, IgG3, and IgG4 to human Fc gamma receptors (FcγR) and their ability to elicit the effector functions of human FcγR-bearing cells, and unlike in humans, find a notable absence of subclasses with dramatically silent Fc regions. Biophysical, in vitro, and in vivo characterization revealed MM IgG1 exhibited the greatest effector function activity followed by IgG2 and then IgG3/4. These findings in rhesus are in contrast with the canonical understanding that IgG1 and IgG3 dominate effector function in humans, indicating that subclass-switching profiles observed in rhesus studies may not strictly recapitulate those observed in human vaccine studies. PMID:28018355

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

PubMed Central

Kuznetsova, Alexandra; Yu, Yue; Hollister-Lock, Jennifer; Opare-Addo, Lynn; Rozzo, Aldo; Sadagurski, Marianna; Norquay, Lisa; Reed, Jessica E.; El Khattabi, Ilham; Bonner-Weir, Susan; Weir, Gordon C.; Sharma, Arun

2016-01-01

The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes. PMID:27152363

Identification of human-to-human transmissibility factors in PB2 proteins of influenza A by large-scale mutual information analysis

PubMed Central

Miotto, Olivo; Heiny, AT; Tan, Tin Wee; August, J Thomas; Brusic, Vladimir

2008-01-01

Background The identification of mutations that confer unique properties to a pathogen, such as host range, is of fundamental importance in the fight against disease. This paper describes a novel method for identifying amino acid sites that distinguish specific sets of protein sequences, by comparative analysis of matched alignments. The use of mutual information to identify distinctive residues responsible for functional variants makes this approach highly suitable for analyzing large sets of sequences. To support mutual information analysis, we developed the AVANA software, which utilizes sequence annotations to select sets for comparison, according to user-specified criteria. The method presented was applied to an analysis of influenza A PB2 protein sequences, with the objective of identifying the components of adaptation to human-to-human transmission, and reconstructing the mutation history of these components. Results We compared over 3,000 PB2 protein sequences of human-transmissible and avian isolates, to produce a catalogue of sites involved in adaptation to human-to-human transmission. This analysis identified 17 characteristic sites, five of which have been present in human-transmissible strains since the 1918 Spanish flu pandemic. Sixteen of these sites are located in functional domains, suggesting they may play functional roles in host-range specificity. The catalogue of characteristic sites was used to derive sequence signatures from historical isolates. These signatures, arranged in chronological order, reveal an evolutionary timeline for the adaptation of the PB2 protein to human hosts. Conclusion By providing the most complete elucidation to date of the functional components participating in PB2 protein adaptation to humans, this study demonstrates that mutual information is a powerful tool for comparative characterization of sequence sets. In addition to confirming previously reported findings, several novel characteristic sites within PB2 are reported. Sequence signatures generated using the characteristic sites catalogue characterize concisely the adaptation characteristics of individual isolates. Evolutionary timelines derived from signatures of early human influenza isolates suggest that characteristic variants emerged rapidly, and remained remarkably stable through subsequent pandemics. In addition, the signatures of human-infecting H5N1 isolates suggest that this avian subtype has low pandemic potential at present, although it presents more human adaptation components than most avian subtypes. PMID:18315849

NaLi-H1: A universal synthetic library of humanized nanobodies providing highly functional antibodies and intrabodies

PubMed Central

Moutel, Sandrine; Bery, Nicolas; Bernard, Virginie; Keller, Laura; Lemesre, Emilie; de Marco, Ario; Ligat, Laetitia; Rain, Jean-Christophe; Favre, Gilles; Olichon, Aurélien; Perez, Franck

2016-01-01

In vitro selection of antibodies allows to obtain highly functional binders, rapidly and at lower cost. Here, we describe the first fully synthetic phage display library of humanized llama single domain antibody (NaLi-H1: Nanobody Library Humanized 1). Based on a humanized synthetic single domain antibody (hs2dAb) scaffold optimized for intracellular stability, the highly diverse library provides high affinity binders without animal immunization. NaLi-H1 was screened following several selection schemes against various targets (Fluorescent proteins, actin, tubulin, p53, HP1). Conformation antibodies against active RHO GTPase were also obtained. Selected hs2dAb were used in various immunoassays and were often found to be functional intrabodies, enabling tracking or inhibition of endogenous targets. Functionalization of intrabodies allowed specific protein knockdown in living cells. Finally, direct selection against the surface of tumor cells produced hs2dAb directed against tumor-specific antigens further highlighting the potential use of this library for therapeutic applications. DOI: http://dx.doi.org/10.7554/eLife.16228.001 PMID:27434673

Protannotator: a semiautomated pipeline for chromosome-wise functional annotation of the "missing" human proteome.

PubMed

Islam, Mohammad T; Garg, Gagan; Hancock, William S; Risk, Brian A; Baker, Mark S; Ranganathan, Shoba

2014-01-03

The chromosome-centric human proteome project (C-HPP) aims to define the complete set of proteins encoded in each human chromosome. The neXtProt database (September 2013) lists 20,128 proteins for the human proteome, of which 3831 human proteins (∼19%) are considered "missing" according to the standard metrics table (released September 27, 2013). In support of the C-HPP initiative, we have extended the annotation strategy developed for human chromosome 7 "missing" proteins into a semiautomated pipeline to functionally annotate the "missing" human proteome. This pipeline integrates a suite of bioinformatics analysis and annotation software tools to identify homologues and map putative functional signatures, gene ontology, and biochemical pathways. From sequential BLAST searches, we have primarily identified homologues from reviewed nonhuman mammalian proteins with protein evidence for 1271 (33.2%) "missing" proteins, followed by 703 (18.4%) homologues from reviewed nonhuman mammalian proteins and subsequently 564 (14.7%) homologues from reviewed human proteins. Functional annotations for 1945 (50.8%) "missing" proteins were also determined. To accelerate the identification of "missing" proteins from proteomics studies, we generated proteotypic peptides in silico. Matching these proteotypic peptides to ENCODE proteogenomic data resulted in proteomic evidence for 107 (2.8%) of the 3831 "missing proteins, while evidence from a recent membrane proteomic study supported the existence for another 15 "missing" proteins. The chromosome-wise functional annotation of all "missing" proteins is freely available to the scientific community through our web server (http://biolinfo.org/protannotator).

Deficient mitochondrial biogenesis in IL-2 activated NK cells correlates with impaired PGC1-α upregulation in elderly humans.

PubMed

Miranda, Dante; Jara, Claudia; Mejias, Sophia; Ahumada, Viviana; Cortez-San Martin, Marcelo; Ibañez, Jorge; Hirsch, Sandra; Montoya, Margarita

2018-05-18

Immunosenescence has been described as age-associated changes in the immune function which are thought to be responsible for the increased morbidity with age. Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in immune defense against tumor and microbial diseases. Interestingly, aging-related NK cell dysfunction is associated with features of aging such as tumor incidence, reduced vaccination efficacy, and short survival due to infection. It is known that NK cell effector functions are critically dependent on cytokines and metabolic activity. Our aim was to determine whether there is a difference in purified human NK cell function in response to high concentration of IL-2 between young and elder donors. Here, we report that the stimulation of human NK cells with IL-2 (2000 U/mL) enhance NK cell cytotoxic activity from both young and elderly donors. However, while NK cells from young people responded to IL-2 signaling by increasing mitochondrial mass and mitochondrial membrane potential, no increase in these mitochondrial functional parameters was seen in purified NK cells from elderly subjects. Moreover, as purified NK cells from the young exhibited an almost three-fold increase in PGC-1α expression after IL-2 (2000 U/mL) stimulation, PGC-1α expression was inhibited in purified NK cells from elders. Furthermore, this response upon PGC-1α expression after IL-2 stimulation promoted an increase in ROS production in NK cells from elderly humans, while no increase in ROS production was observed in NK cells of young donors. Our data show that IL-2 stimulates NK cell effector function through a signaling pathway which involves a PGC-1α-dependent mitochondrial function in young NK cells, however it seems that NK cells from older donors exhibit an altered IL-2 signaling which affects mitochondrial function associated with an increased production of ROS which could represent a feature of NK cell senescence. Copyright © 2018 Elsevier Inc. All rights reserved.

Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis.

PubMed

Nicholas, Dequina; Proctor, Elizabeth A; Raval, Forum M; Ip, Blanche C; Habib, Chloe; Ritou, Eleni; Grammatopoulos, Tom N; Steenkamp, Devin; Dooms, Hans; Apovian, Caroline M; Lauffenburger, Douglas A; Nikolajczyk, Barbara S

2017-01-01

Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular flux (XF96) analyzers, but the technology remains imperfect for analysis of human lymphocytes. Limitations in XF technology include the lack of practical protocols for analysis of archived human cells, and inadequate data analysis tools that require manual quality checks. Current analysis tools for XF outcomes are also unable to automatically assess data quality and delete untenable data from the relatively high number of biological replicates needed to power complex human cell studies. The objectives of work presented herein are to test the impact of common cellular manipulations on XF outcomes, and to develop and validate a new automated tool that objectively analyzes a virtually unlimited number of samples to quantitate mitochondrial function in immune cells. We present significant improvements on previous XF analyses of primary human cells that will be absolutely essential to test the prediction that changes in immune cell mitochondrial function and fuel sources support immune dysfunction in chronic inflammatory diseases like type 2 diabetes.

Simulation of the dusty plasma environment of 65803 Didymos for the Asteroid Impact Mission (AIM)

NASA Astrophysics Data System (ADS)

Cipriani, Fabrice; Rodgers, David; Hilgers, Alain; Hess, Sebastien; Carnelli, Ian

2016-10-01

The Asteroid Impact and Deflection Assessment mission (AIDA) is a joint European-US technology demonstrator mission including the DART asteroid impactor (NASA/JHU/APL) and the AIM asteroid rendezvous platform (ESA/DLR/OCA) set to reach Near Earth binary Object 65803 Didymos in October 2022. Besides technology demonstration in the deep space communications domain and the realization of a kinetic impact on the moonlet to study deflection parameters, this asteroid rendezvous mission is an opportunity to carry out in-situ observations of the close environment of a binary system, addressing some fundamental science questions. The MASCOT-2 lander will be released from the AIM platform and operate at the surface of the moonlet of 65803 Didymos, complemented by the ability of the Cubesat Opportunity Payloads (COPINS) to sample the close environment of the binary.In this context, we have developed an model describing the plasma and charged dust components of the near surface environment of the moonlet (170m in diameter), targeted by the MASCOT-2 lander and of the DART impactor. We performed numerical simulations in order to estimate the electrostatic surface potentials at various locations of the surface, resulting from its interaction with the solar wind plasma and solar photons. In addition, we describe charging levels, density profiles, and velocity distribution of regolith grains lifted out from the surface up to about 70m above the surface.

Ground-based measurements of the solar diameter during the rising phase of solar cycle 24

NASA Astrophysics Data System (ADS)

Meftah, M.; Corbard, T.; Irbah, A.; Ikhlef, R.; Morand, F.; Renaud, C.; Hauchecorne, A.; Assus, P.; Borgnino, J.; Chauvineau, B.; Crepel, M.; Dalaudier, F.; Damé, L.; Djafer, D.; Fodil, M.; Lesueur, P.; Poiet, G.; Rouzé, M.; Sarkissian, A.; Ziad, A.; Laclare, F.

2014-09-01

Context. For the past thirty years, modern ground-based time-series of the solar radius have shown different apparent variations according to different instruments. The origins of these variations may result from the observer, the instrument, the atmosphere, or the Sun. Solar radius measurements have been made for a very long time and in different ways. Yet we see inconsistencies in the measurements. Numerous studies of solar radius variation appear in the literature, but with conflicting results. These measurement differences are certainly related to instrumental effects or atmospheric effects. Use of different methods (determination of the solar radius), instruments, and effects of Earth's atmosphere could explain the lack of consistency on the past measurements. A survey of the solar radius has been initiated in 1975 by Francis Laclare, at the Calern site of the Observatoire de la Côte d'Azur (OCA). Several efforts are currently made from space missions to obtain accurate solar astrometric measurements, for example, to probe the long-term variations of solar radius, their link with solar irradiance variations, and their influence on the Earth climate. Aims: The Picard program includes a ground-based observatory consisting of different instruments based at the Calern site (OCA, France). This set of instruments has been named "Picard Sol" and consists of a Ritchey-Chrétien telescope providing full-disk images of the Sun in five narrow-wavelength bandpasses (centered on 393.37, 535.7, 607.1, 782.2, and 1025.0 nm), a Sun-photometer that measures the properties of atmospheric aerosol, a pyranometer for estimating a global sky-quality index, a wide-field camera that detects the location of clouds, and a generalized daytime seeing monitor allowing us to measure the spatio-temporal parameters of the local turbulence. Picard Sol is meant to perpetuate valuable historical series of the solar radius and to initiate new time-series, in particular during solar cycle 24. Methods: We defined the solar radius by the inflection-point position of the solar-limb profiles taken at different angular positions of the image. Our results were corrected for the effects of refraction and turbulence by numerical methods. Results: From a dataset of more than 20 000 observations carried out between 2011 and 2013, we find a solar radius of 959.78 ± 0.19 arcsec (696 113 ± 138 km) at 535.7 nm after making all necessary corrections. For the other wavelengths in the solar continuum, we derive very similar results. The solar radius observed with the Solar Diameter Imager and Surface Mapper II during the period 2011-2013 shows variations shorter than 50 milli-arcsec that are out of phase with solar activity.

Identification of the Transcriptional Targets of FOXP2, a Gene Linked to Speech and Language, in Developing Human Brain

PubMed Central

Spiteri, Elizabeth ; Konopka, Genevieve ; Coppola, Giovanni ; Bomar, Jamee ; Oldham, Michael ; Ou, Jing ; Vernes, Sonja C. ; Fisher, Simon E. ; Ren, Bing ; Geschwind, Daniel H. 

2007-01-01

Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes. PMID:17999357

Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells

PubMed Central

Coldwell, Martyn C; Boyfield, Izzy; Brown, Tony; Hagan, Jim J; Middlemiss, Derek N

1999-01-01

The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF-104557 (4-[2-(propylamino)ethyl]-2-(3H) indolone), SKF-97930 (4-carboxy-2-(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry.All the receptor agonists tested (ropinirole, SKF-104557, SKF-97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members.At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF-104557, were partial agonists at the hD4 receptor.Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s.The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities.The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF-104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound. PMID:10455328

CLHM-1 is a functionally conserved and conditionally toxic Ca2+-permeable ion channel in Caenorhabditis elegans.

PubMed

Tanis, Jessica E; Ma, Zhongming; Krajacic, Predrag; He, Liping; Foskett, J Kevin; Lamitina, Todd

2013-07-24

Disruption of neuronal Ca(2+) homeostasis contributes to neurodegenerative diseases through mechanisms that are not fully understood. A polymorphism in CALHM1, a recently described ion channel that regulates intracellular Ca(2+) levels, is a possible risk factor for late-onset Alzheimer's disease. Since there are six potentially redundant CALHM family members in humans, the physiological and pathophysiological consequences of CALHM1 function in vivo remain unclear. The nematode Caenorhabditis elegans expresses a single CALHM1 homolog, CLHM-1. Here we find that CLHM-1 is expressed at the plasma membrane of sensory neurons and muscles. Like human CALHM1, C. elegans CLHM-1 is a Ca(2+)-permeable ion channel regulated by voltage and extracellular Ca(2+). Loss of clhm-1 in the body-wall muscles disrupts locomotory kinematics and biomechanics, demonstrating that CLHM-1 has a physiologically significant role in vivo. The motility defects observed in clhm-1 mutant animals can be rescued by muscle-specific expression of either C. elegans CLHM-1 or human CALHM1, suggesting that the function of these proteins is conserved in vivo. Overexpression of either C. elegans CLHM-1 or human CALHM1 in neurons is toxic, causing degeneration through a necrotic-like mechanism that is partially Ca(2+) dependent. Our data show that CLHM-1 is a functionally conserved ion channel that plays an important but potentially toxic role in excitable cell function.

The scavenger activity of the human P2X7 receptor differs from P2X7 pore function by insensitivity to antagonists, genetic variation and sodium concentration: Relevance to inflammatory brain diseases.

PubMed

Ou, Amber; Gu, Ben J; Wiley, James S

2018-04-01

Activation of P2X7 receptors is widely recognised to initiate proinflammatory responses. However P2X7 also has a dual function as a scavenger receptor which is active in the absence of ATP and plasma proteins and may be important in central nervous system (CNS) diseases. Here, we investigated both P2X7 pore formation and its phagocytic function in fresh human monocytes (as a model of microglia) by measuring ATP-induced ethidium dye uptake and fluorescent bead uptake respectively. This was studied in monocytes expressing various polymorphic variants as well as in the presence of different P2X7 antagonists and ionic media. P2X7-mediated phagocytosis was found to account for about half of Latrunculin (or Cytochalasin D)-sensitive bead engulfment by fresh human monocytes. Monocytes harbouring P2X7 Ala348Thr or Glu496Ala polymorphic variants showed increase or loss of ethidium uptake respectively, but these changes in pore formation did not always correspond to the changes in phagocytosis of YG beads. Unlike pore function, P2X7-mediated phagocytosis was not affected by three potent selective P2X7 antagonists and remained identical in Na + and K + media. Taken together, our results show that P2X7 is a scavenger receptor with important function in the CNS but its phagocytic function has features distinct from its pore function. Both P2X7 pore formation and P2X7-mediated phagocytosis should be considered in the design of new P2X7 antagonists for the treatment of CNS diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Evidence for rRNA 2'-O-methylation plasticity: Control of intrinsic translational capabilities of human ribosomes.

PubMed

Erales, Jenny; Marchand, Virginie; Panthu, Baptiste; Gillot, Sandra; Belin, Stéphane; Ghayad, Sandra E; Garcia, Maxime; Laforêts, Florian; Marcel, Virginie; Baudin-Baillieu, Agnès; Bertin, Pierre; Couté, Yohann; Adrait, Annie; Meyer, Mélanie; Therizols, Gabriel; Yusupov, Marat; Namy, Olivier; Ohlmann, Théophile; Motorin, Yuri; Catez, Frédéric; Diaz, Jean-Jacques

2017-12-05

Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2'-O-methylation (2'-O-Me) is the most abundant rRNA chemical modification, and displays a complex pattern in rRNA. 2'-O-Me was shown to be essential for accurate and efficient protein synthesis in eukaryotic cells. However, whether rRNA 2'-O-Me is an adjustable feature of the human ribosome and a means of regulating ribosome function remains to be determined. Here we challenged rRNA 2'-O-Me globally by inhibiting the rRNA methyl-transferase fibrillarin in human cells. Using RiboMethSeq, a nonbiased quantitative mapping of 2'-O-Me, we identified a repertoire of 2'-O-Me sites subjected to variation and demonstrate that functional domains of ribosomes are targets of 2'-O-Me plasticity. Using the cricket paralysis virus internal ribosome entry site element, coupled to in vitro translation, we show that the intrinsic capability of ribosomes to translate mRNAs is modulated through a 2'-O-Me pattern and not by nonribosomal actors of the translational machinery. Our data establish rRNA 2'-O-Me plasticity as a mechanism providing functional specificity to human ribosomes.

Noninvasively measuring oxygen saturation of human finger-joint vessels by multi-transducer functional photoacoustic tomography

NASA Astrophysics Data System (ADS)

Deng, Zijian; Li, Changhui

2016-06-01

Imaging small blood vessels and measuring their functional information in finger joint are still challenges for clinical imaging modalities. In this study, we developed a multi-transducer functional photoacoustic tomography (PAT) system and successfully imaged human finger-joint vessels from ˜1 mm to <0.2 mm in diameter. In addition, the oxygen saturation (SO2) values of these vessels were also measured. Our results demonstrate that PAT can provide both anatomical and functional information of individual finger-joint vessels with different sizes, which might help the study of finger-joint diseases, such as rheumatoid arthritis.

PGC-1α-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells

PubMed Central

Jara, Claudia; Ibañez, Jorge; Ahumada, Viviana; Acuña-Castillo, Claudio; Martin, Adrian; Córdova, Alexandra

2016-01-01

Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell effector functions are critically dependent on cytokines and metabolic activity. Among various cytokines modulating NK cell function, interleukin-2 (IL-2) can induce a more potent cytotoxic activity defined as lymphokine activated killer activity (LAK). Our aim was to determine if IL-2 induces changes at the mitochondrial level in NK cells to support the bioenergetic demand for performing this enhanced cytotoxic activity more efficiently. Purified human NK cells were cultured with high IL-2 concentrations to develop LAK activity, which was assessed by the ability of NK cells to lyse NK-resistant Daudi cells. Here we show that, after 72 h of culture of purified human NK cells with enough IL-2 to induce LAK activity, both the mitochondrial mass and the mitochondrial membrane potential increased in a PGC-1α-dependent manner. In addition, oligomycin, an inhibitor of ATP synthase, inhibited IL-2-induced LAK activity at 48 and 72 h of culture. Moreover, the secretion of IFN-γ from NK cells with LAK activity was also partially dependent on PGC-1α expression. These results indicate that PGC-1α plays a crucial role in regulating mitochondrial function involved in the maintenance of LAK activity in human NK cells stimulated with IL-2. PMID:27413259

PGC-1α-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells.

PubMed

Miranda, Dante; Jara, Claudia; Ibañez, Jorge; Ahumada, Viviana; Acuña-Castillo, Claudio; Martin, Adrian; Córdova, Alexandra; Montoya, Margarita

2016-01-01

Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell effector functions are critically dependent on cytokines and metabolic activity. Among various cytokines modulating NK cell function, interleukin-2 (IL-2) can induce a more potent cytotoxic activity defined as lymphokine activated killer activity (LAK). Our aim was to determine if IL-2 induces changes at the mitochondrial level in NK cells to support the bioenergetic demand for performing this enhanced cytotoxic activity more efficiently. Purified human NK cells were cultured with high IL-2 concentrations to develop LAK activity, which was assessed by the ability of NK cells to lyse NK-resistant Daudi cells. Here we show that, after 72 h of culture of purified human NK cells with enough IL-2 to induce LAK activity, both the mitochondrial mass and the mitochondrial membrane potential increased in a PGC-1α-dependent manner. In addition, oligomycin, an inhibitor of ATP synthase, inhibited IL-2-induced LAK activity at 48 and 72 h of culture. Moreover, the secretion of IFN-γ from NK cells with LAK activity was also partially dependent on PGC-1α expression. These results indicate that PGC-1α plays a crucial role in regulating mitochondrial function involved in the maintenance of LAK activity in human NK cells stimulated with IL-2.

Foxl2 function in ovarian development.

PubMed

Uhlenhaut, Nina Henriette; Treier, Mathias

2006-07-01

Foxl2 is a forkhead transcription factor essential for proper reproductive function in females. Human patients carrying mutations in the FOXL2 gene display blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant disease associated with eyelid defects and premature ovarian failure in females. Recently, animal models for BPES have been developed that in combination with a catalogue of human FOXL2 mutations provide further insight into its molecular function. Mice homozygous mutant for Foxl2 display craniofacial malformations and female infertility. The analysis of the murine phenotype has revealed that Foxl2 is required for granulosa cell function. These ovarian somatic cells surround and nourish the oocyte and play an important role in follicle formation and activation. Mutations upstream of FOXL2 in humans, not affecting the coding sequence itself, have also been shown to cause BPES, which points to the existence of a distant regulatory element necessary for proper gene expression. The same regulatory sequences may be deleted in the goat polled intersex syndrome (PIS), in which FoxL2 expression is severely reduced. Sequence comparison of FoxL2 from several vertebrate species has shown that it is a highly conserved gene involved in ovary development. Thus, the detailed understanding of Foxl2 function and regulation and the identification of its transcriptional targets may open new avenues for the treatment of female infertility in the future.

β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants

PubMed Central

Abbott, Geoffrey W.

2017-01-01

The human ventricular cardiomyocyte transient outward K+ current (Ito) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac Ito is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, diverging only by a C-terminal, S6-proximal, 19-residue stretch unique to Kv4.3L), which are differentially remodeled in HF, but considered functionally alike at baseline. Kv4.3 is regulated in human heart by β subunits including KChIP2b and KCNEs, but their effects were previously assumed to be Kv4.3 isoform-independent. Here, this assumption was tested experimentally using two-electrode voltage-clamp analysis of human subunits co-expressed in Xenopus laevis oocytes. Unexpectedly, Kv4.3L-KChIP2b channels exhibited up to 8-fold lower current augmentation, 40% slower inactivation, and 5 mV-shifted steady-state inactivation compared to Kv4.3S-KChIP2b. A synthetic peptide mimicking the 19-residue stretch diminished these differences, reinforcing the importance of this segment in mediating Kv4.3 regulation by KChIP2b. KCNE subunits induced further functional divergence, including a 7-fold increase in Kv4.3S-KCNE4-KChIP2b current compared to Kv4.3L-KCNE4-KChIP2b. The discovery of β-subunit-dependent functional divergence in human Kv4.3 splice variants suggests a C-terminal signaling hub is crucial to governing β-subunit effects upon Kv4.3, and demonstrates the potential significance of differential Kv4.3 gene-splicing and β subunit expression in myocyte physiology and pathobiology. PMID:28228734

β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants.

PubMed

Abbott, Geoffrey W

2017-01-01

The human ventricular cardiomyocyte transient outward K + current ( I to ) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac I to is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, diverging only by a C-terminal, S6-proximal, 19-residue stretch unique to Kv4.3L), which are differentially remodeled in HF, but considered functionally alike at baseline. Kv4.3 is regulated in human heart by β subunits including KChIP2b and KCNEs, but their effects were previously assumed to be Kv4.3 isoform-independent. Here, this assumption was tested experimentally using two-electrode voltage-clamp analysis of human subunits co-expressed in Xenopus laevis oocytes. Unexpectedly, Kv4.3L-KChIP2b channels exhibited up to 8-fold lower current augmentation, 40% slower inactivation, and 5 mV-shifted steady-state inactivation compared to Kv4.3S-KChIP2b. A synthetic peptide mimicking the 19-residue stretch diminished these differences, reinforcing the importance of this segment in mediating Kv4.3 regulation by KChIP2b. KCNE subunits induced further functional divergence, including a 7-fold increase in Kv4.3S-KCNE4-KChIP2b current compared to Kv4.3L-KCNE4-KChIP2b. The discovery of β-subunit-dependent functional divergence in human Kv4.3 splice variants suggests a C-terminal signaling hub is crucial to governing β-subunit effects upon Kv4.3, and demonstrates the potential significance of differential Kv4.3 gene-splicing and β subunit expression in myocyte physiology and pathobiology.

Development and validation of two methods based on high-performance liquid chromatography-tandem mass spectrometry for determining 1,2-benzopyrone, dihydrocoumarin, o-coumaric acid, syringaldehyde and kaurenoic acid in guaco extracts and pharmaceutical preparations.

PubMed

Gasparetto, João C; de Francisco, Thais M Guimarães; Campos, Francinete R; Pontarolo, Roberto

2011-04-01

In this study, two HPLC-ESI-MS/MS methods were developed and validated for the determination of 1,2-benzopyrone (COU), o-coumaric acid (OCA), kaurenoic acid (KAU), syringaldehyde (SYR), and dihydrocoumarin (DIH) in guaco extracts and pharmaceutical preparations (syrup and oral solution). The chromatographic separation was achieved using a C18 XBridge 150×2.1-mm (5-μm particle size) column maintained at 25°C. The mobile phases consisted of a gradient of water and acetonitrile containing 0.05% formic acid or 5  mM ammonium formate for the positive and negative ion modes, respectively. All of the calibration curves showed excellent coefficients of correlation (r≥0.9970) over the ranges of 1.25-400  ng/mL for coumarin, 10-600  ng/mL for dihydrocoumarin, 5-250  ng/mL for KAU, and 25-500  ng/mL for o-coumaric acid and syringaldehyde. The range of recovery was 96.3-103% with an RSD% of <4.85% for intraday and interday precision. The results indicate that the developed methods are fast, efficient, and sensitive for the quantification of the guaco metabolites in extracts and pharmaceutical forms while avoiding purification and derivatization steps. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Trace elementary concentration in enamel after dental bleaching using HI-ERDA

NASA Astrophysics Data System (ADS)

Added, N.; Rizzutto, M. A.; Curado, J. F.; Francci, C.; Markarian, R.; Mori, M.

2006-08-01

Changes of elementary concentrations in dental enamel after a bleaching treatment with different products, is presented, with special focus on the oxygen contribution. Concentrations for Ca, P, O and C and some other trace elements were obtained for enamel of bovine incisor teeth by HI-ERDA measurements using a 35Cl incident beam and an ionization chamber. Five groups of teeth with five samples each were treated with a different bleaching agents. Each tooth had its crown sectioned in two halves, one for bleaching test and one the other used as a control. Average values of C/Ca, O/Ca, F/Ca enrichment factors were found. The comparison between bleached and non-bleached halves indicates that bleaching treatment did not affect the mineral structure when low-concentration whitening systems were used. The almost constant oxygen concentration in enamel, suggests little changes due to whitening therapy.

Asteroid Impact Mission (aim) & Deflection Assessment: AN Opportunity to Understand Impact Dynamics and Modelling

NASA Astrophysics Data System (ADS)

Galvez, A.; Carnelli, I.; Fontaine, M.; Corral Van Damme, C.

2012-09-01

ESA's Future Preparation and Strategic Studies Office has carried out the Asteroid Impact Mission (AIM) study with the objective of defining an affordable and fully independent mission element that ESA could contribute to an Asteroid Impact Deflection Assessment campaign (AIDA), a joint effort of ESA, JHU/APL, NASA, OCA and DLR. The mission design foresees two independent spacecraft, one impactor (DART) and one rendezvous probe (AIM). The target of this mission is the binary asteroid system (65803) Didymos (1996 GT): one spacecraft, DART, would impact the secondary of the Didymos binary system while AIM would observe and measure any the change in the relative orbit. For this joint project, the timing of the experiment is set (maximum proximity of the target to Earth allowing for ground-based characterisation of the experiment) but the spacecraft are still able to pursue their missions fully independently. This paper describes in particular the AIM rendezvous mission concept.

The MATISSE analysis of large spectral datasets from the ESO Archive

NASA Astrophysics Data System (ADS)

Worley, C.; de Laverny, P.; Recio-Blanco, A.; Hill, V.; Vernisse, Y.; Ordenovic, C.; Bijaoui, A.

2010-12-01

The automated stellar classification algorithm, MATISSE, has been developed at the Observatoire de la Côte d'Azur (OCA) in order to determine stellar temperatures, gravities and chemical abundances for large datasets of stellar spectra. The Gaia Data Processing and Analysis Consortium (DPAC) has selected MATISSE as one of the key programmes to be used in the analysis of the Gaia Radial Velocity Spectrometer (RVS) spectra. MATISSE is currently being used to analyse large datasets of spectra from the ESO archive with the primary goal of producing advanced data products to be made available in the ESO database via the Virtual Observatory. This is also an invaluable opportunity to identify and address issues that can be encountered with the analysis large samples of real spectra prior to the launch of Gaia in 2012. The analysis of the archived spectra of the FEROS spectrograph is currently underway and preliminary results are presented.

Grid of Supergiant B[e] Models from HDUST Radiative Transfer

NASA Astrophysics Data System (ADS)

Domiciano de Souza, A.; Carciofi, A. C.

2012-12-01

By using the Monte Carlo radiative transfer code HDUST (developed by A. C. Carciofi and J..E. Bjorkman) we have built a grid of models for stars presenting the B[e] phenomenon and a bimodal outflowing envelope. The models are particularly adapted to the study of B[e] supergiants and FS CMa type stars. The adopted physical parameters of the calculated models make the grid well adapted to interpret high angular and high spectral observations, in particular spectro-interferometric data from ESO-VLTI instruments AMBER (near-IR at low and medium spectral resolution) and MIDI (mid-IR at low spectral resolution). The grid models include, for example, a central B star with different effective temperatures, a gas (hydrogen) and silicate dust circumstellar envelope with a bimodal mass loss presenting dust in the denser equatorial regions. The HDUST grid models were pre-calculated using the high performance parallel computing facility Mésocentre SIGAMM, located at OCA, France.

Exudation of fluorescent beta-carbolines from Oxalis tuberosa L roots.

PubMed

Bais, Harsh Pal; Park, Sang-Wook; Stermitz, Frank R; Halligan, Kathleen M; Vivanco, Jorge M

2002-11-01

Root fluorescence is a phenomenon in which roots of seedlings fluoresce when irradiated with ultraviolet (UV) light. Soybean (Glycine max) and rye grass (Elymus glaucus) are the only plant species that have been reported to exhibit this occurrence in germinating seedling roots. The trait has been useful as a marker in genetic, tissue culture and diversity studies, and has facilitated selection of plants for breeding purposes. However, the biological significance of this occurrence in plants and other organisms is unknown. Here we report that the Andean tuber crop species Oxalis tuberosa, known as oca in the highlands of South America, secretes a fluorescent compound as part of its root exudates. The main fluorescent compounds were characterized as harmine (7-methoxy-1-methyl-beta-carboline) and harmaline (3, 4-dihydroharmine). We also detected endogenous root fluorescence in other plant species, including Arabidopsis thaliana and Phytolacca americana, a possible indication that this phenomenon is widespread within the plant kingdom.

Inheritance of tristyly in Oxalis tuberosa (Oxalidaceae).

PubMed

Trognitz, B R; Hermann, M

2001-05-01

Frequencies of floral morphs in progenies obtained from a complete set of diallelic crosses among three accessions of tristylous, octoploid oca (Oxalis tuberosa) were used for a Mendelian analysis of floral morph inheritance. The frequencies observed had the best fit to a model of tetrasomic inheritance with two diallelic factors, S, s and M, m, with S being epistatic over M. No explanation could be found for the unexpected formation of a small percentage of short-styled individuals in crosses between the mid-styled and the long-styled parent. For the acceptance of models of disomic and octosomic inheritance several additional assumptions would have to be made and therefore these modes of inheritance are less likely. Dosage-dependent inheritance of floral morph was rejected. Only a small frequency (36%) of the cross progenies flowered, in contrast to the greater propensity for flowering of O. tuberosa accessions held at gene banks.

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica.

PubMed

Cao, Zhouli; Xiao, Qingling; Dai, Xiaoniu; Zhou, Zewei; Jiang, Rong; Cheng, Yusi; Yang, Xiyue; Guo, Huifang; Wang, Jing; Xi, Zhaoqing; Yao, Honghong; Chao, Jie

2017-12-13

Silicosis is characterized by fibroblast accumulation and excessive deposition of extracellular matrix. Although the roles of SiO 2 -induced chemokines and cytokines released from alveolar macrophages have received significant attention, the direct effects of SiO 2 on protein production and functional changes in pulmonary fibroblasts have been less extensively studied. Sigma-1 receptor, which has been associated with cell proliferation and migration in the central nervous system, is expressed in the lung, but its role in silicosis remains unknown. To elucidate the role of sigma-1 receptor in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Both molecular biological assays and pharmacological techniques, combined with functional experiments, such as migration and proliferation, were applied in human pulmonary fibroblasts from adults to analyze the molecular and functional changes induced by SiO 2 . SiO 2 induced endoplasmic reticulum stress in association with enhanced expression of sigma-1 receptor. Endoplasmic reticulum stress promoted migration and proliferation of human pulmonary fibroblasts-adult exposed to SiO 2 , inducing the development of silicosis. Inhibition of sigma-1 receptor ameliorated endoplasmic reticulum stress and fibroblast functional changes induced by SiO 2 . circHIPK2 is involved in the regulation of sigma-1 receptor in human pulmonary fibroblasts-adult exposed to SiO 2 . Our study elucidated a link between SiO 2 -induced fibrosis and sigma-1 receptor signaling, thereby providing novel insight into the potential use of sigma-1 receptor/endoplasmic reticulum stress in the development of novel therapeutic strategies for silicosis treatment.

Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway

PubMed Central

Li, Shiwei; Li, Qi; Kong, Yuanyuan; Wu, Shuang; Cui, Qingpo; Zhang, Mingming; Zhang, Shaobing O.

2017-01-01

Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans. This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12–dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans. This finding suggests the existence of a conserved CYP4V2-POR–nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage. PMID:28760992

Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway.

PubMed

Li, Shiwei; Li, Qi; Kong, Yuanyuan; Wu, Shuang; Cui, Qingpo; Zhang, Mingming; Zhang, Shaobing O

2017-08-15

Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12-dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans This finding suggests the existence of a conserved CYP4V2-POR-nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

Functional expression of cysteinyl leukotriene receptors on human platelets.

PubMed

Hasegawa, Shunji; Ichiyama, Takashi; Hashimoto, Kunio; Suzuki, Yasuo; Hirano, Reiji; Fukano, Reiji; Furukawa, Susumu

2010-01-01

Normal peripheral blood leukocytes, such as basophils, eosinophils, B lymphocytes and monocytes/macrophages, have a cysteinyl leukotriene 1 (CysLT1) receptor, while the cysteinyl leukotriene 2 (CysLT2) receptor is expressed in cardiac Purkinje cells, endothelium, brain and leukocytes. However, it is unknown whether or not platelets express the CysLT1 or CysLT2 receptor. In this study we identify and characterize the biological function of the CysLT receptor of human platelets. We determined the CysLT1 or CysLT2 receptor mRNA expression in normal human platelets by RT-PCR and determined protein expression by Western blotting and flow cytometry. Moreover, we examined the effect of cysteinyl leukotrienes (CysLTs) in platelets on the induction of RANTES (Regulated on Activation, Normal T Expressed, and presumably Secreted). We also investigated whether the CysLT1 receptor antagonist pranlukast inhibits CysLT-induced RANTES release. In conclusion, we showed the functional expression of CysLT receptors on human platelets and demonstrated that CysLTs induced the release of significant amounts of RANTES, which suggests a novel role for human platelets in CysLT-mediated allergic inflammation.

Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma.

PubMed

Bunyavanich, S; Boyce, J A; Raby, B A; Weiss, S T

2012-02-01

Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied. To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure. Nineteen single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n = 1266). Using family based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons. Five SNPs in P2RY12 were associated with multiple lung function measures (P-values 0.006–0.025). Haplotypes in P2RY12 were also associated with lung function (P-values 0.0055–0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P-values 0.0028–0.040). The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.

Cytoarchitectonic identification and probabilistic mapping of two distinct areas within the anterior ventral bank of the human intraparietal sulcus

PubMed Central

Choi, Hi-Jae; Zilles, Karl; Mohlberg, Hartmut; Schleicher, Axel; Fink, Gereon R.; Armstrong, Este; Amunts, Katrin

2008-01-01

Anatomical studies in the macaque cortex and functional imaging studies in humans have demonstrated the existence of different cortical areas within the IntraParietal Sulcus (IPS). Such functional segregation, however, does not correlate with presently available architectonic maps of the human brain. This is particularly true for the classical Brodmann map, which is still widely used as an anatomical reference in functional imaging studies. The aim of this cytoarchitectonic mapping study was to use previously defined algorithms to determine whether consistent regions and borders can be found within the cortex of the anterior IPS in a population of ten postmortem human brains. Two areas, the human IntraParietal area 1 (hIP1) and the human IntraParietal area 2 (hIP2), were delineated in serial histological sections of the anterior, lateral bank of the human IPS. The region hIP1 is located posterior and medial to hIP2, and the former is always within the depths of the IPS. The latter, on the other hand, sometimes reaches the free surface of the superior parietal lobule. The delineations were registered to standard reference space, and probabilistic maps were calculated, thereby quantifying the intersubject variability in location and extent of both areas. In the future, they can be a tool in analyzing structure – function relationships and a basis for determining degrees of homology in the IPS among anthropoid primates. We conclude that the human intraparietal sulcus has a finer grained parcellation than shown in Brodmann’s map. PMID:16432904

Low physiological levels of prostaglandins E2 and F2α improve human sperm functions.

PubMed

Rios, Mariana; Carreño, Daniela V; Oses, Carolina; Barrera, Nelson; Kerr, Bredford; Villalón, Manuel

2016-03-01

Prostaglandins (PGs) have been reported to be present in the seminal fluid and cervical mucus, affecting different stages of sperm maturation from spermatogenesis to the acrosome reaction. This study assessed the effects of low physiological PGE2 and PGF2α concentrations on human sperm motility and on the ability of the spermatozoa to bind to the zona pellucida (ZP). Human spermatozoa were isolated from seminal samples with normal concentration and motility parameters and incubated with 1μM PGE2, 1μM PGF2α or control solution to determine sperm motility and the ability to bind to human ZP. The effects of both PGs on intracellular calcium levels were determined. Incubation for 2 or 18h with PGE2 or PGF2α resulted in a significant (P<0.05) increase in the percentage of spermatozoa with progressive motility. In contrast with PGF2α, PGE2 alone induced an increase in sperm intracellular calcium levels; however, the percentage of sperm bound to the human ZP was doubled for both PGs. These results indicate that incubation of human spermatozoa with low physiological levels of PGE2 or PGF2α increases sperm functions and could improve conditions for assisted reproduction protocols.

Toxic effects of 2,4-dichlorophenoxyacetic acid on human sperm function in vitro.

PubMed

Tan, Zhengyu; Zhou, Jun; Chen, Houyang; Zou, Qianxing; Weng, Shiqi; Luo, Tao; Tang, Yuxin

2016-01-01

The herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D) is globally used in agriculture and has been linked to human sperm abnormalities in vivo. However, its effects on ejaculated human spermatozoa in vitro have not been characterized. Therefore, we examined the effects of 2,4-D on the functions of ejaculated human spermatozoa in vitro, including: sperm motility, the ability to move through a viscous medium, capacitation, and the acrosome reaction. Different doses of 2,4-D (10 nM, 100 nM, 1 µM, 10 µM, 100 µM, and 200 µM) were applied to human spermatozoa prepared from normal fresh semen samples. The results indicated that 2,4-D did not affect the viability, capacitation, or spontaneous acrosome reactions of human spermatozoa, but it dose-dependently inhibited the total motility, progressive motility, ability to penetrate viscous medium, and progesterone-induced capacitation and acrosome reaction rates. These results suggest that exposure to 2,4-D and its accumulation in the seminal plasma and follicular fluid might increase the risk of infertility. Our findings provide new insights for understanding the male reproductive toxicity of 2,4-D.

The human Piwi protein Hiwi2 associates with tRNA-derived piRNAs in somatic cells.

PubMed

Keam, Simon P; Young, Paul E; McCorkindale, Alexandra L; Dang, Thurston H Y; Clancy, Jennifer L; Humphreys, David T; Preiss, Thomas; Hutvagner, Gyorgy; Martin, David I K; Cropley, Jennifer E; Suter, Catherine M

2014-08-01

The Piwi-piRNA pathway is active in animal germ cells where its functions are required for germ cell maintenance and gamete differentiation. Piwi proteins and piRNAs have been detected outside germline tissue in multiple phyla, but activity of the pathway in mammalian somatic cells has been little explored. In particular, Piwi expression has been observed in cancer cells, but nothing is known about the piRNA partners or the function of the system in these cells. We have surveyed the expression of the three human Piwi genes, Hiwi, Hili and Hiwi2, in multiple normal tissues and cancer cell lines. We find that Hiwi2 is ubiquitously expressed; in cancer cells the protein is largely restricted to the cytoplasm and is associated with translating ribosomes. Immunoprecipitation of Hiwi2 from MDAMB231 cancer cells enriches for piRNAs that are predominantly derived from processed tRNAs and expressed genes, species which can also be found in adult human testis. Our studies indicate that a Piwi-piRNA pathway is present in human somatic cells, with an uncharacterised function linked to translation. Taking this evidence together with evidence from primitive organisms, we propose that this somatic function of the pathway predates the germline functions of the pathway in modern animals. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Discovering functional DNA elements using population genomic information: a proof of concept using human mtDNA.

PubMed

Schrider, Daniel R; Kern, Andrew D

2014-06-09

Identifying the complete set of functional elements within the human genome would be a windfall for multiple areas of biological research including medicine, molecular biology, and evolution. Complete knowledge of function would aid in the prioritization of loci when searching for the genetic bases of disease or adaptive phenotypes. Because mutations that disrupt function are disfavored by natural selection, purifying selection leaves a detectable signature within functional elements; accordingly, this signal has been exploited for over a decade through the use of genomic comparisons of distantly related species. While this is so, the functional complement of the genome changes extensively across time and between lineages; therefore, evidence of the current action of purifying selection in humans is essential. Because the removal of deleterious mutations by natural selection also reduces within-species genetic diversity within functional loci, dense population genetic data have the potential to reveal genomic elements that are currently functional. Here, we assess the potential of this approach by examining an ultradeep sample of human mitochondrial genomes (n = 16,411). We show that the high density of polymorphism in this data set precisely delineates regions experiencing purifying selection. Furthermore, we show that the number of segregating alleles at a site is strongly correlated with its divergence across species after accounting for known mutational biases in human mitochondrial DNA (ρ = 0.51; P < 2.2 × 10(-16)). These two measures track one another at a remarkably fine scale across many loci-a correlation that is purely the result of natural selection. Our results demonstrate that genetic variation has the potential to reveal with surprising precision which regions in the genome are currently performing important functions and likely to have deleterious fitness effects when mutated. As more complete human genomes are sequenced, similar power to reveal purifying selection may be achievable in the human nuclear genome. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.