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Sample records for human analog homozygous

  1. Derivation of a Homozygous Human Androgenetic Embryonic Stem Cell Line.

    Science.gov (United States)

    Ding, Chenhui; Huang, Sunxing; Qi, Quan; Fu, Rui; Zhu, Wanwan; Cai, Bing; Hong, Pingping; Liu, Zhengxin; Gu, Tiantian; Zeng, Yanhong; Wang, Jing; Xu, Yanwen; Zhao, Xiaoyang; Zhou, Qi; Zhou, Canquan

    2015-10-01

    Human embryonic stem cells (hESCs) have long been considered as a promising source for cell replacement therapy. However, one major obstacle for the use of these cells is immune compatibility. Histocompatible human parthenogenetic ESCs have been reported as a new method for generating human leukocyte antigen (HLA)-matched hESCs. To further investigate the possibility of obtaining histocompatible stem cells from uniparental embryos, we tried to produce androgenetic haploid human embryos by injecting a single spermatozoon into enucleated human oocyte, and establish human androgenetic embryonic stem (hAGES) cell lines from androgenetic embryos. In the present study, a diploid hAGES cell line has been established, which exhibits typical features of human ESCs, including the expression of pluripotency markers, having differentiation potential in vitro and in vivo, and stable propagation in an undifferentiated state (>P40). Bisulfite sequencing of the H19, Snrpn, Meg3, and Kv imprinting control regions suggested that hAGES cells maintained to a certain extent a sperm methylation pattern. Genome-wide single nucleotide polymorphism, short tandem repeat, and HLA analyses revealed that the hAGES cell genome was highly homozygous. These results suggest that hAGES cells from spermatozoon could serve as a useful tool for studying the mechanisms underlying genomic imprinting in humans. It might also be used as a potential resource for cell replacement therapy as parthenogenetic stem cells.

  2. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.

    Science.gov (United States)

    Ercan-Sencicek, A Gulhan; Jambi, Samira; Franjic, Daniel; Nishimura, Sayoko; Li, Mingfeng; El-Fishawy, Paul; Morgan, Thomas M; Sanders, Stephan J; Bilguvar, Kaya; Suri, Mohnish; Johnson, Michele H; Gupta, Abha R; Yuksel, Zafer; Mane, Shrikant; Grigorenko, Elena; Picciotto, Marina; Alberts, Arthur S; Gunel, Murat; Šestan, Nenad; State, Matthew W

    2015-02-01

    The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.

  3. A Catalog of Genes Homozygously Deleted in Human Lung Cancer and the Candidacy of PTPRD as a Tumor Suppressor Gene

    Science.gov (United States)

    Kohno, Takashi; Otsuka, Ayaka; Girard, Luc; Sato, Masanori; Iwakawa, Reika; Ogiwara, Hideaki; Sanchez-Cespedes, Montse; Minna, John D.; Yokota, Jun

    2010-01-01

    A total of 176 genes homozygously deleted in human lung cancer were identified by DNA array-based whole genome scanning of 52 lung cancer cell lines and subsequent genomic PCR in 74 cell lines, including the 52 cell lines scanned. One or more exons of these genes were homozygously deleted in one (1%) to 20 (27%) cell lines. These genes included known tumor suppressor genes, e.g., CDKN2A/p16, RB1, and SMAD4, and candidate tumor suppressor genes whose hemizygous or homozygous deletions were reported in several types of human cancers, such as FHIT, KEAP1, and LRP1B/LRP-DIP. CDKN2A/p16 and p14ARF located in 9p21 were most frequently deleted (20/74, 27%). The PTPRD gene was most frequently deleted (8/74, 11%) among genes mapping to regions other than 9p21. Somatic mutations, including a nonsense mutation, of the PTPRD gene were detected in 8/74 (11%) of cell lines and 4/95 (4%) of surgical specimens of lung cancer. Reduced PTPRD expression was observed in the majority (>80%) of cell lines and surgical specimens of lung cancer. Therefore, PTPRD is a candidate tumor suppressor gene in lung cancer. Microarray-based expression profiling of 19 lung cancer cell lines also indicated that some of the 176 genes, such as KANK and ADAMTS1, are preferentially inactivated by epigenetic alterations. Genetic/epigenetic as well as functional studies of these 176 genes will increase our understanding of molecular mechanisms behind lung carcinogenesis. PMID:20073072

  4. FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus.

    Science.gov (United States)

    Amorosi, S; D'Armiento, M; Calcagno, G; Russo, I; Adriani, M; Christiano, A M; Weiner, L; Brissette, J L; Pignata, C

    2008-04-01

    The forkhead, Fox, gene family comprises a diverse group of 'winged-helix' transcription factors that play important roles in development, metabolism, cancer and aging. Recently, several forkhead genes have been demonstrated to play critical roles in lymphocyte development and effector functions. Alterations of the FOXN1 gene in both mice and humans result in a severe combined immunodeficiency caused by an intrinsic defect of the thymus associated with congenital alopecia (Nude/severe combined immunodeficiency phenotype). FOXN1 is a member of the class of proteins involved in the development and differentiation of the central nervous system. We identified a human fetus homozygous for a mutation in FOXN1 gene who lacked the thymus and also had abnormal skin, anencephaly and spina bifida. Moreover, we found that FOXN1 gene is expressed in mouse developing choroid plexus. These observations suggest that FOXN1 may be involved in neurulation in humans.

  5. A highly homozygous and parthenogenetic human embryonic stem cell line derived from a one-pronuclear oocyte following in vitro fertilization procedure

    Institute of Scientific and Technical Information of China (English)

    Ge Lin; Qi OuYang; Xiaoying Zhou; Yifan Gu; Ding Yuan; Wen Li; Gang Liu; Tiancheng Liu; Guanexiu Lu

    2007-01-01

    Homozygous human embryonic stem cells (hESCs) are thought to be better cell sources for hESC banking because their human leukocyte antigen (HLA) haplotype would strongly increase the degree of matching for certain populations with relatively smaller cohorts of cell lines. Homozygous hESCs can be generated from parthenogenetic embryos, but only heterozygous hESCs have been established using the current strategy to artificially activate the oocyte without second polar body extrusion. Here we report the first successful derivation of a human homozygous ESC line (chHES-32) from a one-pronuclear oocyte following routine in vitro fertilization treatment. cAHES-32 cells express common markers and genes with normal hESCs. They have been propagated in an undifferentiated state for more than a year (>P50) and have maintained a stable karyotype of 46, XX. When differentiated in vivo and in vitro, c/zHES-32 cells can form derivatives from all three embryonic germ layers. The almost undetectable expression of five paternally expressed imprinted genes and their HLA genotype identical to the oocyte donor indicated their parthenogenetic origin. Using genome-wide single-nucleotide polymorphism analysis and DNA fingerprinting, the homozygosity of c/zHES-32 cells was further confirmed. The results indicated that 'unwanted' one-pronuclear oocytes might be a potential source for human homozygous and parthenogenetic ESCs, and suggested an alternative strategy for obtaining homozygous hESC lines from parthenogenetic haploid oocytes.

  6. Derivation of the human induced pluripotent stem cell line MUi017-A from a patient with homozygous Hemoglobin Constant Spring

    Directory of Open Access Journals (Sweden)

    Wasinee Wongkummool

    2017-04-01

    Full Text Available Hemoglobin Constant Spring (HbCS, HBA2: c.427T>C is a common nondeletional α-thalassemia resulting from a nucleotide substitution at the termination codon of the HBA2 gene. Homozygosity for HbCS is characterized with mild anemia, jaundice, and splenomegaly. In this study, the human induced pluripotent stem cell line MUi017-A was successfully generated from peripheral blood CD34+ hematopoietic progenitors of a 52 year old female with homozygous HbCS. The MUi017-A cell line exhibited embryonic stem cell characteristics with consistent expression of specific pluripotency markers and the capability of differentiating into the three germ layers. The cell line may be used for the disease modeling.

  7. A homozygous Keap1-knockout human embryonic stem cell line generated using CRISPR/Cas9 mediates gene targeting

    Directory of Open Access Journals (Sweden)

    So-Jung Kim

    2017-03-01

    Full Text Available Kelch-like ECH-associated protein 1 (keap1 is a cysteine-rich protein that interacts with transcription factor Nrf2 in a redox-sensitive manner, leading to the degradation of Nrf2 (Kim et al., 2014a. Disruption of Keap1 results in the induction of Nrf2-related signaling pathways involving the expression of a set of anti-oxidant and anti-inflammatory genes. We generated biallelic mutants of the Keap1 gene using a CRISPR-Cas9 genome editing method in the H9 human embryonic stem cell (hESC. The Keap1 homozygous-knockout H9 cell line retained normal morphology, gene expression, and in vivo differentiation potential.

  8. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans.

    Science.gov (United States)

    Krag, Thomas O; Vissing, John

    2015-12-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP in maintaining proper glycosylation of α-dystroglycan. The mild progression in the homozygous FKRP L276I model resembles that in patients with LGMD2I who are homozygous for the L276I mutation. This animal model could, therefore, be relevant for understanding the pathophysiology of and developing a treatment strategy for the human disorder.

  9. Glutamine analogs promote cytoophidium assembly in human and Drosophila cells

    Institute of Scientific and Technical Information of China (English)

    Kangni Chen; Jing Zhang; (O)mür Yilmaz Tastan; Zillah Anne Deussen; Mayte Yu-Yin Siswick; Ji-Long Liu

    2011-01-01

    CTP synthase is compartmentalized within a subcellular structure,termed the cytoophidium,in a range of organisms including bacteria,yeast,fruit fly and rat.Here we show that CTP synthase is also compartmentalized into cytoophidia in human cells.Surprisingly,the occurrence of cyloophidia in human cells increases upon treatment with a glutamine analog 6-diazo-5-oxo-L-norleucine (DON),an inhibitor of glutaminedependent enzymes including CTP synthase.Experiments in flies confirmned that DON globally promotes cytoophidium assembly.Clonal analysis via CTP synthase RNA interference in somatic cells indicates that CTP synthase expression level is critical for the formation of cytoophidia.Moreover,DON facilitates cytoophidium assembly even when CTP synthase level is low.A second glutamine analog azaserine also promotes cytoophidum formation.Our data demonstrate that glutamine analogs serve as useful tools in the study of cytoophidia.

  10. Baboons, like humans, solve analogy by categorical abstraction of relations.

    Science.gov (United States)

    Flemming, Timothy M; Thompson, Roger K R; Fagot, Joël

    2013-05-01

    Reasoning by analogy is one of the most complex and highly adaptive cognitive processes in abstract thinking. For humans, analogical reasoning entails the judgment and conceptual mapping of relations-between-relations and is facilitated by language (Gentner in Cogn Sci 7:155-170, 1983; Premack in Thought without language, Oxford University Press, New York, 1986). Recent evidence, however, shows that monkeys like "language-trained" apes exhibit similar capacity to match relations-between-relations (Fagot and Thompson in Psychol Sci 22:1304-1309, 2011; Flemming et al. in J Exp Psychol: Anim Behav Process 37:353-360, 2011; Truppa et al. in Plos One 6(8):e23809, 2011). Whether this behavior is driven by the abstraction of categorical relations or alternatively by direct perception of variability (entropy) is crucial to the debate as to whether nonhuman animals are capable of analogical reasoning. In the current study, we presented baboons (Papio papio) and humans (Homo sapiens) with a computerized same/different relational-matching task that in principle could be solved by either strategy. Both baboons and humans produced markedly similar patterns of responding. Both species responded different when the perceptual variability of a stimulus array fell exactly between or even closer to that of a same display. Overall, these results demonstrate that categorical abstraction trumped perceptual properties and, like humans, Old World monkeys can solve the analogical matching task by judging the categorical abstract equivalence of same/different relations-between-relations.

  11. Homozygous familial hypercholesterolaemia

    Directory of Open Access Journals (Sweden)

    Dogra A

    1993-01-01

    Full Text Available A boy with multiple xanthomatosis with deranged lipid profile consistent with homozygous familial hypercholesterolaemia is reported for its rarity and exotic presentation and biochemical abnormalities of lipids in parents.

  12. Direct Monitoring of Nucleotide Turnover in Human Cell Extracts and Cells by Fluorogenic ATP Analogs.

    Science.gov (United States)

    Hacker, Stephan M; Buntz, Annette; Zumbusch, Andreas; Marx, Andreas

    2015-11-20

    Nucleotides containing adenosine play pivotal roles in every living cell. Adenosine triphosphate (ATP), for example, is the universal energy currency, and ATP-consuming processes also contribute to posttranslational protein modifications. Nevertheless, detecting the turnover of adenosine nucleotides in the complex setting of a cell remains challenging. Here, we demonstrate the use of fluorogenic analogs of ATP and adenosine tetraphosphate to study nucleotide hydrolysis in lysates of human cell lines and in intact human cells. We found that the adenosine triphosphate analog is completely stable in lysates of human cell lines, whereas the adenosine tetraphosphate analog is rapidly turned over. The observed activity in human cell lysates can be assigned to a single enzyme, namely, the human diadenosine tetraphosphate hydrolase NudT2. Since NudT2 has been shown to be a prognostic factor for breast cancer, the adenosine tetraphosphate analog might contribute to a better understanding of its involvement in cancerogenesis and allow the straightforward screening for inhibitors. Studying hydrolysis of the analogs in intact cells, we found that electroporation is a suitable method to deliver nucleotide analogs into the cytoplasm and show that high FRET efficiencies can be detected directly after internalization. Time-dependent experiments reveal that adenosine triphosphate and tetraphosphate analogs are both processed in the cellular environment. This study demonstrates that these nucleotide analogs indeed bear the potential to be powerful tools for the exploration of nucleotide turnover in the context of whole cells.

  13. Reduced expression of Tis7/IFRD1 protein in murine and human cystic fibrosis airway epithelial cell models homozygous for the F508del-CFTR mutation.

    Science.gov (United States)

    Blanchard, Elise; Marie, Solenne; Riffault, Laure; Bonora, Monique; Tabary, Olivier; Clement, Annick; Jacquot, Jacky

    2011-08-01

    12-O-tetradecanoyl phorbol-13-acetate-induced sequence 7/interferon related development regulator 1 (Tis7/IFRD1) has been recently identified as a modifier gene in lung inflammatory disease severity in patients with cystic fibrosis (CF), based upon its capacity to regulate inflammatory activities in neutrophils. In CF patients, the F508del mutation in the Cftr gene encoding a chloride channel, the CF transmembrane conductance regulator (CFTR) in airway epithelial cells results in an exaggerated inflammatory response of these cells. At present, it is unknown whether the Tis7/IFRD1 gene product is expressed in airway epithelial cells. We therefore investigated the possibility there is an intrinsic alteration in Tis7/IFRD1 protein level in cells lacking CFTR function in tracheal homogenates of F508del-CFTR mice and in a F508del-CFTR human bronchial epithelial cell line (CFBE41o(-) cells). When Tis7/IFRD1 protein was detectable, trachea from F508del-CFTR mice showed a reduction in the level of Tis7/IFRD1 protein compared to wild-type control littermates. A significant reduction of IFRD1 protein level was found in CFBE41o(-) cells compared to normal bronchial epithelial cells 16HBE14o(-). Surprisingly, messenger RNA level of IFRD1 in CFBE41o(-) cells was found elevated. Treating CFBE41o(-) cells with the antioxidant glutathione rescued the IFRD1 protein level closer to control level and also reduced the pro-inflammatory cytokine IL-8 release. This work provides evidence for the first time of reduced level of IFRD1 protein in murine and human F508del-CFTR airway epithelial cell models, possibly mediated in response to oxidative stress which might contribute to the exaggerated inflammatory airway response observed in CF patients homozygous for the F508del mutation.

  14. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans

    DEFF Research Database (Denmark)

    Krag, Thomas O; Vissing, John

    2015-01-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I...... mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely...... caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP...

  15. The CCR5 receptor acts as an alloantigen in CCR5Δ32 homozygous individuals: Identification of chemokineand HIV-1-blocking human antibodies

    OpenAIRE

    1998-01-01

    The chemokine receptor CCR5 is the major coreceptor for infection by macrophage-tropic R5 HIV-1. A 32-bp deletion in the gene coding for CCR5 (CCR5Δ32) occurs with a frequency of 10% in the Caucasian population and results in a receptor protein that is truncated and not expressed at the cell surface. CCR5Δ32 homozygous individuals are apparently normal but resistant to infection with R5 HIV-1. In two individuals homozygous for CCR5Δ32, who had been repeatedly exposed to CCR5-expressing blood ...

  16. Demonstration in human plasma of a lectin activity analogous to that of bovine conglutinin

    DEFF Research Database (Denmark)

    Baatrup, G; Thiel, S; Isager, H

    1987-01-01

    Evidence of the existence in human plasma of an activity analogous to that of bovine conglutinin is presented. The human plasma component was characterized antigenically and functionally. Human plasma was shown to agglutinate complement-coated erythrocytes in the presence of Ca2+, and this conglu...

  17. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice

    OpenAIRE

    1999-01-01

    To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles expre...

  18. Synthesis and biological activities of some human gastrin analogs.

    Science.gov (United States)

    Lima-Leite, A C; Fulcrand, P; Galleyrand, J C; Berge, G; Aumelas, A; Bali, J P; Castel, J; Martinez, J

    1996-10-01

    The synthesis of analogs of the C-terminal tridecapeptide of gastrin is described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethylalcohol or with 2-phenylethylamine, or by replacing the peptide bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38, [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-psi(CH2NH)-Leu11]-HG-13-I 31 and [Trp10-psi(CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-psi(CH2NH)-Asp12]-HG-13-I 30 and [Leu11-psi (CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.

  19. Action of uracil analogs on human immunodeficiency virus type 1 and its reverse transcriptase.

    Science.gov (United States)

    Piras, G; Dutschman, G E; Im, G J; Pan, B C; Chu, S H; Cheng, Y C

    1995-02-01

    Three structural analogs of 5-ethyl-1-benzyloxymethyl-6-(phenylthio)uracil (E-BPU) inhibited human immunodeficiency virus type 1 (HIV-1) replication without cytotoxicity in vitro and were more potent than azidothymidine and were as potent as E-BPU. The target of these compounds is HIV-1 reverse transcriptase. Reverse transcriptases resistant to nevirapine (tyrosine at position 181 to cysteine) and TIBO R82150 (leucine at position 100 to isoleucine) are cross resistant to E-BPU analogs. Nevirapine- or TIBO R82150-resistant HIV-1 were cross resistant to E-BPU analogs but were inhibited at concentrations 11- to 135-fold lower than the cytotoxic doses.

  20. Action of uracil analogs on human immunodeficiency virus type 1 and its reverse transcriptase.

    OpenAIRE

    Piras, G; Dutschman, G E; Im, G J; B.C. Pan; Chu, S H; Cheng, Y C

    1995-01-01

    Three structural analogs of 5-ethyl-1-benzyloxymethyl-6-(phenylthio)uracil (E-BPU) inhibited human immunodeficiency virus type 1 (HIV-1) replication without cytotoxicity in vitro and were more potent than azidothymidine and were as potent as E-BPU. The target of these compounds is HIV-1 reverse transcriptase. Reverse transcriptases resistant to nevirapine (tyrosine at position 181 to cysteine) and TIBO R82150 (leucine at position 100 to isoleucine) are cross resistant to E-BPU analogs. Nevira...

  1. Characterization of a lectin in human plasma analogous to bovine conglutinin

    DEFF Research Database (Denmark)

    Thiel, S; Baatrup, G; Friis-Christiansen, P

    1987-01-01

    The structural characteristics of a human plasma protein analogous to bovine conglutinin were studied. The protein was previously found to bind to complement-reacted IgG in a calcium-dependent and N-acetyl-D-glucosamine-inhibitable manner and it further shows cross-reactivity with anti-bovine con...

  2. Using analogy to learn about phenomena at scales outside human perception.

    Science.gov (United States)

    Resnick, Ilyse; Davatzes, Alexandra; Newcombe, Nora S; Shipley, Thomas F

    2017-01-01

    Understanding and reasoning about phenomena at scales outside human perception (for example, geologic time) is critical across science, technology, engineering, and mathematics. Thus, devising strong methods to support acquisition of reasoning at such scales is an important goal in science, technology, engineering, and mathematics education. In two experiments, we examine the use of analogical principles in learning about geologic time. Across both experiments we find that using a spatial analogy (for example, a time line) to make multiple alignments, and keeping all unrelated components of the analogy held constant (for example, keep the time line the same length), leads to better understanding of the magnitude of geologic time. Effective approaches also include hierarchically and progressively aligning scale information (Experiment 1) and active prediction in making alignments paired with immediate feedback (Experiments 1 and 2).

  3. Biomonitoring of human exposures to chlorinated derivatives and structural analogs of bisphenol A.

    Science.gov (United States)

    Andra, Syam S; Charisiadis, Pantelis; Arora, Manish; van Vliet-Ostaptchouk, Jana V; Makris, Konstantinos C

    2015-12-01

    The high reactivity of bisphenol A (BPA) with disinfectant chlorine is evident in the instantaneous formation of chlorinated BPA derivatives (ClxBPA) in various environmental media that show increased estrogen-activity when compared with that of BPA. The documented health risks associated with BPA exposures have led to the gradual market entry of BPA structural analogs, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), etc. A suite of exposure sources to ClxBPA and BPA analogs in the domestic environment is anticipated to drive the nature and range of halogenated BPA derivatives that can form when residual BPA comes in contact with disinfectant in tap water and/or consumer products. The primary objective of this review was to survey all available studies reporting biomonitoring protocols of ClxBPA and structural BPA analogs (BPS, BPF, BPB, etc.) in human matrices. Focus was paid on describing the analytical methodologies practiced for the analysis of ClxBPA and BPA analogs using hyphenated chromatography and mass spectrometry techniques, because current methodologies for human matrices are complex. During the last decade, an increasing number of ecotoxicological, cell-culture and animal-based and human studies dealing with ClxBPA exposure sources and routes of exposure, metabolism and toxicity have been published. Up to date findings indicated the association of ClxBPA with metabolic conditions, such as obesity, lipid accumulation, and type 2 diabetes mellitus, particularly in in-vitro and in-vivo studies. We critically discuss the limitations, research needs and future opportunities linked with the inclusion of ClxBPA and BPA analogs into exposure assessment protocols of relevant epidemiological studies.

  4. Bioisosteric phentolamine analogs as selective human alpha(2)- versus alpha(1)-adrenoceptor ligands.

    Science.gov (United States)

    Bavadekar, Supriya A; Hong, Seoung-Soo; Lee, Sang-Ii; Miller, Duane D; Feller, Dennis R

    2008-08-20

    Phentolamine is known to act as a competitive, non-subtype-selective alpha-adrenoceptor antagonist. In an attempt to improve alpha(2)- versus alpha(1)-adrenoceptor selectivity and alpha(2)-adrenoceptor subtype-selectivity, two new chemical series of bioisosteric phentolamine analogs were prepared and evaluated. These compounds were evaluated for binding affinities on alpha(1)- (alpha(1A)-, alpha(1B)-, alpha(1D)-) and alpha(2)- (alpha(2A)-, alpha(2B)-, alpha(2C)-) adrenoceptor subtypes that had been stably expressed in human embryonic kidney and Chinese hamster ovary cell lines, respectively. Methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the alpha(2)- versus alpha(1)-adrenoceptors. Within the alpha(2)-adrenoceptors, these analogs bound with higher affinity at the alpha(2A)- and alpha(2C)-subtypes as compared to the alpha(2B)-subtype. In particular, the t-butyl analog was found to be the most selective, its binding at the alpha(2C)-adrenoceptor (Ki=3.6 nM) being 37- to 173-fold higher than that at the alpha(1)-adrenoceptors, and around 2- and 19-fold higher than at the alpha(2A)- and alpha(2B)-adrenoceptors, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities of selected compounds from the bioisosteric series on human alpha(1A)- and alpha(2C)-adrenoceptors. Thus, the results with these bioisosteric analogs of phentolamine provide a lead to the rational design of potent and selective alpha(2)-adrenoceptor ligands that may be useful in improving the therapeutic profile of this drug class for human disorders.

  5. Establishment of MUi009 – A human induced pluripotent stem cells from a 32 year old male with homozygous β°-thalassemia coinherited with heterozygous α-thalassemia 2

    Directory of Open Access Journals (Sweden)

    Wasinee Wongkummool

    2017-04-01

    Full Text Available The thalassemias are a group of genetic disorders characterized by a deficiency in the synthesis of globin chains. In this study the MUi009-A human induced pluripotent stem cell line was successfully generated from peripheral blood CD34+ haematopoietic progenitors of a 32 year old male who had coinherited a homozygous β°-thalassemia mutation at codon 41/42 (-TCTT and a heterozygous α-thalassemia 4.2 deletion. The MUi009-A cell line exhibited embryonic stem cell characteristics with consistent pluripotency marker expression and the capability of differentiating into the three germ layers. The cell line may provide a tool for drug testing and gene therapy studies.

  6. Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs.

    Science.gov (United States)

    Bagley, Rebecca G; Roth, Stephanie; Kurtzberg, Leslie S; Rouleau, Cecile; Yao, Min; Crawford, Jennifer; Krumbholz, Roy; Lovett, Dennis; Schmid, Steven; Teicher, Beverly A

    2009-05-01

    Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 microM, and for human CFU-GM were 8 and 0.11 microM, giving mouse to human differentials of >3.8- and 8.5-fold. Clofarabine produced IC90s of 1.7 microM in mouse and 0.51 microM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

  7. Enzymatically stable 5' mRNA cap analogs: synthesis and binding studies with human DcpS decapping enzyme.

    Science.gov (United States)

    Kalek, Marcin; Jemielity, Jacek; Darzynkiewicz, Zbigniew M; Bojarska, Elzbieta; Stepinski, Janusz; Stolarski, Ryszard; Davis, Richard E; Darzynkiewicz, Edward

    2006-05-01

    Four novel 5' mRNA cap analogs have been synthesized with one of the pyrophosphate bridge oxygen atoms of the triphosphate linkage replaced with a methylene group. The analogs were prepared via reaction of nucleoside phosphor/phosphon-1-imidazolidates with nucleoside phosphate/phosphonate in the presence of ZnCl2. Three of the new cap analogs are completely resistant to degradation by human DcpS, the enzyme responsible for hydrolysis of free cap resulting from 3' to 5' cellular mRNA decay. One of the new analogs has very high affinity for binding to human DcpS. Two of these analogs are Anti Reverse Cap Analogs which ensures that they are incorporated into mRNA chains exclusively in the correct orientation. These new cap analogs should be useful in a variety of biochemical studies, in the analysis of the cellular function of decapping enzymes, and as a basis for further development of modified cap analogs as potential anti-cancer and anti-parasite drugs.

  8. Human performance profiles for planetary analog extra-vehicular activities: 120 day and 30 day analog missions

    Science.gov (United States)

    Swarmer, Tiffany M.

    Understanding performance factors for future planetary missions is critical for ensuring safe and successful planetary extra-vehicular activities (EVAs). The goal of this study was to gain operational knowledge of analog EVAs and develop biometric profiles for specific EVA types. Data was collected for a 120 and 30 day analog planetary exploration simulation focusing on EVA type, pre and post EVA conditions, and performance ratings. From this five main types of EVAs were performed: maintenance, science, survey/exploratory, public relations, and emergency. Each EVA type has unique characteristics and performance ratings showing specific factors in chronological components, environmental conditions, and EVA systems that have an impact on performance. Pre and post biometrics were collected to heart rate, blood pressure, and SpO2. Additional data about issues and specific EVA difficulties provide some EVA trends illustrating how tasks and suit comfort can negatively affect performance ratings. Performance decreases were noted for 1st quarter and 3rd quarter EVAs, survey/exploratory type EVAs, and EVAs requiring increased fine and gross motor function. Stress during the simulation is typically higher before the EVA and decreases once the crew has returned to the habitat. Stress also decreases as the simulation nears the end with the 3rd and 4th quarters showing a decrease in stress levels. Operational components and studies have numerous variable and components that effect overall performance, by increasing the knowledge available we may be able to better prepare future crews for the extreme environments and exploration of another planet.

  9. alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes.

    Science.gov (United States)

    Abdel-Malek, Zalfa A; Ruwe, Andrew; Kavanagh-Starner, Renny; Kadekaro, Ana Luisa; Swope, Viki; Haskell-Luevano, Carrie; Koikov, Leonid; Knittel, James J

    2009-10-01

    One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of alpha-melanocortin (alpha-MSH) that were more potent and stable than the physiological alpha-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified alpha-MSH core His(6)-d-Phe(7)-Arg(8), which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked alpha-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.

  10. A synthetic prostaglandin E1 analog, alprostadil alfadex, relaxes sphincter of Oddi in humans.

    Science.gov (United States)

    Koshitani, Tatsuya; Kodama, Tadashi; Sato, Hideki; Takaaki, Junpei; Imamura, Yoichi; Kato, Keimei; Wakabayashi, Naoki; Tokita, Kazuhiko; Mitsufuji, Shoji

    2002-01-01

    It is well established that prostaglandins (PGs) exert potent pharmacological actions on vascular and nonvascular smooth muscle, although their effects on the sphincter of Oddi (SO) remain to be elucidated. The aim of this study was to investigate the effect of PGE1 on motility of the human SO. Twenty patients appearing for routine endoscopic retrograde cholangiopancreatography (ERCP) examination were studied. Each patient was randomly allocated to receive an intravenous infusion of normal saline (six patients), or alprostadil alfadex, a synthetic PGE1 analog, at a dose of either 0.05 or 0.1 microg/kg/min (seven patients for each condition). Endoscopic biliary manometry was done with a recording of basal SO pressure, amplitude of SO phasic contractions, and phasic contractile frequency before and 5 min after intravenous infusions, using a 4-French microtransducer catheter. There was no significant change in SO motor variables following application of normal saline. Alprostadil alfadex significantly decreased basal SO pressure at a dose of 0.05 microg/kg/min, and significantly decreased all parameters at a dose of 0.1 microg/kg/min. A synthetic PGE1 analog, alprostadil alfadex, effectively inhibits motility of the human SO. This drug may be of clinical application as a SO-relaxing agent.

  11. Generation of a human induced pluripotent stem cell line via CRISPR-Cas9 mediated integration of a site-specific homozygous mutation in CHMP2B

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    2016-07-01

    Full Text Available Frontotemporal dementia (FTD is an early onset neurodegenerative disease. Mutations in several genes cause familial FTD and one of them is charged multivesicular body protein 2B (CHMP2B on chromosome 3 (FTD3, a component of the endosomal sorting complex required for transport III (ESCRT-III. We have generated an induced pluripotent stem cell (iPSC line of a healthy individual and inserted the CHMP2B IVS5AS G-C gene mutation into both alleles, resulting in aberrant splicing. This human iPSC line provides an ideal model to study CHMP2B-dependent phenotypes of FTD3.

  12. Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications.

    Science.gov (United States)

    Lephart, Edwin D; Andrus, Merritt B

    2017-09-01

    Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment

  13. Synthesis, structural characterization and effect on human granulocyte intracellular cAMP levels of abscisic acid analogs.

    Science.gov (United States)

    Bellotti, Marta; Salis, Annalisa; Grozio, Alessia; Damonte, Gianluca; Vigliarolo, Tiziana; Galatini, Andrea; Zocchi, Elena; Benatti, Umberto; Millo, Enrico

    2015-01-01

    The phytohormone abscisic acid (ABA), in addition to regulating physiological functions in plants, is also produced and released by several mammalian cell types, including human granulocytes, where it stimulates innate immune functions via an increase of the intracellular cAMP concentration ([cAMP]i). We synthesized several ABA analogs and evaluated the structure-activity relationship, by the systematical modification of selected regions of these analogs. The resulting molecules were tested for their ability to inhibit the ABA-induced increase of [cAMP]i in human granulocytes. The analogs with modified configurations at C-2' and C-3' abrogated the ABA-induced increase of the [cAMP]i and also inhibited several pro-inflammatory effects induced by exogenous ABA on granulocytes and monocytes. Accordingly, these analogs could be suitable as novel putative anti-inflammatory compounds.

  14. Conformational origin of a difficult coupling in a human growth hormone releasing factor analog.

    Science.gov (United States)

    Deber, C M; Lutek, M K; Heimer, E P; Felix, A M

    1989-01-01

    During the solid-phase synthesis of the human growth hormone releasing factor (GRF) analog [Ala15, Leu27, Asn28] -GRF(1-32)-OH, incorporation of Boc-Gln16 was determined to be incomplete. While aggregation of growing resin-bound peptide chains with concomitant beta-sheet formation and "precipitation" has been proposed to account in general for such "difficult coupling," no feature of sequence in the Gln16 region of this GRF analog provided an immediate rationale for this result. We now report 500 MHz 1H NMR spectra of a series of resin-bound GRF segments surrounding the Gln16 position (19-32 through 14-32), swelled in dimethylsulfoxide-d6 solutions [GRF(14-32) = Leu14-Ala-Gln-Leu-Ser(Bzl)-Ala-Arg(Tos)-Lys(CIZ)-Leu- Leu-Gln-Asp(OcHex)-Ile-Leu-Asn-Arg(Tos)-Gln-Gln-Gly32-PAM resin]. While relatively sharp spectra are observed for GRF(19-32), components with resonances broadened by an order-of-magnitude appear in spectra of the 18-32 and 17-32 peptide-resin, and the entire spectrum of 16-32 is ill-resolved and highly broadened. Subsequent spectra sharpen again (15-32, 14-32). These combined synthesis/spectroscopic experimental results, in conjunction with predictive analyses using standard Chou-Fasman 2 degrees structure parameters, suggest that the completeness of the Gln16 coupling is hindered by formation of a specific, folded beta-sheet/beta-turn structure in GRF(16-32) (with the turn located at 18-21, "upstream" of the difficult coupling site), and accompanying aggregation of peptide chains. This analysis suggests that awareness of such potential beta-sheet/beta-turn sequences can guide analog choices, and/or facilitate pre-programming of synthesis steps in anticipation of problem couplings.

  15. Analogical acts as conceptual strategies in science, engineering and the humanities

    Science.gov (United States)

    Winkler, V. M.

    1981-01-01

    The composing models which operate by means of analogy are identified. The importance of analogical acts in the prewriting stage of the composing process is discussed. The relations between analogical acts and concept formation are explored. A basic correspondence between the analogical thinking employed in successful learning and analogical thinking as a composing strategy is discussed. Teaching analogical acts as conceptual strategies for exploring problems and generating the form and content of discourse is presented in support of the contention that writing is a unique mode of learning.

  16. Generation of a conditional analog-sensitive kinase in human cells using CRISPR/Cas9-mediated genome engineering.

    Science.gov (United States)

    Moyer, Tyler C; Holland, Andrew J

    2015-01-01

    The ability to rapidly and specifically modify the genome of mammalian cells has been a long-term goal of biomedical researchers. Recently, the clustered, regularly interspaced, short palindromic repeats (CRISPR)/Cas9 system from bacteria has been exploited for genome engineering in human cells. The CRISPR system directs the RNA-guided Cas9 nuclease to a specific genomic locus to induce a DNA double-strand break that may be subsequently repaired by homology-directed repair using an exogenous DNA repair template. Here we describe a protocol using CRISPR/Cas9 to achieve bi-allelic insertion of a point mutation in human cells. Using this method, homozygous clonal cell lines can be constructed in 5-6 weeks. This method can also be adapted to insert larger DNA elements, such as fluorescent proteins and degrons, at defined genomic locations. CRISPR/Cas9 genome engineering offers exciting applications in both basic science and translational research.

  17. Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D2 Against Human Malignant Melanoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Anna Piotrowska

    2016-01-01

    Full Text Available Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue. A series of double point modified (DPM analogs of 1,25-dihydroxyvitamin D2 (1,25(OH2D2 induced differentiation of the vitamin D receptor (VDR positive A375 and VDR negative SK-MEL 188b human malignant melanoma cell lines. Surprisingly, the dose of 1,25(OH2D2 required to inhibit the proliferation of the A375 melanoma cell line by was several fold lower than that required in the case of 1,25(OH2D3. To evaluate the impact of the modification in the side chain (additional 22-hydroxyl and in the A-ring (5,6-trans modification, the regular side-chain of vitamin D2 or D3 was retained in the structure of our analogs. As expected, 5,6-trans modification was advantageous to enhancing the anti-proliferative activity of analogs, but not as a single point modification (SPM. Very unexpectedly, the additional 22-hydroxyl in the side-chain reduced significantly the anti-proliferative activity of both the natural and 5,6-trans series analogs. Finally, an induction of pigmentation in melanoma SK-MEL 188b cells was observed to sensitized cells to the effect of vitamin D analogs.

  18. Semi-synthetic analogs of pinitol as potential inhibitors of TNF-alpha cytokine expression in human neutrophils.

    Science.gov (United States)

    Bhat, Khurshid A; Shah, Bhahwal A; Gupta, Kuldeep K; Pandey, Anjali; Bani, Sarang; Taneja, Subhash C

    2009-04-01

    Semi-synthetic analogs of pinitol were subjected to screening by determining TNF-alpha expression in human neutrophils using flowcytometry. Among the tested compounds, three derivatives displayed more than 50% inhibition of TNF-alpha cytokine secretion in LPS induced stimulated neutrophils and can be considered as potent anti-inflammatory moieties.

  19. Pharmacological properties of novel bicyclic isoquinoline analogs in isolated guinea pig atria, trachea and in human platelets: relationship to trimetoquinol.

    Science.gov (United States)

    Shams, G; Fedyna, J; Romstedt, K J; Adejare, A; Miller, D D; Roche, V F; Feller, D R

    1991-01-01

    1. Antiplatelet and beta-adrenoceptor activities of a set of secondary and tertiary N-methyl substituted amine analogs of trimetoquinol (TMQ, I and II, respectively) and 5,8-ethano-l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquin oline (bicyclic isoquinoline compounds III and IV, respectively) were examined. 2. Compounds III and IV induced relaxations of guinea pig trachea which were blocked by propranolol whereas neither compound acted as an agonist nor antagonist of beta-adrenoceptors (chronotropy) in guinea pig atria. TMQ analogs (I and II) were agonists in both beta-adrenoceptor systems. 3. When tested in human platelets, compounds III and IV, like the TMQ analogs, blocked several inducers of the prostaglandin-dependent and -independent pathways, and the alpha 2-adrenoceptor-mediated pathway of platelet activation. 4. The bicyclic isoquinoline analogs (III and IV) possessed more selective beta 2-adrenoceptor stimulatory activity and equal or greater inhibitory activity against inducers of the prostaglandin-independent pathways of platelet function than the corresponding TMQ analogs (I and II). 5. These chemically novel lipophilic bicyclic compounds provide a new lead to the development of agents useful for the treatment of asthma and thrombotic disorders.

  20. Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity.

    Science.gov (United States)

    Jacob, Binu; Park, Il-Seon; Bang, Jeong-Kyu; Shin, Song Yub

    2013-11-01

    KR-12 (residues 18-29 of LL-37) was known to be the smallest peptide of human cathelicidin LL-37 possessing antimicrobial activity. In order to optimize α-helical short antimicrobial peptides having both antimicrobial and antiendotoxic activities without mammalian cell toxicity, we designed and synthesized a series of KR-12 analogs. Highest hydrophobic analogs KR-12-a5 and KR-12-a6 displayed greater inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-α production and higher LPS-binding activity. We have observed that antimicrobial activity is independent of charge, but LPS neutralization requires a balance of hydrophobicity and net positive charge. Among KR-12 analogs, KR-12-a2, KR-12-a3 and KR-12-a4 showed much higher cell specificity for bacteria over erythrocytes and retained antiendotoxic activity, relative to parental LL-37. KR-12-a5 displayed the strongest antiendotoxic activity but almost similar cell specificity as compared with LL-37. Also, these KR-12 analogs (KR-12-a2, KR-12-a3, KR-12-a4 and KR-12-a5) exhibited potent antimicrobial activity (minimal inhibitory concentration: 4 μM) against methicillin-resistant Staphylococcus aureus. Taken together, these KR-12 analogs have the potential for future development as a novel class of antimicrobial and anti-inflammatory therapeutic agents.

  1. Novel 8-hydroxylquinoline analogs induce copper-dependent proteasome inhibition and cell death in human breast cancer cells.

    Science.gov (United States)

    Milacic, Vesna; Jiao, Peifu; Zhang, Bin; Yan, Bing; Dou, Q Ping

    2009-12-01

    An elevated level of copper (Cu), which is necessary for the growth and metastasis of tumor cells, has been found in many types of cancer, including breast, prostate, lung and brain. Although its molecular basis is unclear, this tumor-specific Cu elevation has been proposed to be a novel target for developing selective anti-cancer therapies. We previously reported that 8-hydroxylquinoline (8-OHQ) is able to form a Cu complex that inhibits the proteasome and induces apoptosis in cultured cancer cells. Toward the goal of discovering novel 8-OHQ analogs as potential anti-copper and anti-cancer drugs, in the current study we synthesized several 8-OHQ analogs and their copper complexes and evaluated their biological activities in human breast cancer cells. We report that when substitutions are made on the hydroxyl group of 8-OHQ, their copper mixtures have profound effects on the proteasome-inhibitory and apoptosis-inducing abilities in breast cancer MDA-MB-231 cells. In addition, the proteasome-inhibitory and apoptosis-inducing activities of 8-OHQ analog-copper mixtures are determined by both the polarity and position of the substituents. Finally, a synthetic complex of 8-OHQ analog-copper was able to inhibit the proteasome activity, induce cell death and suppress the growth selectively in breast cancer MDA-MB-231 cells, but not in normal immortalized human breast MCF-10A cells. Our results support the concept that human cancer cells and tissues, which contain an elevated copper level and are highly dependent on proteasome activity for their survival, should be sensitive to treatment with anti-copper drugs such as the novel 8-OHQ analogs described here.

  2. Eryptosis-inducing activity of bisphenol A and its analogs in human red blood cells (in vitro study).

    Science.gov (United States)

    Maćczak, Aneta; Cyrkler, Monika; Bukowska, Bożena; Michałowicz, Jaromir

    2016-04-15

    Bisphenols are important chemicals that are widely used in the manufacturing of polycarbonates, epoxy resin and thermal paper, and thus the exposure of humans to these substances has been noted. The purpose of this study was to assess eryptotic changes in human erythrocytes exposed (in vitro) to bisphenol A (BPA) and its selected analogs, i.e.,bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF). The erythrocytes were incubated with compounds studied at concentrations ranging from 1 to 250μg/mL for 4, 12 or 24h. The results showed that BPA and its analogs increased cytosolic calcium ions level with the strongest effect noted for BPAF. It has also been revealed that all bisphenols analyzed, and BPAF and BPF in particular increased phosphatidylserine translocation in red blood cells, which confirmed that they exhibited eryptotic potential in this cell type. Furthermore, it was shown that BPA and its analogs caused significant increase in calpain and caspase-3 activities, while the strongest effect was noted for BPAF. BPS, which is the main substituent of bisphenol A in polymers and thermal paper production exhibited similar eryptotic potential to BPA. Eryptotic changes in human erythrocytes were provoked by bisphenols at concentrations, which may influence the human body during occupational exposure or subacute poisoning with these compounds.

  3. Bioactive Ti metal analogous to human cancellous bone: Fabrication by selective laser melting and chemical treatments.

    Science.gov (United States)

    Pattanayak, Deepak K; Fukuda, A; Matsushita, T; Takemoto, M; Fujibayashi, S; Sasaki, K; Nishida, N; Nakamura, T; Kokubo, T

    2011-03-01

    Selective laser melting (SLM) is a useful technique for preparing three-dimensional porous bodies with complicated internal structures directly from titanium (Ti) powders without any intermediate processing steps, with the products being expected to be useful as a bone substitute. In this study the necessary SLM processing conditions to obtain a dense product, such as the laser power, scanning speed, and hatching pattern, were investigated using a Ti powder of less than 45 μm particle size. The results show that a fully dense plate thinner than 1.8 mm was obtained when the laser power to scanning speed ratio was greater than 0.5 and the hatch spacing was less than the laser diameter, with a 30 μm thick powder layer. Porous Ti metals with structures analogous to human cancellous bone were fabricated and the compressive strength measured. The compressive strength was in the range 35-120 MPa when the porosity was in the range 75-55%. Porous Ti metals fabricated by SLM were heat-treated at 1300 °C for 1h in an argon gas atmosphere to smooth the surface. Such prepared specimens were subjected to NaOH, HCl, and heat treatment to provide bioactivity. Field emission scanning electron micrographs showed that fine networks of titanium oxide were formed over the whole surface of the porous body. These treated porous bodies formed bone-like apatite on their surfaces in a simulated body fluid within 3 days. In vivo studies showed that new bone penetrated into the pores and directly bonded to the walls within 12 weeks after implantation into the femur of Japanese white rabbits. The percentage bone affinity indices of the chemical- and heat-treated porous bodies were significantly higher than that of untreated implants.

  4. Inhibition of human Na(v)1.5 sodium channels by strychnine and its analogs.

    Science.gov (United States)

    Yuan, Chunhua; Sun, Lirong; Zhang, Meng; Li, Shuji; Wang, Xuemin; Gao, Tianming; Zhu, Xinhong

    2011-08-15

    Strychnine and brucine from the seeds of the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors. In this study, we have characterized the pharmacological properties of strychnine and its analogs on human Na(v)1.5 channels to assess their potential therapeutic advantage in certain arrhythmias. Among the eight alkaloids, only strychnine and icajine exhibited inhibition potency on the Na(v)1.5 channel with the half-maximum inhibition (IC(50)) values of 83.1μM and 104.6μM, respectively. Structure-function analysis indicated that the increased bulky methoxy groups on the phenyl ring or the negatively charged oxygen atom may account for this lack of inhibition on the Na(v)1.5 channel. Strychnine and icajine may bind to the channel by cation-π interactions. The substitution with a large side chain on the phenyl ring or the increased molecular volume may alter the optimized position for the compound close to the binding sites of the channel. Strychnine and icajine bind to the Na(v)1.5 channel with a new mechanism that is different from TTX and local anesthetics. They bind to the outer vestibule of the channel pore with fast association and dissociation rates at resting state. Strychnine and icajine had little effect on steady-state fast inactivation but markedly shifted the slow inactivation of Na(v)1.5 currents toward more hyperpolarized potentials. The property of icajine influencing slow-inactivated state of Na(v)1.5 channel would be potential therapeutic advantages in certain arrhythmias. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.

    Science.gov (United States)

    Fallon, Padraic G; Sasaki, Takashi; Sandilands, Aileen; Campbell, Linda E; Saunders, Sean P; Mangan, Niamh E; Callanan, John J; Kawasaki, Hiroshi; Shiohama, Aiko; Kubo, Akiharu; Sundberg, John P; Presland, Richard B; Fleckman, Philip; Shimizu, Nobuyoshi; Kudoh, Jun; Irvine, Alan D; Amagai, Masayuki; McLean, W H Irwin

    2009-05-01

    Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris and convey major genetic risk for atopic dermatitis (eczema), eczema-associated asthma and other allergic phenotypes. Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of approximately 9% in Europe. Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate flaky tail as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.

  6. A self-regulating cell culture analog device to mimic animal and human toxicological responses.

    Science.gov (United States)

    Shuler, M L; Ghanem, A; Quick, D; Wong, M C; Miller, P

    1996-10-05

    The overall goal of this project is the development of a new methodology for translating advances in molecular level understanding of toxicological responses into a predictive tool for dose response in whole animals and humans exposed to single compounds or mixtures of compounds. The methodology incorporates a mechanistic cellular level model into a PBPK (physiologically based pharmacokinetic) model which simultaneously guides the development of an in vitro cell culture analog (CCA) to the PBPK. Where the PBPK specifies an organ, (e.g., liver) the in vitro or CCA system contains a compartment with the appropriate cell or cell population (e.g., hepatocytes for the liver). The CCA has significant advantages over other in vitro systems and PBPK systems used independently for evaluating metabolic responses to drugs or potentially toxic chemicals where the exchange of metabolites between organs is likely to be important. The CCA system is superior to a PBPK because an a priori description of complete metabolism is not required and secondary, unexpected interactions can be detected. The CCA system, unlike other in vitro systems, gives a dynamic response that realistically simulates in vivo interactions between organs. Furthermore, the CCA allows dosing on the same basis as animal tests (e.g., milligrams per kilogram of body mass equivalent). Because the construction of a CCA is guided by a PBPK, this approach allows extrapolation to low doses and across species, including extrapolation to humans. We have constructed a prototype system and have conducted proof-of-concept experiments using naphthalene as a test chemical. These experiments clearly demonstrate the ability to generate a reactive metabolite in one compartment and detect its effects (on LDH release and glutathione depletion) in a second compartment. However, this prototype device would be expensive to replicate and requires nearly constant supervision from a trained investigator. For this concept to replace

  7. [Magician nature and human magician: on a fundamental analogy of alchemy].

    Science.gov (United States)

    Schott, Heinz

    2010-01-01

    This contribution discusses Paracelsism-influenced early-modern alchemy. There are notably two forms of analogy, each hierarchically arranged: a vertically ordered analogy ("as above, thus below") in which Nature is situated as mediator between God and man, and a horizontally ordered analogy ("as without, thus within") in which Nature's magic is regarded as a model for man, particularly expressed in the metaphor of "Vulcan" (smith) and doctor (e.g., Nature as inner healer). In alchemy the conventional "healing power of Nature" is pin-pointed: The doctor (as alchemist, magician) must unravel Nature's secrets and emulate her magic to perfect her work -particularly medicine production. Diagrams and historical depictions illustrate this.

  8. Sickle cell disease and associated problems: Case study of Homozygous sicklers

    Directory of Open Access Journals (Sweden)

    Jyoti Jhariya

    2016-02-01

    Full Text Available This paper is focused on the problems faced by homozygous individuals of sickle cell disease. In a survey of 500 household of 17 villages of district Mandla, a total of 2316 individuals were covered out of which 13 were found homozygous for the disorder; whereas 3 homozygous children were reported died preceding to one year of the survey. In depth case studies of these children were recorded. The highest age of surviving homozygous individual was 30 years. After 4-5 years of age their survival is very difficult and they require frequent blood transfusion. They face frequent episodes of various infections and unbearable pain. The findings are based on longitudinal and cross sectional study as well as empirical field investigation. It was found that the homozygous children have to face multiple problems, acute pain, priapism, alienation, frequent hospitalization, economic constraints. The families of homozygous children have to face frequent emotional shock as well as economic burden. The problem of homozygous sicklers can be categorized as clinical, educational, economic etc. and is a challenge for achieving the goal of human development. Further to understand the relationship of the prevalence of gene and Human Development, district and state wise gene (HbS frequency were computed. The bivariate correlation analysis between the district wise prevalence of gene and human development index was found positive but insignificant (r2=0.065, p>0.8. At the same time, the correlation of prevalence of the HbS gene and human development index for 11 states was found negative and insignificant (r2=-0.237, p>0.5. It leads to conclude that there is no apparent correlation between the prevalence of gene and the human development in that particular region, although there is lack of sufficient data.

  9. Idiopathic intracranial hypertension in female homozygous twins.

    OpenAIRE

    Fujiwara, S; Sawamura, Y; Kato, T.; Abe, H.; Katusima, H

    1997-01-01

    The authors report on female homozygous twins with idiopathic intracranial hypertension. At the age of 12 years, both twins simultaneously developed visual disturbances with photophobia. At the age of 19 years, an ophthalmological examination disclosed papilloedema in both their eyes. At the age of 22 years, a lumbar puncture showed raised CSF pressure over (200 mm H2O) in both twins. Their neurological and radiological examinations were extremely similar; both of them had severely impaired v...

  10. Stable, synthetic analogs of diadenosine tetraphosphate inhibit rat and human P2X3 receptors and inflammatory pain

    Science.gov (United States)

    Viatchenko-Karpinski, Viacheslav; Novosolova, Natalia; Ishchenko, Yevheniia; Azhar, M Ameruddin; Wright, Michael; Tsintsadze, Vera; Kamal, Ahmed; Burnashev, Nail; Voitenko, Nana; Giniatullin, Rashid; Lozovaya, Natalia

    2016-01-01

    Background A growing body of evidence suggests that ATP-gated P2X3 receptors (P2X3Rs) are implicated in chronic pain. We address the possibility that stable, synthetic analogs of diadenosine tetraphosphate (Ap4A) might induce antinociceptive effects by inhibiting P2X3Rs in peripheral sensory neurons. Results The effects of two stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) are studied firstly in vitro on HEK293 cells expressing recombinant rat P2XRs (P2X2Rs, P2X3Rs, P2X4Rs, and P2X7Rs) and then using native rat brain cells (cultured trigeminal, nodose, or dorsal root ganglion neurons). Thereafter, the action of these stable, synthetic Ap4A analogs on inflammatory pain and thermal hyperalgesia is studied through the measurement of antinociceptive effects in formalin and Hargreaves plantar tests in rats in vivo. In vitro inhibition of rat P2X3Rs (not P2X2Rs, P2X4Rs nor P2X7Rs) is shown to take place mediated by high-affinity desensitization (at low concentrations; IC50 values 100–250 nM) giving way to only weak partial agonism at much higher concentrations (EC50 values ≥ 10 µM). Similar inhibitory activity is observed with human recombinant P2X3Rs. The inhibitory effects of AppNHppA on nodose, dorsal root, and trigeminal neuron whole cell currents suggest that stable, synthetic Ap4A analogs inhibit homomeric P2X3Rs in preference to heteromeric P2X2/3Rs. Both Ap4A analogs mediate clear inhibition of pain responses in both in vivo inflammation models. Conclusions Stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) being weak partial agonist provoke potent high-affinity desensitization-mediated inhibition of homomeric P2X3Rs at low concentrations. Therefore, both analogs demonstrate clear potential as potent analgesic agents for use in the management of chronic pain associated with heightened P2X3R activation. PMID:27030723

  11. Lunar Analog

    Science.gov (United States)

    Cromwell, Ronita L.

    2009-01-01

    In this viewgraph presentation, a ground-based lunar analog is developed for the return of manned space flight to the Moon. The contents include: 1) Digital Astronaut; 2) Bed Design; 3) Lunar Analog Feasibility Study; 4) Preliminary Data; 5) Pre-pilot Study; 6) Selection of Stockings; 7) Lunar Analog Pilot Study; 8) Bed Design for Lunar Analog Pilot.

  12. Human gut microbes use multiple transporters to distinguish vitamin B12 analogs and compete in the gut

    Science.gov (United States)

    Degnan, Patrick H.; Barry, Natasha A.; Mok, Kenny C.; Taga, Michiko E.; Goodman, Andrew L.

    2014-01-01

    Summary Genomic and metagenomic sequencing efforts, including human microbiome projects, reveal that microbes often encode multiple systems that appear to accomplish the same task. Whether these predictions reflect actual functional redundancies is unclear. We report that the prominent human gut symbiont Bacteroides thetaiotaomicron employs three functional, homologous vitamin B12 transporters that in at least two cases confer a competitive advantage in the presence of distinct B12 analogs (corrinoids). In the mammalian gut, microbial fitness can be determined by the presence or absence of a single transporter. The total number of distinct corrinoid transporter families in the human gut microbiome likely exceeds those observed in B. thetaiotaomicron by an order of magnitude. These results demonstrate that human gut microbes use elaborate mechanisms to capture and differentiate corrinoids in vivo and that apparent redundancies observed in these genomes can instead reflect hidden specificities that determine whether a microbe will colonize its host. PMID:24439897

  13. Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model.

    Science.gov (United States)

    Maj, Ewa; Filip-Psurska, Beata; Świtalska, Marta; Kutner, Andrzej; Wietrzyk, Joanna

    2015-11-13

    In previous papers, we presented data on studies on the anticancer activity of the vitamin D₃ analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins.

  14. Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model

    Science.gov (United States)

    Maj, Ewa; Filip-Psurska, Beata; Świtalska, Marta; Kutner, Andrzej; Wietrzyk, Joanna

    2015-01-01

    In previous papers, we presented data on studies on the anticancer activity of the vitamin D3 analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins. PMID:26580599

  15. Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model

    Directory of Open Access Journals (Sweden)

    Ewa Maj

    2015-11-01

    Full Text Available In previous papers, we presented data on studies on the anticancer activity of the vitamin D3 analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins.

  16. Novel acridine-based N-acyl-homoserine lactone analogs induce endoreduplication in the human oral squamous carcinoma cell line SAS.

    Science.gov (United States)

    Chai, Hongbo; Hazawa, Masaharu; Hosokawa, Yoichiro; Igarashi, Jun; Suga, Hiroaki; Kashiwakura, Ikuo

    2012-01-01

    The cytotoxicity of novel acridine-based N-acyl-homoserine lactone (AHL) analogs was investigated on the human oral squamous carcinoma cell line SAS. One analog induced G2/M phase arrest at 5.3-10.6 µM and induced polyploidy at a higher dose (21.2 µM). Importantly, treatment of SAS cells with a combination of the AHL analog and the Jun N-terminal kinase (JNK) inhibitor, SP600125, prevented mitosis and induced polyploidy. The AHL analog synergized with X-irradiation to inhibit clonogenic survival of SAS cells; however, its radiosensitizing effects were relative to not X-irradiation-induced apoptosis but mitotic failure following enhanced expression of Aurora A and B. These results suggest that the active AHL analog showed growth-suppressive and radiosensitizing effects, which involve polyploidy followed by G2/M accumulation and atypical cell death in the SAS cell line.

  17. Weak binding affinity of human 4EHP for mRNA cap analogs.

    Science.gov (United States)

    Zuberek, Joanna; Kubacka, Dorota; Jablonowska, Agnieszka; Jemielity, Jacek; Stepinski, Janusz; Sonenberg, Nahum; Darzynkiewicz, Edward

    2007-05-01

    Ribosome recruitment to the majority of eukaryotic mRNAs is facilitated by the interaction of the cap binding protein, eIF4E, with the mRNA 5' cap structure. eIF4E stimulates translation through its interaction with a scaffolding protein, eIF4G, which helps to recruit the ribosome. Metazoans also contain a homolog of eIF4E, termed 4EHP, which binds the cap structure, but not eIF4G, and thus cannot stimulate translation, but it instead inhibits the translation of only one known, and possibly subset mRNAs. To understand why 4EHP does not inhibit general translation, we studied the binding affinity of 4EHP for cap analogs using two methods: fluorescence titration and stopped-flow measurements. We show that 4EHP binds cap analogs m(7)GpppG and m(7)GTP with 30 and 100 lower affinity than eIF4E. Thus, 4EHP cannot compete with eIF4E for binding to the cap structure of most mRNAs.

  18. Recognition of human telomeric G-quadruplex DNA by berberine analogs: effect of substitution at the 9 and 13 positions of the isoquinoline moiety.

    Science.gov (United States)

    Bhowmik, Debipreeta; Fiorillo, Gaetano; Lombardi, Paolo; Kumar, G Suresh

    2015-12-01

    G-quadruplex forming sequences are widely distributed in human genome and serve as novel targets for regulating gene expression and chromosomal maintenance. They offer unique targets for anticancer drug development. Here, the interaction of berberine (BC) and two of its analogs bearing substitution at 9 and 13-position with human telomeric G-quadruplex DNA sequence has been investigated by biophysical techniques. Both the analogs exhibited several-fold higher binding affinity than berberine. The Scatchard binding isotherms revealed non-cooperative binding. 9-ω-amino hexyl ether analog (BC1) showed highest affinity (1.8 × 10(6) M(-1)) while the affinity of the 13-phenylpropyl analog (BC2) was 1.09 × 10(6) M(-1). Comparative fluorescence quenching and polarization anisotropy of the emission spectra gave evidence for a stronger stacking interaction of the analogs compared to berberine. The thiazole orange displacement assay has clearly established that the analogs were more effective in displacing the end stacked dye in comparison to berberine. However, the binding of the analogs did not induce any major structural perturbation in the G-quadruplex structure, but led to higher thermal stability. Energetics of the binding indicated that the association of the analogs was exothermic and predominantly entropy driven phenomenon. Increasing the temperature resulted in weaker binding; the enthalpic contribution increased and the entropic contribution decreased. A small negative heat capacity change with significant enthalpy-entropy compensation established the involvement of multiple weak noncovalent interactions in the binding process. The 9-ω-amino hexyl ether analog stabilized the G-quadruplex structure better than the 13-phenyl alkyl analog.

  19. A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Deok Hyo; Lim, Mi-Hee [Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Lee, Yu Ran [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Sung, Gi-Ho [Mushroom Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Suwon 404-707 (Korea, Republic of); Lee, Tae-Ho [R and D Center, Dong-A Pharmaceutical Co, Ltd, Yongin 446-905 (Korea, Republic of); Jeon, Byeong Hwa [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Cho, Jae Youl [Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Song, Won O. [Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824 (United States); Park, Haeil [College of Pharmacy, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Choi, Sunga, E-mail: sachoi@cnu.ac.kr [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr [Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of)

    2013-12-15

    A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC{sub 50} of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G{sub 0}/G{sub 1}-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by

  20. Vitamin D3 analog maxacalcitol (OCT) induces hCAP-18/LL-37 production in human oral epithelial cells.

    Science.gov (United States)

    Tada, Hiroyuki; Shimizu, Takamitsu; Nagaoka, Isao; Takada, Haruhiko

    2016-01-01

    Maxacalcitol (22-oxacalcitriol: OCT) is a synthetic vitamin D3 analog with a limited calcemic effect. In this study, we investigated whether OCT increases the production of LL-37/CAP-18, a human cathelicidin antimicrobial peptide, in human gingival/oral epithelial cells. A human gingival epithelial cell line (Ca9-22) and human oral epithelial cell lines (HSC-2, HSC-3, and HSC-4) exhibited the enhanced expression of LL-37 mRNA upon stimulation with OCT as well as active metabolites of vitamins D3 and D2. Among the human epithelial cell lines, Ca9-22 exhibited the strongest response to these vitamin D-related compounds. OCT induced the higher production of CAP-18 (ng/mL order) until 6 days time-dependently in Ca9-22 cells in culture. The periodontal pathogen Porphyromonas gingivalis was killed by treatment with the LL-37 peptide. These findings suggest that OCT induces the production of hCAP-18/LL-37 in a manner similar to that induced by the active metabolite of vitamin D3.

  1. Collective interaction of microscale matters in natural analogy: human cancer cells vs. microspheres

    Science.gov (United States)

    Ahn, Sungsook; Lee, Sang Joon; Postech Team

    2014-11-01

    Collective behaviors have been considered both in living and lifeless things as a natural phenomenon. During the ordering process, a sudden and spontaneous transition is typically generated between an order and a disorder according to the population density of interacting elements. In a cellular level collective behavior, the cells are distributed in the characteristic patterns according to the population density and the mutual interaction of the individual cells undergo density-dependent diffusive motion. On the other hand, density-controlled surface-modified hollow microsphere suspension induces an overpopulation via buoyancy which provides a driving force to induce an assembly. The collective behaviors of the cells and microspheres in a designed liquid medium are explained in terms of the deviation from the interparticle distance distribution and the induced strength to organize the particle position in a specific distance range. as a result, microscale particulate matters exhibit high resemblance in their pair correlation and dynamical heterogeneity in the intermediate range between a single individual and an agglomerate. Therefore, it is suggested that biological systems are analogically explained to be dominated by physically interactive aspects.

  2. Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells.

    Science.gov (United States)

    Milczarek, Magdalena; Chodyński, Michał; Filip-Psurska, Beata; Martowicz, Agnieszka; Krupa, Małgorzata; Krajewski, Krzysztof; Kutner, Andrzej; Wietrzyk, Joanna

    2013-10-31

    Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of tested analogs the diastereomeric analog PRI-2202 showed the strongest antiproliferative activity on the human breast cancer cell line MCF-7, whereas the geometric analog PRI-2205 was the weakest. Both analogs were less potent in antiproliferative activity against HL-60 cells compared to the reference compounds. The ability to potentiate antiproliferative effect of cisplatin or doxorubicin against HL-60 cells or that of tamoxifen against the MCF-7 cell line was observed at higher doses of PRI-2202 or PRI-2205 than those of the reference compounds. The proapoptotic activity of tamoxifen, expressed as the diminished mitochondrial membrane potential, as well as the increased phosphatidylserine expression, was partially attenuated by calcitriol, PRI-2191, PRI-2201 and PRI-2205. The treatment of the MCF-7 cells with tamoxifen alone resulted in an increase in VDR expression. Moreover, a further increase in VDR expression was observed when the analogs PRI-2201 or PRI-2205, but not PRI-2191, were used in combination with tamoxifen. This observation could partially explain the potentiation of the antiproliferative effect of tamoxifen by vitamin D analogs.

  3. Infant Formula Fat Analogs and Human Milk Fat: New Focus on Infant Developmental Needs.

    Science.gov (United States)

    Zou, Long; Pande, Garima; Akoh, Casimir C

    2016-01-01

    Human breast milk is generally and universally recognized as the optimal choice for nutrition during the first year of life. In certain cases in which it is not feasible to breast-feed the infant or the breast milk is not sufficient, especially in the case of preterm infants, infant formula is the next best alternative to provide nutrition to nurture the infant. Therefore, it is highly important that the nutrient composition of the infant formula is as close to breast milk as possible for proper growth and development of the infant. However, human milk is a complex dynamic matrix, and therefore significant research has been done and is still ongoing to fully understand and mimic human breast milk, particularly its fat composition. Lipids play a critical role in infant nutrition. A number of advances have been made in infant formula lipid content and composition so that formula can better simulate or mimic the nutritional functions of human maternal milk.

  4. Analog computing

    CERN Document Server

    Ulmann, Bernd

    2013-01-01

    This book is a comprehensive introduction to analog computing. As most textbooks about this powerful computing paradigm date back to the 1960s and 1970s, it fills a void and forges a bridge from the early days of analog computing to future applications. The idea of analog computing is not new. In fact, this computing paradigm is nearly forgotten, although it offers a path to both high-speed and low-power computing, which are in even more demand now than they were back in the heyday of electronic analog computers.

  5. Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines.

    Directory of Open Access Journals (Sweden)

    Matthew A Bill

    Full Text Available The Janus kinase-2 (Jak2-signal transducer and activator of transcription-3 (STAT3 pathway is critical for promoting an oncogenic and metastatic phenotype in several types of cancer including renal cell carcinoma (RCC and melanoma. This study describes two small molecule inhibitors of the Jak2-STAT3 pathway, FLLL32 and its more soluble analog, FLLL62. These compounds are structurally distinct curcumin analogs that bind selectively to the SH2 domain of STAT3 to inhibit its phosphorylation and dimerization. We hypothesized that FLLL32 and FLLL62 would induce apoptosis in RCC and melanoma cells and display specificity for the Jak2-STAT3 pathway. FLLL32 and FLLL62 could inhibit STAT3 dimerization in vitro. These compounds reduced basal STAT3 phosphorylation (pSTAT3, and induced apoptosis in four separate human RCC cell lines and in human melanoma cell lines as determined by Annexin V/PI staining. Apoptosis was also confirmed by immunoblot analysis of caspase-3 processing and PARP cleavage. Pre-treatment of RCC and melanoma cell lines with FLLL32/62 did not inhibit IFN-γ-induced pSTAT1. In contrast to FLLL32, curcumin and FLLL62 reduced downstream STAT1-mediated gene expression of IRF1 as determined by Real Time PCR. FLLL32 and FLLL62 significantly reduced secretion of VEGF from RCC cell lines in a dose-dependent manner as determined by ELISA. Finally, each of these compounds inhibited in vitro generation of myeloid-derived suppressor cells. These data support further investigation of FLLL32 and FLLL62 as lead compounds for STAT3 inhibition in RCC and melanoma.

  6. The human story of Crew 173- capturing a Mars analog mission

    Science.gov (United States)

    Shaw, Niamh; Musilova, Michaela; Pons Lorente, Arnau; Sisaid, Idriss; Naor, Roy; Blake, Richard

    2017-04-01

    An international crew of six scientists, engineers, artists and entrepreneurs with different space specialisations were selected by the Mars Society to take part in a Martian simulation in January 2017. An ambitious outreach and media strategy was developed, aimed at communicating the benefits of missions to Mars to the public and to capture the public's interest by telling the human story of the crew's mission. Entitled Crew 173 Team PRIMA, they entered the Mars Desert Research Station in the Utah Desert and conducted research in 3D printing, hydroponics, geology and astronomy. Both the scientific and community experience of this mission was documented through still image, video, audio, diary and daily journalling by the resident artist of the mission, Niamh Shaw. The full experience of the crew was documented (before, during and after the expedition), to capture each individual experience of the crew and the human experience of isolation of future human space missions.

  7. Development of a long acting human growth hormone analog suitable for once a week dosing.

    Science.gov (United States)

    Palanki, Moorthy S S; Bhat, Abhijit; Bolanos, Ben; Brunel, Florence; Del Rosario, Joselyn; Dettling, Danielle; Horn, Mark; Lappe, Rodney; Preston, Ryan; Sievers, Annette; Stankovic, Nebojsa; Woodnut, Gary; Chen, Gang

    2013-01-15

    Human growth hormone was conjugated to a carrier aldolase antibody, using a novel linker by connecting a disulphide bond in growth hormone to a lysine-94 amine located on the Fab arm of the antibody. The resulting CovX body showed reduced affinity towards human growth hormone receptor, reduced cell-based activity, but improved pharmacodynamic properties. We have demonstrated that this CovX-body, given once a week, showed comparable activity as growth hormone given daily in an in vivo hypophysectomized rat model.

  8. Bisphenol A and its analogs induce morphological and biochemical alterations in human peripheral blood mononuclear cells (in vitro study).

    Science.gov (United States)

    Michałowicz, Jaromir; Mokra, Katarzyna; Bąk, Agata

    2015-10-01

    Few studies have addressed the cellular effects of bisphenol S (BPS) and bisphenol AF (BPAF) on cells, and no study has been conducted to analyze the mechanism of action of bisphenols in blood cells. In this study, the effect of bisphenol A (BPA), bisphenol F (BPF), BPS and BPAF on human peripheral blood mononuclear cells (PBMCs) was analyzed. It was shown that BPA, BPF and BPAF in particular, decreased cell viability, which was associated with depletion of intracellular ATP level and alterations in PBMCs size and granulation. Bisphenols enhanced ROS (including OH˙) formation, which led to damage to lipids and proteins in PBMCs. The most significant alterations in ROS level were induced by BPF, and particularly BPAF. Moreover, it was shown that BPAF most strongly provoked lipid peroxidation, while BPA and BPS caused the greatest damage to proteins. It may be concluded that BPA and its analogs were capable of inducing oxidative stress and damage in PBMCs in the concentrations ranging from 0.06 to 0.5 μM (0.02-0.1 μg/ml), which may be present in human blood as a result of environmental exposure. Although, most of bisphenols studied decreased cell viability, size and ATP level at higher concentrations, BPAF exhibited its cytotoxic potential at low concentrations ranging from 0.3 to 3 μM (0.1-1.0 μg/ml) that may correspond to concentrations in humans following occupational exposure.

  9. Structure and pharmaceutical formulation development of a new long-acting recombinant human insulin analog studied by NMR and MS.

    Science.gov (United States)

    Bednarek, Elżbieta; Sitkowski, Jerzy; Bocian, Wojciech; Borowicz, Piotr; Płucienniczak, Grażyna; Stadnik, Dorota; Surmacz-Chwedoruk, Weronika; Jaworska, Beata; Kozerski, Lech

    2017-02-20

    A monomer structure of a novel human insulin analog A22(S)-B3(K)-B31(R) (SK3R) has been characterized by NMR in water/acetonitrile solution and compared with the structure of human insulin (HIS) established in the same medium. The composition of the oligomer ensemble for neat insulins in water was qualitatively assessed by monitoring, derived from NMR experiment, translational diffusion coefficient Dix10(-10)m(2)s(-1), whose value is a population averaged of individual coefficients for species in oligomeric ensemble. Nanospray ESI/MS experiment was used to establish the masses of oligomers in pharmaceutical formulation of the SK3R insulin. The pharmacodynamic data were established and compared to insulin glargine characterized by the same profile of action in diabetics. The oligomerization process of insulin during development of pharmaceutical formulation with routinely used excipients has been studied using translation diffusion coefficient Dix10(-10)m(2)s(-1) established in water solution. These properties were compared with those of human insulin (HIS) which is a standard reference for novel recombinant insulins. Copyright © 2016. Published by Elsevier B.V.

  10. Data-driven analysis of analogous brain networks in monkeys and humans during natural vision.

    Science.gov (United States)

    Mantini, Dante; Corbetta, Maurizio; Romani, Gian Luca; Orban, Guy A; Vanduffel, Wim

    2012-11-15

    Inferences about functional correspondences between functional networks of human and non-human primates largely rely on proximity and anatomical expansion models. However, it has been demonstrated that topologically correspondent areas in two species can have different functional properties, suggesting that anatomy-based approaches should be complemented with alternative methods to perform functional comparisons. We have recently shown that comparative analyses based on temporal correlations of sensory-driven fMRI responses can reveal functional correspondent areas in monkeys and humans without relying on spatial assumptions. Inter-species activity correlation (ISAC) analyses require the definition of seed areas in one species to reveal functional correspondences across the cortex of the same and other species. Here we propose an extension of the ISAC method that does not rely on any seed definition, hence a method void of any spatial assumption. Specifically, we apply independent component analysis (ICA) separately to monkey and human data to define species-specific networks of areas with coherent stimulus-related activity. Then, we use a hierarchical cluster analysis to identify ICA-based ISAC clusters of monkey and human networks with similar timecourses. We implemented this approach on fMRI data collected in monkeys and humans during movie watching, a condition that evokes widespread sensory-driven activity throughout large portions of the cortex. Using ICA-based ISAC, we detected seven monkey-human clusters. The timecourses of several clusters showed significant correspondences either with the motion energy in the movie or with eye-movement parameters. Five of the clusters spanned putative homologous functional networks in either primary or extrastriate visual regions, whereas two clusters included higher-level visual areas at topological locations that are not predicted by cortical surface expansion models. Overall, our ICA-based ISAC analysis complemented

  11. NEEMO 18-20: Analog Testing for Mitigation of Communication Latency During Human Space Exploration

    Science.gov (United States)

    Chappell, Steven P.; Beaton, Kara H.; Miller, Matthew J.; Graff, Trevor G.; Abercromby, Andrew F. J.; Gernhardt, Michael L.; Halcon, Christopher

    2016-01-01

    NASA Extreme Environment Mission Operations (NEEMO) is an underwater spaceflight analog that allows a true mission-like operational environment and uses buoyancy effects and added weight to simulate different gravity levels. Three missions were undertaken from 2014-2015, NEEMO's 18-20. All missions were performed at the Aquarius undersea research habitat. During each mission, the effects of communication latencies on operations concepts, timelines, and tasks were studied. METHODS: Twelve subjects (4 per mission) were weighed out to simulate near-zero or partial gravity extravehicular activity (EVA) and evaluated different operations concepts for integration and management of a simulated Earth-based science team (ST) to provide input and direction during exploration activities. Exploration traverses were preplanned based on precursor data. Subjects completed science-related tasks including pre-sampling surveys, geologic-based sampling, and marine-based sampling as a portion of their tasks on saturation dives up to 4 hours in duration that were designed to simulate extravehicular activity (EVA) on Mars or the moons of Mars. One-way communication latencies, 5 and 10 minutes between space and mission control, were simulated throughout the missions. Objective data included task completion times, total EVA times, crew idle time, translation time, ST assimilation time (defined as time available for ST to discuss data/imagery after data acquisition). Subjective data included acceptability, simulation quality, capability assessment ratings, and comments. RESULTS: Precursor data can be used effectively to plan and execute exploration traverse EVAs (plans included detailed location of science sites, high-fidelity imagery of the sites, and directions to landmarks of interest within a site). Operations concepts that allow for pre-sampling surveys enable efficient traverse execution and meaningful Mission Control Center (MCC) interaction across communication latencies and can be

  12. Homozygous Nonsense Mutations in TWIST2 Cause Setleis Syndrome

    Science.gov (United States)

    Tukel, Turgut; Šošić, Dražen; Al-Gazali, Lihadh I.; Erazo, Mónica; Casasnovas, Jose; Franco, Hector L.; Richardson, James A.; Olson, Eric N.; Cadilla, Carmen L.; Desnick, Robert J.

    2010-01-01

    The focal facial dermal dysplasias (FFDDs) are a group of inherited developmental disorders in which the characteristic diagnostic feature is bitemporal scar-like lesions that resemble forceps marks. To date, the genetic defects underlying these ectodermal dysplasias have not been determined. To identify the gene defect causing autosomal-recessive Setleis syndrome (type III FFDD), homozygosity mapping was performed with genomic DNAs from five affected individuals and 26 members of the consanguineous Puerto Rican (PR) family originally described by Setleis and colleagues. Microsatellites D2S1397 and D2S2968 were homozygous in all affected individuals, mapping the disease locus to 2q37.3. Haplotype analyses of additional markers in the PR family and a consanguineous Arab family further limited the disease locus to ∼3 Mb between D2S2949 and D2S2253. Of the 29 candidate genes in this region, the bHLH transcription factor, TWIST2, was initially sequenced on the basis of its known involvement in murine facial development. Homozygous TWIST2 nonsense mutations, c.324C>T and c.486C>T, were identified in the affected members of the Arab and PR families, respectively. Characterization of the expressed mutant proteins, p.Q65X and p.Q119X, by electrophoretic mobility shift assays and immunoblot analyses indicated that they were truncated and unstable. Notably, Setleis syndrome patients and Twist2 knockout mice have similar facial features, indicating the gene's conserved role in mammalian development. Although human TWIST2 and TWIST1 encode highly homologous bHLH transcription factors, the finding that TWIST2 recessive mutations cause an FFDD and dominant TWIST1 mutations cause Saethre-Chotzen craniocynostosis suggests that they function independently in skin and bone development. PMID:20691403

  13. Homozygous familial hypercholesterolaemia: update on management.

    Science.gov (United States)

    France, Michael

    2016-11-01

    Homozygous familial hypercholesterolaemia (HoFH) is an inherited disease causing an approximately fourfold increase in blood low-density lipoprotein cholesterol (LDLC) from birth compared with the age-matched normal population owing to reduced low-density lipoprotein receptor (LDLR) activity. Such elevated cholesterol is associated with accelerated atheromatous disease, particularly of the aortic root and coronary arteries. However, HoFH is clinically heterogeneous, reflecting residual low-density lipoprotein receptor (LDLR) activity. The main objective in treating children may be stated to be the avoidance of irreversible cardiac damage requiring heart transplantation by sufficient lowering of blood cholesterol. Lipoprotein apheresis or plasmapheresis are safe means of lowering cholesterol but may be insufficient on their own. Statin drugs, PCSK9 inhibitors ezetimibe and bile acid sequestrants are relatively ineffective if LDLR activity is lacking, but should be used if effective. Two new drugs, lomitapide and mipomersen, have been licensed specifically for HoFH by some regulatory authorities. They work by reducing LDL production rate. They have been associated with fatty liver in adults. Evidence of safety in children is lacking. An alternative is liver transplantation, which replaces the missing LDLR and normalises cholesterol. Clinicians are faced with a dilemma in choosing between these options or deferring such treatment associated with potential harm. Individual case descriptions are an important means of informing clinical judgement. Management of the two cases described in this issue is discussed in the light of modern developments in transplantation and pharmacotherapy.

  14. Human-Animal Trust as an Analog for Human-Robot Trust: A Review of Current Evidence

    Science.gov (United States)

    2012-03-01

    example, according to the human- horse mutual trust paradigm, a rider must trust their horse to protect them while mounted. They also have to understand... horse - rider relationships (see table 1). For more detailed descriptions of the included human-animal literature, see the appendix. Table 1...Zasloff, 1996 Training dogs, human interaction Greenebaum, 2010 Companion animals/pets Brown, 2007 Horse - rider Keaveney, 2008 Yorke, Adams, and

  15. Histopathological Analogies in Chronic Pulmonary Lesions between Cattle and Humans: Basis for an Alternative Animal Model

    Directory of Open Access Journals (Sweden)

    Rafael Ramírez-Romero

    2012-01-01

    Full Text Available Most of the natural cases of pneumonia in feedlot cattle are characterized by a longer clinical course due to chronic lung lesions. Microscopically, these lesions include interstitial fibroplasia, bronchitis, bronchiectasis, bronchiolitis obliterans, and epithelial metaplasia of the airways. Herein, the aim was to review, under a medical perspective, the pathologic mechanisms operating in these chronic pneumonic lesions in calves. Based on the similarities of these changes to those reported in bronchiolitis obliterans/organising pneumonia (BO/OP and chronic obstructive pulmonary disease (COPD in human beings, calves are proposed as an alternative animal model.

  16. Histopathological Analogies in Chronic Pulmonary Lesions between Cattle and Humans: Basis for an Alternative Animal Model

    Science.gov (United States)

    Ramírez-Romero, Rafael; Nevárez-Garza, Alicia M.; Rodríguez-Tovar, Luis E.; Wong-González, Alfredo; Ledezma-Torres, Rogelio A.; Hernández-Vidal, Gustavo

    2012-01-01

    Most of the natural cases of pneumonia in feedlot cattle are characterized by a longer clinical course due to chronic lung lesions. Microscopically, these lesions include interstitial fibroplasia, bronchitis, bronchiectasis, bronchiolitis obliterans, and epithelial metaplasia of the airways. Herein, the aim was to review, under a medical perspective, the pathologic mechanisms operating in these chronic pneumonic lesions in calves. Based on the similarities of these changes to those reported in bronchiolitis obliterans/organising pneumonia (BO/OP) and chronic obstructive pulmonary disease (COPD) in human beings, calves are proposed as an alternative animal model. PMID:22629176

  17. Temporal Evolution of Design Principles in Engineering Systems: Analogies with Human Evolution

    DEFF Research Database (Denmark)

    Deb, Kalyanmoy; Bandaru, Sunith; Tutum, Cem Celal

    2012-01-01

    constructed later during optimization. Interestingly, there exists a simile between evolution of design principles with that of human evolution. Such information about the hierarchy of key design principles should enable designers to have a deeper understanding of their problems....... among near-Paretooptimal solutions, the main crux of this paper lies in a demonstration of temporal evolution of these principles during the course of optimization. The results reveal that certain important design principles start to evolve early on, whereas some detailed design principles get...

  18. Human Hepatocyte Metabolism of Novel Synthetic Cannabinoids MN-18 and Its 5-Fluoro Analog 5F-MN-18.

    Science.gov (United States)

    Diao, Xingxing; Carlier, Jeremy; Zhu, Mingshe; Huestis, Marilyn A

    2017-08-18

    In 2014, 2 novel synthetic cannabinoids, MN-18 and its 5-fluoro analog, 5F-MN-18, were first identified in an ongoing survey of novel psychoactive substances in Japan. In vitro pharmacological assays revealed that MN-18 and 5F-MN-18 displayed high binding affinities to human CB1 and CB2 receptors, with Ki being 1.65-3.86 nmol/L. MN-18 and 5F-MN-18 were scheduled in Japan and some other countries in 2014. Despite increasing prevalence, no human metabolism data are currently available, making it challenging for forensic laboratories to confirm intake of MN-18 or 5F-MN-18. We incubated 10 μ mol/L of MN-18 and 5F-MN-18 in human hepatocytes for 3 h and analyzed the samples on a TripleTOF 5600(+) high-resolution mass spectrometer to identify appropriate marker metabolites. Data were acquired via full scan and information-dependent acquisition-triggered product ion scans with mass defect filter. In total, 13 MN-18 metabolites were detected, with the top 3 abundant metabolites being 1-pentyl-1H-indazole-3-carboxylic acid, pentyl-carbonylated MN-18, and naphthalene-hydroxylated MN-18. For 5F-MN-18, 20 metabolites were observed, with the top 3 abundant metabolites being 5`-OH-MN-18, MN-18 pentanoic acid, and 1-(5-fluoropentyl)-1H-indazole-3-carboxylic acid. We have characterized MN-18 and 5F-MN-18 metabolism with human hepatocytes and high-resolution mass spectrometry, and we recommend characteristic major metabolites for clinical and forensic laboratories to identify MN-18 and 5F-MN-18 intake and link observed adverse events to these novel synthetic cannabinoids. © 2017 American Association for Clinical Chemistry.

  19. Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.

    Science.gov (United States)

    Reddy, D Rajasekhar; Ballante, Flavio; Zhou, Nancy J; Marshall, Garland R

    2017-02-15

    A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.

  20. Protective Effect of Liposome-Encapsulated Glutathione in a Human Epidermal Model Exposed to a Mustard Gas Analog

    Science.gov (United States)

    Paromov, Victor; Kumari, Sudha; Brannon, Marianne; Kanaparthy, Naga S.; Yang, Hongsong; Smith, Milton G.; Stone, William L.

    2011-01-01

    Sulfur mustard or mustard gas (HD) and its monofunctional analog, 2-chloroethyl ethyl sulfide (CEES), or “half-mustard gas,” are alkylating agents that induce DNA damage, oxidative stress, and inflammation. HD/CEES are rapidly absorbed in the skin causing extensive injury. We hypothesize that antioxidant liposomes that deliver both water-soluble and lipid-soluble antioxidants protect skin cells from immediate CEES-induced damage via attenuating oxidative stress. Liposomes containing water-soluble antioxidants and/or lipid-soluble antioxidants were evaluated using in vitro model systems. Initially, we found that liposomes containing encapsulated glutathione (GSH-liposomes) increased cell viability and attenuated production of reactive oxygen species (ROS) in HaCaT cells exposed to CEES. Next, GSH-liposomes were tested in a human epidermal model, EpiDerm. In the EpiDerm, GSH-liposomes administered simultaneously or 1 hour after CEES exposure (2.5 mM) increased cell viability, inhibited CEES-induced loss of ATP and attenuated changes in cellular morphology, but did not reduce caspase-3 activity. These findings paralleled the previously described in vivo protective effect of antioxidant liposomes in the rat lung and established the effectiveness of GSH-liposomes in a human epidermal model. This study provides a rationale for use of antioxidant liposomes against HD toxicity in the skin considering further verification in animal models exposed to HD. PMID:21776256

  1. Protective Effect of Liposome-Encapsulated Glutathione in a Human Epidermal Model Exposed to a Mustard Gas Analog

    Directory of Open Access Journals (Sweden)

    Victor Paromov

    2011-01-01

    Full Text Available Sulfur mustard or mustard gas (HD and its monofunctional analog, 2-chloroethyl ethyl sulfide (CEES, or “half-mustard gas,” are alkylating agents that induce DNA damage, oxidative stress, and inflammation. HD/CEES are rapidly absorbed in the skin causing extensive injury. We hypothesize that antioxidant liposomes that deliver both water-soluble and lipid-soluble antioxidants protect skin cells from immediate CEES-induced damage via attenuating oxidative stress. Liposomes containing water-soluble antioxidants and/or lipid-soluble antioxidants were evaluated using in vitro model systems. Initially, we found that liposomes containing encapsulated glutathione (GSH-liposomes increased cell viability and attenuated production of reactive oxygen species (ROS in HaCaT cells exposed to CEES. Next, GSH-liposomes were tested in a human epidermal model, EpiDerm. In the EpiDerm, GSH-liposomes administered simultaneously or 1 hour after CEES exposure (2.5 mM increased cell viability, inhibited CEES-induced loss of ATP and attenuated changes in cellular morphology, but did not reduce caspase-3 activity. These findings paralleled the previously described in vivo protective effect of antioxidant liposomes in the rat lung and established the effectiveness of GSH-liposomes in a human epidermal model. This study provides a rationale for use of antioxidant liposomes against HD toxicity in the skin considering further verification in animal models exposed to HD.

  2. Elevated Levels of DNA Strand Breaks Induced by a Base Analog in the Human Cell Line with the P32T ITPA Variant

    Directory of Open Access Journals (Sweden)

    Irina S.-R. Waisertreiger

    2010-01-01

    Full Text Available Base analogs are powerful antimetabolites and dangerous mutagens generated endogenously by oxidative stress, inflammation, and aberrant nucleotide biosynthesis. Human inosine triphosphate pyrophosphatase (ITPA hydrolyzes triphosphates of noncanonical purine bases (i.e., ITP, dITP, XTP, dXTP, or their mimic: 6-hydroxyaminopurine (HAP deoxynucleoside triphosphate and thus regulates nucleotide pools and protects cells from DNA damage. We demonstrate that the model purine base analog HAP induces DNA breaks in human cells and leads to elevation of levels of ITPA. A human polymorphic allele of the ITPA, 94C->A encodes for the enzyme with a P32T amino-acid change and leads to accumulation of nonhydrolyzed ITP. The polymorphism has been associated with adverse reaction to purine base-analog drugs. The level of both spontaneous and HAP-induced DNA breaks is elevated in the cell line with the ITPA P32T variant. The results suggested that human ITPA plays a pivotal role in the protection of DNA from noncanonical purine base analogs.

  3. The genomic structure of the human Charcot-Leyden crystal protein gene is analogous to those of the galectin genes

    Energy Technology Data Exchange (ETDEWEB)

    Dyer, K.D. [National Inst. of Health, Bethesda, MD (United States)]|[Georgetown Univ. Medical Center, Washington, DC (United States); Handen, J.S.; Rosenberg, H.F. [National Inst. of Health, Bethesda, MD (United States)

    1997-03-01

    The Charcot-Leyden crystal (CLC) protein, or eosinophil lysophospholipase, is a characteristic protein of human eosinophils and basophils; recent work has demonstrated that the CLC protein is both structurally and functionally related to the galectin family of {beta}-galactoside binding proteins. The galectins as a group share a number of features in common, including a linear ligand binding site encoded on a single exon. In this work, we demonstrate that the intron-exon structure of the gene encoding CLC is analogous to those encoding the galectins. The coding sequence of the CLC gene is divided into four exons, with the entire {beta}-galactoside binding site encoded by exon III. We have isolated CLC {beta}-galactoside binding sites from both orangutan (Pongo pygmaeus) and murine (Mus musculus) genomic DNAs, both encoded on single exons, and noted conservation of the amino acids shown to interact directly with the {beta}-galactoside ligand. The most likely interpretation of these results suggests the occurrence of one or more exon duplication and insertion events, resulting in the distribution of this lectin domain to CLC as well as to the multiple galectin genes. 35 refs., 3 figs.

  4. Recent Progress of National Banking Project on Homozygous HLA-typed Induced Pluripotent Stem Cells in South Korea.

    Science.gov (United States)

    Rim, Yeri Alice; Park, Narae; Nam, Yoojun; Ham, Dong-Sik; Kim, Ji-Won; Ha, Hye-Yeong; Jung, Ji-Won; Jung, Seung Min; Baek, In Cheol; Kim, Su-Yeon; Kim, Tai-Gyu; Song, Jihwan; Lee, Jennifer; Park, Sung-Hwan; Chung, Nak-Gyun; Yoon, Kun-Ho; Ju, Ji Hyeon

    2017-09-23

    Induced pluripotent stem cells (iPSCs) can be generated by introducing several factors into mature somatic cells. Banking of iPSCs can lead to wider application for treatment and research. In an economical view, it is important to store cells that can cover a high percentage of the population. Therefore, the use of homozygous human leukocyte antigen-iPSCs (HLA-iPSCs) is thought as a potential candidate for effective iPSC banking system for further clinical use. We screened the database stored in the Catholic Hematopoietic Stem Cell Bank of Korea and sorted the most frequent homozygous HLA types of the South Korean population. Blood cells with the selected homozygous HLA types were obtained and transferred to the GMP facility in the Catholic Institute of Cell Therapy. Cells were reprogrammed to iPSCs inside the facility and went through several quality controls. As a result, a total of 13 homozygous GMP-grade iPSC lines were obtained in the facility. The generated iPSCs showed high pluripotency and normal karyotype after reprogramming. Five HLA-homozygous iPSCs had the type that was included in the top five most frequent HLA types. Homozygous HLA-iPSCs can open a new opportunity for further application of iPSCs in clinical research and therapy. This article is protected by copyright. All rights reserved.

  5. Pan-pathway based interaction profiling of FDA-approved nucleoside and nucleobase analogs with enzymes of the human nucleotide metabolism.

    Directory of Open Access Journals (Sweden)

    Louise Egeblad

    Full Text Available To identify interactions a nucleoside analog library (NAL consisting of 45 FDA-approved nucleoside analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of "off target effects." However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA and uridine phosphorylase 1 (UPP1. An acyclic guanosine prodrug analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔT(agg around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside analogs, which could also serve as a starting point for future drug design.

  6. Molecular modeling and docking simulations of scorpion toxins and related analogs on human SKCa2 and SKCa3 channels.

    Science.gov (United States)

    Andreotti, Nicolas; di Luccio, Eric; Sampieri, François; De Waard, Michel; Sabatier, Jean-Marc

    2005-07-01

    The small-conductance Ca2+-activated K+ (SKCa) channels modulate cytosolic Ca2+ concentration in excitable and non-excitable tissues by regulating the membrane potential and are responsible of slow action potential after hyperpolarization that inhibits cell firing. Among these, human SKCa2 and SKCa3 channels differ in the pore region by only two residues: Ala331 and Asn367 (human small-conductance calcium-activated potassium channel, hSKCa2) instead of Val485 and His521 (hSKCa3). To design highly selective blockers of hSKCa channels, a number of known hSKCa2 and/or hSKCa3-active peptides (i.e. scorpion toxins and analogs thereof) were analyzed for their interactions and selectivities toward these channels. Molecular models of hSKCa2 and hSKCa3 channels (S5-H5-S6 portion) were generated, and scorpion toxins/peptides of unsolved three-dimensional (3D) structures were modeled. Models of toxin-channel complexes were generated by the bimolecular complex generation with global evaluation, and ranking (BiGGER) docking software and selected by using a screening method of the docking solutions. A high degree of correlation was found to exist between docking energies and experimental Kd values of peptides that blocked hSKCa2 and/or hSKCa3 channels, suggesting it could be appropriate to predict Kd values of other bioactive peptides. The best scoring complexes were also used to identify key residues of both interacting partners, indicating that such an approach should help the design of more active and/or selective peptide blockers of targeted ion channels.

  7. Analog earthquakes

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, R.B. [Center for Nuclear Waste Regulatory Analyses, San Antonio, TX (United States)

    1995-09-01

    Analogs are used to understand complex or poorly understood phenomena for which little data may be available at the actual repository site. Earthquakes are complex phenomena, and they can have a large number of effects on the natural system, as well as on engineered structures. Instrumental data close to the source of large earthquakes are rarely obtained. The rare events for which measurements are available may be used, with modfications, as analogs for potential large earthquakes at sites where no earthquake data are available. In the following, several examples of nuclear reactor and liquified natural gas facility siting are discussed. A potential use of analog earthquakes is proposed for a high-level nuclear waste (HLW) repository.

  8. Synthesis and evaluation of {sup 18}F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Hanwen; Huang, Ruimin; Pillarsetty, NagaVaraKishore; Thorek, Daniel L.J. [Memorial Sloan-Kettering Cancer Center (MSKCC), Department of Radiology, New York, NY (United States); Vaidyanathan, Ganesan [Duke University School of Medicine, Department of Radiology, Durham, NC (United States); Serganova, Inna [Memorial Sloan-Kettering Cancer Center (MSKCC), Department of Neurology, New York, NY (United States); Blasberg, Ronald G. [Memorial Sloan-Kettering Cancer Center (MSKCC), Department of Radiology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center (MSKCC), Department of Neurology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center (MSKCC), Molecular Pharmacology and Chemistry Program, New York, NY (United States); Lewis, Jason S. [Memorial Sloan-Kettering Cancer Center (MSKCC), Department of Radiology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center (MSKCC), Molecular Pharmacology and Chemistry Program, New York, NY (United States); Molecular Pharmacology and Chemistry Program, SKI, Memorial Sloan-Kettering Cancer Center, Radiochemistry and Imaging Sciences Service, Department of Radiology, New York, NY (United States)

    2014-02-15

    Both {sup 131}I- and {sup 123}I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with {sup 124}I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). {sup 18}F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [{sup 18}F]MFBG and [{sup 18}F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. [{sup 18}F]MFBG and [{sup 18}F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the {sup 18}F-labeled analogs with [{sup 123}I]/[{sup 124}I]MIBG. The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7 %) than meta-isomer (21 ± 5 %). The reaction of [{sup 18}F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2 % (n = 12) for [{sup 18}F]MFBG and 41 ± 12 % (n = 5) for [{sup 18}F]PFBG, respectively. The specific uptakes of [{sup 18}F]MFBG and [{sup 18}F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [{sup 123}I]/[{sup 124}I]MIBG. However, in vivo [{sup 18}F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [{sup 18}F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [{sup 18}F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [{sup 123}I]/[{sup 124}I]MIBG, PET imaging demonstrated that [{sup 18}F]MFBG was able to visualize C6-hNET xenografts better than [{sup 124}I

  9. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    Directory of Open Access Journals (Sweden)

    Jaan-Olle Andressoo

    2006-10-01

    Full Text Available Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

  10. Quantification of DeQi sensation by visual analog scales in healthy humans after immunostimulating acupuncture treatment.

    Science.gov (United States)

    Kou, Wei; Gareus, Isabel; Bell, John D; Goebel, Marion U; Spahn, Günther; Pacheco-López, Gustavo; Bäcker, Marcus; Schedlowski, Manfred; Dobos, Gustav J

    2007-01-01

    Acupuncture is the most popular component of traditional Chinese medicine in Western countries. However, the mechanisms of its effects remain unclear. The therapeutic effect of acupuncture appears when a sensation of DeQi is achieved. We previously reported that repeated, but not single acupuncture treatment affected leukocyte circulation and blood pressure in healthy young humans. The objective of this study was to quantify DeQi sensation by using visual analog scales (VASs) and, to test whether DeQi induction is an important factor for the therapeutic effects of acupuncture in the same cohort. After either acupuncture or sham-acupuncture (placebo) treatment, a questionnaire containing five individual VASs was given to subjects to evaluate their DeQi sensation, including numbness, pressure, heaviness, warmth, and radiating paraesthesia, respectively. A separate VAS to measure their levels of anxiety during the treatment was also included. Our results showed that acupuncture significantly induced higher VAS values for numbness, pressure, warmth, and radiating paraesthesia, but not for heaviness than the placebo across three treatment sessions. Additionally, acupuncture did not induce higher anxiety levels than the placebo. These data confirm that VAS is an objective and reliable way to quantify DeQi sensation and, indicate that DeQi is unique to verum acupuncture treatment. Furthermore, either acupuncture-induced therapeutic effects or DeQi sensation should not be attributed to the stress-mediated effects. In summary, the induction of DeQi in each treatment session is an important factor for the physiological outcomes of repeated acupuncture treatment, and VASs offer objective, an easy and reliable way to assess it.

  11. Factor v Leiden homozygous genotype and pregnancy outcomes.

    Science.gov (United States)

    Biron-Andréani, Christine; Bauters, Anne; Le Cam-Duchez, Véronique; Delahousse, Bénédicte; Lequerrec, Agnès; Dutrillaux, Fabienne; Boinot, Catherine; Saladin-Thiron, Catherine; Polack, Benoit; Gruel, Yves; Morange, Pierre-Emmanuel

    2009-12-01

    To assess the rate of early (first trimester) and late (second and third trimester) fetal loss in women who are factor V Leiden homozygous. Between December 1995 and February 2007, consecutive, unrelated white women who were factor V Leiden homozygous and who had been pregnant at least once were recruited from 10 French hemostasis units. For reasons of comparison, we included women who were factor V Leiden heterozygous and a group of noncarriers. The frequency of early and late fetal loss was assessed retrospectively and compared among the three groups. The effect of concomitant thrombophilic abnormalities was evaluated. The overall pregnancy outcome was reported. We analyzed 240 thromboprophylaxis-free pregnancies in 95 women who were factor V Leiden homozygous, 425 in 195 women who were factor V Leiden heterozygous, and 182 in 73 women who were noncarriers. The risk of late fetal loss was higher in women who were homozygous (13/95, 13.7%) compared with those who were noncarriers (1/73, 1.4%, odds ratio 11.41, 95% confidence interval 1.46-89.46, P=.002), whereas it was similar in women who were heterozygous and in noncarriers (6/195, 3.1% compared with 1/73, 1.4%, P=.68). The percentage of women with early fetal loss was similar in the three groups (P=.81). The live-birth rate was 80%, 84%, and 85%, respectively, for women who where homozygous, heterozygous, and noncarriers (P=.88). The factor V Leiden homozygous genotype increases the risk of late fetal loss. However, the overall likelihood of a positive outcome is high in our series of women who were homozygous. III.

  12. Conformation of an analog of human follicular gonadotropin releasing peptide TF14 in solution by 2D-NMR

    Institute of Scientific and Technical Information of China (English)

    吴宏伟; 翟纯; 王德心; 林克椿

    1996-01-01

    Since the discovery of hF-GRP, several analogs have been synthesized in order to see their effects on the gonadotropin releasing activity, either as agonists or antagonists to this peptide. TF14 is one of these analogs, whose 14th position in the primary sequence is Phe instead of Asn in hF-GRP, while its activity is doubled. 2D-NMR (TOCSY, ROESY) was used to determine the conformation of TF14 in solution. Compared with hF-GRP, the whole peptide is in a non-typical more extended conformation, which may give some due to the relation between structure and function of these two peptides.

  13. Prospects of a mathematical theory of human behavior in complex man-machine systems tasks. [time sharing computer analogy of automobile driving

    Science.gov (United States)

    Johannsen, G.; Rouse, W. B.

    1978-01-01

    A hierarchy of human activities is derived by analyzing automobile driving in general terms. A structural description leads to a block diagram and a time-sharing computer analogy. The range of applicability of existing mathematical models is considered with respect to the hierarchy of human activities in actual complex tasks. Other mathematical tools so far not often applied to man machine systems are also discussed. The mathematical descriptions at least briefly considered here include utility, estimation, control, queueing, and fuzzy set theory as well as artificial intelligence techniques. Some thoughts are given as to how these methods might be integrated and how further work might be pursued.

  14. Managing homozygous familial hypercholesterolaemia from cradle to grave.

    Science.gov (United States)

    Thompson, Gilbert R

    2015-05-01

    To describe the phenotypic and genotypic features and management of clinically homozygous familial hypercholesterolaemia (FH). An analysis of current knowledge based on personal experience and published evidence. Atherosclerotic involvement of the aortic root is common in homozygous FH and can cause death before age 5. Receptor negative patients are at greatest risk, irrespective of whether they have identical mutations (homozygous) or dissimilar mutations (compound heterozygous). Lipoprotein apheresis combined with high dose statin and ezetimibe slows but does not arrest progression of atherosclerosis. Adjunctive use of novel compounds such as lomitapide and evolocumab should facilitate achieving the latter objective by enhancing the reduction in LDL cholesterol. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells

    NARCIS (Netherlands)

    Eisenhut, T; Sinha, B; Gröttrup-Wolfers, E; Semmler, J; Siess, W; Endres, S

    1993-01-01

    Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of

  16. Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells

    NARCIS (Netherlands)

    Eisenhut, T; Sinha, B; Gröttrup-Wolfers, E; Semmler, J; Siess, W; Endres, S

    1993-01-01

    Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of inte

  17. Non-pungent long chain capsaicin-analogs arvanil and olvanil display better anti-invasive activity than capsaicin in human small cell lung cancers.

    Science.gov (United States)

    Hurley, John D; Akers, Austin T; Friedman, Jamie R; Nolan, Nicholas A; Brown, Kathleen C; Dasgupta, Piyali

    2017-01-02

    The nutritional compound capsaicin inhibits the invasion of many types of human cancers. The clinical development of capsaicin as an anti-cancer drug is limited due to its unfavorable side effects like burning sensation, stomach cramps, gut pain and nausea. This study compared the anti-invasive activity of capsaicin to non-pungent long chain capsaicin analogs, namely arvanil and olvanil, in human small cell lung cancer cells. Boyden chamber invasion assays revealed that arvanil and olvanil displayed improved anti-invasive activity relative to capsaicin in human SCLC cells. The results of the Boyden chamber assay were confirmed by the spherical invasion assay, and similar results were obtained. The anti-invasive activity of arvanil, olvanil and capsaicin were independent of TRPV and CB1 receptors. Furthermore, the anti-invasive activity of arvanil, olvanil and capsaicin was mediated by the AMPK pathway. Depletion of AMPK levels by siRNA methodology abrogated the anti-invasive activity of arvanil, olvanil and capsaicin. The non-pungent capsaicin analogs arvanil and olvanil display improved anti-invasive activity relative to capsaicin in human SCLC cells. These agents may represent the second generation of capsaicin-like compounds which are more potent than the parent molecule and have a better side effect profile.

  18. Semaglutide, a Once-Weekly Human GLP-1 Analog, Does Not Reduce the Bioavailability of the Combined Oral Contraceptive, Ethinylestradiol/Levonorgestrel

    OpenAIRE

    Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

    2015-01-01

    The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0....

  19. Analogy, explanation, and proof.

    Science.gov (United States)

    Hummel, John E; Licato, John; Bringsjord, Selmer

    2014-01-01

    People are habitual explanation generators. At its most mundane, our propensity to explain allows us to infer that we should not drink milk that smells sour; at the other extreme, it allows us to establish facts (e.g., theorems in mathematical logic) whose truth was not even known prior to the existence of the explanation (proof). What do the cognitive operations underlying the inference that the milk is sour have in common with the proof that, say, the square root of two is irrational? Our ability to generate explanations bears striking similarities to our ability to make analogies. Both reflect a capacity to generate inferences and generalizations that go beyond the featural similarities between a novel problem and familiar problems in terms of which the novel problem may be understood. However, a notable difference between analogy-making and explanation-generation is that the former is a process in which a single source situation is used to reason about a single target, whereas the latter often requires the reasoner to integrate multiple sources of knowledge. This seemingly small difference poses a challenge to the task of marshaling our understanding of analogical reasoning to understanding explanation. We describe a model of explanation, derived from a model of analogy, adapted to permit systematic violations of this one-to-one mapping constraint. Simulation results demonstrate that the resulting model can generate explanations for novel explananda and that, like the explanations generated by human reasoners, these explanations vary in their coherence.

  20. Modulation of human Nav1.7 channel gating by synthetic α-scorpion toxin OD1 and its analogs.

    Science.gov (United States)

    Motin, Leonid; Durek, Thomas; Adams, David J

    2016-01-01

    Nine different voltage-gated sodium channel isoforms are responsible for inducing and propagating action potentials in the mammalian nervous system. The Nav1.7 channel isoform plays an important role in conducting nociceptive signals. Specific mutations of this isoform may impair gating behavior of the channel resulting in several pain syndromes. In addition to channel mutations, similar or opposite changes in gating may be produced by spider and scorpion toxins binding to different parts of the voltage-gated sodium channel. In the present study, we analyzed the effects of the α-scorpion toxin OD1 and 2 synthetic toxin analogs on the gating properties of the Nav1.7 sodium channel. All toxins potently inhibited channel inactivation, however, both toxin analogs showed substantially increased potency by more than one order of magnitude when compared with that of wild-type OD1. The decay phase of the whole-cell Na(+) current was substantially slower in the presence of toxins than in their absence. Single-channel recordings in the presence of the toxins revealed that Na(+) current inactivation slowed due to prolonged flickering of the channel between open and closed states. Our findings support the voltage-sensor trapping model of α-scorpion toxin action, in which the toxin prevents a conformational change in the domain IV voltage sensor that normally leads to fast channel inactivation.

  1. Role of specific cytochrome P450 isoforms in the conversion of phenoxypropoxybiguanide analogs in human liver microsomes to potent antimalarial dihydrotriazines.

    Science.gov (United States)

    Diaz, Damaris S; Kozar, Michael P; Smith, Kirsten S; Asher, Constance O; Sousa, Jason C; Schiehser, Guy A; Jacobus, David P; Milhous, Wilbur K; Skillman, Donald R; Shearer, Todd W

    2008-02-01

    Phenoxypropoxybiguanides, such as PS-15, are antimalarial prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, WR99210, the active metabolite of PS-15, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Recently, in vitro metabolism of a new series of phenoxypropoxybiguanide analogs has examined the production of the active triazine metabolites by human liver microsomes. The purpose of this investigation was to elucidate the primary cytochrome P450 isoforms involved in the production of active metabolites in the current lead candidate. By using expressed human recombinant isoform preparations, specific chemical inhibitors, and isoform-specific inhibitory antibodies, the primary cytochrome P450 isoforms involved in the in vitro metabolic activation of JPC-2056 were elucidated. Unlike proguanil, which is metabolized primarily by CYP2C19, the results indicate that CYP3A4 plays a more important role in the metabolism of both PS-15 and JPC-2056. Whereas CYP2D6 appears to play a major role in the metabolism of PS-15 to WR99210, it appears less important in the conversion of JPC-2056 to JPC-2067. These results are encouraging, considering the prominence of CYP2C19 and CYP2D6 polymorphisms in certain populations at risk for contracting malaria, because the current clinical prodrug candidate from this series may be less dependent on these enzymes for metabolic activation.

  2. Inhibition of TNF-{alpha}-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Young-Rae [Department of Biochemistry, Research Institute for Endocrine Sciences and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Jin, Guo Hua [College of Pharmacy, Sookmyung Women' s University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742 (Korea, Republic of); Lee, Sang-Myeong [Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan, Jeonbuk 570-752 (Korea, Republic of); Park, Jin-Woo [Department of Biochemistry, Research Institute for Endocrine Sciences and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Ryu, Jae-Ha [College of Pharmacy, Sookmyung Women' s University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742 (Korea, Republic of); Jeon, Raok, E-mail: rjeon@sm.ac.kr [College of Pharmacy, Sookmyung Women' s University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742 (Korea, Republic of); Park, Byung-Hyun, E-mail: bhpark@jbnu.ac.kr [Department of Biochemistry, Research Institute for Endocrine Sciences and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756 (Korea, Republic of)

    2011-05-20

    Highlights: {yields} We synthesized SPA0537, a benzothiazole analog. {yields} SPA0537 is a potent NF-{kappa}B inhibitor. {yields} SPA0537 suppresses the production of proinflammatory mediators in human rheumatoid fibroblast-like synoviocytes. {yields} SPA0537 is effective at suppressing osteoclast differentiation. -- Abstract: The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-{kappa}B. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-{kappa}B activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-{kappa}B subunits, which correlated with the inhibitory effects on IKK phosphorylation and I{kappa}B{alpha} degradation in TNF-{alpha}-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-{alpha}-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-{kappa}B ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-{kappa}B pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis.

  3. Human amniotic fluid derived cells can competently substitute dermal fibroblasts in a tissue-engineered dermo-epidermal skin analog

    NARCIS (Netherlands)

    Hartmann-Fritsch, Fabienne; Hosper, Nynke; Luginbuehl, Joachim; Biedermann, Thomas; Reichmann, Ernst; Meuli, Martin

    Human amniotic fluid comprises cells with high differentiation capacity, thus representing a potential cell source for skin tissue engineering. In this experimental study, we investigated the ability of human amniotic fluid derived cells to substitute dermal fibroblasts and support epidermis

  4. Design of a modified mouse protein with ligand binding properties of its human analog by molecular dynamics simulations: the case of C3 inhibition by compstatin.

    Science.gov (United States)

    Tamamis, Phanourios; Pierou, Panayiota; Mytidou, Chrystalla; Floudas, Christodoulos A; Morikis, Dimitrios; Archontis, Georgios

    2011-11-01

    The peptide compstatin and its derivatives inhibit the complement-component protein C3 in primate mammals and are potential therapeutic agents against the unregulated activation of complement in humans, but are inactive against C3 from lower mammals. Recent molecular dynamics (MD) simulations showed that the most potent compstatin analog comprised entirely of natural amino acids (W4A9) had a smaller affinity for rat C3, due to reproducible changes in the rat protein structure with respect to the human protein, which eliminated or weakened specific protein-ligand interactions seen in the human C3:W4A9 complex. Here, we study by MD simulations three W4A9 complexes with the mouse C3 protein, and two "transgenic" mouse derivatives, containing a small number (6-9) of human C3 substitutions. The mouse complex experiences the conformational changes and affinity reduction of the rat complex. In the "transgenic" complexes, the conformation remains closer to that of the human complex, the protein-ligand interactions are improved, and the affinity for compstatin becomes "human-like." The present work creates new avenues for a compstatin-sensitive animal model. A similar strategy, involving the comparison of a series of complexes by MD simulations, could be used to design "transgenic" sequences in other systems.

  5. Analysis of movement kinematics on analogous spatial learning tasks demonstrates conservation of direction and distance estimation across humans (Homo sapiens) and rats (Rattus norvegicus).

    Science.gov (United States)

    Köppen, Jenny R; Winter, Shawn S; Loda, Eileah L; Apger, Brianne P; Grimelli, Danielle; Hamilton, Derek A; Wallace, Douglas G

    2013-05-01

    This series of experiments evaluates the nature of the representation that mediates human (Homo sapiens) and rat (Rattus norvegicus) movement characteristics on analogous spatial learning tasks. The results of Experiment 1 demonstrated that self-movement cues were sufficient to guide the performance of human participants during place training and matching-to-place testing tasks adapted to tabletop or manipulatory scale. Experiment 2 investigated the effect of manipulating access to environmental cues during place training on the nature of the representation used to guide performance. Blindfolded human participants appeared to encode the absolute location of the goal, whereas participants with access to environmental cues appeared to encode the relative location of the goal. The results of Experiment 3 demonstrated that human participants with access to environmental cues exhibited a similar response tendency (as observed in Experiment 2) after half as many trials of place training. During Experiment 4, rats exhibited movement characteristics in the water maze that were similar to movement characteristics observed in human participants who were provided access to environmental cues. These observations provide evidence that direction and distance estimation processes mediate performance on spatial tasks that are conserved across humans and rats.

  6. Homozygous SLC2A9 mutations cause severe renal hypouricemia.

    Science.gov (United States)

    Dinour, Dganit; Gray, Nicola K; Campbell, Susan; Shu, Xinhua; Sawyer, Lindsay; Richardson, William; Rechavi, Gideon; Amariglio, Ninette; Ganon, Liat; Sela, Ben-Ami; Bahat, Hilla; Goldman, Michael; Weissgarten, Joshua; Millar, Michael R; Wright, Alan F; Holtzman, Eliezer J

    2010-01-01

    Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 +/- 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.

  7. Differential half-maximal effects of human insulin and its analogs for in situ glucose transport and protein synthesis in rat soleus muscle

    Science.gov (United States)

    Weinstein, Randi B.; Eleid, Noura; LeCesne, Catherine; Durando, Bianca; Crawford, Julie T.; Heffner, Michelle; Layton, Christle; O'Keefe, Matthew; Robinson, Jennifer; Rudinsky, Suzy; Henriksen, Erik J.; Tischler, Marc E.

    2002-01-01

    Analogs of human insulin have been used to discriminate between responses of metabolic and mitogenic (growth-related) pathways. This study compared the stimulatory effects of human insulin (HI) and 2 analogs (X2, B-Asp(9), B-Glu(27) and H2, A-His(8),B-His(4),B-Glu(10), B-His(27)) on glucose uptake and protein synthesis in rat soleus muscle in situ. Glucose uptake, estimated by intramuscular (IM) injection of 2-deoxy[1,2-3H]glucose with or without insulin, was maximally increased at 10(-6) mol/L for HI and X2 and 10(-7) mol/L for H2. HI had a larger effect (318%) than either X2 (156%) or H2 (124%). The half-maximal effect (ED(50)) values for HI, X2, and H2 were 3.3 x10(-8) mol/L, 1.7 x 10(-7) mol/L, and 1.6 x 10(-9) mol/L, respectively. Protein synthesis, estimated by protein incorporation of [(3)H]phenylalanine injected into muscles with or without insulin, was maximally increased at 10(-5) mol/L for HI and 10(-6) for X2 and H2. HI had a larger effect in stimulating protein synthesis (34%) than either X2 (25%) or H2 (19.8%). The ED(50) values for HI, X2, and H2 were 3.0 x 10(-7) mol/L, 3.2 x 10(-7) mol/L, and 1.0 x 10(-9) mol/L, respectively. The biological potency of each analog (ED(50)insulin/ED(50)analog) showed X2 to be less potent than HI for both glucose uptake (0.2) and protein synthesis (0.9), whereas H2 is more potent than HI with ratios of 20 and 300, respectively. These data suggest that this approach for studying insulin responsiveness in a single muscle in situ may be a useful tool for investigating insulin signaling in muscle in vivo. Copyright 2002, Elsevier Science (USA). All rights reserved.

  8. An update on the treatment of type 1 and type 2 diabetes mellitus: focus on insulin detemir, a long-acting human insulin analog

    Directory of Open Access Journals (Sweden)

    Katarina Raslova

    2010-05-01

    Full Text Available Katarina RaslovaMetabolic Center Ltd and Slovak Medical University, Bratislava, Slovak RepublicAbstract: Basal insulin analogs are used to minimize unpredictable processes of NPH insulin. Modification of the human insulin molecule results in a slower distribution to peripheral target tissues, a longer duration of action with stable concentrations and thus a lower rate of hypoglycemia. Insulin detemir is a basal insulin analog that provides effective therapeutic options for patients with type 1 and type 2 diabetes. For glycemic control, no significant differences were found in HbA1c levels compared with NPH and insulin glargine. It is comparable with insulin glargine in significantly reducing rates of all types of hypoglycemia. Clinical studies have demonstrated that detemir is responsible for significantly lower within-subject variability and no or less weight gain than NPH insulin and glargine. Recent pharmacodynamic studies have shown that detemir can be used once daily in many patients with diabetes. Together with patient-friendly injection devices and dose adjustments, it provides a treatment option with the potential to lower the key barriers of adherence to insulin therapy in type 2 diabetes. Recent guidelines for treatment of type 2 diabetes suggest starting intensive therapy of hyperglycemia at an early stage of diabetes and recommend therapeutic options that provide the possibility of reaching HbA1c goals individually, with a low risk of hypoglycemia or other adverse effects of treatment. The properties of insulin detemir match these requirements.Keywords: insulin analog, insulin detemir, diabetes mellitus, hypoglycemia, within-subject variability

  9. Human amniotic fluid derived cells can competently substitute dermal fibroblasts in a tissue-engineered dermo-epidermal skin analog

    OpenAIRE

    2013-01-01

    PURPOSE: Human amniotic fluid comprises cells with high differentiation capacity, thus representing a potential cell source for skin tissue engineering. In this experimental study, we investigated the ability of human amniotic fluid derived cells to substitute dermal fibroblasts and support epidermis formation and stratification in a humanized animal model. METHODS: Dermo-epidermal skin grafts with either amniocytes or with fibroblasts in the dermis were compared in a rat model. Full-thicknes...

  10. The Integrated Impact of Diet On Human Immune Response, the Gut Microbiota, and Nutritional Status During Adaptation to a Spaceflight Analog

    Science.gov (United States)

    Douglas, G. L.; Zwart, S. R.; Young, M.; Kloeris, V.; Crucian, B.; Smith, S. M.; Lorenzi, H.

    2017-01-01

    Spaceflight impacts human physiology, including well documented immune system dysregulation. Diet, immune function, and the microbiome are interlinked, but diet is the only one of these factors that we have the ability to easily, and significantly, alter on Earth or during flight. As we understand dietary impacts on physiology more thoroughly, we may then improve the spaceflight diet to improve crew health and potentially reduce flight-associated physiological alterations. It is expected that increasing the consumption of fruits and vegetables and bioactive compounds (e.g.,omega-3 fatty acids, lycopene, flavonoids) and therefore enhancing overall nutritional intake from the nominal shelf-stable, fully-processed space food system could serve as a countermeasure to improve human immunological profiles, the taxonomic profile of the gut microbiota, and nutritional status, especially where currently dysregulated during spaceflight. This interdisciplinary study will determine the effect of the current shelf-stable spaceflight diet compared to an "enhanced" shelf-stable spaceflight diet (25% more foods rich in omega-3 fatty acids, lycopene, flavonoids, fruits, and vegetables). The NASA Human Exploration Research Analog (HERA) 2017 missions, consisting of closed chamber confinement, realistic mission simulation, in a high-fidelity mock space vehicle, will serve as a platform to replicate mission stressors and the dysregulated physiology observed in astronauts. Biosampling of crew members will occur at selected intervals, with complete dietary tracking. Outcome measures will include immune markers (e.g., peripheral leukocyte distribution, inflammatory cytokine profiles, T cell function), the taxonomic and metatranscriptomic profile of the gut microbiome, and nutritional status biomarkers and metabolites. Data collection will also include complete dietary tracking. Statistical evaluations will determine physiological and biochemical shifts in relation to nutrient in take and

  11. Human amniotic fluid derived cells can competently substitute dermal fibroblasts in a tissue-engineered dermo-epidermal skin analog

    NARCIS (Netherlands)

    Hartmann-Fritsch, Fabienne; Hosper, Nynke; Luginbuehl, Joachim; Biedermann, Thomas; Reichmann, Ernst; Meuli, Martin

    2013-01-01

    Human amniotic fluid comprises cells with high differentiation capacity, thus representing a potential cell source for skin tissue engineering. In this experimental study, we investigated the ability of human amniotic fluid derived cells to substitute dermal fibroblasts and support epidermis formati

  12. MC37, a new mono-carbonyl curcumin analog, induces G2/M cell cycle arrest and mitochondria-mediated apoptosis in human colorectal cancer cells.

    Science.gov (United States)

    Liang, Baoxia; Liu, Ziyi; Cao, Yingnan; Zhu, Cuige; Zuo, Yinglin; Huang, Lei; Wen, Gesi; Shang, Nana; Chen, Yu; Yue, Xin; Du, Jun; Li, Baojian; Zhou, Binhua; Bu, Xianzhang

    2017-02-05

    (E)-1-(3'-fluoro-[1,1'-biphenyl-3-yl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one) (MC37), a novel mono-carbonyl curcumin analog, was previously synthesized in our laboratory as a nuclear factor kappa B (NF-κB) inhibitor with excellent cytotoxicity against several cancer cell lines. In this study, our further investigations showed that the potent growth inhibitory activity of MC37 in human colorectal cancer cells was associated with the arrest of cell cycle progression and the induction of apoptosis. As a multi-targeted agent, MC37 inhibited the intracellular microtubule assembly, altered the expression of cyclin-dependent kinase 1 (CDK1), and ultimately induced G2/M cell cycle arrest. Moreover, MC37 collapsed the mitochondrial membrane potential (MMP), increased the Bax/Bcl-2 ratio, activated the caspase-9/3 cascade, and finally led to cancer cells apoptosis, suggesting that the mitochondrial-mediated apoptotic pathway was involved in MC37-induced apoptosis. In conclusion, these observations demonstrated that mono-carbonyl curcumin analogs would serve as multi-targeted lead for promising anti-colorectal cancer agent development. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Analogy, Explanation, and Proof

    Directory of Open Access Journals (Sweden)

    John eHummel

    2014-11-01

    Full Text Available People are habitual explanation generators. At its most mundane, our propensity to explain allows us to infer that we should not drink milk that smells sour; at the other extreme, it allows us to establish facts (e.g., theorems in mathematical logic whose truth was not even known prior to the existence of the explanation (proof. What do the cognitive operations underlying the (inductive inference that the milk is sour have in common with the (deductive proof that, say, the square root of two is irrational? Our ability to generate explanations bears striking similarities to our ability to make analogies. Both reflect a capacity to generate inferences and generalizations that go beyond the featural similarities between a novel problem and familiar problems in terms of which the novel problem may be understood. However, a notable difference between analogy-making and explanation-generation is that the former is a process in which a single source situation is used to reason about a single target, whereas the latter often requires the reasoner to integrate multiple sources of knowledge. This small-seeming difference poses a challenge to the task of marshaling our understanding of analogical reasoning in the service of understanding explanation. We describe a model of explanation, derived from a model of analogy, adapted to permit systematic violations of this one-to-one mapping constraint. Simulation results demonstrate that the resulting model can generate explanations for novel explananda and that, like the explanations generated by human reasoners, these explanations vary in their coherence.

  14. Α-galactosylceramide analogs with weak agonist activity for human iNKT cells define new candidate anti-inflammatory agents.

    Science.gov (United States)

    Bricard, Gabriel; Venkataswamy, Manjunatha M; Yu, Karl O A; Im, Jin S; Ndonye, Rachel M; Howell, Amy R; Veerapen, Natacha; Illarionov, Petr A; Besra, Gurdyal S; Li, Qian; Chang, Young-Tae; Porcelli, Steven A

    2010-12-17

    CD1d-restricted natural killer T cells with invariant T cell receptor α chains (iNKT cells) are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of α-galactosylceramide (αGalCer), the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-γ (IFNγ), and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-γ secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans.

  15. Α-galactosylceramide analogs with weak agonist activity for human iNKT cells define new candidate anti-inflammatory agents.

    Directory of Open Access Journals (Sweden)

    Gabriel Bricard

    Full Text Available CD1d-restricted natural killer T cells with invariant T cell receptor α chains (iNKT cells are a unique lymphocyte subset that responds to recognition of specific lipid and glycolipid antigens. They are conserved between mice and humans and exert various immunoregulatory functions through their rapid secretion of a variety of cytokines and secondary activation of dendritic cells, B cells and NK cells. In the current study, we analyzed the range of functional activation states of human iNKT cells using a library of novel analogs of α-galactosylceramide (αGalCer, the prototypical iNKT cell antigen. Measurement of cytokines secreted by human iNKT cell clones over a wide range of glycolipid concentrations revealed that iNKT cell ligands could be classified into functional groups, correlating with weak versus strong agonistic activity. The findings established a hierarchy for induction of different cytokines, with thresholds for secretion being consistently lowest for IL-13, higher for interferon-γ (IFNγ, and even higher for IL-4. These findings suggested that human iNKT cells can be intrinsically polarized to selective production of IL-13 by maintaining a low level of activation using weak agonists, whereas selective polarization to IL-4 production cannot be achieved through modulating the strength of the activating ligand. In addition, using a newly designed in vitro system to assess the ability of human iNKT cells to transactivate NK cells, we found that robust secondary induction of interferon-γ secretion by NK cells was associated with strong but not weak agonist ligands of iNKT cells. These results indicate that polarization of human iNKT cell responses to Th2-like or anti-inflammatory effects may best be achieved through selective induction of IL-13 and suggest potential discrepancies with findings from mouse models that may be important in designing iNKT cell-based therapies in humans.

  16. Analogical Inference and Analogical Access.

    Science.gov (United States)

    1987-08-04

    Arbor, M[ 48109 Dr. Sherrie Got% AFHRLIMODJ Dr. Wayne Harvey Ms. Julia S. HoughBrooks AFB, TX 78235 SRI International Lawrence Erlbaum Associates -13...Department of Psychology Catholic University of Evanston, U. 60201 AmericaDr. Wayne Cray Washington. DC 20064 Army Research Institute 5001 Eisenhower Avenue...ScienceDr. Lynne Roer Dr. David Rumelhart Towson State UniversityDepartment of Psychology Center for Human Towson , NoD 21204Carnegie-Mellon University

  17. 15q13.3 homozygous knockout mouse model display epilepsy-, autism- and schizophrenia-related phenotypes

    DEFF Research Database (Denmark)

    Forsingdal, A; Fejgin, K; Nielsen, V;

    2016-01-01

    The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder...... and schizophrenia, though the clinical profile varies considerably. Two mouse models of this syndrome, with hemizygous deletion of the orthologous region in the murine genome, have recently been shown to recapitulate a number of the behavioral and physiological deficits that characterize the human condition. Still......, little is known of the underlying biological mechanisms. Eleven human cases with homozygous deletion of the 15q13.3 region have been reported, all with severe functional and physiological impairments. We therefore hypothesized that a 15q13.3 homozygous knockout would confer more pronounced behavioral...

  18. Long-acting insulin analog detemir displays reduced effects on adipocyte differentiation of human subcutaneous and visceral adipose stem cells.

    Science.gov (United States)

    Cignarelli, A; Perrini, S; Nigro, P; Ficarella, R; Barbaro, M; Peschechera, A; Porro, S; Natalicchio, A; Laviola, L; Puglisi, F; Giorgino, F

    2016-04-01

    Since treatment with insulin detemir results in a lower weight gain compared to human insulin, we investigated whether detemir is associated with lower ability to promote adipogenesis and/or lipogenesis in human adipose stem cells (ASC). Human ASC isolated from both the subcutaneous and visceral adipose tissues were differentiated for 30 days in the presence of human insulin or insulin detemir. Nile Red and Oil-Red-O staining were used to quantify the rate of ASC conversion to adipocytes and lipid accumulation, respectively. mRNA expression levels of early genes, including Fos and Cebpb, as well as of lipogenic and adipogenic genes, were measured at various phases of differentiation by qRT-PCR. Activation of insulin signaling was assessed by immunoblotting. ASC isolated from subcutaneous and visceral adipose tissue were less differentiated when exposed to insulin detemir compared to human insulin, showing lower rates of adipocyte conversion, reduced triglyceride accumulation, and impaired expression of late-phase adipocyte marker genes, such as Pparg2, Slc2a4, Adipoq, and Cidec. However, no differences in activation of insulin receptor, Akt and Erk and induction of the early genes Fos and Cebpb were observed between insulin detemir and human insulin. Insulin detemir displays reduced induction of the Pparg2 adipocyte master gene and diminished effects on adipocyte differentiation and lipogenesis in human subcutaneous and visceral ASC, in spite of normal activation of proximal insulin signaling reactions. These characteristics of insulin detemir may be of potential relevance to its weight-sparing effects observed in the clinical setting. Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  19. The antiarrhythmic peptide analog rotigaptide (ZP123) stimulates gap junction intercellular communication in human osteoblasts and prevents decrease in femoral trabecular bone strength in ovariectomized rats

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye; Teilmann, Stefan Cuoni; Henriksen, Zanne

    2005-01-01

    and strength in vivo. Cell coupling and calcium signaling were assessed in vitro on human, primary, osteoblastic cells. In vivo effects of rotigaptide on bone strength and density were determined 4 wk after ovariectomy in rats treated with either vehicle, sc injection twice daily (300 nmol per kilogram body......Gap junctions play an important role in bone development and function, but the lack of pharmacological tools has hampered the gap junction research. The antiarrhythmic peptides stimulate gap junction communication between cardiomyocytes, but effects in noncardiac tissue are unknown. The purpose...... of this study was to examine whether antiarrhythmic peptides, which are small peptides increasing gap junctional conductivity, show specific binding to osteoblasts and investigate the effect of the stable analog rotigaptide (ZP123) on gap junctional intercellular communication in vitro and on bone mass...

  20. Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation

    Directory of Open Access Journals (Sweden)

    B. Jaeger

    2016-03-01

    Full Text Available We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C>T; p.(Arg161Cys. Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency. With pyridoxine monotherapy the patient is seizure free and neurodevelopmental outcome at the age of 14 months is normal.

  1. Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation☆

    Science.gov (United States)

    Jaeger, B.; Abeling, N.G.; Salomons, G.S.; Struys, E.A.; Simas-Mendes, M.; Geukers, V.G.; Poll-The, B.T.

    2016-01-01

    We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C > T; p.(Arg161Cys)). Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency. With pyridoxine monotherapy the patient is seizure free and neurodevelopmental outcome at the age of 14 months is normal. PMID:27014579

  2. Generation of iPSC line MU011.A-hiPS from homozygous α-thalassemia fetal skin fibroblasts

    Directory of Open Access Journals (Sweden)

    Amornrat Tangprasittipap

    2015-11-01

    Full Text Available Human iPSC line MU011.A-hiPS was generated from homozygous α-thalassemia (−SEA/−SEA fetal skin fibroblasts using a non-integrative reprogramming method. Reprogramming factors OCT3/4, SOX2, KLF4, L-MYC, LIN28, and shRNA of TP53 contained in three episomal vectors were delivered using electroporation.

  3. The rapid immunosuppression in phytohemagglutinin-activated human T cells is inhibited by the proliferative Ca(2+) influx induced by progesterone and analogs.

    Science.gov (United States)

    Lin, Veronica Hui-Chen; Chen, Jiann-Jong; Liao, Chen-Chung; Lee, Shinn-Shing; Chien, Eileen Jea

    2016-07-01

    Progesterone, an endogenous immunomodulator, suppresses human T-cell activation during pregnancy. A sustained Ca(2 +) influx is an important signal for T-cell proliferation after crosslinking of T-cell receptor/CD3 complexes by anti-CD3 antibodies or phytohemagglutinin (PHA). Progesterone targets cell membrane sites inducing rapid responses including elevated intracellular free calcium concentration ([Ca(2+)]i) and suppressed T-cell PHA-activated proliferation. Interestingly, both PHA and progesterone induce [Ca(2+)]i elevation, but it remains unclear whether the PHA-induced Ca(2+) influx is affected by progesterone leading to T-cell immunosuppression. Primary T-cells were isolated from human peripheral blood and the quench effect on intracellular fura-2 fluorescence of Mn(2+) was used to explore the responses to Ca(2+) influx with cell proliferation being determined by MTT assay. PHA-stimulated Ca(2+) influx was dose-dependently suppressed by progesterone and its agonist R5020, which correlated with PHA-activated T-cell proliferation inhibition. A similar dose-dependent suppression effect on cellular Ca(2+) influx and proliferation occurred with the TRPC channel inhibitor BTP2 and selective TRPC3 channel inhibitor Pyr3. In addition, two progesterone analogs, Org OD 02-0 and 20α-hydroxyprogesterone (20α-OHP), also produced dose-dependent suppression of Ca(2+) influx, but had no effect on proliferation. Finally, inhibition of PHA-activated T-cell proliferation by progesterone is further suppressed by 20α-OHP, but not by Org OD 02-0. Overall, progesterone and R5020 are able to rapidly decrease PHA-stimulated sustained Ca(2+) influx, probably via blockade of TRPC3 channels, which suppresses T-cell proliferation. Taken together, the roles of progesterone and its analogs regarding the rapid response Ca(2+) influx need to be further explored in relation to cytokine secretion and proliferation in activated T-cells.

  4. Analog and VLSI circuits

    CERN Document Server

    Chen, Wai-Kai

    2009-01-01

    Featuring hundreds of illustrations and references, this book provides the information on analog and VLSI circuits. It focuses on analog integrated circuits, presenting the knowledge on monolithic device models, analog circuit cells, high performance analog circuits, RF communication circuits, and PLL circuits.

  5. When Gesture Becomes Analogy.

    Science.gov (United States)

    Cooperrider, Kensy; Goldin-Meadow, Susan

    2017-07-01

    Analogy researchers do not often examine gesture, and gesture researchers do not often borrow ideas from the study of analogy. One borrowable idea from the world of analogy is the importance of distinguishing between attributes and relations. Gentner (, ) observed that some metaphors highlight attributes and others highlight relations, and called the latter analogies. Mirroring this logic, we observe that some metaphoric gestures represent attributes and others represent relations, and propose to call the latter analogical gestures. We provide examples of such analogical gestures and show how they relate to the categories of iconic and metaphoric gestures described previously. Analogical gestures represent different types of relations and different degrees of relational complexity, and sometimes cohere into larger analogical models. Treating analogical gestures as a distinct phenomenon prompts new questions and predictions, and illustrates one way that the study of gesture and the study of analogy can be mutually informative. Copyright © 2017 Cognitive Science Society, Inc.

  6. A REVIEW OF HUMAN-SYSTEM INTERFACE DESIGN ISSUES OBSERVED DURING ANALOG-TO-DIGITAL AND DIGITAL-TO-DIGITAL MIGRATIONS IN U.S. NUCLEAR POWER PLANTS

    Energy Technology Data Exchange (ETDEWEB)

    Kovesdi, C.; Joe, J.

    2017-05-01

    The United States (U.S.) Department of Energy (DOE) Light Water Reactor Sustainability (LWRS) program is developing a scientific basis through targeted research and development (R&D) to support the U.S. nuclear power plant (NPP) fleet in extending their existing licensing period and ensuring their long-term reliability, productivity, safety, and security. Over the last several years, human factors engineering (HFE) professionals at the Idaho National Laboratory (INL) have supported the LWRS Advanced Instrumentation, Information, and Control (II&C) System Technologies pathway across several U.S. commercial NPPs in analog-to-digital migrations (i.e., turbine control systems) and digital-to-digital migrations (i.e., Safety Parameter Display System). These efforts have included in-depth human factors evaluation of proposed human-system interface (HSI) design concepts against established U.S. Nuclear Regulatory Commission (NRC) design guidelines from NUREG-0700, Rev 2 to inform subsequent HSI design prior to transitioning into Verification and Validation. This paper discusses some of the overarching design issues observed from these past HFE evaluations. In addition, this work presents some observed challenges such as common tradeoffs utilities are likely to face when introducing new HSI technologies into NPP hybrid control rooms. The primary purpose of this work is to distill these observed design issues into general HSI design guidance that industry can use in early stages of HSI design.

  7. Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents.

    Science.gov (United States)

    Khan, Tapan K; Wender, Paul A; Alkon, Daniel L

    2017-06-07

    Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin-1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin-1 protected the structural integrity of HSEs. Bryostatin-1 and picolog prolonged activation of Erk in fibroblasts to promote cell survival. Chronic stress promotes the progression of apoptosis. Dermal fibroblasts constitutively express all components of Fas associated apoptosis, including caspase-8, an initiator enzyme of apoptosis. Prolong bryostatin-1 treatment reduced apoptosis by decreasing caspase-8 and protected dermal fibroblasts. Our data suggest that bryostatin-1 and picolog could be useful in anti-aging skincare, and could have applications in tissue engineering and regenerative medicine. © 2017 Wiley Periodicals, Inc.

  8. Vincristine-induced central neurotoxicity in a collie homozygous for the ABCB1Δ mutation.

    Science.gov (United States)

    Krugman, L; Bryan, J N; Mealey, K L; Chen, A

    2012-03-01

    A six-year-old, neutered, female collie was presented to an oncology specialty service after developing tetraparesis and self-mutilation that progressively worsened while receiving chemotherapy for lymphoma. Neurologic examination revealed ataxia, paresis and diminished conscious proprioception in all limbs with entire spinal reflexes. Magnetic resonance imaging of the brain and spinal cord was normal. Electromyography of the limbs ruled out a vincristine-induced peripheral neuropathy. Cerebrospinal fluid analysis and cerebrospinal fluid and serum testing for Neospora and Toxoplasma were normal. Results of MDR1 genotyping revealed that the dog was homozygous for the ABCB1-1Δ (MDR1) mutation. This clinical presentation strongly resembled the effects seen from inadvertent intrathecal administration of vincristine in humans. Dogs that are homozygous for the ABCB1-1Δ (MDR1) mutation should not receive standard dosages of chemotherapy drugs known to be eliminated by P-glycoprotein, the gene product of ABCB1. Testing for this mutation is strongly recommended before chemotherapy initiation for at-risk breeds.

  9. Successful Treatment Of Homozygous Familial Hypercholesterolemia Using Cascade Filtration Plasmapheresis

    Directory of Open Access Journals (Sweden)

    Fatih Kardas

    2012-12-01

    Full Text Available OBJECTIVE: The aim of our study is to discuss the efficacy of low-density lipoprotein-cholesterol (LDL-C apheresis procedure using the cascade filtration system for pediatric patients with homozygous familial hypercholesterolemia (FH, and to clarify the adverse effects and difficulties. METHODS: LDL apheresis using the cascade filtration system was performed in 3 pediatric patients with homozygous FH. In total, 120 apheresis sessions were performed for all patients. RESULTS: Cascade filtration therapy significantly reduced the mean LDL-C values from 418 ± 62 mg/dl to 145 ± 43 mg/dl (p<0.05. We determined an acute mean reduction in the plasma levels of total cholesterol (57.9%, LDL cholesterol (70.8%, and high-density lipoprotein (HDL cholesterol (40.7%. Treatments were well tolerated. The most frequent clinical adverse effects were hypotension in 3 sessions (2.5%, chills/feeling cold (1.7% in 2 sessions, and nausea and vomiting in 3 sessions (2.5%. CONCLUSION: Our experience with three patients using the cascade filtration system were, good clinical outcomes, laboratory findings, safety of usage, minor adverse effects and technical problems.

  10. Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells.

    Science.gov (United States)

    Zhu, Qingsong; Huang, Yi; Marton, Laurence J; Woster, Patrick M; Davidson, Nancy E; Casero, Robert A

    2012-02-01

    Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 and me2). Additionally, LSD1 is highly expressed in estrogen receptor α negative (ER-) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analog inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231 to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of 12 up-regulated genes by 2d and 14 up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogs is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9act, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential.

  11. Extravehicular Activity Testing in Analog Environments: Evaluating the Effects of Center of Gravity and Environment on Human Performance

    Science.gov (United States)

    Chappell, Steve P.; Gernhardt, Michael L.

    2009-01-01

    Center of gravity (CG) is likely to be an important variable in astronaut performance during partial gravity extravehicular activity (EVA). The Apollo Lunar EVA experience revealed challenges with suit stability and control. The EVA Physiology, Systems and Performance Project (EPSP) in conjunction with the Constellation EVA Systems Project Office have developed plans to systematically understand the role of suit weight, CG and suit pressure on astronaut performance in partial gravity environments. This presentation based upon CG studies seeks to understand the impact of varied CG on human performance in lunar gravity.

  12. The Integrated Impact of Diet on Human Immune Response, the Gut Microbiota, and Nutritional Status During Adaptation to a Spaceflight Analog

    Science.gov (United States)

    Douglas, G. L.; Zwart, S. R.; Young, M.; Kloeris, V.; Crucian, B.; Smith, S. M.; Lorenzi, H.

    2018-01-01

    Spaceflight impacts human physiology, including well documented immune system dysregulation. Diet, immune function, and the microbiome are interlinked, but diet is the only one of these factors that we have the ability to easily, and significantly, alter on Earth or during flight. As we understand dietary impacts on physiology more thoroughly, we may then improve the spaceflight diet to improve crew health and potentially reduce spaceflight-associated physiological alterations. It is expected that increasing the consumption of fruits and vegetables and bioactive compounds (e.g., omega-3 fatty acids, lycopene, flavonoids) and therefore enhancing overall nutritional intake from the nominal shelf-stable, fully-processed space food system could serve as a countermeasure to improve human immunological profiles, the taxonomic profile of the gut microbiota, and nutritional status, especially where currently dysregulated during spaceflight. This interdisciplinary study will determine the effect of the current shelf-stable spaceflight diet compared to an "enhanced" shelf-stable spaceflight diet (25% more foods rich in omega-3 fatty acids, lycopene, flavonoids, and more fruits, and vegetables in general). The NASA Human Exploration Research Analog (HERA) 2017 missions, consisting of four 45-day missions with closed chamber confinement and realistic mission simulation in a high-fidelity mock space vehicle, will serve as a platform to replicate mission stressors and the effects on crew biochemistry, immunology, and the gut microbiome. Bio sampling of crewmembers is scheduled for selected intervals pre- and in-mission. Data collection also includes dietary intake recording. Outcome measures will include immune markers (e.g., peripheral leukocyte distribution, inflammatory cytokine profiles, T cell function), the taxonomic and metatranscriptomic profile of the gut microbiome, and nutritional status biomarkers and metabolites. Statistical evaluations will determine physiological

  13. Learning by Analogy: Discriminating between Potential Analogs

    Science.gov (United States)

    Richland, Lindsey E.; McDonough, Ian M.

    2010-01-01

    The ability to successfully discriminate between multiple potentially relevant source analogs when solving new problems is crucial to proficiency in a mathematics domain. Experimental findings in two different mathematical contexts demonstrate that providing cues to support comparative reasoning during an initial instructional analogy, relative to…

  14. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    Energy Technology Data Exchange (ETDEWEB)

    Perl, S; Kushner, J A; Buchholz, B A; Meeker, A K; Stein, G M; Hsieh, M; Kirby, M; Pechhold, S; Liu, E H; Harlan, D M; Tisdale, J F

    2010-03-15

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ({sup 14}C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). {sup 14}C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA {sup 14}C content relative to a well-established {sup 14}C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA {sup 14}C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  15. The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates.

    Science.gov (United States)

    Gotfredsen, Carsten F; Mølck, Anne-Marie; Thorup, Inger; Nyborg, Niels C Berg; Salanti, Zaki; Knudsen, Lotte Bjerre; Larsen, Marianne O

    2014-07-01

    Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks' duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks' dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.

  16. Hominin geographical range dynamics and relative brain size: Do non-human primates provide a good analogy?

    Science.gov (United States)

    MacDonald, Katharine; Smaers, Jeroen B; Steele, James

    2015-10-01

    We use climatic and satellite remote sensing data to characterize environmental seasonality in the geographical ranges of extant non-human primates in order to assess the effect of relative brain size on tolerance of more seasonal habitats. Demonstration of such an effect in living non-human primates could provide a comparative framework for modeling hominin dispersals and geographical range dynamics in the Pliocene and Pleistocene. Our analyses found no such effect: there are neither positive nor negative correlations between relative brain size and either geographical range size or the average and range of values for environmental seasonality, whether analysed at the level of all primates, or within parvorders (strepsirrhine, catarrhine, platyrrhine). Independent analyses by other researchers comparing feeding behaviour and ecology at individual primate study sites demonstrate that in seasonal environments, the year-round metabolic costs of maintaining a relatively large brain are met by adaptive behavioural/dietary strategies. However, consistent with our own results, those comparative studies found that there was no overall association, whether positive or negative, between 'raw' environmental seasonality and primate relative brain size. We must therefore look elsewhere for a comparative model of hominin geographical range dynamics in the Pleistocene.

  17. Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts.

    Science.gov (United States)

    Nanke, Yuki; Kobashigawa, Tsuyoshi; Yago, Toru; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

    2016-01-01

    Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis.

  18. Rebamipide, an Amino Acid Analog of 2(1H-Quinolinone, Inhibits the Formation of Human Osteoclasts

    Directory of Open Access Journals (Sweden)

    Yuki Nanke

    2016-01-01

    Full Text Available Objectives. Drug repositioning or drug reprofiling (DR has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors. Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM, was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP. Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis.

  19. Mapping of homozygous deletions in verified esophageal adenocarcinoma cell lines and xenografts.

    Science.gov (United States)

    Boonstra, Jurjen J; van Marion, Ronald; Douben, Hannie J C W; Lanchbury, Jerry S; Timms, Kirsten M; Abkevich, Victor; Tilanus, Hugo W; de Klein, Annelies; Dinjens, Winand N M

    2012-03-01

    Human esophageal adenocarcinoma (EAC) cell lines and xenografts are powerful tools in the search for genetic alterations because these models are composed of pure human cancer cell populations without admixture of normal human cells. In particular detection of homozygous deletions (HDs) is easier using these pure populations of cancer cells. Identification of HDs could potentially lead to the subsequent identification of new tumor suppressor genes (TSGs) involved in esophageal adenocarcinogenesis. Genome wide single nucleotide polymorphism (SNP) arrays were used to identify HDs in 10 verified EAC cell lines and nine EAC xenografts. In total, 61 HDs (range 1-6 per sample) were detected and confirmed by polymerase chain reaction. Besides HDs observed in common fragile genomic regions (n = 26), and gene deserts (n = 8), 27 HDs were located in gene-containing regions. HDs were noted for known TSGs, including CDKN2A, SMAD4 and CDH3/CDH1. Twenty-two new chromosomal regions were detected harboring potentially new TSGs involved in EAC carcinogenesis. Two of these regions of homozygous loss, encompassing the ITGAV and RUNX1 gene, were detected in multiple samples indicating a potential role in the carcinogenesis of EAC. To exclude culturing artifacts, these last two deletions were confirmed by fluorescent in situ hybridization in the primary tumors of which the involved cell lines and xenografts were derived. In summary, in this report we describe the identification of HDs in a series of verified EAC cell lines and xenografts. The deletions documented here are a step forward identifying the key genes involved in EAC development.

  20. Geometrical Analogies in Mathematics Lessons

    Science.gov (United States)

    Eid, Wolfram

    2007-01-01

    A typical form of thinking to approach problem solutions humanly is thinking in analogous structures. Therefore school, especially mathematical lessons should help to form and to develop corresponding heuristic abilities of the pupils. In the contribution, a summary of possibilities of mathematics lessons regarding this shall particularly be…

  1. Paper Analogies Enhance Biology Teaching.

    Science.gov (United States)

    Stencel, John E.

    1997-01-01

    Describes how to use paper analogies as models to illustrate various concepts in biology, human anatomy, and physiology classes. Models include biochemical paper models, protein papergrams, a paper model of early brain development, and a 3-D paper model of a eukaryotic cell. (AIM)

  2. Intuitive analog circuit design

    CERN Document Server

    Thompson, Marc

    2013-01-01

    Intuitive Analog Circuit Design outlines ways of thinking about analog circuits and systems that let you develop a feel for what a good, working analog circuit design should be. This book reflects author Marc Thompson's 30 years of experience designing analog and power electronics circuits and teaching graduate-level analog circuit design, and is the ideal reference for anyone who needs a straightforward introduction to the subject. In this book, Dr. Thompson describes intuitive and ""back-of-the-envelope"" techniques for designing and analyzing analog circuits, including transistor amplifi

  3. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.

    Science.gov (United States)

    Chamberlain, Philip P; Lopez-Girona, Antonia; Miller, Karen; Carmel, Gilles; Pagarigan, Barbra; Chie-Leon, Barbara; Rychak, Emily; Corral, Laura G; Ren, Yan J; Wang, Maria; Riley, Mariko; Delker, Silvia L; Ito, Takumi; Ando, Hideki; Mori, Tomoyuki; Hirano, Yoshinori; Handa, Hiroshi; Hakoshima, Toshio; Daniel, Thomas O; Cathers, Brian E

    2014-09-01

    The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.

  4. Modulated regeneration of acid-etched human tooth enamel by a functionalized dendrimer that is an analog of amelogenin.

    Science.gov (United States)

    Chen, Mei; Yang, Jiaojiao; Li, Jiyao; Liang, Kunneng; He, Libang; Lin, Zaifu; Chen, Xingyu; Ren, Xiaokang; Li, Jianshu

    2014-10-01

    In the bioinspired repair process of tooth enamel, it is important to simultaneously mimic the organic-matrix-induced biomineralization and increase the binding strength at the remineralization interface. In this work, a fourth-generation polyamidoamine dendrimer (PAMAM) is modified by dimethyl phosphate to obtain phosphate-terminated dendrimer (PAMAM-PO3H2) since it has a similar dimensional scale and peripheral functionalities to that of amelogenin, which plays important role in the natural development process of enamel. Its phosphate group has stronger affinity for calcium ion than carboxyl group and can simultaneously provide strong hydroxyapatite (HA)-binding capability. The MTT assay demonstrates the low cytotoxicity of PAMAM-PO3H2. Adsorption tests indicate that PAMAM-PO3H2 can be tightly adsorbed on the human tooth enamel. Scanning electron microscopy and X-ray diffraction are used to analyze the remineralization process. After being incubated in artificial saliva for 3weeks, there is a newly generated HA layer of 11.23μm thickness on the acid-etched tooth enamel treated by PAMAM-PO3H2, while the thickness for the carboxyl-terminated one (PAMAM-COOH) is only 6.02μm. PAMAM-PO3H2 can regulate the remineralization process to form ordered new crystals oriented along the Z-axis and produce an enamel prism-like structure that is similar to that of natural tooth enamel. The animal experiment also demonstrates that PAMAM-PO3H2 can induce significant HA regeneration in the oral cavity of rats. Thus PAMAM-PO3H2 shows great potential as a biomimetic restorative material for human tooth enamel.

  5. Homozygous and compound heterozygous MMP20 mutations in amelogenesis imperfecta.

    Science.gov (United States)

    Gasse, B; Karayigit, E; Mathieu, E; Jung, S; Garret, A; Huckert, M; Morkmued, S; Schneider, C; Vidal, L; Hemmerlé, J; Sire, J-Y; Bloch-Zupan, A

    2013-07-01

    In this article, we focus on hypomaturation autosomal-recessive-type amelogenesis imperfecta (type IIA2) and describe 2 new causal Matrix metalloproteinase 20 (MMP20) mutations validated in two unrelated families: a missense mutation p.T130I at the expected homozygous state, and a compound heterozygous mutation having the same mutation combined with a nucleotide deletion, leading to a premature stop codon (p.N120fz*2). We characterized the enamel structure of the latter case using scanning electron microscopy analysis and microanalysis (Energy-dispersive X-ray Spectroscopy, EDX) and confirmed the hypomaturation-type amelogenesis imperfecta as identified in the clinical diagnosis. The mineralized content was slightly decreased, with magnesium substituting for calcium in the crystal structure. The anomalies affected enamel with minimal inter-rod enamel present and apatite crystals perpendicular to the enamel prisms, suggesting a possible new role for MMP20 in enamel formation.

  6. A pedigree analysis of two homozygous mutant Gitelman syndrome cases.

    Science.gov (United States)

    Luo, Jiewei; Yang, Xiao; Liang, Jixing; Li, Weihua

    2015-01-01

    Gitelman syndrome (GS) is a salt-wasting tubulointerstitial disease of autosomal recessive inheritance (OMIM613395) caused by genic mutation of SLC12A3, which codes thiazide-sensitive Na-Cl cotransporter (NCCT) gene. The gene mutation of the majority of GS patients is compound heterozygous. This study analyzes two cases of GS gene mutation and the clinical phenotype. Twenty patients of two GS pedigrees underwent direct sequence alignment of 26 exons of SLC12A3 to spot and locate mutant site. Proband A of Pedigree I had three mutant sites: Arg928Cys, a homozygote, missense mutation, and two homozygous silent mutations, Ala122Ala and Thr465Thr, and 8 members of Pedigree I carried Arg928Cy heterozygous mutation. Proband B of Pedigree II had a homozygote, Ser710X, and a termination codon was spotted, which would inevitably be translated into abridged and defective protein, and 7 members had Ser710X heterozygous mutation. The heterozygous mutation carriers of the two pedigrees often have stimulus-controlled hypokalemia after strenuous exercise. The parents of Proband A are cousins, a case of intermarriage. Both probands show hypokalemia, hypochloraemia, hypocalcinuria, hyperreninemia, and hyperaldosteronemia; Proband A has normal serum magnesium and increased urinary sodium excretion, while Proband B has hypomagnesemia and increased urinary magnesium ion excretion. Both probands have normal or lower blood pressure, weakness and numbness of lower extremities, muscular soreness, and occasional palpitations and chest discomfort. Proband A wearies easily and Proband B has occasional joint numbness and pain. These two homozygous mutations are responsible for the morbidity of two GS families and they show heterogenicity of clinical phenotype.

  7. Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Antje Willuweit

    Full Text Available BACKGROUND: Transgenic mice expressing mutated amyloid precursor protein (APP and presenilin (PS-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues. METHODOLOGY/PRINCIPAL FINDINGS: The transgenic mouse line (ARTE10 was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP(swe and the M146V mutated presenilin 1 (PS1 both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral beta-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a gamma-secretase inhibitor we show a dose dependent reduction of soluble amyloid beta levels in the brain. CONCLUSIONS: ARTE10 mice develop a cerebral beta-amyloidosis closely resembling the beta-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for

  8. Homozygous and Heterozygous p53 Knockout Rats Develop Metastasizing Sarcomas with High Frequency

    Science.gov (United States)

    van Boxtel, Ruben; Kuiper, Raoul V.; Toonen, Pim W.; van Heesch, Sebastiaan; Hermsen, Roel; de Bruin, Alain; Cuppen, Edwin

    2011-01-01

    The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies. PMID:21854749

  9. Stanol esters attenuate the aggravating effect of dietary cholesterol on atherosclerosis in homozygous Watanabe rabbits

    DEFF Research Database (Denmark)

    Schrøder, Malene; Husche, Constanze; Pilegaard, Kirsten

    2009-01-01

    Plant stanols are marketed as natural means to lower blood cholesterol in humans; hence the effect on combined familial hyperlipidemia is not known. The objective was to investigate the effect of stanol esters on blood lipids and aortic atherosclerosis in homozygous WHHL rabbits challenged...... with dietary cholesterol. A total of 36 rabbits, 6 weeks of age, with initial plasma cholesterol of 22.5 mmol/L were assigned to two treatment groups fed a standard rabbit chow with 1 g/kg cholesterol or this diet added 34 g/kg stanol ester, respectively, for 16 weeks. Plasma cholesterol was measured initially...... and at termination, also in lipoproteins. Aortic atherosclerosis was evaluated as cholesterol content and area covered by plaque. Plasma cholesterol was not significantly different between the groups at termination (35.7 mmol/L vs. 35.5 mmol/L). A significant increase in LDL was seen (13.1 mmol/L vs. 16.5 mmol...

  10. Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes

    NARCIS (Netherlands)

    Angeloni, Debora; ter Elst, Arja; Wei, Ming Hui; van der Veen, Anneke Y.; Braga, Eleonora A.; Klimov, Eugene A.; Timmer, Tineke; Korobeinikova, Luba; Lerman, Michael I.; Buys, Charles H. C. M.

    2006-01-01

    Homozygous deletions or loss of heterozygosity (LOH) at human chromosome band 3p12 are consistent features of lung and other malignancies, suggesting the presence of a tumor suppressor gene(s) (TSG) at this location. Only one gene has been cloned thus far from the overlapping region deleted in lung

  11. Prokaryotic Selectivity, Anti-endotoxic Activity and Protease Stability of Diastereomeric and Enantiomeric Analogs of Human Antimicrobial Peptide LL-37

    Energy Technology Data Exchange (ETDEWEB)

    Nan, Yong Hai; Lee, Bongju; Shin, Song Yub [Chosun Univ., Gwangju (Korea, Republic of)

    2012-09-15

    LL-37 is the only antimicrobial peptide (AMP) of the human cathelicidin family. In addition to potent antimicrobial activity, LL-37 is known to have the potential to inhibit lipolysaccharide (LPS)-induced endotoxic effects. To provide the stability to proteolytic digestion and increase prokaryotic selectivity and/or anti-endotoxic activity of two Lys/Trp-substituted 19-meric anti-microbial peptides (a4-W1 and a4-W2) designed from IG-19 (residues 13-31 of LL-37), we synthesized the diastereomeric peptides (a4-W1-D and a4-W2-D) with D-amino acid substitution at positions 3, 7, 10, 13 and 17 of a4-W1 and a4-W2, respectively and the enantiomeric peptides (a4-W1-E and a4-W2-E) composed D-amino acids. The diastereomeric peptides exhibited the best prokaryotic selectivity and effective protease stability, but no or less anti-endotoxic activity. In contrast, the enantiomeric peptides had not only prokaryotic selectivity and anti-endotoxic activity but also protease stability. Our results suggest that the hydrophobicity and α-helicity of the peptide is important for anti-endotoxic activity. In particular, the enantiomeric peptides showed potent anti-endotoxic and LPS-neutralizing activities comparable to that of LL-37. Taken together, both a4-W1-E and a4-W2-E holds promise as a template for the development of peptide antibiotics for the treatment of endotoxic shock and sepsis.

  12. Determination of structure-activity relationships between fentanyl analogs and human μ-opioid receptors based on active binding site models

    Institute of Scientific and Technical Information of China (English)

    Ming Liu; Xiaoli Liu; Ping Wan; Qiangsan Wu; Wenxiang Hu

    2011-01-01

    Fentanyl is a potent and widely used clinical narcotic analgesic, as well as a highly selective μ-opioid agonist. The present study established a homologous model of the human μ-opioid receptor; an intercomparison of three types of μ-opioid receptor protein sequence homologous rates was made. The secondary receptor structure was predicted, the model reliability was assessed and verified using the Ramachandran plot and ProTab analysis. The predictive ability of the CoMFA model was further validated using an external test set. Using the Surflex-Dock program, a series of fentanyl analog molecules were docked to the receptor, the calculation results from Biopolymer/SiteID showed that the receptor had a deep binding area situated in the extracellular side of the transmembrane domains (TM) among TM3, TM5, TM6, and TM7. Results suggested that there might be 5 active areas in the receptor. The important residues were Asp147, Tyr148, and Tyr149 in TM3, Trp293, and His297 in TM6, and Trp318, His319, Ile322, and Tyr326 in TM7, which were located at the 5 active areas. The best fentanyl docking orientation position was the piperidine ring, which was nearly perpendicular to the membrane surface in the 7 TM domains. Molecular dynamic simulations were applied to evaluate potential relationships between ligand conformation and fentanyl substitution.

  13. Cytotoxicity Induced by a Redox-silent Analog of Tocotrienol in Human Mesothelioma H2452 Cell Line via Suppression of Cap-dependent Protein Translation.

    Science.gov (United States)

    Sato, Ayami; Ueno, Haruka; Takase, Akari; Ando, Akira; Sekine, Yuko; Yano, Tomohiro

    2016-04-01

    De novo synthesis of proteins is regulated by cap-dependent protein translation. Aberrant activation of the translation is a hallmark of many cancer types including malignant mesothelioma (MM). We previously reported that a redox-silent analog of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) induces potent cytotoxicity against human MM cells. However, the detailed mechanism of cytotoxicity of T3E remains unclear. In this study, we investigated if T3E induced potent cytotoxicity aganist MM cells. T3E reduced the formation of the cap-dependent translation complex and induced inactivation of oncogene from rat sarcoma virus (RAS). These events were associated with T3E cytotoxicity in MM cells. Furthermore, atorvastatin, an inhibitor of RAS function, had similar effects on MM cells. Moreover, 4EGI-1, a specific inhibitor of the cap-dependent translation complex, induced severe cytotoxicity in MM cells. Overall, T3E had a cytotoxic effect on MM cells via disruption of the activated cap-dependent translation complex through inactivation of RAS.

  14. Analog and hybrid computing

    CERN Document Server

    Hyndman, D E

    2013-01-01

    Analog and Hybrid Computing focuses on the operations of analog and hybrid computers. The book first outlines the history of computing devices that influenced the creation of analog and digital computers. The types of problems to be solved on computers, computing systems, and digital computers are discussed. The text looks at the theory and operation of electronic analog computers, including linear and non-linear computing units and use of analog computers as operational amplifiers. The monograph examines the preparation of problems to be deciphered on computers. Flow diagrams, methods of ampl

  15. Structured Analog CMOS Design

    CERN Document Server

    Stefanovic, Danica

    2008-01-01

    Structured Analog CMOS Design describes a structured analog design approach that makes it possible to simplify complex analog design problems and develop a design strategy that can be used for the design of large number of analog cells. It intentionally avoids treating the analog design as a mathematical problem, developing a design procedure based on the understanding of device physics and approximations that give insight into parameter interdependences. The proposed transistor-level design procedure is based on the EKV modeling approach and relies on the device inversion level as a fundament

  16. Differential interference of vitamin D analogs PRI-1906, PRI-2191, and PRI-2205 with the renewal of human colon cancer cells refractory to treatment with 5-fluorouracil.

    Science.gov (United States)

    Kotlarz, Agnieszka; Przybyszewska, Małgorzata; Swoboda, Paweł; Miłoszewska, Joanna; Grygorowicz, Monika Anna; Kutner, Andrzej; Markowicz, Sergiusz

    2016-04-01

    This study was aimed to determine whether hypocalcemic analogs of active forms of vitamins D modulate expression of genes related to stem-like phenotype in colon cancer cell lines HT-29 and HCT-116 undergoing renewal after the treatment with 5-fluorouracil (5-FU). Both lines express vitamin D receptor, but differ in differentiation stage and vitamin D sensitivity. Cells that resisted the 5-FU exposure were treated with synthetic analog of 1,25-dihydroxyvitamin D2 (PRI-1906) and analogs of 1,25-dihydroxyvitamin D3 (PRI-2191 and PRI-2205). Proliferative activity was more profoundly affected by vitamin D analogs in HT-29/5-FU than in HCT-116/5-FU cells. In HT-29/5-FU cells, analogs PRI-1906 and PRI-2191 downregulated the expression of genes related to survival, re-growth, and invasiveness during renewal, while PRI-2205 increased expression of genes related to differentiation only. In HCT-116/5-FU cells, PRI-2191 decreased the expression of stemness- and angiogenesis-related genes, whereas PRI-1906 augmented their expression. The effects in HCT-116/5-FU cells were observed at higher concentrations of the analogs than those used for HT-29/5-FU cells. Out of the series of analogs studied, PRI-2191 might be used to counteract the renewal of both moderately and poorly differentiated cancer cells following conventional treatment.

  17. Homozygous factor V Leiden and double heterozygosity for factor V Leiden and prothrombin mutation.

    Science.gov (United States)

    Saemundsson, Ymir; Sveinsdottir, Signý Vala; Svantesson, Henrik; Svensson, Peter J

    2013-10-01

    The most common forms of familial thrombophilia are factor V Leiden (FVL) and prothrombin mutation (PTM). Homozygous FVL and PTM have long been feared conditions thought to cause high rates of morbidity and mortality. To analyse clinical features in patients with homozygous FVL and PTM, as well as patients with double heterozygosity for FVL and PTM. All patients with homozygous FVL, PTM or double heterozygosity in the MATS database of 1465 consecutive unselected patients were analysed regarding age at inclusion venous thromboembolism (VTE), age at first thrombosis, recurrence, clinical course and acquired risk factors. We found 36 patients homozygous for FVL. Patients homozygous for FVL were younger than controls at group level (56 ± 18 vs. 63 ± 17, p < 0.02). Homozygous women were younger than female controls (50 ± 19 vs. 63 ± 18, p < 0.002). No difference was observed when comparing male subjects. Women were younger than men at inclusion thrombosis (50 ± 19 vs. 65 ± 14, p < 0.02) and at first thrombosis (47 ± 19 vs. 64 ± 14, p < 0.01). Deep venous thrombosis (DVT) was seen in 33 patients (92 %), 6 (17 %) had pulmonary embolism (PE) and 3 (8 %) had combined DVT and PE. PE was less frequent in homozygous FVL women compared to female controls (p < 0.03). VTE recurred in 3 subjects during the duration of the study. Odds ratio for VTE in homozygous FVL patients compared to controls was 13.9 (95 % CI 9.9-19.7). We found no subjects with homozygous PTM. Double heterozygosity for FVL and PTM was seen in 12 subjects. There was no difference in age at inclusion VTE between double heterozygotes and controls (59 ± 16 vs. 63 ± 17, ns.). DVT was seen in 92 % at inclusion, 8 % had PE. Mean age at first VTE was 52 ± 17 (27-82). Consecutive homozygous FVL patients had a higher age at first thrombosis than previously described. Homozygous females are affected at an earlier age than homozygous men and female controls. It seems that

  18. Vectorial transport of nucleoside analogs from the apical to the basolateral membrane in double-transfected cells expressing the human concentrative nucleoside transporter hCNT3 and the export pump ABCC4.

    Science.gov (United States)

    Rius, Maria; Keller, Daniela; Brom, Manuela; Hummel-Eisenbeiss, Johanna; Lyko, Frank; Keppler, Dietrich

    2010-07-01

    The identification of the transport proteins responsible for the uptake and the efflux of nucleosides and their metabolites enables the characterization of their vectorial transport and a better understanding of their absorption, distribution, and elimination. Human concentrative nucleoside transporters (hCNTs/SLC28A) are known to mediate the transport of natural nucleosides and some nucleoside analogs into cells in a sodium-dependent and unidirectional manner. On the other hand, several human multidrug resistance proteins [human ATP-binding cassette transporter, subfamily C (ABCC)] cause resistance against nucleoside analogs and mediate transport of phosphorylated nucleoside derivatives out of the cells in an ATP-dependent manner. For the integrated analysis of uptake and efflux of these compounds, we established a double-transfected Madin-Darby canine kidney (MDCK) II cell line stably expressing the human uptake transporter hCNT3 in the apical membrane and the human efflux pump ABCC4 in the basolateral membrane. The direction of transport was from the apical to the basolateral compartment, which is in line with the unidirectional transport and the localization of both recombinant proteins in the MDCKII cells. Recombinant hCNT3 mediated the transport of several known nucleoside substrates, and we identified 5-azacytidine as a new substrate for hCNT3. It is of interest that coexpression of both transporters was confirmed in pancreatic adenocarcinomas, which represent an important clinical indication for the therapeutic use of nucleoside analogs. Thus, our results establish a novel cell system for studies on the vectorial transport of nucleosides and their analogs from the apical to the basolateral compartment. The results contribute to a better understanding of the cellular transport characteristics of nucleoside drugs.

  19. Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts.

    Science.gov (United States)

    Barros-Álvarez, Ximena; Kerchner, Keshia M; Koh, Cho Yeow; Turley, Stewart; Pardon, Els; Steyaert, Jan; Ranade, Ranae M; Gillespie, J Robert; Zhang, Zhongsheng; Verlinde, Christophe L M J; Fan, Erkang; Buckner, Frederick S; Hol, Wim G J

    2017-07-01

    The crystal structure of Leishmania donovani tyrosyl-tRNA synthetase (LdTyrRS) in complex with a nanobody and the tyrosyl adenylate analog TyrSA was determined at 2.75 Å resolution. Nanobodies are the variable domains of camelid heavy chain-only antibodies. The nanobody makes numerous crystal contacts and in addition reduces the flexibility of a loop of LdTyrRS. TyrSA is engaged in many interactions with active site residues occupying the tyrosine and adenine binding pockets. The LdTyrRS polypeptide chain consists of two pseudo-monomers, each consisting of two domains. Comparing the two independent chains in the asymmetric unit reveals that the two pseudo-monomers of LdTyrRS can bend with respect to each other essentially as rigid bodies. This flexibility might be useful in the positioning of tRNA for catalysis since both pseudo-monomers in the LdTyrRS chain are needed for charging tRNA(Tyr). An "extra pocket" (EP) appears to be present near the adenine binding region of LdTyrRS. Since this pocket is absent in the two human homologous enzymes, the EP provides interesting opportunities for obtaining selective drugs for treating infections caused by L. donovani, a unicellular parasite causing visceral leishmaniasis, or kala azar, which claims 20,000 to 30,000 deaths per year. Sequence and structural comparisons indicate that the EP is a characteristic which also occurs in the active site of several other important pathogenic protozoa. Therefore, the structure of LdTyrRS could inspire the design of compounds useful for treating several different parasitic diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  20. Analogies of Information Security

    OpenAIRE

    Sole, Amund Bauck

    2016-01-01

    In this thesis it will be tested wither analogies and metaphors would make it easier to teach the fundamental subjects of information security and hacking to people with no previous background in computer science and only basic computer skills. This will be done by conducting interview on people with no background in computer science to see what analogies work the best for different topics in information security. From the analogy getting the best response, a small game will be designed with ...

  1. Analog circuit design

    CERN Document Server

    Dobkin, Bob

    2012-01-01

    Analog circuit and system design today is more essential than ever before. With the growth of digital systems, wireless communications, complex industrial and automotive systems, designers are being challenged to develop sophisticated analog solutions. This comprehensive source book of circuit design solutions aids engineers with elegant and practical design techniques that focus on common analog challenges. The book's in-depth application examples provide insight into circuit design and application solutions that you can apply in today's demanding designs. <

  2. Analogy in CLAM

    OpenAIRE

    Melis, Erica

    1999-01-01

    CL A M is a proof planner, developed by the Dream group in Edinburgh,that mainly operates for inductive proofs. This paper addresses the questionhow an analogy model that I developed independently of CL A M can beapplied to CL A M and it presents analogy-driven proof plan construction as acontrol strategy of CL A M . This strategy is realized as a derivational analogythat includes the reformulation of proof plans. The analogical replay checkswhether the reformulated justifications of the sour...

  3. Crows spontaneously exhibit analogical reasoning.

    Science.gov (United States)

    Smirnova, Anna; Zorina, Zoya; Obozova, Tanya; Wasserman, Edward

    2015-01-19

    Analogical reasoning is vital to advanced cognition and behavioral adaptation. Many theorists deem analogical thinking to be uniquely human and to be foundational to categorization, creative problem solving, and scientific discovery. Comparative psychologists have long been interested in the species generality of analogical reasoning, but they initially found it difficult to obtain empirical support for such thinking in nonhuman animals (for pioneering efforts, see [2, 3]). Researchers have since mustered considerable evidence and argument that relational matching-to-sample (RMTS) effectively captures the essence of analogy, in which the relevant logical arguments are presented visually. In RMTS, choice of test pair BB would be correct if the sample pair were AA, whereas choice of test pair EF would be correct if the sample pair were CD. Critically, no items in the correct test pair physically match items in the sample pair, thus demanding that only relational sameness or differentness is available to support accurate choice responding. Initial evidence suggested that only humans and apes can successfully learn RMTS with pairs of sample and test items; however, monkeys have subsequently done so. Here, we report that crows too exhibit relational matching behavior. Even more importantly, crows spontaneously display relational responding without ever having been trained on RMTS; they had only been trained on identity matching-to-sample (IMTS). Such robust and uninstructed relational matching behavior represents the most convincing evidence yet of analogical reasoning in a nonprimate species, as apes alone have spontaneously exhibited RMTS behavior after only IMTS training. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Production of Fully Homozygous Genotypes from Various Edible Alliums

    Directory of Open Access Journals (Sweden)

    A. R. ALAN

    2014-06-01

    Full Text Available Allium is a very large genus containing over 700 distinct species including the various edible onions, garlics, chives, and leeks. About a dozen of the species are economically important as crops or garden vegetables where as many others are cultivated as ornamental plants. Allium breeding programs generally take very long time with low success due to problems such as long life cycle, sterility, polyploidy, high levels of heterozygosity. Development of inbreed lines is a very difficult process due to severe inbreeding depression. Doubled haploid (DH techniques can be utilized to obtain fully homozygous Allium materials. In Alliums, gynogenesis is the major technique used to produce haploid and DH plants from unfertilized female gamets with reduced chromosome number. We are in the process of developing gynogenesis induction protocols for several edible Allium species. We showed that gynogenic embryos can be obtained from a wide range of Allium materials. About half of the gynogenic embryos continue to grow and become plantlets. In general, gynogenic plantlets are green, but some of them show chlorophyll abnomalities. Results obtained from flow cytometric analysis of nuclei isolated from gynogenic materials indicate that majority of the gynogenic Allium materials are haploid and DH plants. DH onion lines developed in our program are generally vigorous plants with high levels of fecundity. The seeds obtained from DH onions show high germination. Plants of DH onion lines grow uniformly and produce bulbs very uniform in size, shape, color and quality features. These DH lines are excellent inbreds to be used as male parents in the production of F1 hybrid onion lines. Success obtained in DH onion materials indicates that a similar approach can be applied in the breeding programs of other important Alliums.

  5. Analogies in Medicine: Valuable for Learning, Reasoning, Remembering and Naming

    Science.gov (United States)

    Pena, Gil Patrus; Andrade-Filho, Jose de Souza

    2010-01-01

    Analogies are important tools in human reasoning and learning, for resolving problems and providing arguments, and are extensively used in medicine. Analogy and similarity involve a structural alignment or mapping between domains. This cognitive mechanism can be used to make inferences and learn new abstractions. Through analogies, we try to…

  6. “One-shot” analysis of polybrominated diphenyl ethers and their hydroxylated and methoxylated analogs in human breast milk and serum using gas chromatography-tandem mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Butryn, Deena M.; Gross, Michael S. [Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260 (United States); Chi, Lai-Har [Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY 14214 (United States); Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, NY 14214 (United States); Schecter, Arnold [Department of Pharmacology and Toxicology, University of Louisville College of Medicine, Louisville, KY 40202 (United States); Olson, James R. [Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY 14214 (United States); Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, NY 14214 (United States); Aga, Diana S., E-mail: dianaaga@buffalo.edu [Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260 (United States)

    2015-09-10

    The presence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-BDE) and methoxylated (MeO-BDE) analogs in humans is an area of high interest to scientists and the public due to their neurotoxic and endocrine disrupting effects. Consequently, there is a rise in the investigation of the occurrence of these three classes of compounds together in environmental matrices and in humans in order to understand their bioaccumulation patterns. Analysis of PBDEs, OH-BDEs, and MeO-BDEs using liquid chromatography-mass spectrometry (LC-MS) can be accomplished simultaneously, but detection limits for PBDEs and MeO-BDEs in LC-MS is insufficient for trace level quantification. Therefore, fractionation steps of the phenolic (OH-BDEs) and neutral (PBDEs and MeO-BDEs) compounds during sample preparation are typically performed so that different analytical techniques can be used to achieve the needed sensitivities. However, this approach involves multiple injections, ultimately increasing analysis time. In this study, an analytical method was developed for a “one-shot” analysis of 12 PBDEs, 12 OH-BDEs, and 13 MeO-BDEs using gas chromatography with tandem mass spectrometry (GC-MS/MS). This overall method includes simultaneous extraction of all analytes via pressurized liquid extraction followed by lipid removal steps to reduce matrix interferences. The OH-BDEs were derivatized using N-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide (TBDMS-MTFA), producing OH-TBDMS derivatives that can be analyzed together with PBDEs and MeO-BDEs by GC-MS/MS in “one shot” within a 25-min run time. The overall recoveries were generally higher than 65%, and the limits of detection ranged from 2 to 14 pg in both breast milk and serum matrices. The applicability of the method was successfully validated on four paired human breast milk and serum samples. The mean concentrations of total PBDEs, OH-BDEs, and MeO-BDEs in breast milk were 59, 2.2, and 0.57 ng g{sup −1} lipid

  7. Resolving pathways of interaction of mipafox and a sarin analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches.

    Science.gov (United States)

    Mangas, I; Taylor, P; Vilanova, E; Estévez, J; França, T C C; Komives, E; Radić, Z

    2016-03-01

    The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here, our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF/TOF. The ACP was detected with a diethyl-phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl-phosphonylated and a methyl-phosphonylated adduct after Flu-MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diisopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However, with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand calculated

  8. Resolving pathways of interaction of mipafox and a sarin-analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches

    Science.gov (United States)

    Mangas, I; Taylor, P; Vilanova, E; Estévez, J; Franca, T; Radić, Z

    2016-01-01

    The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide mass fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF-TOF. The ACP was detected with a diethyl phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl phosphonylated and a methyl phosphonylated adduct after Flu-MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diidopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand

  9. Novel receptor-derived cyclopeptides to treat heart failure caused by anti-β1-adrenoceptor antibodies in a human-analogous rat model.

    Directory of Open Access Journals (Sweden)

    Valérie Boivin

    Full Text Available Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the β1 adrenergic receptor (β1EC2. In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195-225 every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking β1EC2 (β1EC2-CP, 1.0 mg/kg every 4 weeks or administration of the β1-blocker bisoprolol (15 mg/kg/day orally was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated; n = 8/52 rats from the therapy-study received β1EC2-CP/bisoprolol co-treatment. We found that β1EC2-CP prevented and (alone or as add-on drug treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, β1EC2-CP mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free anti-β1EC2-antibodies and by targeting β1EC2-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful anti-β1EC2-antibodies and also selectively depletes memory B-cells involved in the production of such

  10. Detection of Homozygous Deletions and Mutations in the CDKN2A Gene in Hydatidiform Moles

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Shuying Wu; Ying Gu; Yan Zhu; Xiaowei Zhang

    2008-01-01

    OBJECTIVE To investigate homozygous deletions and mutations in the CDKN2A gene (p16INK4a and p14ARF gene) in hydatidiform moles.METHODS A total of 38 hydatidiform mole samples and 30 villi samples were examined for homozygous deletions in the CDKN2A gene by PCR and for mutations by DHPLC.RESULTS I) Among 38 hydatidiform mole samples,homozygous deletions in the p16INK4a exon 1 were identified in 5 cases (13.2%), while no homozygous deletions were found in the p16INK4a exon 1 of 30 early-pregnancy samples. The rates of those deletions in hydatidiform compared to early-pregnancy villi samples was statistically significant (P = 0.036). Ii) No homozygous deletions in the p14ARF exon 1 or p16INK4a exon 2 were found in any of the hydatidiform moles or early-preganancy samples, iii)In all hydatidiform moles and early-pregnancy villi samples, no mutations were detected by DHPLC.CONCLUSION We suggest there may be a close correlation between homozygous deletions in the CDKN2A gene and occurrence of hydatidiform moles variation in the CDKN2A gene is mainly caused by homozygous deletions, while mutations may be not a major cause.

  11. Hydraulic Capacitor Analogy

    Science.gov (United States)

    Baser, Mustafa

    2007-01-01

    Students have difficulties in physics because of the abstract nature of concepts and principles. One of the effective methods for overcoming students' difficulties is the use of analogies to visualize abstract concepts to promote conceptual understanding. According to Iding, analogies are consistent with the tenets of constructivist learning…

  12. Challenges in Using Analogies

    Science.gov (United States)

    Lin, Shih-Yin; Singh, Chandralekha

    2011-01-01

    Learning physics requires understanding the applicability of fundamental principles in a variety of contexts that share deep features. One way to help students learn physics is via analogical reasoning. Students can be taught to make an analogy between situations that are more familiar or easier to understand and another situation where the same…

  13. Expert analogy use in a naturalistic setting

    Science.gov (United States)

    Kretz, Donald R.; Krawczyk, Daniel C.

    2014-01-01

    The use of analogy is an important component of human cognition. The type of analogy we produce and communicate depends heavily on a number of factors, such as the setting, the level of domain expertise present, and the speaker's goal or intent. In this observational study, we recorded economics experts during scientific discussion and examined the categorical distance and structural depth of the analogies they produced. We also sought to characterize the purpose of the analogies that were generated. Our results supported previous conclusions about the infrequency of superficial similarity in subject-generated analogs, but also showed that distance and depth characteristics were more evenly balanced than in previous observational studies. This finding was likely due to the nature of the goals of the participants, as well as the broader nature of their expertise. An analysis of analogical purpose indicated that the generation of concrete source examples of more general target concepts was most prevalent. We also noted frequent instances of analogies intended to form visual images of source concepts. Other common purposes for analogies were the addition of colorful speech, inclusion (i.e., subsumption) of a target into a source concept, or differentiation between source and target concepts. We found no association between depth and either of the other two characteristics, but our findings suggest a relationship between purpose and distance; i.e., that visual imagery typically entailed an outside-domain source whereas exemplification was most frequently accomplished using within-domain analogies. Overall, we observed a rich and diverse set of spontaneously produced analogical comparisons. The high degree of expertise within the observed group along with the richly comparative nature of the economics discipline likely contributed to this analogical abundance. PMID:25505437

  14. Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.

    Directory of Open Access Journals (Sweden)

    Ethiraj Ravindran

    2017-04-01

    Full Text Available Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.

  15. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.

    Science.gov (United States)

    Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

    2015-05-01

    The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

  16. The sugar ring of the nucleoside is required for productive substrate positioning in the active site of human deoxycytidine kinase (dCK): implications for the development of dCK-activated acyclic guanine analogs

    Science.gov (United States)

    Hazra, Saugata; Konrad, Manfred; Lavie, Arnon

    2010-01-01

    The low toxicity of acyclovir (ACV) is mainly due to the fact that human nucleoside kinases have undetectable phosphorylation rates with this acyclic guanine analog. In contrast, herpes virus thymidine kinase (HSV1-TK) readily activates ACV. We wanted to understand why human deoxycytidine kinase (dCK), which is related to HSV1-TK and phosphorylates deoxyguanosine, does not accept acyclic guanine analogs as substrates. Therefore, we crystallized dCK in complex with ACV at the nucleoside phosphoryl acceptor site, and UDP at the phosphoryl donor site. The structure reveals that while ACV does bind at the dCK active site, it does so adopting a non-productive conformation. Despite binding ACV, the enzyme remains in the open, inactive state. In comparison to ACV binding to HSV1-TK, in dCK the nucleoside base adopts a different orientation related by about a 60 degree rotation. Our analysis suggests that dCK would phosphorylate acyclic guanine analogs if they can induce a similar rotation. PMID:20684612

  17. Troubleshooting analog circuits

    CERN Document Server

    Pease, Robert A

    1991-01-01

    Troubleshooting Analog Circuits is a guidebook for solving product or process related problems in analog circuits. The book also provides advice in selecting equipment, preventing problems, and general tips. The coverage of the book includes the philosophy of troubleshooting; the modes of failure of various components; and preventive measures. The text also deals with the active components of analog circuits, including diodes and rectifiers, optically coupled devices, solar cells, and batteries. The book will be of great use to both students and practitioners of electronics engineering. Other

  18. Elevated heart rate triggers action potential alternans and sudden death. translational study of a homozygous KCNH2 mutation.

    Directory of Open Access Journals (Sweden)

    Ulrich Schweigmann

    Full Text Available BACKGROUND: Long QT syndrome (LQTS leads to arrhythmic events and increased risk for sudden cardiac death (SCD. Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. METHODS AND RESULTS: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q in the index patient (QTc ∼506 ms with notched T waves. Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother. Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. CONCLUSION: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.

  19. Challenges in Analogical Reasoning

    CERN Document Server

    Lin, Shih-Yin

    2016-01-01

    Learning physics requires understanding the applicability of fundamental principles in a variety of contexts that share deep features. One way to help students learn physics is via analogical reasoning. Students can be taught to make an analogy between situations that are more familiar or easier to understand and another situation where the same physics principle is involved but that is more difficult to handle. Here, we examine introductory physics students' ability to use analogies in solving problems involving Newton's second law. Students enrolled in an algebra-based introductory physics course were given a solved problem involving tension in a rope and were then asked to solve another problem for which the physics is very similar but involved a frictional force. They were asked to point out the similarities between the two problems and then use the analogy to solve the friction problem.

  20. TV Analog Station Transmitters

    Data.gov (United States)

    Department of Homeland Security — This file is an extract from the Consolidated Database System (CDBS) licensed by the Media Bureau. It consists of Analog Television Stations (see Rule Part47 CFR...

  1. Analog multivariate counting analyzers

    CERN Document Server

    Nikitin, A V; Armstrong, T P

    2003-01-01

    Characterizing rates of occurrence of various features of a signal is of great importance in numerous types of physical measurements. Such signal features can be defined as certain discrete coincidence events, e.g. crossings of a signal with a given threshold, or occurrence of extrema of a certain amplitude. We describe measuring rates of such events by means of analog multivariate counting analyzers. Given a continuous scalar or multicomponent (vector) input signal, an analog counting analyzer outputs a continuous signal with the instantaneous magnitude equal to the rate of occurrence of certain coincidence events. The analog nature of the proposed analyzers allows us to reformulate many problems of the traditional counting measurements, and cast them in a form which is readily addressed by methods of differential calculus rather than by algebraic or logical means of digital signal processing. Analog counting analyzers can be easily implemented in discrete or integrated electronic circuits, do not suffer fro...

  2. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC.

    Science.gov (United States)

    Rubio-Cabezas, Oscar; Puri, Vishwajeet; Murano, Incoronata; Saudek, Vladimir; Semple, Robert K; Dash, Satya; Hyden, Caroline S S; Bottomley, William; Vigouroux, Corinne; Magré, Jocelyne; Raymond-Barker, Philippa; Murgatroyd, Peter R; Chawla, Anil; Skepper, Jeremy N; Chatterjee, V Krishna; Suliman, Sara; Patch, Ann-Marie; Agarwal, Anil K; Garg, Abhimanyu; Barroso, Inês; Cinti, Saverio; Czech, Michael P; Argente, Jesús; O'Rahilly, Stephen; Savage, David B

    2009-08-01

    Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.

  3. Homozygous N396T mutation in Gaucher disease: Portuguese sisters with markedly different phenotypes

    Directory of Open Access Journals (Sweden)

    Samantha Kimball

    2011-03-01

    Full Text Available Samantha Kimball1,2, Francis Choy4, Agnes Zay5, Dominick Amato31Department of Nutritional Sciences, University of Toronto, Canada; 2Department of Laboratory Medicine and Pathology, 3Department of Medicine, Division of Hematology, Mt Sinai Hospital, Toronto, Canada; 4Department of Biology, University of Victoria, Victoria, Canada; 5MRC Center for Regenerative Medicine, University of Edinburgh, Edinburgh, ScotlandAbstract: Gaucher disease (GD is characterized by reduced activity of glucocerebrosidase leading to complications in the reticuloendothelial system. N396T, a rarer mutation of the glucocerebrosidase gene, has been encountered in Portuguese populations and has generally been associated with milder phenotypes. This report presents brief histories of two Portuguese sisters, both with homozygous N396T mutations. These patients are phenotypically very different despite the fact that in both patients residual enzyme activity is very low. The case of patient 1 is complicated by comorbid diabetes mellitus and human immunodeficiency virus (HIV infection. Enzyme replacement therapy (ERT improved this patient's clinical picture sufficiently to enable antiretroviral treatment to proceed for the HIV. This report demonstrates the poor correlation of clinical GD with genotype as well as with residual enzyme activity. It further illustrates how treatment of the underlying GD with ERT improved symptoms allowing for antiretroviral therapy thereby improving both the GD and HIV.Keywords: Gaucher disease, N396T mutation, glucocerebrosidase, HIV

  4. Homozygous Inactivating Mutation in NANOS3 in Two Sisters with Primary Ovarian Insufficiency

    Directory of Open Access Journals (Sweden)

    Mariza G. Santos

    2014-01-01

    Full Text Available Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lys mutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology.

  5. Synthesis of Paclitaxel Analogs

    OpenAIRE

    Xu, Zhibing

    2010-01-01

    Paclitaxel is one of the most successful anti-cancer drugs, particularly in the treatment of breast cancer and ovarian cancer. For the investigation of the interaction between paclitaxel and MD-2 protein, and development of new antagonists for lipopolysaccharide, several C10 A-nor-paclitaxel analogs have been synthesized and their biological activities have been evaluated. In order to reduce the myelosuppression effect of the paclitaxel, several C3â ² and C4 paclitaxel analogs have been synth...

  6. FGF growth factor analogs

    Science.gov (United States)

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  7. Analog circuits cookbook

    CERN Document Server

    Hickman, Ian

    2013-01-01

    Analog Circuits Cookbook presents articles about advanced circuit techniques, components and concepts, useful IC for analog signal processing in the audio range, direct digital synthesis, and ingenious video op-amp. The book also includes articles about amplitude measurements on RF signals, linear optical imager, power supplies and devices, and RF circuits and techniques. Professionals and students of electrical engineering will find the book informative and useful.

  8. Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: a double-blind placebo-controlled study

    National Research Council Canada - National Science Library

    Nauck, Michael A; Ratner, Robert E; Kapitza, Christoph; Berria, Rachele; Boldrin, Mark; Balena, Raffaella

    2009-01-01

    To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin. Type 2 diabetic (n = 306...

  9. Electrical Circuits and Water Analogies

    Science.gov (United States)

    Smith, Frederick A.; Wilson, Jerry D.

    1974-01-01

    Briefly describes water analogies for electrical circuits and presents plans for the construction of apparatus to demonstrate these analogies. Demonstrations include series circuits, parallel circuits, and capacitors. (GS)

  10. Lack of T Cell Response to iPSC-Derived Retinal Pigment Epithelial Cells from HLA Homozygous Donors

    Directory of Open Access Journals (Sweden)

    Sunao Sugita

    2016-10-01

    Full Text Available Allografts of retinal pigment epithelial (RPE cells have been considered for the treatment of ocular diseases. We recently started the transplantation of induced pluripotent stem cell (iPSC-derived RPE cells for patients with age-related macular degeneration (autogenic grafts. However, there are at least two problems with this approach: (1 high cost, and (2 uselessness for acute patients. To resolve these issues, we established RPE cells from induced iPSCs in HLA homozygote donors. In vitro, human T cells directly recognized allogeneic iPSC-derived RPE cells that expressed HLA class I/II antigens. However, these T cells failed to respond to HLA-A, -B, and -DRB1-matched iPSC-derived RPE cells from HLA homozygous donors. Because of the lack of T cell response to iPSC-derived RPE cells from HLA homozygous donors, we can use these allogeneic iPSC-derived RPE cells in future clinical trials if the recipient and donor are HLA matched.

  11. A novel homozygous variant in the dsp gene underlies the first case of non-syndromic form of alopecia.

    Science.gov (United States)

    Jan, Abid; Basit, Sulman; Wakil, Salma M; Ramzan, Khushnooda; Ahmad, Wasim

    2015-11-01

    Autosomal recessive forms of hair loss (alopecia) disorders have previously been associated with variants in at least five different genes including hairless (HR), desmoglein-4 (DSG4), desmocollin-3 (DSC3), lipase-H (LIPH), and lysophosphatidic acid receptor 6 (LPAR6). Here, we report the first familial case of alopecia resulting from a novel homozygous variant in the DSP gene. Since previous reports indicated the presence of heart abnormalities in patients carrying variants in the DSP gene; therefore, the echocardiographic evaluations of all affected members were performed. The results clearly excluded the presence of any form of heart abnormality in patients of the present family. Human genome scan mapped a disease locus on chromosome 6p25.1-p23, harboring DSP gene. Sequence analysis identified a novel homozygous missense variant [c.1493C > T (p.Pro498Leu)] in the DSP gene as the underlying genetic cause of non-syndromic alopecia in the family. The transition alters the completely conserved Pro498 residue in the SH3 domain of plakin that contributes to the stability and rigidity of this subfamily of spectrin repeats (SRs) containing proteins. Our study strengthens the evidence that hereditary hair loss disorders are genetically heterogeneous and imply that isolated form of alopecia is allelic with cardiocutaneous syndromes.

  12. 15q13.3 homozygous knockout mouse model display epilepsy-, autism- and schizophrenia-related phenotypes

    DEFF Research Database (Denmark)

    Forsingdal, A; Fejgin, Kim; Nielsen, Viggo

    2016-01-01

    The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder and schi......The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder......, little is known of the underlying biological mechanisms. Eleven human cases with homozygous deletion of the 15q13.3 region have been reported, all with severe functional and physiological impairments. We therefore hypothesized that a 15q13.3 homozygous knockout would confer more pronounced behavioral...

  13. Identifying Solar Analogs in the Kepler Field

    Science.gov (United States)

    Buzasi, Derek L.; Lezcano, Andrew; Preston, Heather L.

    2014-06-01

    Since human beings live on a planet orbiting a G2 V star, to us perhaps the most intrinsically interesting category of stars about which planets have been discovered is solar analogs. While Kepler has observed more than 26000 targets which have effective temperatures within 100K of the Sun, many of these are not true solar analogs due to activity, surface gravity, metallicity, or other considerations. Here we combine ground-based measurements of effective temperature and metallicity with data on rotational periods and surface gravities derived from 16 quarters of Kepler observations to produce a near-complete sample of solar analogs in the Kepler field. We then compare the statistical distribution of stellar physical parameters, including activity level, for subsets of solar analogs consisting of KOIs and those with no detected exoplanets. Finally, we produce a list of potential solar twins in the Kepler field.

  14. Feline congenital erythropoietic porphyria: two homozygous UROS missense mutations cause the enzyme deficiency and porphyrin accumulation.

    Science.gov (United States)

    Clavero, Sonia; Bishop, David F; Giger, Urs; Haskins, Mark E; Desnick, Robert J

    2010-01-01

    The first feline model of human congenital erythropoietic porphyria (CEP) due to deficient uroporphyrinogen III synthase (URO-synthase) activity was identified by its characteristic clinical phenotype, and confirmed by biochemical and molecular genetic studies. The proband, an adult domestic shorthair cat, had dark-red urine and brownish discolored teeth with red fluorescence under ultraviolet light. Biochemical studies demonstrated markedly increased uroporphyrinogen I in urine and plasma (2,650- and 10,700-fold greater than wild type, respectively), whereas urinary 5-aminolevulinic acid and porphobilinogen were lower than normal. Erythrocytic URO-synthase activity was UROS gene revealed two missense mutations, c.140C>T (p.S47F) in exon 3 and c.331G>A (p.G111S) in exon 6, both of which were homozygous, presumably owing to parental consanguinity. Neither was present in 100 normal cat alleles. Prokaryotic expression and thermostability studies of the purified monomeric wild-type, p.S47F, p.G111S, and p.S47F/G111S enzymes showed that the p.S47F enzyme had 100% of wild-type specific activity but ~50% decreased thermostability, whereas the p.G111S and p.S47F/G111S enzymes had about 60% and 20% of wild-type specific activity, respectively, and both were markedly thermolabile. Molecular modeling results indicated that the less active/less stable p.G111S enzyme was further functionally impaired by a structural interaction induced by the presence of the S47F substitution. Thus, the synergistic interaction of two rare amino acid substitutions in the URO-synthase polypeptide caused the feline model of human CEP.

  15. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    NARCIS (Netherlands)

    J.-O. Andressoo (Jaan-Olle); J. Jans (Judith); J. de Wit (Jan); F. Coin (Frédéric); D. Hoogstraten (Deborah); H.W.M. van de Ven (Marieke); W. Toussaint (Wendy); J. Huijmans (Jan); H.B. Thio (Bing); W.J. van Leeuwen (Wibeke); J. de Boer (Jan); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James); J-M. Egly (Jean-Marc)

    2006-01-01

    textabstractAlthough compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specifi

  16. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    NARCIS (Netherlands)

    J.-O. Andressoo (Jaan-Olle); J. Jans (Judith); J. de Wit (Jan); F. Coin (Frédéric); D. Hoogstraten (Deborah); H.W.M. van de Ven (Marieke); W. Toussaint (Wendy); J. Huijmans (Jan); H.B. Thio (Bing); W.J. van Leeuwen (Wibeke); J. de Boer (Jan); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James); J-M. Egly (Jean-Marc)

    2006-01-01

    textabstractAlthough compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specifi

  17. Digital and analog communication systems

    Science.gov (United States)

    Shanmugam, K. S.

    1979-01-01

    The book presents an introductory treatment of digital and analog communication systems with emphasis on digital systems. Attention is given to the following topics: systems and signal analysis, random signal theory, information and channel capacity, baseband data transmission, analog signal transmission, noise in analog communication systems, digital carrier modulation schemes, error control coding, and the digital transmission of analog signals.

  18. Analogical Reasoning in Geometry Education

    Science.gov (United States)

    Magdas, Ioana

    2015-01-01

    The analogical reasoning isn't used only in mathematics but also in everyday life. In this article we approach the analogical reasoning in Geometry Education. The novelty of this article is a classification of geometrical analogies by reasoning type and their exemplification. Our classification includes: analogies for understanding and setting a…

  19. Amplified and homozygously deleted genes in glioblastoma: impact on gene expression levels.

    Directory of Open Access Journals (Sweden)

    Inês Crespo

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown. METHODOLOGY: Single-nucleotide polymorphism (SNP-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46, and to evaluate the impact of copy number alterations (CNA on mRNA levels of the genes involved. PRINCIPAL FINDINGS: Recurrent amplicons were detected for chromosomes 7 (50%, 12 (22%, 1 (11%, 4 (9%, 11 (4%, and 17 (4%, whereas homozygous deletions involved chromosomes 9p21 (52% and 10q (22%. Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2, while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1-q15 and 4q12, respectively. Despite homozygous del(9p21 and del(10q23.31 included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene. CONCLUSIONS: Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes.

  20. The human analog of murine cystein rich protein 61 [correction of 16] is a 1alpha,25-dihydroxyvitamin D3 responsive immediate early gene in human fetal osteoblasts: regulation by cytokines, growth factors, and serum.

    Science.gov (United States)

    Schütze, N; Lechner, A; Groll, C; Siggelkow, H; Hüfner, M; Köhrle, J; Jakob, F

    1998-04-01

    1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is a potent mediator of differentiation and maintenance of specific functions of osteoblasts. To detect novel targets for 1,25-(OH)2D3 action, we applied differential display PCR to human fetal osteoblast-like cells and identified the human analog of murine cystein rich protein 61 (hCYR61) as a 1,25-(OH)2D3-responsive immediate early gene in differentiated fetal osteoblast-like cells. The murine gene CYR61 is important for cell-cell and cell-matrix interactions, and it belongs to an emerging gene family of cysteine-rich proteins. hCYR61 messenger RNA (mRNA) steady-state levels were stimulated 11-fold by 10 nM 1,25-(OH)2D3 by 1 h and declined to control levels by 4 h. This transient stimulation of hCYR61 mRNA was not inhibited by cycloheximide but was prevented by actinomycin D, indicating that the 1,25-(OH)2D3 effect involves transcriptional events and does not require de novo protein synthesis. hCYR61 mRNA stability was not influenced by 1,25(OH)2D3, whereas cycloheximide treatment stabilized hCYR61 mRNA. FCS, as well as growth factors and cytokines such as basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor alpha, and interleukin-1, strongly elevated hCYR61 mRNA steady-state levels within 1 h. hCYR61 mRNA was expressed also in primary human osteoblasts and osteosarcoma cell lines. Using a commercial tissue blot, hCYR61 mRNA was only observed in skeletal muscle. The fast and transient response of hCYR 61 to 1,25-(OH)2D3, serum, growth factors, and cytokines suggests an important role of hCYR61 for osteoblast function and differentiation.

  1. [Efficacy of initial antiretroviral therapy based on lopinavir/ritonavir plus 2 nucleoside/nucleotide analogs in patients with human immunodeficiency virus type 1 infection].

    Science.gov (United States)

    Zamora, Laura; Gatell, José M

    2014-11-01

    Triple combination regimens consisting of lopinavir/ritonavir (LPV/r) plus 2 nucleoside/nucleotide analogs continue to be a valid option in initial antiretroviral therapy. Other protease inhibitors boosted with ritonavir (and in future with cobicistat) have been introduced, as well as other non-nucleoside analogs (rilpivirin) and 3 integrase inhibitors. None of the new regimens have shown superiority over LPV/r or comparisons are lacking. Therefore, regimens including LPV/r continue to be recommended as initial first-line or alternative strategies in most treatment guidelines. Dual combinations with LPV/r (plus raltegravir or lamivudine) are described in another article and can provide a similar response rate to triple combinations, better tolerance, and an improved cost-efficacy ratio, both for initial therapy and in simplification strategies. In contrast, LPV/r or darunavir/r monotherapy does not seem an acceptable option in treatment-naïve patients and is becoming increasingly less acceptable in simplification strategies. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  2. Pregnancy in a Woman with Homozygous Familial Hypercholesterolemia Not on Low-Density Lipoprotein Apheresis

    Directory of Open Access Journals (Sweden)

    Akl C. Fahed

    2012-11-01

    Full Text Available Pregnancy in women with homozygous familial hypercholesterolemia (FH has been rarely reported and might pose risks on the mother and her fetus. Although most reported cases remained on low-density lipoprotein (LDL apheresis, there are no clear guidelines regarding the management of this entity. We report the first case of an uncomplicated pregnancy in a 24-year-old homozygous FH woman who was not maintained on LDL apheresis. FH expresses a wide variability in the phenotype, and management of homozygous FH cases who desire to become pregnant should be individualized based on preconceptional assessment with frequent antenatal follow-up. Decisions on management should be made after weighing the risks versus benefits of LDL apheresis.

  3. Selection of Homozygous Cotton Lines Transformed with Two Insect-Resistant Genes

    Institute of Scientific and Technical Information of China (English)

    WU Jia-he; TIAN Ying-chuan; LUO Xiao-li; GUO Hong-nian; SHI Yue-jin; CHEN Xiao-ying; JIA Yan-tao; XIAO Juan-li; ZHANG Xian-long

    2003-01-01

    A plant expression vector containing a chimeric Bt29K gene coding for the activated Cry1Ac protein and the arrowhead proteinase inhibitior gene API-B were introduced into the cotton cultivar Jihe321 mediated by Agrobactertium tumefaciens. Based on the results of kanamycin resistant testing, PCR detection for both foreign genes and insect bioassay using Heliethis armigera, nine transgenic homozygous cotton lines with insect-resistance of more than 90% and better agronomic traits were bred through six generations from the original transgenic plants. Results from insect bioassay and sequence analysis of the PCR products of plants from some homozygous lines indicated that the chimeric Bt29K gene was stably inherited in these transgenic cotton lines. The main agronomic characters of these homozygous cotton lines, such as boll productivity and fibre strength, were better than that of the original cotton cv. Jihe321.

  4. Are Scientific Analogies Metaphors?

    Science.gov (United States)

    1981-02-01

    psychospiritual processes. A more modern example of unclarified analogy is Freud’s (1973; reprinted from 1955) discussion of anal- eroticism , in which...299-304. Freud, S. On transformations of instinct as exemplified in anal eroticism . In J. Strachey (Ed.), The standard 37 edition of the complete

  5. Quantum Analog Computing

    Science.gov (United States)

    Zak, M.

    1998-01-01

    Quantum analog computing is based upon similarity between mathematical formalism of quantum mechanics and phenomena to be computed. It exploits a dynamical convergence of several competing phenomena to an attractor which can represent an externum of a function, an image, a solution to a system of ODE, or a stochastic process.

  6. Peptide-binding motifs associated with MHC molecules common in Chinese rhesus macaques are analogous to those of human HLA supertypes and include HLA-B27-like alleles

    DEFF Research Database (Denmark)

    Mothé, Bianca R.; Southwood, Scott; Sidney, John

    2013-01-01

    and deciphering outcomes of infection and vaccine efficacy. In this study, we have provided detailed characterization of six prevalent Chinese rhesus macaque MHC class I alleles, yielding a combined phenotypic frequency of 29 %. The peptide-binding specificity of two of these alleles, Mamu-A2*01:02 and Mamu-B*010...... in humans. All six alleles characterized in the present study were found to have specificities analogous to HLA supertype alleles. These data contribute to the concept that Chinese rhesus macaque MHC immunogenetics is more similar to HLA than their Indian rhesus macaque counterparts and thereby warrants......Chinese rhesus macaques are of particular interest in simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) research as these animals have prolonged kinetics of disease progression to acquired immunodeficiency syndrome (AIDS), compared to their Indian counterparts, suggesting...

  7. Analogies in medicine: valuable for learning, reasoning, remembering and naming.

    Science.gov (United States)

    Pena, Gil Patrus; Andrade-Filho, José de Souza

    2010-10-01

    Analogies are important tools in human reasoning and learning, for resolving problems and providing arguments, and are extensively used in medicine. Analogy and similarity involve a structural alignment or mapping between domains. This cognitive mechanism can be used to make inferences and learn new abstractions. Through analogies, we try to explain a knowledge to be achieved (the target), with pieces of information already familiar to the learner (the source), keeping in mind the constraints of similarity, structure and purpose. The purpose of this essay is to examine the use of analogies in medicine. We provide a brief review of the theoretical basis of analogical reasoning. This theoretical background is discussed in the light of actual examples of analogies retrieved from medical literature. In medicine, analogies have long been used to explain several physiologic and pathologic processes. Besides deeper structural relations, superficial attribute similarity is extensively used in many medical specialties. These attribute similarities are important in naming, categorizing and classifying, and play a role as learning and memorizing tools. Analogies also serve as basis for medical nomenclature. The choice of the source of analogies is highly dependent on cultural background, and may derive from ancient or diverse cultures. Learning by analogies may thus require research on culture diversity in order to establish an adequate justification and to comprehend the purpose of an analogy.

  8. Low-Latency Science Exploration of Planetary Bodies: How ISS Might Be Used as Part of a Low-Latency Analog Campaign for Human Exploration

    Science.gov (United States)

    Thronson, Harley; Valinia, Azita; Bleacher, Jacob; Eigenbrode, Jennifer; Garvin, Jim; Petro, Noah

    2014-01-01

    We suggest that the International Space Station be used to examine the application and validation of low-latency telepresence for surface exploration from space as an alternative, precursor, or potentially as an adjunct to astronaut "boots on the ground." To this end, controlled experiments that build upon and complement ground-based analog field studies will be critical for assessing the effects of different latencies (0 to 500 milliseconds), task complexity, and alternate forms of feedback to the operator. These experiments serve as an example of a pathfinder for NASA's roadmap of missions to Mars with low-latency telerobotic exploration as a precursor to astronaut's landing on the surface to conduct geological tasks.

  9. Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure.

    Science.gov (United States)

    Gao, Shan; Jakobs, Tatjana C

    2016-04-01

    A genomic region located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a transgenic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. Homozygous mice of this strain were previously reported to show persistent hyperplastic primary vitreous. Fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram, and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, whereas glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by approximately 50% in the heterozygous mice and by 90% in the homozygous mice, which suggested that the CDKN2B knock down had no deleterious consequences for the retina under normal conditions. However, compared with wild-type and heterozygous animals, the homozygous mice are more vulnerable to retinal ganglion cell loss in response to elevated intraocular pressure.

  10. Terrestrial Spaceflight Analogs: Antarctica

    Science.gov (United States)

    Crucian, Brian

    2013-01-01

    Alterations in immune cell distribution and function, circadian misalignment, stress and latent viral reactivation appear to persist during Antarctic winterover at Concordia Station. Some of these changes are similar to those observed in Astronauts, either during or immediately following spaceflight. Others are unique to the Concordia analog. Based on some initial immune data and environmental conditions, Concordia winterover may be an appropriate analog for some flight-associated immune system changes and mission stress effects. An ongoing smaller control study at Neumayer III will address the influence of the hypoxic variable. Changes were observed in the peripheral blood leukocyte distribution consistent with immune mobilization, and similar to those observed during spaceflight. Alterations in cytokine production profiles were observed during winterover that are distinct from those observed during spaceflight, but potentially consistent with those observed during persistent hypobaric hypoxia. The reactivation of latent herpesviruses was observed during overwinter/isolation, that is consistently associated with dysregulation in immune function.

  11. Analogy Construction versus Analogy Solution, and Their Influence on Transfer

    Science.gov (United States)

    Harpaz-Itay, Yifat; Kaniel, Shlomo; Ben-Amram, Einat

    2006-01-01

    This study compares transfer performed by subjects trained to solve verbal analogies, with transfer by subjects trained to construct them. The first group (n = 57) received instruction in a strategy to solve verbal analogies and the second group (n = 66) was trained in strategies for constructing such analogies. Before and after intervention, all…

  12. A Transiting Jupiter Analog

    CERN Document Server

    Kipping, David M; Henze, Chris; Teachey, Alex; Isaacson, Howard T; Petigura, Erik A; Marcy, Geoffrey W; Buchhave, Lars A; Chen, Jingjing; Bryson, Steve T; Sandford, Emily

    2016-01-01

    Decadal-long radial velocity surveys have recently started to discover analogs to the most influential planet of our solar system, Jupiter. Detecting and characterizing these worlds is expected to shape our understanding of our uniqueness in the cosmos. Despite the great successes of recent transit surveys, Jupiter analogs represent a terra incognita, owing to the strong intrinsic bias of this method against long orbital periods. We here report on the first validated transiting Jupiter analog, Kepler-167e (KOI-490.02), discovered using Kepler archival photometry orbiting the K4-dwarf KIC-3239945. With a radius of $(0.91\\pm0.02)$ $R_{\\mathrm{Jup}}$, a low orbital eccentricity ($0.06_{-0.04}^{+0.10}$) and an equilibrium temperature of $(131\\pm3)$ K, Kepler-167e bears many of the basic hallmarks of Jupiter. Kepler-167e is accompanied by three Super-Earths on compact orbits, which we also validate, leaving a large cavity of transiting worlds around the habitable-zone. With two transits and continuous photometric ...

  13. Increased frequency of minimal homozygous deletions is associated with poor prognosis in primary malignant melanoma patients.

    Science.gov (United States)

    Boi, Sebastiana; Tebaldi, Toma; Re, Angela; Cantaloni, Chiara; Adami, Valentina; Barbareschi, Mattia; Cristofolini, Mario; Pasini, Luigi; Quattrone, Alessandro

    2014-06-01

    Identification of prognostic melanoma-associated copy number alterations (CNAs) is still an area of active research. Here, we investigated by high-resolution array comparative genomic hybridization (aCGH) a cohort of 31 paraffin-preserved primary malignant melanomas (MMs), whose prognosis was not predictable on the basis of conventional histopathological parameters. Although we identified a variety of highly recurrent sites of genomic lesions, the total number of CNAs per patient was not a discriminator of MM outcome. Furthermore, validation of aCGH by quantitative PCR on an extended population of 65 MM samples confirmed the absence of predictive value for the most recurrent CNA loci. Instead, our analysis revealed specific prognostic potential of the frequency of homozygous deletions (representing less than 3% of the total CNAs on average per sample), which was strongly associated with sentinel lymph node (SLN) invasion (P = 0.003), and distant metastasis (P = 0.003). Increased number of homozygous deletions was also indicative of poor patient survival (P = 0.01), both in our samples and in an independent validation of public dataset of primary and metastatic MMs. Moreover, we identified 77 hotspots of minimal common homozygous deletions, enriched in genes involved in cell adhesion processes and cell-communication functions, which preferentially accumulated in primary MMs showing the most severe outcome. Therefore, specific loss of gene loci in regions of minimal homozygous deletion may represent a pivotal type of genomic alteration accumulating during MM progression with potential prognostic implication.

  14. Limb defects and congenital anomalies of the genitalia in an infant with homozygous alpha-thalassemia.

    Science.gov (United States)

    Abuelo, D N; Forman, E N; Rubin, L P

    1997-01-20

    We describe an infant with homozygous alpha-thalassemia, genital abnormalities, and terminal transverse limb defects, whose limbs demonstrate evidence of loss of tissue and abnormal morphogenesis. We propose these defects were due to either severe fetal anemia or to vascular occlusion by abnormal erythrocytes, resulting in hypoxia of the developing distal limbs and genitalia.

  15. Insulin analogs and cancer: A note of caution

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractIn view of the lifelong exposure and large patient populations involved, insulin analogs with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogs may possibly induce the growth of pre-existing neoplasms. At p

  16. Insulin analogs and cancer: A note of caution

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractIn view of the lifelong exposure and large patient populations involved, insulin analogs with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogs may possibly induce the growth of pre-existing neoplasms. At

  17. Human Factor Investigation of Waste Processing System During the HI-SEAS 4 Month Mars Analog Mission in Support of NASA's Logistic Reduction and Repurposing Project: Trash to Gas

    Science.gov (United States)

    Caraccio, Anne; Hintze, Paul; Miles, John D.

    2014-01-01

    NASAs Logistics Reduction and Repurposing (LRR) project is a collaborative effort in which NASA is tasked with reducing total logistical mass through reduction, reuse and recycling of various wastes and components of long duration space missions and habitats. Trash to Gas (TtG) is a sub task to LRR with efforts focused on development of a technology that converts wastes generated during long duration space missions into high-value products such as methane, water for life support, raw material production feedstocks, and other energy sources. The reuse of discarded materials is a critical component to reducing overall mission mass. The 120 day Hawaii Space Exploration and Analog Simulation provides a unique opportunity to answer questions regarding crew interface and system analysis for designing and developing future flight-like versions of a TtG system. This paper will discuss the human factors that would affect the design of a TtG or other waste processing systems. An overview of the habitat, utility usage, and waste storage and generation is given. Crew time spent preparing trash for TtG processing was recorded. Gas concentrations were measured near the waste storage locations and at other locations in the habitat. In parallel with the analog mission, experimental processing of waste materials in a TtG reactor was performed in order to evaluate performance with realistic waste materials.

  18. Human Factor Investigation of Waste Processing System During the HI-SEAS 4-month Mars Analog Mission in Support of NASA's Logistic Reduction and Repurposing Project: Trash to Gas

    Science.gov (United States)

    Caraccio, Anne; Hintze, Paul E.; Miles, John D.

    2014-01-01

    NASA's Logistics Reduction and Repurposing (LRR) project is a collaborative effort in which NASA is tasked with reducing total logistical mass through reduction, reuse and recycling of various wastes and components of long duration space missions and habitats. Trash to Gas (TtG) is a sub task to LRR with efforts focused on development of a technology that converts wastes generated during long duration space missions into high-value products such as methane, water for life support, raw material production feedstocks, and other energy sources. The reuse of discarded materials is a critical component to reducing overall mission mass. The 120 day Hawaii Space Exploration and Analog Simulation provides a unique opportunity to answer questions regarding crew interface and system analysis for designing and developing future flight-like versions of a TtG system. This paper will discuss the human factors that would affect the design of a TtG or other waste processing systems. An overview of the habitat, utility usage, and waste storage and generation is given. Crew time spent preparing trash for TtG processing was recorded. Gas concentrations were measured near the waste storage locations and at other locations in the habitat. In parallel with the analog mission, experimental processing of waste materials in a TtG reactor was performed in order to evaluate performance with realistic waste materials.

  19. Inductive, Analogical, and Communicative Generalization

    Directory of Open Access Journals (Sweden)

    Adri Smaling

    2003-03-01

    Full Text Available Three forms of inductive generalization - statistical generalization, variation-based generalization and theory-carried generalization - are insufficient concerning case-to-case generalization, which is a form of analogical generalization. The quality of case-to-case generalization needs to be reinforced by setting up explicit analogical argumentation. To evaluate analogical argumentation six criteria are discussed. Good analogical reasoning is an indispensable support to forms of communicative generalization - receptive and responsive (participative generalization — as well as exemplary generalization.

  20. CRC handbook of neurohypophyseal hormone analogs. Volume 2

    Energy Technology Data Exchange (ETDEWEB)

    Jost, K.; Lebl, M.; Brtnik, F.

    1987-01-01

    This book is discussed in two parts. The Part 1 discusses the: Prohormones and Hormonogens of Neuro-hypophyseal Hormones, Analogs with Inhibitory properties. Analogs with Dissociated and/or High activities. Introduction. Uterotonic Activity. Galactogogic Activity. Pressor Activity. Antidiuretic Activity. References. Part 2 discusses the Other Important Activities. CNS Activities. Corticotropin- and ..beta..-Entriuretic Action. Natriferic Action. References. Practical Use in Human and Veterinary Medicine. Introduction. Methyloxytocin. Deamino-Oxytocin. Cargutocin. Glypressin. Octapressin. Desmopressin. Analogs Clinically Tried But Not Introduced into Production and Routine Clinical Practice. References. Tables of Analogs and Index.

  1. Increased microerythrocyte count in homozygous alpha(+-thalassaemia contributes to protection against severe malarial anaemia.

    Directory of Open Access Journals (Sweden)

    Freya J I Fowkes

    2008-03-01

    Full Text Available The heritable haemoglobinopathy alpha(+-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb. Individuals homozygous for alpha(+-thalassaemia have microcytosis and an increased erythrocyte count. Alpha(+-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA (Hb concentration 1.1 x 10(12/l as a result of the reduced mean cell Hb in homozygous alpha(+-thalassaemia. In addition, children homozygous for alpha(+-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02 for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for alpha(+-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09.The increased erythrocyte count and microcytosis in children homozygous for alpha(+-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.

  2. Multilateral Research Opportunities in Ground Analogs

    Science.gov (United States)

    Corbin, Barbara J.

    2015-01-01

    The global economy forces many nations to consider their national investments and make difficult decisions regarding their investment in future exploration. International collaboration provides an opportunity to leverage other nations' investments to meet common goals. The Humans In Space Community shares a common goal to enable safe, reliable, and productive human space exploration within and beyond Low Earth Orbit. Meeting this goal requires efficient use of limited resources and International capabilities. The International Space Station (ISS) is our primary platform to conduct microgravity research targeted at reducing human health and performance risks for exploration missions. Access to ISS resources, however, is becoming more and more constrained and will only be available through 2020 or 2024. NASA's Human Research Program (HRP) is actively pursuing methods to effectively utilize the ISS and appropriate ground analogs to understand and mitigate human health and performance risks prior to embarking on human exploration of deep space destinations. HRP developed a plan to use ground analogs of increasing fidelity to address questions related to exploration missions and is inviting International participation in these planned campaigns. Using established working groups and multilateral panels, the HRP is working with multiple Space Agencies to invite International participation in a series of 30- day missions that HRP will conduct in the US owned and operated Human Exploration Research Analog (HERA) during 2016. In addition, the HRP is negotiating access to Antarctic stations (both US and non-US), the German :envihab and Russian NEK facilities. These facilities provide unique capabilities to address critical research questions requiring longer duration simulation or isolation. We are negotiating release of international research opportunities to ensure a multilateral approach to future analog research campaigns, hoping to begin multilateral campaigns in the

  3. Homozygosity mapping and whole exome sequencing reveal a novel homozygous COL18A1 mutation causing Knobloch syndrome.

    Directory of Open Access Journals (Sweden)

    Alireza Haghighi

    Full Text Available The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES was performed with the patients' DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS. Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.

  4. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.

    Directory of Open Access Journals (Sweden)

    Anatoly Urisman

    2006-03-01

    Full Text Available Ribonuclease L (RNase L is an important effector of the innate antiviral response. Mutations or variants that impair function of RNase L, particularly R462Q, have been proposed as susceptibility factors for prostate cancer. Given the role of this gene in viral defense, we sought to explore the possibility that a viral infection might contribute to prostate cancer in individuals harboring the R462Q variant. A viral detection DNA microarray composed of oligonucleotides corresponding to the most conserved sequences of all known viruses identified the presence of gammaretroviral sequences in cDNA samples from seven of 11 R462Q-homozygous (QQ cases, and in one of eight heterozygous (RQ and homozygous wild-type (RR cases. An expanded survey of 86 tumors by specific RT-PCR detected the virus in eight of 20 QQ cases (40%, compared with only one sample (1.5% among 66 RQ and RR cases. The full-length viral genome was cloned and sequenced independently from three positive QQ cases. The virus, named XMRV, is closely related to xenotropic murine leukemia viruses (MuLVs, but its sequence is clearly distinct from all known members of this group. Comparison of gag and pol sequences from different tumor isolates suggested infection with the same virus in all cases, yet sequence variation was consistent with the infections being independently acquired. Analysis of prostate tissues from XMRV-positive cases by in situ hybridization and immunohistochemistry showed that XMRV nucleic acid and protein can be detected in about 1% of stromal cells, predominantly fibroblasts and hematopoietic elements in regions adjacent to the carcinoma. These data provide to our knowledge the first demonstration that xenotropic MuLV-related viruses can produce an authentic human infection, and strongly implicate RNase L activity in the prevention or clearance of infection in vivo. These findings also raise questions about the possible relationship between exogenous infection and cancer

  5. TOWARDS A MATHEMATICAL THEORY OF ANALOGY

    OpenAIRE

    Haraguchi, Makoto

    1985-01-01

    This paper presents a mathematical theory of analogy, which should be a basis in developing analogical reasoning by a computer. The analogy is a partial identity between two sets of facts. In order to compare several analogies, we introduce an ordering of analogies, and we define two types of optimal analogies, maximal analogies and greatest ones. We show a condition under which the greatest analogy exists, and also present a top-down procedure to find the maximal analogies.

  6. NaturAnalogs for the Unsaturated Zone

    Energy Technology Data Exchange (ETDEWEB)

    A. Simmons; A. Unger; M. Murrell

    2000-03-08

    The purpose of this Analysis/Model Report (AMR) is to document natural and anthropogenic (human-induced) analog sites and processes that are applicable to flow and transport processes expected to occur at the potential Yucca Mountain repository in order to build increased confidence in modeling processes of Unsaturated Zone (UZ) flow and transport. This AMR was prepared in accordance with ''AMR Development Plan for U0135, Natural Analogs for the UZ'' (CRWMS 1999a). Knowledge from analog sites and processes is used as corroborating information to test and build confidence in flow and transport models of Yucca Mountain, Nevada. This AMR supports the Unsaturated Zone (UZ) Flow and Transport Process Model Report (PMR) and the Yucca Mountain Site Description. The objectives of this AMR are to test and build confidence in the representation of UZ processes in numerical models utilized in the UZ Flow and Transport Model. This is accomplished by: (1) applying data from Boxy Canyon, Idaho in simulations of UZ flow using the same methodologies incorporated in the Yucca Mountain UZ Flow and Transport Model to assess the fracture-matrix interaction conceptual model; (2) Providing a preliminary basis for analysis of radionuclide transport at Pena Blanca, Mexico as an analog of radionuclide transport at Yucca Mountain; and (3) Synthesizing existing information from natural analog studies to provide corroborating evidence for representation of ambient and thermally coupled UZ flow and transport processes in the UZ Model.

  7. Neurotoxic Alkaloids: Saxitoxin and Its Analogs

    Directory of Open Access Journals (Sweden)

    Troco K. Mihali

    2010-07-01

    Full Text Available Saxitoxin (STX and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs. PSTs are the causative agents of paralytic shellfish poisoning (PSP and are mostly associated with marine dinoflagellates (eukaryotes and freshwater cyanobacteria (prokaryotes, which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs—each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids.

  8. Analogical scaffolding: Making meaning in physics through representation and analogy

    Science.gov (United States)

    Podolefsky, Noah Solomon

    This work reviews the literature on analogy, introduces a new model of analogy, and presents a series of experiments that test and confirm the utility of this model to describe and predict student learning in physics with analogy. Pilot studies demonstrate that representations (e.g., diagrams) can play a key role in students' use of analogy. A new model of analogy, Analogical Scaffolding, is developed to explain these initial empirical results. This model will be described in detail, and then applied to describe and predict the outcomes of further experiments. Two large-scale (N>100) studies will demonstrate that: (1) students taught with analogies, according to the Analogical Scaffolding model, outperform students taught without analogies on pre-post assessments focused on electromagnetic waves; (2) the representational forms used to teach with analogy can play a significant role in student learning, with students in one treatment group outperforming students in other treatment groups by factors of two or three. It will be demonstrated that Analogical Scaffolding can be used to predict these results, as well as finer-grained results such as the types of distracters students choose in different treatment groups, and to describe and analyze student reasoning in interviews. Abstraction in physics is reconsidered using Analogical Scaffolding. An operational definition of abstraction is developed within the Analogical Scaffolding framework and employed to explain (a) why physicists consider some ideas more abstract than others in physics, and (b) how students conceptions of these ideas can be modeled. This new approach to abstraction suggests novel approaches to curriculum design in physics using Analogical Scaffolding.

  9. ESD analog circuits and design

    CERN Document Server

    Voldman, Steven H

    2014-01-01

    A comprehensive and in-depth review of analog circuit layout, schematic architecture, device, power network and ESD design This book will provide a balanced overview of analog circuit design layout, analog circuit schematic development, architecture of chips, and ESD design.  It will start at an introductory level and will bring the reader right up to the state-of-the-art. Two critical design aspects for analog and power integrated circuits are combined. The first design aspect covers analog circuit design techniques to achieve the desired circuit performance. The second and main aspect pres

  10. Anti-Plasmodium activity of ceramide analogs

    Directory of Open Access Journals (Sweden)

    Gatt Shimon

    2004-12-01

    Full Text Available Abstract Background Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs. Methods The anti-Plasmodium activity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite. Results Analogs containing methylene linkage showed a considerably higher anti-Plasmodium activity (IC50 in the low nanomolar range than PPMP and their counterparts with a natural amide linkage (IC50 in the micromolar range. The methylene analogs blocked irreversibly P. falciparum development leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target. Conclusions It has been shown that ceramide analogs were potent inhibitors of P. falciparum growth in culture. Interestingly, the nature of the linkage between the fatty acid part and the

  11. Albert Einstein, Analogizer Extraordinaire

    CERN Document Server

    CERN. Geneva

    2007-01-01

    Where does deep insight in physics come from? It is tempting to think that it comes from the purest and most precise of reasoning, following ironclad laws of thought that compel the clear mind completely rigidly. And yet the truth is quite otherwise. One finds, when one looks closely at any major discovery, that the greatest of physicists are, in some sense, the most crazily daring and irrational of all physicists. Albert Einstein exemplifies this thesis in spades. In this talk I will describe the key role, throughout Albert Einstein's fabulously creative life, played by wild guesses made by analogy lacking any basis whatsoever in pure reasoning. In particular, in this year of 2007, the centenary of 1907, I will describe how over the course of two years (1905 through 1907) of pondering, Einstein slowly came, via analogy, to understand the full, radical consequences of the equation that he had first discovered and published in 1905, arguably the most famous equation of all time: E = mc2.

  12. Fluorinated Analogs of Malachite Green: Synthesis and Toxicity

    Directory of Open Access Journals (Sweden)

    Bahram Parvin

    2008-04-01

    Full Text Available A series of fluorinated analogs of malachite green (MG have been synthesizedand their toxicity to Saccharomyces cerevisiae and a human ovarian epithelial cell lineexamined. The toxicity profiles were found to be different for these two species. Twoanalogs, one with 2,4-difluoro substitution and the other with 2-fluoro substitution seem tobe the most promising analogs because they showed the lowest toxicity to the human cells.

  13. Acute splenic sequestration in a pregnant woman with homozygous sickle-cell anemia

    Directory of Open Access Journals (Sweden)

    Carolina Bastos Maia

    Full Text Available CONTEXT Homozygous (SS sickle-cell anemia complicated by acute splenic sequestration in adults is a rare event, and it has never been reported during pregnancy. CASE REPORT A 25-year-old woman with homozygous (SS sickle-cell disease was hospitalized at 32 weeks' of gestation presenting weakness, abdominal pain, fever and hemoglobin of 2.4 g/dl. Abnormal fetal heart rate was detected by means of cardiotocography, and 5 units of packed red cells were transfused. Cesarean was performed at 37 weeks. Both mother and baby were discharged in a good general condition. CONCLUSION This case report demonstrates the importance of immediate blood transfusion for treatment of fetal distress in cases of splenic sequestration during pregnancy. This treatment is essential for avoiding maternal and fetal complications.

  14. A novel HYLS1 homozygous mutation in living siblings with Joubert syndrome.

    Science.gov (United States)

    Oka, M; Shimojima, K; Yamamoto, T; Hanaoka, Y; Sato, S; Yasuhara, T; Yoshinaga, H; Kobayashi, K

    2016-06-01

    The p.Asp211Gly homozygous HYLS1 mutation is so far known to cause only hydrolethalus syndrome, a lethal malformation syndrome. We report living sibling patients with a homozygous no-stop mutation in exon 4 of HYLS1, NM_145014.2:c.900A>C (p.Ter300TyrextTer11) in the second decade of life. The proband has Joubert syndrome (JS). The younger brother also has JS and an enlarged posterior fossa that was initially diagnosed as Dandy-Walker malformation. The present mutation is unique as it affects the stop codon. The product protein HYLS1 plays an essential role in the formation of the primary cilium. This report provides insight into the spectrum of disorders involving midline brain defects closely related to cilium dysfunction or ciliopathy.

  15. Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation

    Directory of Open Access Journals (Sweden)

    Eng Christine M

    2011-07-01

    Full Text Available Abstract Isolated hypocortisolism due to ACTH deficiency is a rare condition that can be caused by homozygous or compound heterozygous mutations in the gene encoding proopiomelanocortin (POMC. Loss of function mutations of POMC gene typically results in adrenal insufficiency, obesity and red hair. We describe an 18 month old Hispanic female with congenital adrenal insufficiency, a novel POMC mutation and atypical clinical features. The patient presented at the age of 9 months with hypoglycemia and the endocrine evaluation resulted in a diagnosis of ACTH deficiency. She developed extreme weight gain prompting sequence analysis of POMC, which revealed a homozygous c.231C > A change which is predicted to result in a premature termination codon. The case we report had obesity, hypocortisolism but lacked red hair which is typical for subjects with POMC mutations. Mutations of POMC should be considered in individuals with severe early onset obesity and adrenal insufficiency even when they lack the typical pigmentary phenotype.

  16. Rapidly progressive atherosclerosis after domino liver transplantation from a teenage donor with homozygous familial hypercholesterolemia.

    Science.gov (United States)

    Golbus, Jessica R; Farhat, Linda; Fontana, Robert J; Rubenfire, Melvyn

    2017-07-22

    Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by impaired clearance of low-density lipoprotein cholesterol. Given limitations in pharmacologic therapy and the significant morbidity and mortality associated with this disease, liver transplantation may be offered to select homozygous FH patients in childhood in an effort to slow progression of atherosclerotic cardiovascular disease. In rare cases, domino liver transplantation can be performed, transplanting the livers of patients with various metabolic disorders into elderly recipients whose projected survival precludes prolonged waiting on the transplant list. Herein, we report a case of domino liver transplantation using the liver of a 14-year-old boy with homozygous FH into a 65-year-old man with primary sclerosing cholangitis and cirrhosis who developed rapidly progressive atherosclerotic cardiovascular disease involving the arteries of his proximal bilateral lower extremities, carotid arteries and superior mesenteric artery. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  17. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

    DEFF Research Database (Denmark)

    Wainwright, Claire E; Elborn, J Stuart; Ramsey, Bonnie W

    2015-01-01

    BACKGROUND: Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. METHODS: We conducted two phase 3, randomized, double-blind, placebo......-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly...... homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.)....

  18. Assessment of factors influencing the within-batch seroprevalence of human enteropathogenic Yersinia spp. of pigs at slaughter age and the analogy with microbiology.

    Science.gov (United States)

    Vanantwerpen, G; Berkvens, D; De Zutter, L; Houf, K

    2017-02-01

    The microbiologically and serologically-based prevalence of human enteropathogenic Yersinia spp. at moment of slaughter varies between pig farms due to different herd-level factors. A face-to-face questionnaire concerning a broad range of farm aspects (e.g., management and housing system, biosecurity, and hygiene measurements) was performed on one hundred farms. Factors influencing the seropositivity of 7047 pigs against human pathogenic Yersinia spp. were determined and compared to the microbiology. At the slaughterhouse, pieces of diafragm of on average 70 slaughter pigs per batch were sampled to determine the level of antibodies against enteropathogenic Yersinia spp. After univariable mixed-effect logistic regressions, variables that were related to the seropositivity (pYersinia spp. at moment of slaughter or during rearing is possible by changing farm management factors. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line

    OpenAIRE

    Kedei Noémi; Telek Andrea (1977-) (élettanász); Czap Alexandra; Lubart, Emanuel S.; Czifra Gabriella (1975-) (élettanász); Yang, Dazhi; Chen, Jinqiu; Morrison, Tyler; Goldsmith, Paul K.; Lim, Langston; Mannan, Poonam; Garfield, Susan H.; Kraft, Matthew B.; Li, Wei; Keck, Gary E.

    2011-01-01

    Bryostatin 1 has attracted considerable attention both as a cancer chemotherapeutic agent and for its unique activity. Although it functions, like phorbol esters, as a potent protein kinase C (PKC) activator, it paradoxically antagonizes many phorbol ester responses in cells. Because of its complex structure, little is known of its structure-function relations. Merle 23 is a synthetic derivative, differing from bryostatin 1 at only four positions. However, in U-937 human leukemia cells, Merle...

  20. Characterization of the regulatory region of the zebrafish Prep1.1 gene: analogies to the promoter of the human PREP1.

    Directory of Open Access Journals (Sweden)

    Elisa Bernardi

    Full Text Available Prep1 is a developmentally essential TALE class homeodomain transcription factor. In zebrafish and mouse, Prep1 is already ubiquitously expressed at the earliest stages of development, with important tissue-specific peculiarities. The Prep1 gene in mouse is developmentally essential and has haploinsufficient tumor suppressor activity [1]. We have determined the human Prep1 transcription start site (TSS by primer extension analysis and identified, within 20 bp, the transcription start region (TSR of the zebrafish Prep1.1 promoter. The functions of the zebrafish 5' upstream sequences were analyzed both by transient transfections in Hela Cells and by injection in zebrafish embryos. This analysis revealed a complex promoter with regulatory sequences extending up to -1.8, possibly -5.0 Kb, responsible for tissue specific expression. Moreover, the first intron contains a conserved tissue-specific enhancer both in zebrafish and in human cells. Finally, a two nucleotides mutation of an EGR-1 site, conserved in all species including human and zebrafish and located at a short distance from the TSS, destroyed the promoter activity of the -5.0 Kb promoter. A transgenic fish expressing GFP under the -1.8 Kb zebrafish promoter/enhancer co-expressed GFP and endogenous Prep1.1 during embryonic development. In the adult fish, GFP was expressed in hematopoietic regions like the kidney, in agreement with the essential function of Prep1 in mouse hematopoiesis. Sequence comparison showed conservation from man to fish of the sequences around the TSS, within the first intron enhancer. Moreover, about 40% of the sequences spread throughout the 5 Kbof the zebrafish promoter are concentrated in the -3 to -5 Kb of the human upstream region.

  1. A homozygous mutation in PEX16 identified by whole-exome sequencing ending a diagnostic odyssey

    Directory of Open Access Journals (Sweden)

    Carlos A. Bacino

    2015-12-01

    Full Text Available We present a patient with a unique neurological phenotype with a progressive neurodegenerative. An 18-year diagnostic odyssey for the patient ended when exome sequencing identified a homozygous PEX16 mutation suggesting an atypical peroxisomal biogenesis disorder (PBD. Interestingly, the patient's peroxisomal biochemical abnormalities were subtle, such that plasma very-long-chain fatty acids initially failed to provide a diagnosis. This case suggests that next-generation sequencing may be diagnostic in some atypical peroxisomal biogenesis disorders.

  2. Dataset for a case report of a homozygous PEX16 F332del mutation.

    Science.gov (United States)

    Bacino, Carlos; Chao, Yu-Hsin; Seto, Elaine; Lotze, Tim; Xia, Fan; Jones, Richard O; Moser, Ann; Wangler, Michael F

    2016-03-01

    This dataset provides a clinical description along with extensive biochemical and molecular characterization of a patient with a homozygous mutation in PEX16 with an atypical phenotype. This patient described in Molecular Genetics and Metabolism Reports was ultimately diagnosed with an atypical peroxisomal disorder on exome sequencing. A clinical timeline and diagnostic summary, results of an extensive plasma and fibroblast analysis of this patient׳s peroxisomal profile is provided. In addition, a table of additional variants from the exome analysis is provided.

  3. Secretory component as the mucosal transport receptor: separation of physicochemically analogous human IgA fractions with different receptor-binding capacities.

    Science.gov (United States)

    Schiff, J M; Fisher, M M; Underdown, B J

    1986-01-01

    This paper describes the separation and characterization of several IgA fractions from the same human monoclonal source, based on their ability to bind secretory component (SC). The study was undertaken to elucidate features of the immunoglobulin-binding site for SC, and to examine the dependence of mucosal transport on IgA-SC interaction. Enrichment or depletion of SC-binding activity was accomplished on an affinity adsorbant made with SC from human colostral whey. The affinity-purified human IgA fractions contained IgA polymers and were 77% active in rebinding to the adsorbant; this activity was diminished significantly by direct radioiodination. The non-adherent IgA fractions contained both polymer and monomer, and were only 8% active in rebinding to the adsorbant. When the polymer and monomer components were separated from each other, the non-adherent polymer was found to resemble the affinity-purified fraction by all criteria examined including J-chain content, except that the SC-binding capacity was greater than five-fold lower. These findings have two implications for the SC-binding site on human IgA: first, the presence of J-chain is insufficient to bestow IgA with SC-binding activity; second, a critical tyrosine participates in maintaining the SC-binding region, possibly on the IgA heavy chain. The relationship between SC binding and mucosal transport was tested in the rat hepatobiliary model. All radiolabeled human IgA fractions were captured rapidly from blood by the rat liver, but only the SC-binding fractions underwent substantial intact transport to bile (greater than 70% of the injected dose). Even though a nominal proportion of the SC-non-adherent IgA appeared in bile (4-15% of the dose), most IgA in these fractions was rapidly degraded within the liver. Thus, only a small amount of monomeric and polymeric IgA can use alternative receptors to get to bile by diversion from the degradative pathway. Polymeric IgA can undergo efficient transport across

  4. Transgenic rice homozygous lines expressing GNA showed enhanced resistance to rice brown planthopper

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Mature seed-derived calli from two elite Chinese japonica rice (Oryza sativa L.) cultivars Eyi 105 and Ewan 5 were co-transformed with two plasmids, pWRG1515 and pRSSGNA1, containing the selectable marker hygromycin phosphotransferase gene (hpt), the reporter β-glucuronidase gene (gusA) and the snowdrop (Galanthus nivalis)lectin gene (gna) via particle bombardment. 61 independent transgenic rice plants were regenerated from 329 bombarded calli. 79% transgenic plants contained all the three genes, revealed by PCR/Southern blot analysis. Western blot analysis revealed that 36 out of 48 gna-containing transgenic plants expressed GNA (75 %) at various levels with the highest expression being approximately 0.5% of total soluble protein. Genetic analysis confirmed Mendelian segregation of transgenes in progeny. From the R2 generations whose R1 parent plants showing 3:1 Mendelian segregation patterns,we identified five independent homozygous lines containing and expressing all the three transgenes. Insect bioassay and feeding tests showed that these homozygous lines had significant inhibition to rice brown planthopper (Nilaparvata lugens, BPH) by decreasing BPH survival and overall fecundity, retarding BPH development and declining BPH feeding.These BPH-resistant lines have been incorporated into rice insect resistance breeding program. This is the first report that homozygous transgenic rice lines expressing GNA, developed by genetic transformation and through genetic analysis-based selection, conferred enhanced resistance to BPH, one of the most damaging insect pests in rice.

  5. Microsatellite diversity and crossover regions within homozygous and heterozygous SLA haplotypes of different pig breeds.

    Science.gov (United States)

    Ando, Asako; Uenishi, Hirohide; Kawata, Hisako; Tanaka-Matsuda, Maiko; Shigenari, Atsuko; Flori, Laurence; Chardon, Patrick; Lunney, Joan K; Kulski, Jerzy K; Inoko, Hidetoshi

    2008-07-01

    Our aim was to investigate microsatellite (MS) diversity and find crossover regions at 42 polymorphic MS loci in the swine leukocyte antigen (SLA) genomic region of 72 pigs with different well-defined homozygous and heterozygous SLA haplotypes. We analyzed the genetic polymorphisms of 42 MS markers in 23 SLA homozygous-heterozygous, common pig breeds with 12 SLA serological haplotypes and 49 National Institutes of Health (NIH) and Clawn homozygous-heterozygous miniature pigs with nine SLA serological or genotyped haplotypes including four recombinant haplotypes. In comparing the same and different haplotypes, both haplospecific patterns and allelic variations were observed at the MS loci. Some of the shared haplotype blocks extended over 2 Mb suggesting the existence of strong linkage disequilibrium (LD) in the entire SLA region. Crossover regions were easily defined by the MS markers within the class I and/or III region in the NIH and Clawn recombinant haplotypes. The present haplotype comparison shows that our set of MS markers provides a fast and cost-efficient alternative, or complementary, method to the serological or sequence-based determination of the SLA alleles for the characterization of SLA haplotypes and/or the crossover regions between different haplotypes.

  6. Laryngeal and pharyngeal dysfunction in horses homozygous for hyperkalemic periodic paralysis.

    Science.gov (United States)

    Carr, E A; Spier, S J; Kortz, G D; Hoffman, E P

    1996-08-15

    Evaluate histories, clinical signs, and laboratory data of 69 horses homozygous by DNA testing for hyperkalemic periodic paralysis (HPP). Cohort study. 69 of 189 horses testing homozygous for HPP between October 1992 and November 1994. Questionnaires addressing signalment, training regimes, medical history, and current status of affected horses were sent to owners, trainers, or attending veterinarians. Data from completed questionnaires were tabulated and evaluated, using descriptive statistics. Sixty-nine (37%) of 189 questionnaires were completed and returned. Clinical episodes of muscle weakness or paralysis varied in severity and frequency from mild muscle fasciculations to recumbency and death. Sixty-three of 68 HPP-affected horses were reported to have had stridor associated with exercise, excitement, stress, or episodes of muscle paralysis. Common endoscopic findings in affected horses included pharyngeal collapse, pharyngeal edema, laryngopalatal dislocation, and laryngeal paralysis. Twelve of 27 horses receiving acetazolamide had decreases in stridor while receiving medication. Most horses testing homozygous for HPP had clinical signs associated with pharyngeal and laryngeal dysfunction. Hyperkalemic periodic paralysis should be included on a differential list for horses examined for signs of laryngeal or pharyngeal dysfunction or stridor. Treatment with acetazolamide may help to control respiratory tract signs associated with this disease.

  7. Feedback in analog circuits

    CERN Document Server

    Ochoa, Agustin

    2016-01-01

    This book describes a consistent and direct methodology to the analysis and design of analog circuits with particular application to circuits containing feedback. The analysis and design of circuits containing feedback is generally presented by either following a series of examples where each circuit is simplified through the use of insight or experience (someone else’s), or a complete nodal-matrix analysis generating lots of algebra. Neither of these approaches leads to gaining insight into the design process easily. The author develops a systematic approach to circuit analysis, the Driving Point Impedance and Signal Flow Graphs (DPI/SFG) method that does not require a-priori insight to the circuit being considered and results in factored analysis supporting the design function. This approach enables designers to account fully for loading and the bi-directional nature of elements both in the feedback path and in the amplifier itself, properties many times assumed negligible and ignored. Feedback circuits a...

  8. Vorticity in analog gravity

    Science.gov (United States)

    Cropp, Bethan; Liberati, Stefano; Turcati, Rodrigo

    2016-06-01

    In the analog gravity framework, the acoustic disturbances in a moving fluid can be described by an equation of motion identical to a relativistic scalar massless field propagating in curved space-time. This description is possible only when the fluid under consideration is barotropic, inviscid, and irrotational. In this case, the propagation of the perturbations is governed by an acoustic metric that depends algebrically on the local speed of sound, density, and the background flow velocity, the latter assumed to be vorticity-free. In this work we provide a straightforward extension in order to go beyond the irrotational constraint. Using a charged—relativistic and nonrelativistic—Bose-Einstein condensate as a physical system, we show that in the low-momentum limit and performing the eikonal approximation we can derive a d’Alembertian equation of motion for the charged phonons where the emergent acoustic metric depends on flow velocity in the presence of vorticity.

  9. Parabolic flight as a spaceflight analog.

    Science.gov (United States)

    Shelhamer, Mark

    2016-06-15

    Ground-based analog facilities have had wide use in mimicking some of the features of spaceflight in a more-controlled and less-expensive manner. One such analog is parabolic flight, in which an aircraft flies repeated parabolic trajectories that provide short-duration periods of free fall (0 g) alternating with high-g pullout or recovery phases. Parabolic flight is unique in being able to provide true 0 g in a ground-based facility. Accordingly, it lends itself well to the investigation of specific areas of human spaceflight that can benefit from this capability, which predominantly includes neurovestibular effects, but also others such as human factors, locomotion, and medical procedures. Applications to research in artificial gravity and to effects likely to occur in upcoming commercial suborbital flights are also possible. Copyright © 2016 the American Physiological Society.

  10. Beginning analog electronics through projects

    CERN Document Server

    Singmin, Andrew

    2001-01-01

    Analog electronics is the simplest way to start a fun, informative, learning program. Beginning Analog Electronics Through Projects, Second Edition was written with the needs of beginning hobbyists and students in mind. This revision of Andrew Singmin's popular Beginning Electronics Through Projects provides practical exercises, building techniques, and ideas for useful electronics projects. Additionally, it features new material on analog and digital electronics, and new projects for troubleshooting test equipment.Published in the tradition of Beginning Electronics Through Projects an

  11. Design of Chemical Conjugate for Targeted Therapy of Multiple Sclerosis Based of Constant Fragment of Human Antibody Heavy Chain and Peptoid Analog of Autoantigen MOG35-55.

    Science.gov (United States)

    Lomakin, Y A; Stepanov, A V; Balabashin, D S; Ponomarenko, N A; Smirnov, I V; Belogurov, A A

    2017-04-01

    Elimination of B cells producing autoantibodies to neuroantigens is considered as beneficial in the treatment of multiple sclerosis. Myelin oligodendrocyte glycoprotein (MOG) is a significant autoantigen in multiple sclerosis. It was shown that MOG-like peptoid AMogP3 can bind autoantibodies produced by pathological lymphocytes. We propose a structure of an innovative drug for targeted elimination of the pool of autoreactive B cells responsible for multiple sclerosis pathogenesis; this compound is a complex of peptoid AMogP3 with Fc fragment of human immunoglobulin. The obtained Fc-PEG-AMogP3 conjugate effectively interact with autoreactive antibodies, which attests to their high therapeutic potential.

  12. Mathematical problem solving by analogy.

    Science.gov (United States)

    Novick, L R; Holyoak, K J

    1991-05-01

    We report the results of 2 experiments and a verbal protocol study examining the component processes of solving mathematical word problems by analogy. College students first studied a problem and its solution, which provided a potential source for analogical transfer. Then they attempted to solve several analogous problems. For some problems, subjects received one of a variety of hints designed to reduce or eliminate the difficulty of some of the major processes hypothesized to be involved in analogical transfer. Our studies yielded 4 major findings. First, the process of mapping the features of the source and target problems and the process of adapting the source solution procedure for use in solving the target problem were clearly distinguished: (a) Successful mapping was found to be insufficient for successful transfer and (b) adaptation was found to be a major source of transfer difficulty. Second, we obtained direct evidence that schema induction is a natural consequence of analogical transfer. The schema was found to co-exist with the problems from which it was induced, and both the schema and the individual problems facilitated later transfer. Third, for our multiple-solution problems, the relation between analogical transfer and solution accuracy was mediated by the degree of time pressure exerted for the test problems. Finally, mathematical expertise was a significant predictor of analogical transfer, but general analogical reasoning ability was not. The implications of the results for models of analogical transfer and for instruction were considered.

  13. The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line.

    Science.gov (United States)

    Kedei, Noemi; Telek, Andrea; Czap, Alexandra; Lubart, Emanuel S; Czifra, Gabriella; Yang, Dazhi; Chen, Jinqiu; Morrison, Tyler; Goldsmith, Paul K; Lim, Langston; Mannan, Poonam; Garfield, Susan H; Kraft, Matthew B; Li, Wei; Keck, Gary E; Blumberg, Peter M

    2011-06-01

    Bryostatin 1 has attracted considerable attention both as a cancer chemotherapeutic agent and for its unique activity. Although it functions, like phorbol esters, as a potent protein kinase C (PKC) activator, it paradoxically antagonizes many phorbol ester responses in cells. Because of its complex structure, little is known of its structure-function relations. Merle 23 is a synthetic derivative, differing from bryostatin 1 at only four positions. However, in U-937 human leukemia cells, Merle 23 behaves like a phorbol ester and not like bryostatin 1. Here, we characterize the behavior of Merle 23 in the human prostate cancer cell line LNCaP. In this system, bryostatin 1 and phorbol ester have contrasting activities, with the phorbol ester but not bryostatin 1 blocking cell proliferation or tumor necrosis factor alpha secretion, among other responses. We show that Merle 23 displays a highly complex pattern of activity in this system. Depending on the specific biological response or mechanistic change, it was bryostatin-like, phorbol ester-like, intermediate in its behavior, or more effective than either. The pattern of response, moreover, varied depending on the conditions. We conclude that the newly emerging bryostatin derivatives such as Merle 23 provide powerful tools to dissect subsets of bryostatin mechanism and response. Published by Elsevier Inc.

  14. In vitro prediction of human intestinal absorption and blood-brain barrier partitioning: development of a lipid analog for micellar liquid chromatography.

    Science.gov (United States)

    De Vrieze, Mike; Janssens, Pieter; Szucs, Roman; Van der Eycken, Johan; Lynen, Frédéric

    2015-09-01

    Over the past decades, several in vitro methods have been tested for their ability to predict either human intestinal absorption (HIA) or penetration across the blood-brain barrier (BBB) of drugs. Micellar liquid chromatography (MLC) has been a successful approach for retention time measurements of drugs to establish models together with other molecular descriptors. Thus far, MLC approaches have only made use of commercial surfactants such as sodium dodecyl sulfate (SDS) and polyoxyethylene (23) lauryl ether (Brij35), which are not representative for the phospholipids present in human membranes. Miltefosine, a phosphocholine-based lipid, is presented here as an alternative surfactant for MLC measurements. By using the obtained retention factors and several computed descriptors for a set of 48 compounds, two models were constructed: one for the prediction of HIA and another for the prediction of penetration across the BBB expressed as log BB. All data were correlated to experimental HIA and log BB values, and the performance of the models was evaluated. Log BB prediction performed better than HIA prediction, although HIA prediction was also improved a lot (from 0.5530 to 0.7175) compared to in silico predicted HIA values.

  15. Camptothecin analog (CPT-11)-sensitive human pancreatic tumor cell line QGP-1N shows resistance to SN-38, an active metabolite of CPT-11.

    Science.gov (United States)

    Takeda, S; Shimazoe, T; Kuga, H; Sato, K; Kono, A

    1992-10-15

    In the course of our study to determine the cross-sensitivity between CPT-11 and its active metabolite, SN-38, we found a SN-38-resistant human pancreatic tumor cell line, QGP-1N, which shows sensitivity to CPT-11. The IC50 of SN-38 was 152 times greater for QGP-1N than for SUIT-2, also a human pancreatic tumor cell line, whose IC50 of CPT-11 was similar to that for QGP-1N. The uptakes of CPT-11 and SN-38 and the intracellular conversion of CPT-11 to SN-38 could not explain the difference in sensitivity. DNA synthesis of QGP-1N cells was inhibited by CPT-11 which did not affect that of SUIT-2, while SN-38 inhibited the DNA synthesis of SUIT-2 at lower concentrations than that of QGP-1N. The inhibition test of topoisomerase I catalytic activity by CPT-11 or SN-38 revealed no difference in the biochemical properties of the topoisomerase I enzymes to the compounds between these two cell lines. These results indicate that CPT-11 should have its own inhibitory effect on DNA synthesis through a yet unknown mechanism in QGP-1N cells, although SN-38 plays an essential role in the antitumor activity of CPT-11 in SUIT-2 cells. In some cases, the antitumor effect of CPT-11 might be consequent not only on SN-38 but also on CPT-11 itself.

  16. Inhibitory effects of a benz[f]indole-4,9-dione analog on cancer cell metastasis mediated by the down-regulation of matrix metalloproteinase expression in human HT1080 fibrosarcoma cells.

    Science.gov (United States)

    Park, Hyen Joo; Lee, Hyun-Jung; Min, Hye-Young; Chung, Hwa-Jin; Suh, Myung Eun; Park-Choo, Hye-Young; Kim, Choonmi; Kim, Hwa Jung; Seo, Eun-Kyung; Lee, Sang Kook

    2005-12-19

    In our previous study, a synthetic benz[f]indole-4,9-dione analog, 2-amino-3-ethoxycarbonyl-N-methylbenz[f]indole-4,9-dione (SME-6), exhibited a potential anti-tumor activity. We, in this study, further explored the anti-metastatic and anti-invasive effect of SME-6 by determining the regulation of matrix metalloproteinases (MMPs). MMPs, zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. On this line, we examined the influence of SME-6 on the expressions of MMP-2, -9, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-1, -2), and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent suppressions of MMPs and TIMP-2 mRNA levels were observed in SME-6-treated HT1080 human fibrosarcoma cells detected by reverse transcriptase-polymerase chain reaction. TIMP-1 mRNA level, however, was induced in a dose-dependent manner. Gelatin zymographic analysis also exhibited a significant down-regulation of MMP-2 and -9 expression in HT1080 cells treated with SME-6 compared to controls. Furthermore, SME-6 inhibited the invasion, motility, and migration of tumor cells. Taken together, these data provide a possible role of SME-6 as a potential antitumor agent with the markedly inhibition of the metastatic and invasive capacity of malignant cells.

  17. [Analogies and analogy research in technical biology and bionics].

    Science.gov (United States)

    Nachtigall, Werner

    2010-01-01

    The procedural approaches of Technical Biology and Bionics are characterized, and analogy research is identified as their common basis. The actual creative aspect in bionical research lies in recognizing and exploiting technically oriented analogies underlying a specific biological prototype to indicate a specific technical application.

  18. Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

    Science.gov (United States)

    Winters, Mark A.; Merigan, Thomas C.

    2001-01-01

    The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected. PMID:11451685

  19. Synthesis of human pancreatic growth hormone-releasing factor and two omission analogs by segment-coupling method in aqueous solution

    Energy Technology Data Exchange (ETDEWEB)

    Blake, J.; Westphal, M.; Li, C.H. (Laboratory of Molecular Endocrinology, University of California, San Francisco, USA)

    1984-01-01

    The human growth hormone-releasing factor (GRF) peptides (GlyS/sup 15/)-GRF-(1-15) (IV), trifluoroacetyl-GRF-(20-44) (VI), trifluoroacetyl-GRF-(18-44) (VIII), and trifluoroacetyl-GRF-(16-44) (X) were synthesized by the solidphase method. Each of the peptides was reacted with citraconic anhydride and the trifluoroacetyl group was removed by reaction with 10% hydrazine in water. The citraconylated GRF-(1-15) peptide was coupled to the (20-44), (18-44) or (16-44) peptides by reaction with silver nitrate/N-hydroxysuccinimide to give GRF-(1-15)-(20-44) (XII), GRF-(1-15)-(18-44) (XIII), or GRF-(1-44), respectively. GRF-(1-44) was shown to stimulate the release of rat growth hormone from rat pituitary cells with an ED/sub 50/=8.8 x 10/sup -11/M. Peptides XII and XIII were inactive, either as agonists or as antagonists of the action of GRF-(1-44).

  20. Natural analog studies: Licensing perspective

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, J.W. [Nuclear Regulatory Commission, Washington, DC (United States)

    1995-09-01

    This report describes the licensing perspective of the term {open_quotes}natural analog studies{close_quotes} as used in CFR Part 60. It describes the misunderstandings related to its definition which has become evident during discussions at the U.S Nuclear Regulatory Commission meetings and tries to clarify the appropriate applications of natural analog studies to aspects of repository site characterization.

  1. Conjecturing via Reconceived Classical Analogy

    Science.gov (United States)

    Lee, Kyeong-Hwa; Sriraman, Bharath

    2011-01-01

    Analogical reasoning is believed to be an efficient means of problem solving and construction of knowledge during the search for and the analysis of new mathematical objects. However, there is growing concern that despite everyday usage, learners are unable to transfer analogical reasoning to learning situations. This study aims at facilitating…

  2. Musik som analogi og metafor

    DEFF Research Database (Denmark)

    2014-01-01

    Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser......Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser...

  3. Musik som analogi og metafor

    DEFF Research Database (Denmark)

    2014-01-01

    Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser......Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser...

  4. NASA HRP Immunology Discipline - Use of Terrestrial Analogs

    Science.gov (United States)

    Crucian, Brian

    2014-01-01

    Due to the cost and operational constraints, as well as technical implementation limitations, it is desirous to perform relevant space physiology investigations first in terrestrial 'space analogs'. This is particularly true for initial investigations, which may then provide appropriate focus for subsequent flight investigations, or for mechanistic investigations that simply cannot be performed during spaceflight. Appropriate analog choice is extremely important. There are a wide variety of terrestrial space analogs, each relevant to a particular physiological discipline (or disciplines) and each with a particular fidelity (or lack thereof) to spaceflight, and each with unique operational constraints. The HRP Immunology Discipline is tasked with managing the HRP Risk concerning clinical risk for Astronaut crews related to spaceflight-associated immune dysregulation. Such dysregulation has been documented to occur during spaceflight, and found to persist for the duration of a 6-month ISS mission. Studies continue to characterize the onorbit phenomenon, but it generally consists of diminished immunocyte function, dysregulated cytokine profiles, and persistent herpesvirus reactivation. Causes are thought to synergistically include microgravity, psychological or physiological stress, radiation, and/or circadian misalignment. An appropriate terrestrial analog for immune dysregulation would replicate as many of these influences as possible. Such analogs may include clinostat or bioreactor cell culture (microgravity), hindlimb suspension (stress, fluid shifts, hypokinesis), or human deployment to remote or extreme environments (isolation, stress, circadian). Also, the laboratory setting may be used as an analog, or to augment analogs, such as sleep deprivation/misalignment or human centrifugation to replicate gravitational stress. As an appropriate example of a NASA Disciplines use of Terrestrial space analogs, this talk will discuss spaceflight associated immune

  5. Receptor-binding, biodistribution, dosimetry, and micro-SPECT/CT imaging of 111In-[DTPA(1), Lys(3), Tyr(4)]-bombesin analog in human prostate tumor-bearing mice.

    Science.gov (United States)

    Ho, Chung-Li; Chen, Liang-Cheng; Lee, Wan-Chi; Chiu, Shu-Pei; Hsu, Wei-Chuan; Wu, Yu-Hsien; Yeh, Chung-Hsin; Stabin, Michael G; Jan, Meei-Ling; Lin, Wuu-Jyh; Lee, Te-Wei; Chang, Chih-Hsien

    2009-08-01

    Gastrin-releasing peptide receptors (GRPRs) are overexpressed on a variety of human tumors, such as prostate, breast, and lung cancer. Bombesin (BN) is a 14-amino-acid peptide with high affinity for these GRPRs. We synthesized DTPA-Q-K-Y-G-N-Q-W-A-V-G-H-L-M, a 13-amino-acid peptide chelated with diethylenetriaminepentaacetic acid (DTPA), and radiolabeled this BN analog with 111InCl(3). Biologic activity of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN was evaluated in PC-3 prostate tumor-bearing severely compromised immunodeficient (SCID) mice. The purity of synthesized [DTPA(1), Lys(3), Tyr(4)]-BN was greater than 95%. The radiolabeling efficiency of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN was 96.9% +/- 2.46%. The IC(50) and K(i) of [DTPA(1), Lys(3), Tyr(4)]-BN in the human bombesin 2 receptor were 1.05 +/- 0.46 and 0.83 +/- 0.36 nM, respectively. The K(d) of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN in GRPR-expressing PC-3 tumor cells was 22.9 +/- 6.81 nM. Both biodistribution and micro-SPECT/CT (single-photon emission computed tomography/computed tomography) imaging studies with 111In-[DTPA(1), Lys(3), Tyr(4)]-BN demonstrated the highest uptake at 8 hours postinjection. The Pearson correlation analysis showed a positive correlation of tumor uptake between biodistribution and micro-SPECT/CT semiquantification imaging analysis (r = 0.832). Our results revealed 111In-[DTPA(1), Lys(3), Tyr(4)]-BN has high affinity with BN type 2 receptor. The results demonstrated a good uptake in the GRPR-overexpression of PC-3 tumor-bearing SCID mice. 111In-[DTPA(1), Lys(3), Tyr(4)]-BN is a potential agent for imaging GRPR-positive tumors in humans.

  6. Homozygous familial hypercholesterolemia (HoFH in Germany: an epidemiological survey

    Directory of Open Access Journals (Sweden)

    Walzer S

    2013-05-01

    Full Text Available S Walzer,1 K Travers,2 S Rieder,3 E Erazo-Fischer,3 D Matusiewicz41MArS Market Access and Pricing Strategy UG (hb, Weil am Rhein, Germany; 2United Biosource Corporation, Lexington, USA; 3Alcimed GmbH, Cologne, Germany; 4Institute for Health Care Management and Research, Faculty of Economics and Business Administration, University of Duisburg-Essen, Essen, GermanyIntroduction: In Europe a disease is recognized as rare if less than 1 in 2000 people suffer from the specific disease. In patients with familial homozygous hypercholesterolemia (HoFH the accumulation of low-density lipoprotein cholesterol (LDL-C leads to generalized atherosclerosis due to an insufficient functioning of the LDL-C receptors. Patients die early sometimes even in the mid-30s, from myocardial infarction or stroke. For the German population, insufficient epidemiological evidence exists.Methods: A systematic literature search in EMBASE and Medline was performed in conjunction with a targeted manual search for epidemiological HoFH studies. Additionally a nationwide survey was conducted in Germany in all identified apheresis- and lipid centers. The purpose of the survey was the validation of the systematic literature search results based on empirical (practice data.Results: In total 961 publications were found, 874 were excluded based on pre-defined exclusion criteria leaving only 87 for further review. After review of the identified abstracts (n = 87 23 publications were identified as epidemiological studies. Only one publication was found which reported a prevalence of 1:1,000,000. The qualitative survey among 187 physicians in Germany also revealed a low prevalence: 95 HoFH patients were identified in 35 centers.Conclusion: The estimated frequency of homozygous familial hypercholesterolemia patients in Germany is around 95 (1:860,000 and the disease should be recognized as rare according to the definition of the European Medical Agency.Keywords: epidemiology, homozygous

  7. Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse.

    Science.gov (United States)

    Choi, Eun-Jung; Walker, Espen J; Shen, Fanxia; Oh, S Paul; Arthur, Helen M; Young, William L; Su, Hua

    2012-01-01

    Brain arteriovenous malformations (bAVMs) represent a high risk for hemorrhagic stroke, leading to significant neurological morbidity and mortality in young adults. The etiopathogenesis of bAVM remains unclear. Research progress has been hampered by the lack of animal models. Hereditary Hemorrhagic Telangiectasia (HHT) patients with haploinsufficiency of endoglin (ENG, HHT1) or activin receptor-like kinase 1 (ALK1, HHT2) have a higher incidence of bAVM than the general population. We previously induced cerebrovascular dysplasia in the adult mouse that resembles human bAVM through Alk1 deletion plus vascular endothelial growth factor (VEGF) stimulation. We hypothesized that Eng deletion plus VEGF stimulation would induce a similar degree of cerebrovascular dysplasia as the Alk1-deleted brain. Ad-Cre (an adenoviral vector expressing Cre recombinase) and AAV-VEGF (an adeno-associated viral vector expressing VEGF) were co-injected into the basal ganglia of 8- to 10-week-old Eng(2f/2f) (exons 5 and 6 flanked by loxP sequences), Alk1(2f/2f) (exons 4-6 flanked by loxP sequences) and wild-type (WT) mice. Vascular density, dysplasia index, and gene deletion efficiency were analyzed 8 weeks later. AAV-VEGF induced a similar degree of angiogenesis in the brain with or without Alk1- or Eng-deletion. Abnormally patterned and dilated dysplastic vessels were found in the viral vector-injected region of Alk1(2f/2f) and Eng(2f/2f) brain sections, but not in WT. Alk1(2f/2f) mice had about 1.8-fold higher dysplasia index than Eng(2f/2f) mice (4.6 ± 1.9 vs. 2.5 ± 1.1, p Eng(2f/2f): 1%), we found that about 8-fold higher dysplasia was induced per copy of Eng deletion (2.5) than that of Alk1 deletion (0.3). ENG-negative endothelial cells were detected in the Ad-Cre-treated brain of Eng(2f/2f) mice, suggesting homozygous deletion of Eng in the cells. VEGF induced more severe vascular dysplasia in the Ad-Cre-treated brain of Eng(2f/2f) mice than that of Eng(+/-) mice. (1) Deletion of

  8. A homozygous frameshift mutation in the HOXC13 gene underlies pure hair and nail ectodermal dysplasia in a Syrian family.

    Science.gov (United States)

    Farooq, Muhammad; Kurban, Mazen; Fujimoto, Atsushi; Fujikawa, Hiroki; Abbas, Ossama; Nemer, Georges; Saliba, Jessica; Sleiman, Rima; Tofaili, Mona; Kibbi, Abdul-Ghani; Ito, Masaaki; Shimomura, Yutaka

    2013-04-01

    Pure hair and nail ectodermal dysplasia (PHNED) is a rare genetic disorder characterized by hypotrichosis or complete alopecia, as well as nail dystrophy. Mutations in the type II hair keratin gene KRT85 and the HOXC13 gene on chromosome 12q have recently been identified in families with autosomal-recessive PHNED. In the present study, we have analyzed a consanguineous Syrian family with an affected girl having complete alopecia and nail dystrophy since birth. The family clearly showed linkage to chromosome 12q13.13-12q14.3, which excluded the KRT85 gene. Sequencing of another candidate gene HOXC13 within the linkage interval identified a homozygous frameshift mutation (c.355delC; p.Leu119Trpfs*20). Expression studies in cultured cells revealed that the mutant HOXC13 protein mislocalized within the cytoplasm, and failed to upregulate the promoter activities of its target genes. Our results strongly suggest crucial roles of the HOXC13 gene in the development of hair and nails in humans.

  9. Clinical and biochemical signs in Fleckvieh cattle with genetically confirmed Fanconi-Bickel syndrome (cattle homozygous for Fleckvieh haplotype 2).

    Science.gov (United States)

    Burgstaller, Johann; Url, Angelika; Pausch, Hubert; Schwarzenbacher, Hermann; Egerbacher, Monika; Wittek, Thomas

    2016-01-01

    Fanconi-Bickel Syndrome (FBS) is an autosomal recessive disorder of the carbohydrate metabolism, which has been reported in human and some animals (OMIA 000366-9913). In Fleckvieh cattle it is caused by mutations in SLC2A2, a gene encoding for glucose transporter protein 2 (GLUT2), which is primarily expressed in liver, kidney, pancreas and intestines. The causal mutation resides in a previously reported Fleckvieh Haplotype 2 (FH-2). FH-2 homozygous individuals are rare, but due to widespread use of heterozygous bulls in artificial insemination, heterozygous animals are likely to be present in a larger number in the cattle population. Two clinical cases of Fleckvieh cattle with a syndrome resembling the phenotypic appearance of FBS are presented in the present study describing the association between the clinical manifestations of FBS and the postulated frameshift mutation in bovine SLC2A2. Clinical examination showed poor growth, retarded development, polyuria, and polydipsia. Laboratory analyses showed an increased plasma glucose but normal insulin concentration and increased renal glucose excretion. Histopathological examination of kidney and liver samples revealed massively increased liver glycogen storage and nephrosis. Sires of both cases were tested positive for being heterozygous carriers for the same frameshift mutation in SLC2A2 as was originally reported in Fleckvieh cattle. DNA of both cases described was analyzed and Sanger sequencing confirmed homozygosity for the frameshift mutation in SLC2A2.

  10. Characterization of Alu and recombination-associated motifs mediating a large homozygous SPG7 gene rearrangement causing hereditary spastic paraplegia.

    Science.gov (United States)

    López, Eva; Casasnovas, Carlos; Giménez, Javier; Matilla-Dueñas, Antoni; Sánchez, Ivelisse; Volpini, Víctor

    2015-04-01

    Spastic paraplegia type 7 (SPG7) is one of the most common forms of autosomal recessive hereditary spastic paraplegia (AR-HSP). Although over 77 different mutations have been identified in SPG7 patients, only 9 gross deletions have been reported with only a few of them being fully characterized. Here, we present a detailed description of a large homozygous intragenic SPG7 gene rearrangement involving a 5144-base pair (bp) genomic loss (c. 1450-446_1779 + 746 delinsAAAGTGCT) encompassing exons 11 to 13, identified in a Spanish AR-HSP family. Analysis of the deletion junction sequences revealed that the 5' breakpoint of this SPG7 gene deletion was located within highly homologous Alu sequences where the 3' breakpoint appears to be flanked by the core crossover hotspot instigator (chi)-like sequence (GCTGG). Furthermore, an 8-bp (AAAGTTGCT) conserved sequence at the breakpoint junction was identified, suggesting that the most likely mechanism for the occurrence of this rearrangement is by Alu microhomology and chi-like recombination-associated motif-mediated multiple exon deletion. Our results are consistent with non-allelic homologous recombination and non-homologous end joining in deletion mutagenesis for the generation of rearrangements. This study provides more evidence associating repeated elements as a genetic mechanism underlying neurodegenerative disorders, highlighting their importance in human diseases.

  11. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome.

    Science.gov (United States)

    Melo, Uirá S; Macedo-Souza, Lucia I; Figueiredo, Thalita; Muotri, Alysson R; Gleeson, Joseph G; Coux, Gabriela; Armas, Pablo; Calcaterra, Nora B; Kitajima, João P; Amorim, Simone; Olávio, Thiago R; Griesi-Oliveira, Karina; Coatti, Giuliana C; Rocha, Clarissa R R; Martins-Pinheiro, Marinalva; Menck, Carlos F M; Zaki, Maha S; Kok, Fernando; Zatz, Mayana; Santos, Silvana

    2015-12-15

    SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy (SPOAN). Affected patients are wheelchair bound after 15 years old, with progressive joint contractures and spine deformities. SPOAN patients also have sub normal vision secondary to apparently non-progressive congenital optic atrophy. A potential causative gene was mapped at 11q13 ten years ago. Here we performed next-generation sequencing in SPOAN-derived samples. While whole-exome sequencing failed to identify the causative mutation, whole-genome sequencing allowed to detect a homozygous 216-bp deletion (chr11.hg19:g.66,024,557_66,024,773del) located at the non-coding upstream region of the KLC2 gene. Expression assays performed with patient's fibroblasts and motor neurons derived from SPOAN patients showed KLC2 overexpression. Luciferase assay in constructs with 216-bp deletion confirmed the overexpression of gene reporter, varying from 48 to 74%, as compared with wild-type. Knockdown and overexpression of klc2 in Danio rerio revealed mild to severe curly-tail phenotype, which is suggestive of a neuromuscular disorder. Overexpression of a gene caused by a small deletion in the non-coding region is a novel mechanism, which to the best of our knowledge, was never reported before in a recessive condition. Although the molecular mechanism of KLC2 up-regulation still remains to be uncovered, such example adds to the importance of non-coding regions in human pathology.

  12. Corneal arcus and xanthomas in homozygous familial hypercholesterolemia: First report from China

    Directory of Open Access Journals (Sweden)

    Xin Meng

    2013-01-01

    Full Text Available We report the case of a 12-year-old male who developed corneal arcus and multiple skin lesions with a 10-year history of xanthomas. The lesions appeared over his fingers, hands, elbows, knees, buttocks and feet. Laboratory studies showed a total serum cholesterol level of 752.1 mg/dL; a triglyceride level of 96.6 mg/dL; a low-density lipoprotein cholesterol level of 661.3 mg/dL. Findings were consistent with homozygous familial hypercholesterolemia. To our knowledge, this is the first such case to be reported from China.

  13. Dataset for a case report of a homozygous PEX16 F332del mutation

    Directory of Open Access Journals (Sweden)

    Carlos Bacino

    2016-03-01

    Full Text Available This dataset provides a clinical description along with extensive biochemical and molecular characterization of a patient with a homozygous mutation in PEX16 with an atypical phenotype. This patient described in Molecular Genetics and Metabolism Reports was ultimately diagnosed with an atypical peroxisomal disorder on exome sequencing. A clinical timeline and diagnostic summary, results of an extensive plasma and fibroblast analysis of this patient׳s peroxisomal profile is provided. In addition, a table of additional variants from the exome analysis is provided.

  14. Analog-to-digital conversion

    CERN Document Server

    Pelgrom, Marcel J M

    2010-01-01

    The design of an analog-to-digital converter or digital-to-analog converter is one of the most fascinating tasks in micro-electronics. In a converter the analog world with all its intricacies meets the realm of the formal digital abstraction. Both disciplines must be understood for an optimum conversion solution. In a converter also system challenges meet technology opportunities. Modern systems rely on analog-to-digital converters as an essential part of the complex chain to access the physical world. And processors need the ultimate performance of digital-to-analog converters to present the results of their complex algorithms. The same progress in CMOS technology that enables these VLSI digital systems creates new challenges for analog-to-digital converters: lower signal swings, less power and variability issues. Last but not least, the analog-to-digital converter must follow the cost reduction trend. These changing boundary conditions require micro-electronics engineers to consider their design choices for...

  15. Distributed Episodic and Analogical Reasoning (DEAR)

    Science.gov (United States)

    2010-04-01

    ends analysis Carbonell 1983 Modeling of Analogy Making Structure Mapping Theory (SMT) Gentner 1984 Agent based approach to analogy making...Mapping Engine (SME) Forbus 1990 Learning by analogy with larger domains Prodigy/Analogy Veloso and Carbonell 1991 Analogical Retrieval Engine MAC/FAC

  16. Molecular modeling of fentanyl analogs

    Directory of Open Access Journals (Sweden)

    LJILJANA DOSEN-MICOVIC

    2004-11-01

    Full Text Available Fentanyl is a highly potent and clinically widely used narcotic analgesic. A large number of its analogs have been synthesized, some of which (sufentanil and alfentanyl are also in clinical use. Theoretical studies, in recent years, afforded a better understanding of the structure-activity relationships of this class of opiates and allowed insight into the molecular mechanism of the interactions of fentanyl analogs with their receptors. An overview of the current computational techniques for modeling fentanyl analogs, their receptors and ligand-receptor interactions is presented in this paper.

  17. Sulfonimidamide analogs of oncolytic sulfonylureas.

    Science.gov (United States)

    Toth, J E; Grindey, G B; Ehlhardt, W J; Ray, J E; Boder, G B; Bewley, J R; Klingerman, K K; Gates, S B; Rinzel, S M; Schultz, R M; Weir, L C; Worzalla, J F

    1997-03-14

    A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for (1) in vitro cytotoxicity against CEM cells, (2) in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and (3) metabolic breakdown to the o-sulfate of p-chloroaniline. The separated enantiomers of one sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or intraperitoneally. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.

  18. A homozygous balanced reciprocal translocation suggests LINC00237 as a candidate gene for MOMO (macrosomia, obesity, macrocephaly, and ocular abnormalities) syndrome.

    Science.gov (United States)

    Vu, Phi Yen; Toutain, Jérôme; Cappellen, David; Delrue, Marie-Ange; Daoud, Hussein; El Moneim, Azza Abd; Barat, Pascal; Montaubin, Orianne; Bonnet, Françoise; Dai, Zong Qi; Philippe, Christophe; Tran, Cong Toai; Rooryck, Caroline; Arveiler, Benoît; Saura, Robert; Briault, Sylvain; Lacombe, Didier; Taine, Laurence

    2012-11-01

    Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array-comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability. Copyright © 2012 Wiley Periodicals, Inc.

  19. Heart valve surgery in patients with homozygous sickle cell disease: A management strategy

    Directory of Open Access Journals (Sweden)

    El Mehdi Moutaouekkil

    2015-01-01

    Full Text Available Background: Patients with the homozygous sickle cell disease have increased perioperative mortality. Some indications like heart valve surgery, may justify an exchange blood transfusion to reduce the proportion of hemoglobin S (HbS and complications. Subjects and Methods: We report two female cases aged 20 and 27, of African origin with homozygous sickle cell anemia who underwent heart valve surgery to treat mitral valve regurgitation. This presentation describes the perioperative considerations including anesthesia and postoperative care. Results: A partial exchange blood transfusion decreased HbS levels from respectively, 90% and 84%, 9% to 27% and 34%, and simultaneously treated the anemia. Neither sickling crisis nor acidosis occurred in any patient, and no special postoperative complication occurred. Average hospital stay was 10 days. Currently, the two patients remain alive and free of cardiac symptoms. Discussion: Although the presence of sickle cell disorders is associated with increased risk of sickling and thus vaso-occlusive complications, they should not be taken as a contraindication for heart valve surgery. Nevertheless, monitoring of certain parameters such as venous, arterial oxygen content, pH, and body temperature is mandatory for a better outcome. Furthermore, preoperative exchange transfusion has a positive influence on the outcome of surgery and on the survival of patients undergoing heart valves surgery. Avoiding intraoperative hypoxia, hypothermia, and vaso-constrictive agents, minimizing HbS levels with preoperative exchange transfusion, and ensuring a stress-free environment with the judicious use of sedatives made surgery relatively safe in these cases.

  20. [Patient with homozygous sickle cell disease and free flap surgery: Ensuring the success of the procedure].

    Science.gov (United States)

    Deneuve, S; Maire, L; Bachelot, V; Dammacco, M-A; Zrounba, P; Delay, E

    2017-04-01

    Sickle cell anaemia is rare in France but frequent in Africa, leading to rigid, sickle-like shape red blood cells which bind together blocking microcirculation under certain circumstances. The vaso-occlusive crisis is the most frequent clinical manifestation especially in case of homozygous disease. Sickle cells disease is therefore usually considerated as a contraindication to microsurgery, however sometimes, a free flap procedure is mandatory. We here report the case of a 47-year-old man suffering with homozygous sickle cell anaemia and needing an antebrachial free flap procedure for a tongue reconstruction. The postoperative course was unremarkable apart from a delayed healing which is common in this particular localization. A review of the litterature allows to list the precautions to be taken to ensure a microsurgical procedure with this medical background. The preoperative examination has to assess usual sickle cell disease comorbidities such as kidney failure, heart failure or pulmonary hypertension. All the events leading to either low output syndrome, hypoxia, hypothermia, or a stress caused by uncontrolled pain should be avoided per- and postoperatively. With an optimum medical care, microsurgery is possible even in patients suffering with sickle cells anaemia. This case is rare in France but will become frequent in Africa with the improvement of the healthcare system, allowing to give all patients the best medical care.

  1. A potential trigger for pine mouth: a case of a homozygous phenylthiocarbamide taster.

    Science.gov (United States)

    Risso, Davide S; Howard, Louisa; VanWaes, Carter; Drayna, Dennis

    2015-12-01

    Pine mouth, also known as pine nut syndrome, is an uncommon dysgeusia that generally begins 12 to 48 hours after consuming pine nuts. It is characterized by a bitter metallic taste, usually amplified by the consumption of other foods, which lasts 2 to 4 weeks. Recent findings have correlated this disorder with the consumption of nuts of the species Pinus armandii, but no potential triggers or common underlying medical causes have been identified in individuals affected by this syndrome. We report a 23-year-old patient affected by pine mouth who also underwent a phenylthiocarbamide taste test and was found to be a taster for this compound. TAS2R38 genotyping demonstrated that this subject was a homozygous carrier of the proline-alanine-valine taster haplotype. We, therefore, hypothesize that homozygous phenylthiocarbamide taster status may be a potential contributor for pine mouth events. Although based on a single observation, this research suggests a connection between genetically determined bitter taste perception and the occurrence of pine nut dysgeusia events.

  2. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.

    Science.gov (United States)

    Synofzik, Matthis; Schicks, Julia; Lindig, Tobias; Biskup, Saskia; Schmidt, Thorsten; Hansel, Jochen; Lehmann-Horn, Frank; Schöls, Ludger

    2011-10-01

    Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2, and drug treatments have remained elusive. Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions. The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL. This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2-associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2-mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

  3. Factors Affecting the Difficulty of Verbal Analogies.

    Science.gov (United States)

    Roccas, Sonia; Moshinsky, Avital

    2003-01-01

    Examined factors affecting the difficulty of verbal analogies in a psychometric examination by characterizing 104 analogies using 5 defined attributes. Both knowledge and process attributes were found to contribute to the difficulty of verbal analogies assessed by 10 judges. (SLD)

  4. Solving a problem by analogy

    Science.gov (United States)

    Easton, Don

    1999-03-01

    This note is a description of a student solution to a problem. I found the solution exciting because it exemplifies the kind of solution by analogy that Feynman describes in The Feynman Lectures on Physics.

  5. Analog CMOS contrastive Hebbian networks

    Science.gov (United States)

    Schneider, Christian; Card, Howard

    1992-09-01

    CMOS VLSI circuits implementing an analog neural network with on-chip contrastive Hebbian learning and capacitive synaptic weight storage have been designed and fabricated. Weights are refreshed by periodic repetition of the training data. To evaluate circuit performance in a medium-sized system, these circuits were used to build a 132 synapse neural network. An adaptive neural system, such as the one described in this paper, can compensate for imperfections in the components from which it is constructed, and thus it is possible to build this type of system using simple, silicon area-efficient analog circuits. Because these analog VLSI circuits are far more compact than their digital counterparts, analog VLSI neural network implementations are potentially more efficient than digital ones.

  6. Verbal Analogies in the ITPA

    Science.gov (United States)

    Levinson, Philip J.; Kunze, Luvern H.

    1973-01-01

    This study examined the extent to which the Auditory Association subtest of the revised Illinois Test of Psycholinguistic Abilities (ITPA) measures the ability of children to complete verbal analogies. (Author)

  7. Analog filters in nanometer CMOS

    CERN Document Server

    Uhrmann, Heimo; Zimmermann, Horst

    2014-01-01

    Starting from the basics of analog filters and the poor transistor characteristics in nanometer CMOS 10 high-performance analog filters developed by the authors in 120 nm and 65 nm CMOS are described extensively. Among them are gm-C filters, current-mode filters, and active filters for system-on-chip realization for Bluetooth, WCDMA, UWB, DVB-H, and LTE applications. For the active filters several operational amplifier designs are described. The book, furthermore, contains a review of the newest state of research on low-voltage low-power analog filters. To cover the topic of the book comprehensively, linearization issues and measurement methods for the characterization of advanced analog filters are introduced in addition. Numerous elaborate illustrations promote an easy comprehension. This book will be of value to engineers and researchers in industry as well as scientists and Ph.D students at universities. The book is also recommendable to graduate students specializing on nanoelectronics, microelectronics ...

  8. Analog electronic neural network circuits

    Energy Technology Data Exchange (ETDEWEB)

    Graf, H.P.; Jackel, L.D. (AT and T Bell Labs., Holmdel, NJ (USA))

    1989-07-01

    The large interconnectivity and moderate precision required in neural network models present new opportunities for analog computing. This paper discusses analog circuits for a variety of problems such as pattern matching, optimization, and learning. Most of the circuits build so far are relatively small, exploratory designs. The most mature circuits are those for template matching. Chips performing this function are now being applied to pattern recognition problems.

  9. Clinical utility of insulin and insulin analogs

    Science.gov (United States)

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  10. Analog approach to mixed analog-digital circuit simulation

    Science.gov (United States)

    Ogrodzki, Jan

    2013-10-01

    Logic simulation of digital circuits is a well explored research area. Most up-to-date CAD tools for digital circuits simulation use an event driven, selective trace algorithm and Hardware Description Languages (HDL), e.g. the VHDL. This techniques enable simulation of mixed circuits, as well, where an analog part is connected to the digital one through D/A and A/D converters. The event-driven mixed simulation applies a unified, digital-circuits dedicated method to both digital and analog subsystems. In recent years HDL techniques have been also applied to mixed domains, as e.g. in the VHDL-AMS. This paper presents an approach dual to the event-driven one, where an analog part together with a digital one and with converters is treated as the analog subsystem and is simulated by means of circuit simulation techniques. In our problem an analog solver used yields some numerical problems caused by nonlinearities of digital elements. Efficient methods for overriding these difficulties have been proposed.

  11. Antiproliferative potential of a novel parthenin analog P16 as evident by apoptosis accompanied by down-regulation of PI3K/AKT and ERK pathways in human acute lymphoblastic leukemia MOLT-4 cells.

    Science.gov (United States)

    Goswami, Akshra; Shah, Bhahwal Ali; Kumar, Ajay; Rizvi, Masood Ahmad; Kumar, Suresh; Bhushan, Shashi; Malik, Fayaz Ahmed; Batra, Navneet; Joshi, Amit; Singh, Jagtar

    2014-10-05

    Leukemia is one of the deadliest types of cancer. Lack of effective treatment strategies has resulted in an extensive quest for new therapeutic molecules against it. This study explores the molecular mechanism of anticancer activity of P16, a semisynthetic analog of parthenin, against the human acute lymphoblastic leukemia MOLT-4 cells. P16 displayed antiproliferative activity in different cancer cell lines; however, MOLT-4 cells showed highest sensitivity for P16 with IC50 value of 0.6μM. Further studies revealed that P16 induced cell death by apoptosis. It caused mitochondrial stress, which was mediated by the translocation of Bax from cytosol to mitochondria and release of cytochrome c into the cytosol and consequent activation of caspase-9. However, P16 was also able to activate caspase-8, thus involving both extrinsic and intrinsic pathways of apoptosis. Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage. P16 induced apoptosis was accompanied by the down-regulation of important leukemic cell survival proteins like pAKT (S473), pAKT (T308), pP70S6K, pCRAF, and pERK1/2. However, inhibition of caspases by Z-VAD-FMK reversed the down-regulatory effect of P16 on pAKT (S473) and pP70S6K, as evident by the cell viability assay and flow cytometric analysis but this inhibition did not completely reverse the antiproliferative effect of P16, thereby indicating the role of additional factors apart from caspases in P16 induced apoptosis in MOLT-4 cells. Owing to its antiproliferative potential against leukemia cells, P16 can further be explored as an effective therapeutics against leukemia. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2'-deoxy-2'-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models.

    Science.gov (United States)

    Russell, James; Pillarsetty, Nagavarakishore; Kramer, Robin M; Romesser, Paul B; Desai, Pooja; Haimovitz-Friedman, Adriana; Lowery, Maeve A; Humm, John L

    2017-03-27

    Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug. [(18)F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [(14)C]gemcitabine and [(18)F]FAC were mapped with autoradiography. The inter-tumor correlation between [(14)C]gemcitabine and [(18)F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [(3)H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [(18)F]FAC and [(14)C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [(14)C]gemcitabine and [(18)F]FAC were largely co-localized. In the lines examined here, [(18)F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [(18)F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors.

  13. Novel Gemini vitamin D3 analogs

    DEFF Research Database (Denmark)

    Okamoto, Ryoko; Gery, Sigal; Kuwayama, Yoshio

    2014-01-01

    anticancer potency, but similar toxicity causing hypercalcemia. We focused on the effect of these compounds on the stimulation of expression of human cathelicidin antimicrobial peptide (CAMP) whose gene has a vitamin D response element in its promoter. Expression of CAMP mRNA and protein increased in a dose......-response fashion after exposure of acute myeloid leukemia (AML) cells to the Gemini analog, BXL-01-126, in vitro. A xenograft model of AML was developed using U937 AML cells injected into NSG-immunodeficient mice. Administration of vitamin D3 compounds to these mice resulted in substantial levels of CAMP...

  14. Novel homozygous likely-pathogenic intronic variant in INS causing permanent neonatal diabetes in siblings.

    Science.gov (United States)

    Courtney, Rachel; Gamble, Candace; Arango, Monica L; Shah, Avni; Rubio, Nunilo I; Nguyen, Joanne; Rodriguez-Buritica, David

    2016-09-01

    Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, insulinopenia, and failure to thrive beginning in the first 6 months of life. Recessive mutations in INS lead to decreased production of insulin via a variety of mechanisms. We present a case of two brothers, born to consanguineous parents, with a novel homozygous intronic variant in the INS gene. Each patient presented with intrauterine growth restriction (IUGR) and significant hyperglycemia within the first 24 h of life. All the grandparents have a diagnosis of diabetes, one of them requiring insulin treatment and the parents currently deny personal histories of diabetes. Although this mutation has not previously been described, given the segregation of the mutation, absence of heterozygosity (AOH) in the genomic region encompassing the INS locus, documented insulinopenia, and high neonatal insulin requirements, we suspect that this variant is pathogenic. Possible implications for personalized treatment of the underlying molecular etiology for an individual's diabetes are discussed.

  15. Limb defects in homozygous {alpha}-thalassemia: Report of three cases

    Energy Technology Data Exchange (ETDEWEB)

    Chitayat, D.; Thomas, M.; Silver, M.M. [Univ. of Toronto, Ontario (Canada)] [and others

    1997-01-20

    Homozygosity for the South-Asian {alpha}-thalassemia (--{sup SEA}/) deletion is a serious hematological condition that results, in most cases, in intrauterine or postnatal death due to anemia and severe hypoxia of prenatal onset. A relationship between congenital abnormalities and intrauterine hypoxia has been postulated. However, since homozygosity for the (--{sup SEA}/) deletion is most common in underdeveloped countries where detailed autopsies are lacking, the incidence of congenital abnormalities among these babies has not been well delineated. We report on three newborn infants, homozygous for the (--{sup SEA}/) deletion, who were born with limb defects. We postulate that this combination is the result of prenatal hypoxia which may affect other fetal body organs. This should be taken into consideration when prenatal treatment of affected fetuses, with intrauterine blood transfusion, is suggested. 47 refs., 3 figs.

  16. Lumacaftor/ivacaftor combination for cystic fibrosis patients homozygous for Phe508del-CFTR.

    Science.gov (United States)

    Zhang, W; Zhang, X; Zhang, Y H; Strokes, D C; Naren, A P

    2016-04-01

    Cystic fibrosis (CF) is a life-shortening inherited disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity resulting from mutations in the CFTR gene. Phe508del is the most prevalent mutation, with approximately 90% of all CF patients carrying it on at least one allele. Over the past two or three decades, significant progress has been made in understanding the pathogenesis of CF, and in the development of effective CF therapies. The approval of Orkambi® (lumacaftor/ivacaftor) marks another milestone in CF therapeutics development, which, with the advent of personalized medicine, could potentially revolutionize CF care and management. This article reviews the rationale, progress and future direction in the development of lumacaftor/ivacaftor combination to treat CF patients homozygous for the Phe508del-CFTR mutation.

  17. Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia.

    Science.gov (United States)

    Gouni-Berthold, Ioanna; Berthold, Heiner K

    2015-05-01

    Familial hypercholesterolemia (FH) is a disease associated with very high plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. It is difficult in these high risk patients, exposed lifelong to very high LDL-C, to reach target LDL-C concentrations, which require >50% LDL-C reduction, even when on maximally tolerated statin therapy and on apheresis if available. Therefore, there is an unmet need for new therapeutic options for these patients. In 2013 two new drugs were approved for the treatment of homozygous FH, namely the apolipoprotein B synthesis inhibitor mipomersen and the microsomal transfer protein inhibitor lomitapide. Objective of this narrative review is to discuss the available evidence on the safety and efficacy profile of these new drugs.

  18. All-optical analog comparator

    Science.gov (United States)

    Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai

    2016-08-01

    An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function.

  19. Congenital erythropoietic porphyria: report of a novel mutation with absence of clinical manifestations in a homozygous mutant sibling.

    Science.gov (United States)

    Ged, Cécile; Mégarbané, Hala; Chouery, Eliane; Lalanne, Magalie; Mégarbané, André; de Verneuil, Hubert

    2004-09-01

    In a Palestinian family, four siblings were shown to express typical and severe congenital erythropoietic porphyria (CEP). A new mutation of the uroporphyrinogen III synthase (UROS) gene was evidenced by systematic sequencing of the UROS gene: the substitution of serine by proline at the amino acid residue 47 (S47P) was present at the homozygous state in the four patients. The mother was heterozygous, the father was not examined. Surprisingly, in one unaffected sister, UROS activity was markedly deficient and UROS gene analysis showed a homozygous mutant profile. The deleterious role of the mutant S47P protein on UROS activity was demonstrated by prokaryotic expression. This observation is the first report of a healthy status associated with homozygosity for a mutation of UROS gene in a severely affected family. We then draw hypotheses to explain the protective phenotype in the homozygous healthy subject.

  20. Homozygous Deletions and Recurrent Amplifications Implicate New Genes Involved in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Wennuan Liu

    2008-08-01

    Full Text Available Prostate cancer cell lines provide ideal in vitro systems for the identification and analysis of prostate tumor suppressors and oncogenes. A detailed characterization of the architecture of prostate cancer cell line genomes would facilitate the study of precise roles of various genes in prostate tumorigenesis in general. To contribute to such a characterization, we used the GeneChip 500K single nucleotide polymorphic (SNP array for analysis of genotypes and relative DNA copy number changes across the genome of 11 cell lines derived from both normal and cancerous prostate tissues. For comparison purposes, we also examined the alterations observed in the cell lines in tumor/normal pairs of clinical samples from 72 patients. Along with genome-wide maps of DNA copy number changes and loss of heterozygosity for these cell lines, we report previously unreported homozygous deletions and recurrent amplifications in prostate cancers in this study. The homozygous deletions affected a number of biologically important genes, including PPP2R2A and BNIP3L identified in this study and CDKN2A/CDKN2B reported previously. Although most amplified genomic regions tended to be large, amplifications at 8q24.21 were of particular interest because the affected regions are relatively small, are found in multiple cell lines, are located near MYC, an oncogene strongly implicated in prostate tumorigenesis, and are known to harbor SNPs that are associated with inherited susceptibility for prostate cancer. The genomic alterations revealed in this study provide an important catalog of positional information relevant to efforts aimed at deciphering the molecular genetic basis of prostate cancer.

  1. Thiamine responsive megaloblastic anemia syndrome: a novel homozygous SLC19A2 gene mutation identified.

    Science.gov (United States)

    Mikstiene, Violeta; Songailiene, Jurgita; Byckova, Jekaterina; Rutkauskiene, Giedre; Jasinskiene, Edita; Verkauskiene, Rasa; Lesinskas, Eugenijus; Utkus, Algirdas

    2015-07-01

    Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease - megaloblastic anemia, early onset deafness, and non-type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania - a 3-year-old boy born to a non-consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis - novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition. © 2015 Wiley Periodicals, Inc.

  2. Prevalence and correlates of metabolic acidosis among patients with homozygous sickle cell disease.

    Science.gov (United States)

    Maurel, Stéphane; Stankovic Stojanovic, Katia; Avellino, Virginie; Girshovich, Alexey; Letavernier, Emmanuel; Grateau, Gilles; Baud, Laurent; Girot, Robert; Lionnet, Francois; Haymann, Jean-Philippe

    2014-04-01

    Very few studies report acid base disorders in homozygous patients with sickle cell anemia (SCA) and describe incomplete renal acidosis rather than true metabolic acidosis, the prevalence of which is unknown and presumably low. This study aimed to assess the prevalence of metabolic acidosis and to identify its risk factors and mechanisms. This study retrospectively analyzed 411 homozygous patients with SCA with a GFR ≥ 60 ml/min per 1.73 m(2), referred in a single center between 2007 and 2012. Acidosis and nonacidosis groups were compared for clinical and biologic data including SCA complications and hemolytic parameters. A subgroup of 65 patients with SCA, referred for a measured GFR evaluation in the setting of sickle cell-associated nephropathy, was further analyzed in order to better characterize metabolic acidosis. Metabolic acidosis was encountered in 42% of patients with SCA, with a higher prevalence in women (52% versus 27% in men; Pacidosis and nonacidosis groups (P=0.02 and P=0.03 in men and women, respectively), suggesting higher hemolytic activity in the former group. To note, fasting urine osmolality was low in the whole study population and was significantly lower in men with SCA in the acidosis group (392 versus 427 mOsm/kg; P=0.01). SCA subgroup analysis confirmed metabolic acidosis with a normal anion gap in 14 patients, characterized by a lower urinary pH (Pacidosis in patients with SCA is underestimated and related to impaired ammonium availability possibly due to an altered corticopapillary gradient. Future studies should evaluate whether chronic metabolic acidosis correction may be beneficial in this population, especially in bone remodeling.

  3. Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia.

    Science.gov (United States)

    Tekin, M; Oztürkmen Akay, H; Fitoz, S; Birnbaum, S; Cengiz, F B; Sennaroğlu, L; Incesulu, A; Yüksel Konuk, E B; Hasanefendioğlu Bayrak, A; Sentürk, S; Cebeci, I; Utine, G E; Tunçbilek, E; Nance, W E; Duman, D

    2008-06-01

    Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 - LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co-segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non-syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.

  4. Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma.

    Science.gov (United States)

    Ali, Manir; Buentello-Volante, Beatriz; McKibbin, Martin; Rocha-Medina, J Alberto; Fernandez-Fuentes, Narcis; Koga-Nakamura, Wilson; Ashiq, Aruna; Khan, Kamron; Booth, Adam P; Williams, Grange; Raashid, Yasmin; Jafri, Hussain; Rice, Aine; Inglehearn, Chris F; Zenteno, Juan Carlos

    2010-06-23

    To investigate the genetic basis of recessively-inherited congenital, non syndromic, bilateral, total sclerocornea in two consanguineous pedigrees, one from the Punjab province of Pakistan and the other from the Tlaxcala province of Mexico. Ophthalmic examinations were conducted on each family member to confirm their diagnosis and magnetic resonance imaging (MRI) or ultrasonography of the eyes was performed on some family members. Genomic DNA was analyzed by homozygosity mapping using the Affymetrix 6.0 SNP array and linkage was confirmed with polymorphic microsatellite markers. Candidate genes were sequenced. A diagnosis of autosomal recessive sclerocornea was established for 7 members of the Pakistani and 8 members of the Mexican pedigrees. In the Pakistani family we established linkage to a region on chromosome 1p that contained Forkhead Box E3 (FOXE3), a strong candidate gene since FOXE3 mutations had previously been associated with various anterior segment abnormalities. Sequencing FOXE3 identified the previously reported nonsense mutation, c.720C>A, p.C240X, in the Pakistani pedigree and a novel missense mutation which disrupts an evolutionarily conserved residue in the forkhead domain, c.292T>C, p.Y98H, in the Mexican pedigree. Individuals with heterozygous mutations had no ocular abnormalities. MRI or ultrasonography confirmed that the patients with sclerocornea were also aphakic, had microphthalmia and some had optic disc coloboma. This is the fourth report detailing homozygous FOXE3 mutations causing anterior segment abnormalities in human patients. Previous papers have emphasized aphakia and microphthalmia as the primary phenotype, but we find that the initial diagnosis - and perhaps the only one possible in a rural setting - is one of non-syndromic, bilateral, total sclerocornea. Dominantly inherited anterior segment defects have also been noted in association with heterozygous FOXE3 mutations. However the absence of any abnormalities in the FOXE3

  5. Analog electronics for radiation detection

    CERN Document Server

    2016-01-01

    Analog Electronics for Radiation Detection showcases the latest advances in readout electronics for particle, or radiation, detectors. Featuring chapters written by international experts in their respective fields, this authoritative text: Defines the main design parameters of front-end circuitry developed in microelectronics technologies Explains the basis for the use of complementary metal oxide semiconductor (CMOS) image sensors for the detection of charged particles and other non-consumer applications Delivers an in-depth review of analog-to-digital converters (ADCs), evaluating the pros and cons of ADCs integrated at the pixel, column, and per-chip levels Describes incremental sigma delta ADCs, time-to-digital converter (TDC) architectures, and digital pulse-processing techniques complementary to analog processing Examines the fundamental parameters and front-end types associated with silicon photomultipliers used for single visible-light photon detection Discusses pixel sensors ...

  6. SSERVI Analog Regolith Simulant Testbed Facility

    Science.gov (United States)

    Minafra, Joseph; Schmidt, Gregory; Bailey, Brad; Gibbs, Kristina

    2016-10-01

    The Solar System Exploration Research Virtual Institute (SSERVI) at NASA's Ames Research Center in California's Silicon Valley was founded in 2013 to act as a virtual institute that provides interdisciplinary research centered on the goals of its supporting directorates: NASA Science Mission Directorate (SMD) and the Human Exploration & Operations Mission Directorate (HEOMD).Primary research goals of the Institute revolve around the integration of science and exploration to gain knowledge required for the future of human space exploration beyond low Earth orbit. SSERVI intends to leverage existing JSC1A regolith simulant resources into the creation of a regolith simulant testbed facility. The purpose of this testbed concept is to provide the planetary exploration community with a readily available capability to test hardware and conduct research in a large simulant environment.SSERVI's goals include supporting planetary researchers within NASA, other government agencies; private sector and hardware developers; competitors in focused prize design competitions; and academic sector researchers.SSERVI provides opportunities for research scientists and engineers to study the effects of regolith analog testbed research in the planetary exploration field. This capability is essential to help to understand the basic effects of continued long-term exposure to a simulated analog test environment.The current facility houses approximately eight tons of JSC-1A lunar regolith simulant in a test bin consisting of a 4 meter by 4 meter area, including dust mitigation and safety oversight.Facility hardware and environment testing scenarios could include, Lunar surface mobility, Dust exposure and mitigation, Regolith handling and excavation, Solar-like illumination, Lunar surface compaction profile, Lofted dust, Mechanical properties of lunar regolith, Surface features (i.e. grades and rocks)Numerous benefits vary from easy access to a controlled analog regolith simulant testbed, and

  7. When Are Analogies the Right Tool? A Look at the Strategic Use of Analogies in Teaching Cellular Respiration to Middle-School Students.

    Science.gov (United States)

    Else, Mary Jane; Ramirez, Mary Anne; Clement, John

    In this paper, the ways in which analogies are used in the Energy and the Human Body curriculum will be examined and some preliminary assessments of successes and difficulties will be discussed. Also investigated will be what the first year's study trials suggest about the effective use of analogies in the middle-school classroom. Characteristics…

  8. Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

    Science.gov (United States)

    Hong, Seoung-Soo; Bavadekar, Supriya A; Lee, Sang-Il; Patil, Popat N; Lalchandani, S G; Feller, Dennis R; Miller, Duane D

    2005-11-01

    The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

  9. All-optical analog comparator

    OpenAIRE

    Pu Li; Xiaogang Yi; Xianglian Liu; Dongliang Zhao; Yongpeng Zhao; Yuncai Wang

    2016-01-01

    An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical device...

  10. International Alligator Rivers Analog Project

    Energy Technology Data Exchange (ETDEWEB)

    Bichard, G.F.

    1988-01-01

    The Australian Nuclear Science and Technology Organization (ANSTO), the Japan Atomic Energy Research Institute, the Swedish Nuclear Power Inspectorate, the U.K. Department of the Environment, the US Nuclear Regulatory Commission (NRC), and the Power Reactor and Nuclear Fuel Development Corporation of Japan are participating under the aegis of the Nuclear Energy Agency in the International Alligator Rivers Analog Project. The project has a duration of 3 yr, starting in 1988. The project has grown out of a research program on uranium ore bodies as analogs of high-level waste (HLW) repositories undertaken by ANSTO supported by the NRC. A primary objective of the project is to develop an approach to radionuclide transport model validation that may be used by the participants to support assessments of the safety of radioactive waste repositories. The approach involves integrating mathematical and physical modeling with hydrological and geochemical field and laboratory investigations of the analog site. The Koongarra uranium ore body has been chosen as the analog site because it has a secondary ore body that has formed over the past million years as a result of leaching by groundwater flowing through fractures in the primary ore body.

  11. 49205 ANALOGE OG DIGITALE FILTRE

    DEFF Research Database (Denmark)

    Gaunholt, Hans

    1997-01-01

    Theese lecture notes treats the fundamental theory and the most commonly used design methods for passive- active and digital filters with special emphasis on microelectronic realizations. The lecture notes covers 75% of the material taught in the course 49205 Analog and Digital Filters...

  12. Analog Input Data Acquisition Software

    Science.gov (United States)

    Arens, Ellen

    2009-01-01

    DAQ Master Software allows users to easily set up a system to monitor up to five analog input channels and save the data after acquisition. This program was written in LabVIEW 8.0, and requires the LabVIEW runtime engine 8.0 to run the executable.

  13. Mathematical Analogy and Metaphorical Insight

    Science.gov (United States)

    Zwicky, Jan

    2010-01-01

    How are we to understand the power of certain literary metaphors? The author argues that the apprehension of good metaphors is importantly similar to the apprehension of fruitful mathematical analogies: both involve a structural realignment of vision. The author then explores consequences of this claim, drawing conceptually significant parallels…

  14. Schema Training in Analogical Reasoning.

    Science.gov (United States)

    Robins, Shani; Mayer, Richard E.

    1993-01-01

    In 3 experiments, 93, 97, and 86 college students, respectively, learned how to solve 20 verbal analogy problems and took transfer and memory tests. Results are inconsistent with active responding theory and further indicate that schema induction is maximized when the schemas are made salient and the cognitive system is not overloaded. (SLD)

  15. 49205 ANALOGE OG DIGITALE FILTRE

    DEFF Research Database (Denmark)

    Gaunholt, Hans

    1997-01-01

    Theese lecture notes treats the fundamental theory and the most commonly used design methods for passive- active and digital filters with special emphasis on microelectronic realizations. The lecture notes covers 75% of the material taught in the course 49205 Analog and Digital Filters...

  16. Understanding & Teaching Genetics Using Analogies

    Science.gov (United States)

    Woody, Scott; Himelblau, Ed

    2013-01-01

    We present a collection of analogies that are intended to help students better understand the foreign and often nuanced vocabulary of the genetics curriculum. Why is it called the "wild type"? What is the difference between a locus, a gene, and an allele? What is the functional (versus a rule-based) distinction between dominant and…

  17. Processes in Verbal Analogy Solution.

    Science.gov (United States)

    Grudin, Jonathan

    1980-01-01

    Verbal analogy solution is more flexible than is suggested by either the standard process theory or Sternberg's theory. It was determined that subjects initially examine terms A and B; if this strategy is not successful, they examine the relationship between A and C. (Author/CP)

  18. Structure- and isoform-specific glucuronidation of six curcumin analogs.

    Science.gov (United States)

    Lu, Danyi; Liu, Hui; Ye, Wencai; Wang, Ying; Wu, Baojian

    2017-04-01

    1. In the present study, we aimed to characterize the glucuronidation of six curcumin analogs (i.e. RAO-3, RAO-8, RAO-9, RAO-18, RAO-19, and RAO-23) derived from galangal using human liver microsomes (HLM) and twelve expressed UGT enzymes. 2. Formation of glucuronide was confirmed using high-resolution mass spectrometry. Single glucuronide metabolite was generated from each of six curcumin analogs. The fragmentation patterns were analyzed and were found to differ significantly between alcoholic and phenolic glucuronides. 3. All six curcumin analogs except one (RAO-23) underwent significant glucuronidation in HLM and expressed UGT enzymes. In general, the methoxy group (close to the phenolic hydroxyl group) enhanced the glucuronidation liability of the curcumin analogs. 4. UGT1A9 and UGT2B7 were primarily responsible for the glucuronidation of two alcoholic analogs (RAO-3 and RAO-18). By contrast, UGT1A9 and four UGT2Bs (UGT2B4, 2B7, 2B15 and 2B17) played important roles in conjugating three phenolic analogs (RAO-8, RAO-9, and RAO-19). Interestingly, the conjugated double bonds system (in the aliphatic chain) was crucial to the substrate selectivity of gastrointestinal UGTs (i.e. UGT1A7, 1A8 and 1A10). 5. In conclusion, glucuronidation of six curcumin analogs from galangal were structure- and isoform-specific. The knowledge should be useful in identifying a curcumin analog with improved metabolic property.

  19. A homozygous M694V mutation of the MEFV gene in a patient with periodic fever and thoracic pain

    NARCIS (Netherlands)

    van de Loosdrecht, AA; van der Kleij, FGH; van Minnen, CA; Hazenberg, BPC

    2000-01-01

    A Turkish patient with episodic fever and thoracic pain is described in whom a homozygous M694V mutation of the MEFV gene confirmed the clinical diagnosis of familial Mediterranean fryer. The role of DNA analysis is discussed with respect to understanding the pathogenesis of the fever and assessing

  20. A homozygous M694V mutation of the MEFV gene in a patient with periodic fever and thoracic pain

    NARCIS (Netherlands)

    van de Loosdrecht, AA; van der Kleij, FGH; van Minnen, CA; Hazenberg, BPC

    A Turkish patient with episodic fever and thoracic pain is described in whom a homozygous M694V mutation of the MEFV gene confirmed the clinical diagnosis of familial Mediterranean fryer. The role of DNA analysis is discussed with respect to understanding the pathogenesis of the fever and assessing

  1. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden

    NARCIS (Netherlands)

    Middeldorp, S; Libourel, EJ; Hamulyak, K; van der Meer, J; Buller, HR

    The risk of venous thromboembolism (VTE) is increased in pregnancy and during the post-partum period, The absolute risk for pregnancy-related VTE in heterozygous women with the factor V Leiden mutation is approximately 2%, but studies on this risk for homozygous women show conflicting results. In a

  2. Life-threatening aortic thrombosis in a trauma patient homozygous for factor V Leiden mutation: Case report

    Directory of Open Access Journals (Sweden)

    Kopterides Petros

    2011-05-01

    Full Text Available Abstract We report a case of near fatal aortic thrombosis in a trauma patient homozygous for mutation of Factor V Leiden. He responded well to vascular surgery and intensive care unit management and was discharged successfully from the hospital one month later.

  3. Segregation of microsatellite alleles and residual heterogosity at single loci in homozygous androgenetic common carp (Cyprino carpio L.)

    NARCIS (Netherlands)

    Tanck, M.W.T.; Palstra, A.P.; Weerd, van de M.; Leffering, C.P.; Poel, van der J.J.; Bovenhuis, H.; Komen, J.

    2001-01-01

    Thirty-three androgenetic progeny groups of common carp were analysed using 11 microsatellite markers to (i) verify the homozygous status of the 566 androgenetic individuals, (ii) analyse the microsatellite allele segregation, and (iii) study the possible association of microsatellite alleles with p

  4. Comparison of Switching and Biofilm Formation between MTL-Homozygous Strains of Candida albicans and Candida dubliniensis.

    Science.gov (United States)

    Pujol, Claude; Daniels, Karla J; Soll, David R

    2015-12-01

    Candida albicans and Candida dubliniensis are highly related species that share the same main developmental programs. In C. albicans, it has been demonstrated that the biofilms formed by strains heterozygous and homozygous at the mating type locus (MTL) differ functionally, but studies rarely identify the MTL configuration. This becomes a particular problem in studies of C. dubliniensis, given that one-third of natural strains are MTL homozygous. For that reason, we have analyzed MTL-homozygous strains of C. dubliniensis for their capacity to switch from white to opaque, the stability of the opaque phenotype, CO2 induction of switching, pheromone induction of adhesion, the effects of minority opaque cells on biofilm thickness and dry weight, and biofilm architecture in comparison with C. albicans. Our results reveal that C. dubliniensis strains switch to opaque at lower average frequencies, exhibit a far lower level of opaque phase stability, are not stimulated to switch by high CO2, exhibit more variability in biofilm architecture, and most notably, form mature biofilms composed predominately of pseudohyphae rather than true hyphae. Therefore, while several traits of MTL-homozygous strains of C. dubliniensis appear to be degenerating or have been lost, others, most notably several related to biofilm formation, have been conserved. Within this context, the possibility is considered that C. dubliniensis is transitioning from a hypha-dominated to a pseudohypha-dominated biofilm and that aspects of C. dubliniensis colonization may provide insights into the selective pressures that are involved.

  5. Homozygous c.1160C>T (P38L) in the MECP2 gene in a female Rett syndrome patient.

    Science.gov (United States)

    Bhanushali, Aparna A; Mandsaurwala, A; Das, Bibhu R

    2016-03-01

    Rett syndrome is a severe X-linked dominant neurodevelopmental disorder. Mutations in the MECP2 gene on chromosome Xq28 have been shown to be the cause of Rett syndrome. Sequencing of the MECP2 gene in a patient with clinical suspicion of Rett syndrome revealed c.1160C>T (P387L) in exon 4 of the MECP2 gene homozygously. Females with Rett syndrome are usually heterozygous for a mutation in MECP2. Uniparental disomy as a probable cause for the homozygous presence of this mutation was ruled out by quantitative fluorescence-polymerase chain reaction. Moreover to our knowledge this mutation has only been reported in males with X-linked mental retardation (MRX). We hypothesize that the presence of this mutation c.1160C>T (P387L) in the homozygous form is responsible for the Rett syndrome-like phenotype seen in this patient. This novel report reveals for the first time the homozygous presence of a mutation which has hitherto only been reported in males with MRX.

  6. MRI at 3 Tesla detects no evidence for ischemic brain damage in intensively treated patients with homozygous familial hypercholesterolemia

    Energy Technology Data Exchange (ETDEWEB)

    Schmitz, Stephan A.; O' Regan, Declan P.; Fitzpatrick, Julie; Hajnal, Joseph V. [Hammersmith Hospital Campus, Imaging Sciences Department, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London (United Kingdom); Neuwirth, Clare; Potter, Elizabeth; Tosi, Isabella; Naoumova, Rossi P. [MRC Clinical Sciences Centre, Clinical Research Facility, London (United Kingdom); Hammersmith Hospital, Lipid Clinic, London (United Kingdom)

    2007-11-15

    Homozygous familial hypercholesterolemia (FH) is considered a model disease for excessive plasma cholesterol levels. Patients with untreated homozygous FH have a markedly increased risk for premature atherosclerosis. The frequency and extent of ischemic brain damage detectable by high-field magnetic resonance imaging (MRI) after long-term intensive treatment are unknown. In a case control study, five patients with homozygous FH (one male and four females; mean age: 23.6 {+-} 9.2, range: 12-36 years; mean pre-treatment serum total cholesterol level: 26.9 {+-} 3.24 mmol/L; all patients with documented atherosclerotic plaques in the carotid arteries) and five age- and sex-matched healthy controls were studied. All patients had been on maximal lipid-lowering medication since early childhood, and four of them were also on treatment with low-density lipoprotein (LDL) apheresis at bi-weekly intervals. Brain MRI was performed at 3 Tesla field strength with fluid-attenuated T2-weighted inversion recovery and T1-weighted spin-echo MR pulse sequences and subsequently evaluated by two independent readers. The maximal lipid-lowering treatment reduced the total serum cholesterol by more than 50% in the patients, but their serum concentrations were still 3.6-fold higher than those found in the controls (11.9 {+-} 4.2 vs. 4.5 {+-} 0.5 mmol/L; p < 0.0047). No brain abnormality was observed in any of the patients with homozygous FH. Homozygous FH patients on intensive cholesterol-lowering therapy have no evidence of ischemic brain damage at 3 Tesla MRI despite the remaining high cholesterol levels. (orig.)

  7. Analog circuit design art, science and personalities

    CERN Document Server

    Williams, Jim

    1991-01-01

    This book is far more than just another tutorial or reference guide - it's a tour through the world of analog design, combining theory and applications with the philosophies behind the design process. Readers will learn how leading analog circuit designers approach problems and how they think about solutions to those problems. They'll also learn about the `analog way' - a broad, flexible method of thinking about analog design tasks.A comprehensive and useful guide to analog theory and applications. Covers visualizing the operation of analog circuits. Looks at how to rap

  8. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.

    Science.gov (United States)

    Cario, Holger; Smith, Desirée E C; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

    2011-02-11

    The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  9. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease

    Science.gov (United States)

    Rajakulendran, Sanjeev; Pitceathly, Robert D. S.; Taanman, Jan-Willem; Costello, Harry; Sweeney, Mary G.; Woodward, Cathy E.; Jaunmuktane, Zane; Holton, Janice L.; Jacques, Thomas S.; Harding, Brian N.; Fratter, Carl; Hanna, Michael G.; Rahman, Shamima

    2016-01-01

    Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors. PMID:26735972

  10. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease.

    Directory of Open Access Journals (Sweden)

    Sanjeev Rajakulendran

    Full Text Available Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA. Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS, one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO. All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.

  11. Eculizumab in neonatal hemolytic uremic syndrome with homozygous factor H deficiency.

    Science.gov (United States)

    Michaux, Katell; Bacchetta, Justine; Javouhey, Etienne; Cochat, Pierre; Frémaux-Bacchi, Véronique; Sellier-Leclerc, Anne-Laure

    2014-12-01

    Neonatal atypical hemolytic uremic syndrome (aHUS) is a rare but severe disease that is mainly due to methylmalonic aciduria or genetic complement abnormalities. Traditional management of aHUS includes plasma infusion/exchange, but in small or unstable infants, plasma exchange can be challenging because of high extracorporeal volume and difficulty to obtain an adequate venous access. The C5 complement blocker eculizumab has become a cornerstone of first-line management of aHUS due to complement deregulation in older patients. However, little data are available on its use in neonatal aHUS. We report on an 11-day-old neonate with severe aHUS (myocardial impairment, respiratory failure, acute kidney disease requiring hemodiafiltration) due to homozygous factor-H deficiency. She received early treatment with eculizumab as first-line therapy and completely recovered within 5 days. A second dose of eculizumab was administered 7 days after the first infusion, followed by a dose every 2 weeks for 2 months and then every 3 weeks, at the same dosage (300 mg). With more than 24 months of follow-up, renal function remains normal. We report on the long-term efficacy and safety of eculizumab as first-line therapy in neonatal aHUS. However its use still requires optimization in terms of indications and administration (frequency, dosage).

  12. [Formation of para-Bombay phenotype caused by homozygous or heterozygous mutation of FUT1 gene].

    Science.gov (United States)

    Zhang, Jin-Ping; Zheng, Yan; Sun, Dong-Ni

    2014-02-01

    This study was aimed to explore the molecular mechanisms for para-Bombay phenotype formation. The H antigen of these individuals were identified by serological techniques. The full coding region of alpha (1, 2) fucosyltransferase (FUT1) gene of these individuals was amplified by high-fidelity polymerase chain reaction (PCR). PCR product was identified by TOPO cloning sequencing. Analysis and comparison were used to explore the mechanisms of para-bombay phenotype formation in individuals. The results indicated that the full coding region of FUT1 DNA was successfully amplified by PCR and gel electrophoresis. DNA sequencing and analysis found that h1 (547-552delAG) existed in one chromosome and h4 (35C > T) existed in the other chromosome of NO.1 individual. Meantime, h1 (547-552delAG) was found in two chromosomes of NO.2 and NO.3 individual. It also means that FUT1 gene of NO.1 individual was h1h4 heterozygote, FUT1 gene of NO.2 and NO.3 individuals were h1h1 homozygote. It is concluded that homozygous and heterozygous mutation of FUT1 gene can lead to the formation of para-Bombay phenotype.

  13. HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom.

    Science.gov (United States)

    France, Michael; Rees, Alan; Datta, Dev; Thompson, Gilbert; Capps, Nigel; Ferns, Gordon; Ramaswami, Uma; Seed, Mary; Neely, Dermot; Cramb, Robert; Shoulders, Carol; Barbir, Mahmoud; Pottle, Alison; Eatough, Ruth; Martin, Steven; Bayly, Graham; Simpson, Bill; Halcox, Julian; Edwards, Ray; Main, Linda; Payne, Jules; Soran, Handrean

    2016-12-01

    This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

  14. Neuropsychological profiles of three sisters homozygous for the fragile X premutation

    Energy Technology Data Exchange (ETDEWEB)

    Mazzocco, M.M.M. [Johns Hopkins School of Medicine, Baltimore, MD (United States); Holden, J.J.A. [Ongwanada Resource Centre, Kingston, Ontario (Canada)

    1996-08-09

    Fragile X syndrome (fraX) is associated with an amplification of a CGG repeat within the fraX mental retardation (FMR-1) gene. We describe an exceptional family in which 3 adult sisters are homozygous for the FMR-1 premutation. Each sister inherited 2 premutation alleles (ca. 80 CGG repeats) from their biologically unrelated parents. The 3 sisters were administered measures of executive function, visual spatial, memory, and verbal skills. Deficiencies in the first 2 of these domains have been reported among females with the full mutation. The sisters` performances were compared with available normative data and with published group means for females affected by fraX. These women did not appear to have verbal or memory difficulties. None of the women demonstrated a global executive function deficit, and none had global deficits in spatial ability. The profiles of these sisters are consistent with reports that the fragile X premutation does not affect cognitive performance. 31 refs., 1 fig., 4 tabs.

  15. Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients.

    Science.gov (United States)

    Akpolat, Tekin; Özkaya, Ozan; Özen, Seza

    2012-01-15

    Secondary amyloidosis is the most severe complication of familial Mediterranean fever (FMF). Since the M694V mutation was associated with clinical severity, it was expected to be associated with amyloidosis as well. However, a number of contradicting reports have been published, especially pertinent to Turkish patients nearly 10years ago. The aim of this study was to analyze recent data regarding the association between M694V mutation and amyloidosis among FMF patients in Turkey. We conducted a comprehensive review of the literature regarding the role of M694V mutation in the development of amyloidosis secondary to FMF. Twenty-seven papers from 20 centers including 3505 Turkish subjects were reviewed. Four-hundred patients had amyloidosis and homozygous M694V was detected in 189 (47%) of the 400 amyloidotic patients which was significantly higher than that in the FMF patients not developing amyloidosis (pFMF patients with this genotype, even in countries where amyloidosis is rare, should be considered carefully. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. QTL mapping under truncation selection in homozygous lines derived from biparental crosses.

    Science.gov (United States)

    Melchinger, Albrecht E; Orsini, Elena; Schön, Chris C

    2012-02-01

    In plant breeding, a large number of progenies that will be discarded later in the breeding process must be phenotyped and marker genotyped for conducting QTL analysis. In many cases, phenotypic preselection of lines could be useful. However, in QTL analyses even moderate preselection can have a significant effect on the power of QTL detection and estimation of effects of the target traits. In this study, we provide exact formulas for quantifying the change of allele frequencies within marker classes, expectations of marker contrasts and the variance of the marker contrasts under truncation selection, for the general case of two QTL affecting the target trait and a correlated trait. We focused on homozygous lines derived at random from biparental crosses. The effects of linkage between the marker and the QTL under selection as well as the effect of selection on a correlated trait can be quantified with the given formulas. Theoretical results clearly show that depending on the magnitude of QTL effects, high selection intensities can lead to a dramatic reduction in power of QTL detection and that approximations based on the infinitesimal model deviate substantially from exact solutions. The presented formulas are valuable for choosing appropriate selection intensity when performing QTL mapping experiments on the data on phenotypically preselected traits and enable the calculation and bias correction of the effects of QTL under selection. Application of our theory to experimental data revealed that selection-induced bias of QTL effects can be successfully corrected.

  17. Comparison of two low-density lipoprotein apheresis systems in patients with homozygous familial hypercholesterolemia.

    Science.gov (United States)

    Drouin-Chartier, Jean-Philippe; Tremblay, André J; Bergeron, Jean; Pelletier, Maude; Laflamme, Nathalie; Lamarche, Benoît; Couture, Patrick

    2016-08-01

    Low-density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL-C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin-induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (-63.3% vs. -59.9%; P = 0.05), LDL-C (-70.5% vs. -63.0%; P = 0.02), CRP (-75.3% vs. -48.8%; P Apheresis 31:359-367, 2016. © 2015 Wiley Periodicals, Inc.

  18. Severe combined immunodeficiency caused by a new homozygous RAG1 mutation with progressive encephalopathy.

    Science.gov (United States)

    Dhingra, Nivedita; Yadav, Satya Prakash; de Villartay, Jean-Pierre; Picard, Capucine; Sabharwal, R K; Dinand, Veronique; Ghuman, Samarjit Singh; Sachdeva, Anupam

    2014-03-01

    We describe an unusual case of severe combined immunodeficiency (SCID) with neutropenia and central nervous system (CNS) manifestations in which a novel RAG1 mutation was identified. A 15-month-old boy presented with failure to thrive, neutropenia and recurrent infections. He was diagnosed with T-B-NK+ SCID. He subsequently developed right partial seizures with ipsilateral hemiparesis and became comatose. Magnetic resonance imaging (MRI) of the brain revealed an inflammatory lesion in the left thalamus which later progressed to diffuse meningo-encephalitis on serial imaging. No CNS infection was documented. Genetic work-up in the child revealed a novel homozygous deleterious mutation in the RAG1 gene (c:2881T>C; p:I794T), for which both parents were heterozygous. He underwent a haploidentical bone marrow transplant without conditioning and died on day +35 with no improvement in his neurological status. The features of neutropenia and progressive encephalopathy could be linked to the novel genetic defect but more data is required to establish this conclusively.

  19. Operational Lessons Learned from NASA Analog Missions

    Science.gov (United States)

    Arnold, Larissa S.

    2010-01-01

    National Aeronautics and Space Administration s (NASA) efforts in human space flight are currently focused on the Space Shuttle and International Space Station (ISS) programs, with efforts beginning on the future exploration opportunities. Both the Space Shuttle and ISS programs are important to the development of a capability for human exploration beyond Low Earth Orbit (LEO). The ISS provides extensive research capabilities to determine how the human body reacts to long duration stays in space. Also, the ISS and Shuttle can serve as a limited testbed for equipment or entire systems that may be used on missions to the Moon, Mars, or to a near-Earth asteroid. It has been nearly 35 years since the Apollo astronauts visited the Moon. Future space explorers will have to re-learn how to work and live on planetary surfaces, and how to do that for extended periods of time. Exploration crews will perform a wide assortment of scientific tasks, including material sampling and emplacement of automated instruments. Surface mission operations include the activities of the crew living and working, mission support from the Earth, and the operation of robotic and other remotely commanded equipment on the surface and in planetary orbit. Other surface activities will include the following: exploring areas surrounding a habitat; using rovers to collect rock and soil samples; setting up experiments on the surface to monitor the radiation environment and any seismic or thermal activity; and conducting scientific analyses and experiments inside a habitat laboratory. Of course, the astronauts will also have to spend some of their surface time "doing chores" and maintaining their habitat and other systems. In preparation for future planetary exploration, NASA must design the answers to many operational questions. What will the astronauts do on the surface? How will they accomplish this? What tools will they require for their tasks? How will robots and astronauts work together? What

  20. Production of hemizygous and homozygous embryonic stem cell-derived neural progenitor cells from the transgenic alszheimer göttingen minipis

    DEFF Research Database (Denmark)

    Hall, Vanessa Jane; Jacobsen, J.; Gunnarsson, A.

    2011-01-01

    Production of hemizygous and homozygous embryonic stem cell-derived neural progenitor cells from the transgenic alszheimer göttingen minipis......Production of hemizygous and homozygous embryonic stem cell-derived neural progenitor cells from the transgenic alszheimer göttingen minipis...

  1. Efficient selection of homozy-gous lines of hybrid rice restorer with the transgene Xa21 using test cross and PCR

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The homozygous restorer lines with a single copy of the transgene Xa21 have been obtained from the progenies of transgenic Minghui63 and Yanhui559 plants through PCR marker-assisted selection and test cross. These homozygous transgenic restorer lines can be used to breed hybrid rice with high resistance to bacterial leaf blight.

  2. Synaptic dynamics in analog VLSI.

    Science.gov (United States)

    Bartolozzi, Chiara; Indiveri, Giacomo

    2007-10-01

    Synapses are crucial elements for computation and information transfer in both real and artificial neural systems. Recent experimental findings and theoretical models of pulse-based neural networks suggest that synaptic dynamics can play a crucial role for learning neural codes and encoding spatiotemporal spike patterns. Within the context of hardware implementations of pulse-based neural networks, several analog VLSI circuits modeling synaptic functionality have been proposed. We present an overview of previously proposed circuits and describe a novel analog VLSI synaptic circuit suitable for integration in large VLSI spike-based neural systems. The circuit proposed is based on a computational model that fits the real postsynaptic currents with exponentials. We present experimental data showing how the circuit exhibits realistic dynamics and show how it can be connected to additional modules for implementing a wide range of synaptic properties.

  3. Holism and nonseparability by analogy

    Science.gov (United States)

    Arageorgis, Aristidis

    2013-08-01

    This paper explores the issues of holism and nonseparability in relativistic quantum field theory (QFT) by focusing on an analog of the typical model featuring in many discussions of holism and nonseparability in nonrelativistic quantum mechanics. It is argued that the quantum field theoretic model does exhibit holism in a metaphysical sense and that there are plausible grounds to view QFT holistic in an epistemological sense. However, the complexities arising from the fact that quantum fields have infinite degrees of freedom prohibit the exploitation of the elaborated analogy toward demonstrating that the QFT model exhibits the kind of state nonseparability familiar from ordinary quantum mechanics. Still, it is argued that the QFT model does satisfy a rather weak epistemological criterion for state nonseparability.

  4. Analog-to-digital conversion

    CERN Document Server

    Pelgrom, Marcel

    2017-01-01

    This textbook is appropriate for use in graduate-level curricula in analog-to-digital conversion, as well as for practicing engineers in need of a state-of-the-art reference on data converters. It discusses various analog-to-digital conversion principles, including sampling, quantization, reference generation, nyquist architectures and sigma-delta modulation. This book presents an overview of the state of the art in this field and focuses on issues of optimizing accuracy and speed, while reducing the power level. This new, third edition emphasizes novel calibration concepts, the specific requirements of new systems, the consequences of 22-nm technology and the need for a more statistical approach to accuracy. Pedagogical enhancements to this edition include additional, new exercises, solved examples to introduce all key, new concepts and warnings, remarks and hints, from a practitioner’s perspective, wherever appropriate. Considerable background information and practical tips, from designing a PCB, to lay-o...

  5. Mechanical Analogies of Fractional Elements

    Institute of Scientific and Technical Information of China (English)

    HU Kai-Xin; ZHU Ke-Qin

    2009-01-01

    A Fractional element model describes a special kind of viscoelastic material.Its stress is proportional to the fractional-order derivative of strain. Physically the mechanical analogies of fractional elements can be represented by spring-dashpot fractal networks. We introduce a constitutive operator in the constitutive equations of viscoelastic materials.To derive constitutive operators for spring-dashpot fractal networks, we use Heaviside operational calculus, which provides explicit answers not otherwise obtainable simply.Then the series-parallel formulas for the constitutive operator are derived. Using these formulas, a constitutive equation of fractional element with 1/2-order derivative is obtained.Finally we find the way to derive the constitutive equations with other fractional-order derivatives and their mechanical analogies.

  6. Palytoxin and Analogs: Biological and Ecological Effects

    Directory of Open Access Journals (Sweden)

    Vítor Ramos

    2010-06-01

    Full Text Available Palytoxin (PTX is a potent marine toxin that was originally found in soft corals from tropical areas of the Pacific Ocean. Soon after, its occurrence was observed in numerous other marine organisms from the same ecological region. More recently, several analogs of PTX were discovered, remarkably all from species of the dinoflagellate genus Ostreopsis. Since these dinoflagellates are also found in other tropical and even in temperate regions, the formerly unsuspected broad distribution of these toxins was revealed. Toxicological studies with these compounds shows repeatedly low LD50 values in different mammals, revealing an acute toxic effect on several organs, as demonstrated by different routes of exposure. Bioassays tested for some marine invertebrates and evidences from environmental populations exposed to the toxins also give indications of the high impact that these compounds may have on natural food webs. The recognition of its wide distribution coupled with the poisoning effects that these toxins can have on animals and especially on humans have concerned the scientific community. In this paper, we review the current knowledge on the effects of PTX and its analogs on different organisms, exposing the impact that these toxins may have in coastal ecosystems.

  7. Low Power CMOS Analog Multiplier

    Directory of Open Access Journals (Sweden)

    Shipra Sachan

    2015-12-01

    Full Text Available In this paper Low power low voltage CMOS analog multiplier circuit is proposed. It is based on flipped voltage follower. It consists of four voltage adders and a multiplier core. The circuit is analyzed and designed in 0.18um CMOS process model and simulation results have shown that, under single 0.9V supply voltage, and it consumes only 31.8µW quiescent power and 110MHZ bandwidth.

  8. Analog versus digital: extrapolating from electronics to neurobiology.

    Science.gov (United States)

    Sarpeshkar, R

    1998-10-01

    We review the pros and cons of analog and digital computation. We propose that computation that is most efficient in its use of resources is neither analog computation nor digital computation but, rather, a mixture of the two forms. For maximum efficiency, the information and information-processing resources of the hybrid form must be distributed over many wires, with an optimal signal-to-noise ratio per wire. Our results suggest that it is likely that the brain computes in a hybrid fashion and that an underappreciated and important reason for the efficiency of the human brain, which consumes only 12 W, is the hybrid and distributed nature of its architecture.

  9. A global analog of Cheshire charge

    CERN Document Server

    McGraw, P

    1994-01-01

    It is shown that a model with a spontaneously broken global symmetry can support defects analogous to Alice strings, and a process analogous to Cheshire charge exchange can take place. A possible realization in superfluid He-3 is pointed out.

  10. Investigating visual analogies for visual insight problems

    OpenAIRE

    Corina Sas; Eric Luchian; Linden Ball

    2010-01-01

    Much research has focused on the impact of analogies in insight problem solving, but less work has investigated how the visual analogies for insight are actually constructed. Thus, it appears that in the search for their facilitative impact on the incubation effect, the understanding of what makes good visual analogies has somehow been lost. This paper presents preliminary work of constructing a set of 6 visual analogies and evaluating their impact on solving the visual problem of eight coins...

  11. Inherently analog quantity representations in olive baboons (Papio anubis

    Directory of Open Access Journals (Sweden)

    Allison M Barnard

    2013-05-01

    Full Text Available Strong evidence indicates that non-human primates possess a numerical representation system, but the inherent nature of that system is still debated. Two cognitive mechanisms have been proposed to account for non-human primate numerical performance: (1 a discrete object-file system limited to quantities <4, and (2 an analog system which represents quantities comparatively but is limited by the ratio between two quantities. To test the underlying nature of non-human primate quantification, we asked eight experiment -naive olive baboons (Papio anubis to discriminate between number pairs containing small (<4, large (>4, or span (small vs. large numbers of food items presented simultaneously or sequentially. The prediction from the object-file hypothesis is that baboons will only accurately choose the larger quantity in small pairs, but not large or span pairs. Conversely, the analog system predicts that baboons will be successful with all numbers, and that success will be dependent on numerical ratio. We found that baboons successfully discriminated all pair types at above chance levels. In addition, performance significantly correlated with the ratio between the numerical values. Although performance was better for simultaneous trials than sequential trials, evidence favoring analog numerical representation emerged from both conditions, and was present even in the first exposure to number pairs. Together, these data favor the interpretation that a single, coherent analog representation system underlies spontaneous quantitative abilities in primates.

  12. Hegel, Analogy, and Extraterrestrial Life

    Science.gov (United States)

    Ross, Joseph T.

    Georg Wilhelm Friedrich Hegel rejected the possibility of life outside of the Earth, according to several scholars of extraterrestrial life. Their position is that the solar system and specifically the planet Earth is the unique place in the cosmos where life, intelligence, and rationality can be. The present study offers a very different interpretation of Hegel's statements about the place of life on Earth by suggesting that, although Hegel did not believe that there were other solar systems where rationality is present, he did in fact suggest that planets in general, not the Earth exclusively, have life and possibly also intelligent inhabitants. Analogical syllogisms are superficial, according to Hegel, insofar as they try to conclude that there is life on the Moon even though there is no evidence of water or air on that body. Similar analogical arguments for life on the Sun made by Johann Elert Bode and William Herschel were considered by Hegel to be equally superficial. Analogical arguments were also used by astronomers and philosophers to suggest that life could be found on other planets in our solar system. Hegel offers no critique of analogical arguments for life on other planets, and in fact Hegel believed that life would be found on other planets. Planets, after all, have meteorological processes and therefore are "living" according to his philosophical account, unlike the Moon, Sun, and comets. Whereas William Herschel was already finding great similarities between the Sun and the stars and had extended these similarities to the property of having planets or being themselves inhabitable worlds, Hegel rejected this analogy. The Sun and stars have some properties in common, but for Hegel one cannot conclude from these similarities to the necessity that stars have planets. Hegel's arguments against the presence of life in the solar system were not directed against other planets, but rather against the Sun and Moon, both of which he said have a different

  13. Analogical Reasoning: A Review of the Literature.

    Science.gov (United States)

    Dawis, Rene V.; Siojo, Luis T.

    The mathematical and philosophical origins of "analogy" are described and their influence on the thinking of intelligence theorists is traced. Theories of intelligence and cognition bearing on analogical reasoning are examined, specifically those of Spearman, Thorndike, Guilford and Piaget. The analogy test item is shown to be a paradigm…

  14. Reasoning by Analogy in Constructing Mathematical Ideas.

    Science.gov (United States)

    English, Lyn D.

    A powerful way of understanding something new is by analogy with something already known. An analogy is defined as a mapping from one structure, which is already known (the base or source), to another structure that is to be inferred or discovered (the target). The research community has given considerable attention to analogical reasoning in the…

  15. Ethnographic analogy, the comparative method, and archaeological special pleading.

    Science.gov (United States)

    Currie, Adrian

    2016-02-01

    Ethnographic analogy, the use of comparative data from anthropology to inform reconstructions of past human societies, has a troubled history. Archaeologists often express concern about, or outright reject, the practice--and sometimes do so in problematically general terms. This is odd, as (or so I argue) the use of comparative data in archaeology is the same pattern of reasoning as the 'comparative method' in biology, which is a well-developed and robust set of inferences which play a central role in discovering the biological past. In pointing out this continuity, I argue that there is no 'special pleading' on the part of archaeologists in this regard: biologists must overcome analogous epistemic difficulties in their use of comparative data. I then go on to emphasize the local, empirically tractable ways in which particular ethnographic analogies may be licensed.

  16. A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family.

    Science.gov (United States)

    Singh, Nivedita; Kumble Bhat, Vishwanath; Tiwari, Ankana; Kodaganur, Srinivas G; Tontanahal, Sagar J; Sarda, Astha; Malini, K V; Kumar, Arun

    2017-01-13

    Anencephaly is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to anencephaly. Anencephaly shows a heterogeneous etiology, ranging from environmental to genetic causes. The autosomal recessive inheritance of anencephaly has been reported in several populations. In this study, we employed whole-exome sequencing and identified a homozygous missense mutation c.1522C>A (p.Pro508Thr) in the TRIM36 gene as the cause of autosomal recessive anencephaly (APH) in an Indian family. The TRIM36 gene is expressed in the developing brain, suggesting a role in neurogenesis. In silco analysis showed that proline at codon position 508 is highly conserved in 26 vertebrate species, and the mutation is predicted to affect the conformation of the B30.2/SPRY domain of TRIM36. Both in vitro and in vivo results showed that the mutation renders the TRIM36 protein less stable. TRIM36 is known to associate with microtubules. Transient expression of the mutant TRIM36 in HeLa and LN229 cells resulted in microtubule disruption, disorganized spindles, loosely arranged chromosomes, multiple spindles, abnormal cytokinesis, reduced cell proliferation and increased apoptosis as compared to cells transfected with its wild-type counterpart. The siRNA knock down of TRIM36 in HeLa and LN229 cells also led to reduced cell proliferation and increased apoptosis. We suggest that microtubule disruption and disorganized spindles mediated by mutant TRIM36 affect neural cell proliferation during neural tube formation, leading to anencephaly.

  17. Pregnancy Outcomes in Women with Homozygous Beta Thalassaemia; A single-centre experience from Oman

    Directory of Open Access Journals (Sweden)

    Nihal Al-Riyami

    2014-08-01

    Full Text Available Objectives: Pregnancy in women with homozygous beta thalassaemia (HBT carries a high risk to both the mother and fetus. The aim of this study was to investigate pregnancy outcomes among this group at a single tertiary centre. Methods: This retrospective descriptive study was conducted between January 2006 and December 2012 on all women with HBT who received prenatal care and subsequently delivered at Sultan Qaboos University Hospital, Muscat, Oman. Women who delivered elsewhere and women with the beta thalassaemia trait were excluded. Results: Ten women with HBT were studied with a total of 15 pregnancies and 14 live births. The mean maternal age ± standard deviation (SD was 27.9 ± 3.7 years, with a range of 24‒35 years. There were 14 spontaneous pregnancies and one pregnancy following hormone treatment. Eight women had been on chelation therapy before pregnancy, one of whom needed chelation during late pregnancy. Of the pregnancies, 93% had a successful outcome with a mean ± SD gestational age at delivery of 38.6 ± 0.9 weeks, with a range of 37‒40 weeks. Eight babies (57% were delivered by Caesarean section. The mean ± SD birth weight was 2.6 ± 0.2 kg, with a range of 1.9‒3.0 kg. Three babies (21% were born with low birth weights. Conclusion: Pregnancy is safe and usually has a favourable outcome in patients with HBT, provided that a multidisciplinary team is available. This is the first study of Omani patients with HBT whose pregnancies have resulted in a successful outcome.

  18. Urinary iron excretion induced by intravenous infusion of deferoxamine in ß-thalassemia homozygous patients

    Directory of Open Access Journals (Sweden)

    Boturão-Neto E.

    2002-01-01

    Full Text Available The purpose of the present study was to identify noninvasive methods to evaluate the severity of iron overload in transfusion-dependent ß-thalassemia and the efficiency of intensive intravenous therapy as an additional tool for the treatment of iron-overloaded patients. Iron overload was evaluated for 26 ß-thalassemia homozygous patients, and 14 of them were submitted to intensive chelation therapy with high doses of intravenous deferoxamine (DF. Patients were classified into six groups of increasing clinical severity and were divided into compliant and non-compliant patients depending on their adherence to chronic chelation treatment. Several methods were used as indicators of iron overload. Total gain of transfusion iron, plasma ferritin, and urinary iron excretion in response to 20 to 60 mg/day subcutaneous DF for 8 to 12 h daily are useful to identify iron overload; however, urinary iron excretion in response to 9 g intravenous DF over 24 h and the increase of urinary iron excretion induced by high doses of the chelator are more reliable to identify different degrees of iron overload because of their correlation with the clinical grades of secondary hemochromatosis and the significant differences observed between the groups of compliant and non-compliant patients. Finally, the use of 3-9 g intravenous DF for 6-12 days led to a urinary iron excretion corresponding to 4.1 to 22.4% of the annual transfusion iron gain. Therefore, continuous intravenous DF at high doses may be an additional treatment for these patients, as a complement to the regular subcutaneous infusion at home, but requires individual planning and close monitoring of adverse reactions.

  19. Assessment of Iron Overload in Homozygous and Heterozygous Beta Thalassemic Children below 5 Years of Age

    Directory of Open Access Journals (Sweden)

    Dhiraj J. Trivedi

    2014-07-01

    Full Text Available Background: Thalassemia is a genetic disease having 3-7% carrier rate in Indians. It is transfusion dependent anemia having high risk of iron overloading. A clinical symptom of iron overload becomes detectable in second decade causing progressive liver, heart and endocrine glands damage. There is a need to assess iron overload in thalassemics below 5 years of age to protect them from complications at later age of life. Aims and objectives: Present study was undertaken to estimate serum iron status and evaluate serum transferrin saturation in both homozygous & heterozygous form of thalassemia as an index of iron overload among children of one to five years of age. Materials and Methods: Clinically diagnosed thirty cases of β thalassemia major & thirty cases of β thalassemia minor having severe anemia, hepatospleenomegaly and between 1 year to 5 years of age were included in study group and same age matched healthy controls were included in the study. RBC indices and HbA, HbA2 and HbF were estimated along with serum iron & serum Total Iron Binding Capacity (TIBC and serum transferrin levels. Results: Significant difference was observed in hemoglobin levels between control and both beta thalassemia groups. Mean Corpuscular Volume (MCV and Mean Corpuscular Hemoglobin (MCH values were reduced. Hemoglobin electrophoresis showed the elevated levels of HbF and HbA2 in both beta thalassemia groups. Among serum iron parameters, serum iron, TIBC and transferrin saturation were elevated whereas serum transferrin levels were low in thalassemia major in children below 5 years of age. Conclusion: Although clinical symptoms of iron overload have been absent in thalassemic children below five years of age, biochemical iron overloading has started at much lower age which is of great concern.

  20. High efficiency production and genomic in situ hybridization analysis of Brassica aneuploids and homozygous plants

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Interspecific and intergeneric hybridizations have been widely used in plant genetics and breeding to construct stocks for genetic analysis and to introduce into crops the desirable traits and genes from their relatives. The intergeneric crosses between Brassica juncea (L.) Czern. & Coss., B. carinata A. Braun and Orychophragmus violaceus (L.) O. E. Schulz were made and the plants produced were subjected to genomic in situ hybridization analysis. The mixoploids from the cross with B. juncea were divided into three groups. The partially fertile mixoploids in the first group (2n = 36-42) mainly contained the somatic cells and pollen mother cells (PMCs) with the 36 chromosomes of B. juncea and additional chromosomes of O. violaceus. The mixoploids (2n = 30-36) in the second and third groups were morphologically quite similar to the mother plants B. juncea and showed nearly normal fertility. The plants in the second group produced the majority of PMCs (2n = 36) with their chromosomes paired and segregated normally, but 1-4 pairs of the O. violaceus chromosomes were included in some PMCs. The plants in the third group produced only PMCs with the 36 B. juncea chromosomes, which were paired and segregated normally. The mixoploids (2n = 29-34) from the cross with B. carinata produced the majority of PMCs (2n = 34) with normal chromosome pairing and segregation, but some plants had some PMCs with 1-3 pairs of chromosomes from O. violaceus and other plants had only PMCs with the B. carinata chromosomes. The Brassica homozygous plants and aneuploids with complete or partial chromosome complements of Brassica parents and various numbers of O. violaceus chromosomes were derived from these progeny plants. The results in this study provided the molecular cytogenetic evidence for the separation of parental genomes which was previously proposed to occur in the hybridizations of these two genera.

  1. Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation.

    Science.gov (United States)

    Ben Yaou, Rabah; Navarro, Claire; Quijano-Roy, Susana; Bertrand, Anne T; Massart, Catherine; De Sandre-Giovannoli, Annachiara; Cadiñanos, Juan; Mamchaoui, Kamel; Butler-Browne, Gillian; Estournet, Brigitte; Richard, Pascale; Barois, Annie; Lévy, Nicolas; Bonne, Gisèle

    2011-06-01

    Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T>C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general.

  2. A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma.

    Directory of Open Access Journals (Sweden)

    Shazia Micheal

    Full Text Available Anterior segment dysgenesis (ASD disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders.We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10 or aniridia (n = 5. All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes.Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75* was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217* in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma.Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development.

  3. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison.

    Science.gov (United States)

    Pisciotta, Livia; Priore Oliva, Claudio; Pes, Giovanni Mario; Di Scala, Lilla; Bellocchio, Antonella; Fresa, Raffaele; Cantafora, Alfredo; Arca, Marcello; Calandra, Sebastiano; Bertolini, Stefano

    2006-10-01

    Autosomal recessive hypercholesterolemia (ARH) is a rare disorder, due to complete loss of function of an adaptor protein (ARH protein) required for receptor-mediated hepatic uptake of LDL. ARH is a phenocopy of homozygous familial hypercholesterolemia (HoFH) due to mutations in LDL receptor (LDLR) gene; however, previous studies suggested that ARH phenotype is less severe than that of HoFH. To test this hypothesis we compared 42 HoFH and 42 ARH patients. LDLR and ARH genes were analysed by Southern blotting and sequencing. LDLR activity was measured in cultured fibroblasts. In ARH plasma LDL cholestrol (LDL-C) level (14.25+/-2.29 mmol/L) was lower than in receptor-negative HoFH (21.38+/-3.56 mmol/L) but similar to that found in receptor-defective HoFH (15.52+/-2.39 mmol/L). The risk of coronary artery disease (CAD) was 9-fold lower in ARH patients. No ARH patients

  4. Study on CCR5 analogs and affinity peptides.

    Science.gov (United States)

    Wu, Yingping; Deng, Riqiang; Wu, Wenyan

    2012-03-01

    The G protein-coupled receptor of human chemokine receptor 5 (CCR5) is a key target in the human immunodeficiency virus (HIV) infection process due to its major involvement in binding to the HIV type 1 (HIV-1) envelope glycoprotein gp120 and facilitating virus entry into the cells. The identification of naturally occurring CCR5 mutations (especially CCR5 delta-32) has allowed us to address the CCR5 molecule as a promising target to prevent or resist HIV infection in vivo. To obtain high-affinity peptides that can be used to block CCR5, CCR5 analogs with high conformational similarity are required. In this study, two recombinant proteins named CCR5 N-Linker-E2 and CCR5 mN-E1-E2 containing the fragments of the CCR5 N-terminal, the first extracellular loop or the second extracellular loop are cloned from a full-length human CCR5 cDNA. The recombinant human CCR5 analogs with self-cleavage activity of the intein Mxe or Ssp in the vector pTwinI were then produced with a high-yield expression and purification system in Escherichia coli. Experiments of extracellular epitope-activity identification (such as immunoprecipitation and indirective/competitive enzyme-linked immunosorbent assay) confirmed the close similarity between the epitope activity of the CCR5 analogs and that of the natural CCR5, suggesting the applicability of the recombinant CCR5 analogs as antagonists of the chemokine ligands. Subsequent screening of high-affinity peptides from the phage random-peptides library acquired nine polypeptides, which could be used as CCR5 peptide antagonists. The CCR5 analogs and affinity peptides elucidated in this paper provide us with a basis for further study of the mechanism of inhibition of HIV-1 infection.

  5. Are all analogies created equal? Prefrontal cortical functioning may predict types of analogical reasoning.

    Science.gov (United States)

    Chrysikou, Evangelia G; Thompson-Schill, Sharon L

    2010-06-01

    Abstract The proposed theory can account for analogies based on learned relationships between elements in the source and target domains. However, its explanatory power regarding the discovery of new relationships during analogical reasoning is limited. We offer an alternative perspective for the role of PFC in analogical thought that may better address different types of analogical mappings.

  6. A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

    DEFF Research Database (Denmark)

    Roos, L; Fang, M; Dali, C;

    2013-01-01

    to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where...... three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented...... with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations....

  7. Sickle cell anemia and α-thalassemia: a modulating factor in homozygous HbS/S patients in Oman.

    Science.gov (United States)

    Hassan, S M; Al Muslahi, M; Al Riyami, M; Bakker, E; Harteveld, C L; Giordano, P C

    2014-01-01

    We report the general phenotype severity and the hematological presentation in a cohort of 125 sickle cell anemia (SCA) patients with identical homozygous HbS/S genotype and categorized by identical β(S) haplotype, both with and without alpha thalassemia. No clear general phenotype correlation was found when patients were compared regardless of the haplotype but overall, patients with homozygous alpha thalassemia (α-/α-) had the highest Hb, HCT, RBC and the lowest MCV, MCH and MCHC levels. When patients with identical haplotype were compared, the mildest hematological and clinical conditions were observed in patients of the Asian/Asian haplotype, also known as Arab-Indian haplotype, and carriers of α-thalassemia, suggesting an additional ameliorating effect of alpha thalassemia. In conclusion, our results show that alpha thalassemia improves the hematological conditions but amelioration of the general disease severity is only noticed when compared in cohorts of the same haplotype.

  8. Analog and mixed-signal electronics

    CERN Document Server

    Stephan, Karl

    2015-01-01

    A practical guide to analog and mixed-signal electronics, with an emphasis on design problems and applications This book provides an in-depth coverage of essential analog and mixed-signal topics such as power amplifiers, active filters, noise and dynamic range, analog-to-digital and digital-to-analog conversion techniques, phase-locked loops, and switching power supplies. Readers will learn the basics of linear systems, types of nonlinearities and their effects, op-amp circuits, the high-gain analog filter-amplifier, and signal generation. The author uses system design examples to motivate

  9. Analog circuit design art, science, and personalities

    CERN Document Server

    Williams, Jim

    1991-01-01

    Analog Circuit Design: Art, Science, and Personalities discusses the many approaches and styles in the practice of analog circuit design. The book is written in an informal yet informative manner, making it easily understandable to those new in the field. The selection covers the definition, history, current practice, and future direction of analog design; the practice proper; and the styles in analog circuit design. The book also includes the problems usually encountered in analog circuit design; approach to feedback loop design; and other different techniques and applications. The text is

  10. Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia

    Directory of Open Access Journals (Sweden)

    Parhofer KG

    2012-05-01

    Full Text Available Klaus G ParhoferMedical Department II, Grosshadern, University Munich, Munich, GermanyAbstract: Familial hypercholesterolemia (FH is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous to one in 1,000,000 (homozygous. Mutations of the low-density lipoprotein (LDL receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH or in adulthood (heterozygous FH. Current treatment modalities include lifestyle modification, combination drug therapy (statin-based, and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%–47%, lipoprotein(a levels by 20%–40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%–100%, flu-like symptoms (29%–46%, and elevated transaminases associated with an increased liver fat content (6%–15%. Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated.Keywords: antisense oligonucleotide, statin intolerance, apolipoprotein B

  11. Practical analog electronics for technicians

    CERN Document Server

    Kimber, W A

    2013-01-01

    'Practical Analog Electronics for Technicians' not only provides an accessible introduction to electronics, but also supplies all the problems and practical activities needed to gain hands-on knowledge and experience. This emphasis on practice is surprisingly unusual in electronics texts, and has already gained Will Kimber popularity through the companion volume, 'Practical Digital Electronics for Technicians'. Written to cover the Advanced GNVQ optional unit in electronics, this book is also ideal for BTEC National, A-level electronics and City & Guilds courses. Together with 'Practical Digit

  12. Homozygous mutation of MYBPC3 associated with severe infantile hypertrophic cardiomyopathy at high frequency among the Amish.

    Science.gov (United States)

    Zahka, K; Kalidas, K; Simpson, M A; Cross, H; Keller, B B; Galambos, C; Gurtz, K; Patton, M A; Crosby, A H

    2008-10-01

    Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death among young and apparently healthy people. Autosomal dominant mutations within genes encoding sarcomeric proteins have been identified. An autosomal recessive form of HCM has been discovered in a group of Amish children that is associated with poor prognosis and death within the first year of life. Affected patients experienced progressive cardiac failure despite maximal medical treatment. Postmortem histology showed myofibre disarray and myocyte loss consistent with refractory clinical deterioration in affected infants. To conduct a genome-wide screen for linkage and try to identify an autozygous region which cosegregates with the infant cardiac phenotype An autozygous region of chromosome 11 which cosegregates with the infant cardiac phenotype was identified. This region contained the MYBPC3 gene, which has previously been associated with autosomal dominant adult-onset HCM. Sequence analysis of the MYBPC3 gene identified a splice site mutation in intron 30 which was homozygous in all affected infants. All surviving patients with the homozygous MYBPC3 gene mutations (3330+2T>G) underwent an orthotopic heart transplantation. Homozygous mutations in the MYBPC3 gene have been identified as the cause of severe infantile HCM among the Amish population.

  13. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension.

    Science.gov (United States)

    Navas Tejedor, P; Tenorio Castaño, J; Palomino Doza, J; Arias Lajara, P; Gordo Trujillo, G; López Meseguer, M; Román Broto, A; Lapunzina Abadía, P; Escribano Subía, P

    2017-03-01

    Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by a high genetic heterogeneity with several related genes recently described, including BMPR2,TBX4 and KCNK3. The association between KCNK3 and PAH has been recently identified, but the prognosis and phenotype associated with these mutations have been poorly described. We studied a series of 136 idiopathic and hereditary PAH Spanish patients for BMPR2, TBX4 and KCNK3 mutations. We report the results of KCNK3 in which we were able to describe two new mutations (p.Gly106Arg and p.Leu214Arg) in three patients. The first one was found in a patient belonging to a consanguineous Romani family, who carried a homozygous mutation in KCNK3 and developed a severe and early form of the disease. To the best of our knowledge, this is the first time that a homozygous mutation in KCNK3 is reported in a PAH patient. The second one was found in a patient who presented at the young adult age a severe form of the disease. The present report supports the contribution of KCNK3 mutations to the genetic etiology of PAH and strongly suggests that mutations in KCNK3 follow incomplete dominance with worsening of the clinical features in homozygous patients.

  14. Normal cholesterol levels with lovastatin (Mevinolin) therapy in a child with homozygous familial hypercholesterolemia following liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    East, C.; Grundy, S.M.; Bilheimer, D.W.

    1986-11-28

    Patients with homozygous familial hypercholesterolemia produce no normal low-density lipoprotein (LDL) receptors, and as a result, LDL accumulates in plasma, causing severe premature atherosclerosis. Two years ago, liver transplantation was performed in a child with homozygous familial hypercholesterolemia, restoring LDL receptor activity to about 60% of normal and reducing the LDL cholesterol level by 81%. However, the patient's lipoprotein levels remained significantly elevated for her age and sex. Treatment with lovastatin (mevinolin) one year after transplantation produced a marked improvement in the patient's lipoprotein profile. The total and LDL cholesterol levels fell 40% and 49%, respectively, to values within the normal range. The level of very low-density lipoprotein cholesterol fell 41%, and the level of total triglycerides declined 28%. While lovastatin therapy decreased the production rate of LDL by 35%, it did not affect the LDL fractional clearance rate. Thus, the combination of liver transplantation and lovastatin restored total and LDL cholesterol levels to normal in this patient with homozygous familial hypercholesterolemia.

  15. Transfer Between Analogies: How Solving One Analogy Problem Helps to Solve Another

    OpenAIRE

    Keane, Mark T.

    1995-01-01

    This paper deals with transfer between analogies; with what people acquire from one analogy problem-solving episode that can be re-applied to a subsequent analogy, problem-solving episode. This issue must be resolved if we are to understand the nature of expertise and the appropriate use of analogy in education. There are two main explanations of what subjects acquire from an analogy problem-solving episode. The schema-induction hypothesis maintains that subjects acquire an abs...

  16. The Nitty Gritty: How We Make Analogs Work

    Science.gov (United States)

    Self, A. L.; Huppman, S. R.; Spence, L. A.

    2017-01-01

    NASA's Human Research Program (HRP) is becoming increasingly reliant on Isolated, Confined and Controlled (ICC) analogs to accomplish many of its research objectives. Compared to other research platforms, ICC analogs present a unique set of operational challenges that must be addressed in order to ensure a high fidelity research environment. In particular, the Human Exploration Research Analog (HERA) habitat, which is classified as an ICC environment, has been developed over the past three years to accommodate the operational needs of research investigations from each of the HRP Elements. During the development period, various types of requirements have contributed to the current operational model, which strives to achieve the highest possible level of mission fidelity with limited resources. This presentation will focus on the operational aspects of the HERA habitat, with emphasis on how we develop the analog research environment to meet researchers' needs. Specific discussion topics include mission scenario development, operational tasks, mission timeline integration, stressor implementation, console support, and improvements based on lessons learned. The information is intended to help investigators better understand the details behind HERA operations and the benefits to their research goals.

  17. Radiolabeled Escherichia coli heat-stable enterotoxin analogs for in vivo imaging of colorectal cancer

    Science.gov (United States)

    Giblin, M. F.; Sieckman, G. L.; Owen, N. K.; Hoffman, T. J.; Forte, L. R.; Volkert, W. A.

    2005-12-01

    The human Escherichia coli heat-stable enterotoxin (STh, amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. In the current study, two STh analogs were synthesized and evaluated in vitro and in vivo. Both analogs shared identical 6-19 core sequences, and had N-terminal pendant DOTA moieties. The analogs differed in the identity of a 6 amino acid peptide sequence intervening between DOTA and the 6-19 core. In one analog, the peptide was an RGD-containing sequence found in human fibronectin (GRGDSP), while in the other this peptide sequence was randomly scrambled (GRDSGP). The results indicated that the presence of the human fibronectin sequence in the hybrid peptide did not affect tumor localization in vivo.

  18. Analog-to-digital conversion

    CERN Document Server

    Pelgrom, Marcel J. M

    2013-01-01

    This textbook is appropriate for use in graduate-level curricula in analog to digital conversion, as well as for practicing engineers in need of a state-of-the-art reference on data converters.  It discusses various analog-to-digital conversion principles, including sampling, quantization, reference generation, nyquist architectures and sigma-delta modulation.  This book presents an overview of the state-of-the-art in this field and focuses on issues of optimizing accuracy and speed, while reducing the power level. This new, second edition emphasizes novel calibration concepts, the specific requirements of new systems, the consequences of 45-nm technology and the need for a more statistical approach to accuracy.  Pedagogical enhancements to this edition include more than twice the exercises available in the first edition, solved examples to introduce all key, new concepts and warnings, remarks and hints, from a practitioner’s perspective, wherever appropriate.  Considerable background information and pr...

  19. Reliability of analog quantum simulation

    Energy Technology Data Exchange (ETDEWEB)

    Sarovar, Mohan [Sandia National Laboratories, Digital and Quantum Information Systems, Livermore, CA (United States); Zhang, Jun; Zeng, Lishan [Shanghai Jiao Tong University, Joint Institute of UMich-SJTU, Key Laboratory of System Control and Information Processing (MOE), Shanghai (China)

    2017-12-15

    Analog quantum simulators (AQS) will likely be the first nontrivial application of quantum technology for predictive simulation. However, there remain questions regarding the degree of confidence that can be placed in the results of AQS since they do not naturally incorporate error correction. Specifically, how do we know whether an analog simulation of a quantum model will produce predictions that agree with the ideal model in the presence of inevitable imperfections? At the same time there is a widely held expectation that certain quantum simulation questions will be robust to errors and perturbations in the underlying hardware. Resolving these two points of view is a critical step in making the most of this promising technology. In this work we formalize the notion of AQS reliability by determining sensitivity of AQS outputs to underlying parameters, and formulate conditions for robust simulation. Our approach naturally reveals the importance of model symmetries in dictating the robust properties. To demonstrate the approach, we characterize the robust features of a variety of quantum many-body models. (orig.)

  20. 'Quality of life' and the analogy with the Nazis.

    Science.gov (United States)

    Cohen, C B

    1983-05-01

    The introduction of 'quality of life' judgments into treatment decisions is viewed as pernicious by some who claim that these presuppose the Nazi position that those who are 'devoid of value' must be exterminated. 'Quality of life' judgments are said to deny the equal value of human beings and to assume that some lives are not 'worthy to be lived'. It is argued that the analogy misconstrues the senses of 'value' and 'quality' employed by Naziism and a 'quality of life' position. This leads the analogizers incorrectly to claim that both views assimilate the value of human beings to the value of their condition. A 'quality of life' position is grounded in recognition of the logical priority of the value of human beings as self-reflective evaluators and agents, which is a matter of kind, not degree. The 'quality of life' is explicated in terms of the standards of well-being of individuals, which are derived from their basic human needs and their individual priorities and goals. The use of 'quality of life' judgments is morally required to ensure that considerations of justice and individual autonomy govern treatment decisions. The purported analogy misconstrues the views of both the Nazi position and a 'quality of life' position and so is seriously misdirected.

  1. 重组人碱性成纤维细胞生长因子结构类似物在大肠杆菌中的高效稳定表达研究%High and stable expression of an analog of human basic fibroblast growth factor in Escherichia coli

    Institute of Scientific and Technical Information of China (English)

    陈琼玉; 孙奋勇; 陈小佳; 谢秋玲; 孙晋华; 洪岸

    2006-01-01

    AIM: To obtain a high and stable expression analog of human basic fibroblast growth factor by genetic engineering. METHODS: The cysteins 78 and 96 of natural hbFGF polypeptide was substituted with serines by means of site-directed mutagenesis. Using pET- 3c as vector, the mutated polynucleotide was cloned and then transferred into BL21 (DE3)plysS. After induction by IPTG, the analog was obtained and analyzed by SDS - PAGE. RESULTS: After purification the form of soluble mutant increased remarkably but the forms of dimmer and higher multimer were reduced greatly to no more than 8% of the total recombinant protein. By MTT assay, the analog showed the same biological activity. This new analog represented a desirable complementation for native hbFGF to develop pharmaceutical drug in clinical use. CONCLUSION: Substitution of certain amino acids of polypeptide without altering native protein' s bioactivity to get the analog is an effective means to increase stability of foreign protein and its solubility in E. coli.%目的:用基因工程的方法获得高效稳定表达的重组人碱性成纤维细胞生长因子结构类似物.方法:利用定点突变技术,将天然hbFGF的第78与96位半胱氨酸替换为丝氨酸,通过载体pET-3c,突变基因被克隆并转化至大肠杆菌BL21(DE3)plysS,IPTG诱导表达后,SDS-PAGE分析蛋白表达结果.结果:纯化后突变蛋白的可溶性成分大幅度增加,而二聚体与多聚体显著减少至纯化后总蛋白的8%以下.MTT法的结果表明,结构类似物蛋白具有良好的生物学活性.这种新的结构类似物蛋白能较好地替代天然hbFGF在临床上的使用.结论:在不影响生物学活性的条件下,对个别氨基酸残基进行突变以获得新的结构类似物的方法,能够有效提高外源蛋白在大肠杆菌中表达的稳定性及可溶性.

  2. Analog computing by Brewster effect.

    Science.gov (United States)

    Youssefi, Amir; Zangeneh-Nejad, Farzad; Abdollahramezani, Sajjad; Khavasi, Amin

    2016-08-01

    Optical computing has emerged as a promising candidate for real-time and parallel continuous data processing. Motivated by recent progresses in metamaterial-based analog computing [Science343, 160 (2014)SCIEAS0036-807510.1126/science.1242818], we theoretically investigate the realization of two-dimensional complex mathematical operations using rotated configurations, recently reported in [Opt. Lett.39, 1278 (2014)OPLEDP0146-959210.1364/OL.39.001278]. Breaking the reflection symmetry, such configurations could realize both even and odd Green's functions associated with spatial operators. Based on such an appealing theory and by using the Brewster effect, we demonstrate realization of a first-order differentiator. Such an efficient wave-based computation method not only circumvents the major potential drawbacks of metamaterials, but also offers the most compact possible device compared to conventional bulky lens-based optical signal and data processors.

  3. The MARS2013 Mars analog mission.

    Science.gov (United States)

    Groemer, Gernot; Soucek, Alexander; Frischauf, Norbert; Stumptner, Willibald; Ragonig, Christoph; Sams, Sebastian; Bartenstein, Thomas; Häuplik-Meusburger, Sandra; Petrova, Polina; Evetts, Simon; Sivenesan, Chan; Bothe, Claudia; Boyd, Andrea; Dinkelaker, Aline; Dissertori, Markus; Fasching, David; Fischer, Monika; Föger, Daniel; Foresta, Luca; Fritsch, Lukas; Fuchs, Harald; Gautsch, Christoph; Gerard, Stephan; Goetzloff, Linda; Gołebiowska, Izabella; Gorur, Paavan; Groemer, Gerhard; Groll, Petra; Haider, Christian; Haider, Olivia; Hauth, Eva; Hauth, Stefan; Hettrich, Sebastian; Jais, Wolfgang; Jones, Natalie; Taj-Eddine, Kamal; Karl, Alexander; Kauerhoff, Tilo; Khan, Muhammad Shadab; Kjeldsen, Andreas; Klauck, Jan; Losiak, Anna; Luger, Markus; Luger, Thomas; Luger, Ulrich; McArthur, Jane; Moser, Linda; Neuner, Julia; Orgel, Csilla; Ori, Gian Gabriele; Paternesi, Roberta; Peschier, Jarno; Pfeil, Isabella; Prock, Silvia; Radinger, Josef; Ramirez, Barbara; Ramo, Wissam; Rampey, Mike; Sams, Arnold; Sams, Elisabeth; Sandu, Oana; Sans, Alejandra; Sansone, Petra; Scheer, Daniela; Schildhammer, Daniel; Scornet, Quentin; Sejkora, Nina; Stadler, Andrea; Stummer, Florian; Taraba, Michael; Tlustos, Reinhard; Toferer, Ernst; Turetschek, Thomas; Winter, Egon; Zanella-Kux, Katja

    2014-05-01

    We report on the MARS2013 mission, a 4-week Mars analog field test in the northern Sahara. Nineteen experiments were conducted by a field crew in Morocco under simulated martian surface exploration conditions, supervised by a Mission Support Center in Innsbruck, Austria. A Remote Science Support team analyzed field data in near real time, providing planning input for the management of a complex system of field assets; two advanced space suit simulators, four robotic vehicles, an emergency shelter, and a stationary sensor platform in a realistic work flow were coordinated by a Flight Control Team. A dedicated flight planning group, external control centers for rover tele-operations, and a biomedical monitoring team supported the field operations. A 10 min satellite communication delay and other limitations pertinent to human planetary surface activities were introduced. The fields of research for the experiments were geology, human factors, astrobiology, robotics, tele-science, exploration, and operations research. This paper provides an overview of the geological context and environmental conditions of the test site and the mission architecture, in particular the communication infrastructure emulating the signal travel time between Earth and Mars. We report on the operational work flows and the experiments conducted, including a deployable shelter prototype for multiple-day extravehicular activities and contingency situations.

  4. Priming analogical reasoning with false memories.

    Science.gov (United States)

    Howe, Mark L; Garner, Sarah R; Threadgold, Emma; Ball, Linden J

    2015-08-01

    Like true memories, false memories are capable of priming answers to insight-based problems. Recent research has attempted to extend this paradigm to more advanced problem-solving tasks, including those involving verbal analogical reasoning. However, these experiments are constrained inasmuch as problem solutions could be generated via spreading activation mechanisms (much like false memories themselves) rather than using complex reasoning processes. In three experiments we examined false memory priming of complex analogical reasoning tasks in the absence of simple semantic associations. In Experiment 1, we demonstrated the robustness of false memory priming in analogical reasoning when backward associative strength among the problem terms was eliminated. In Experiments 2a and 2b, we extended these findings by demonstrating priming on newly created homonym analogies that can only be solved by inhibiting semantic associations within the analogy. Overall, the findings of the present experiments provide evidence that the efficacy of false memory priming extends to complex analogical reasoning problems.

  5. RADIATION HARDENED ANALOG IC FOR SENSOR

    Directory of Open Access Journals (Sweden)

    O. V. Dvornikov

    2011-01-01

    Full Text Available Problems of specialized analog integrated circuit design for sensor equipments are considered. It is offered to produce of radiation hardened analog IC on structured chips for economic efficiency at small production volume. The approach to analog IC design is described, including recommendations for choice of: types and quantities of structured chip analogue components; active and passive components; schematic decisions of analogue components with programmed parameters and small sensitivity to radiation. 

  6. Design and Analysis of Reconfigurable Analog System

    Science.gov (United States)

    2011-02-01

    34010010" �" �" �" �" �" �" �±" N3 N2 N± P1 P2 P3 * Current sources $RR = 1; *Ramp Rate (slope of the...2008/12/12/31e83bac-500f-4182- acca -4d360295fd9c.pdf, Analog Devices, Analog Dialogue 39-06, June 2005. [15] D. A. Johns, K. Martin "Analog Integrated

  7. Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines.

    NARCIS (Netherlands)

    Heidenblad, M.; Schoenmakers, E.F.P.M.; Jonson, T.; Gorunova, L.; Veltman, J.A.; Geurts van Kessel, A.H.M.; Hoglund, M.

    2004-01-01

    Pancreatic carcinomas display highly complex chromosomal abnormalities, including many structural and numerical aberrations. There is ample evidence indicating that some of these abnormalities, such as recurrent amplifications and homozygous deletions, contribute to tumorigenesis by altering express

  8. Basalt: Biologic Analog Science Associated with Lava Terrains

    Science.gov (United States)

    Lim, D. S. S.; Abercromby, A.; Kobs-Nawotniak, S. E.; Kobayashi, L.; Hughes, S. S.; Chappell, S.; Bramall, N. E.; Deans, M. C.; Heldmann, J. L.; Downs, M.; Cockell, C. S.; Stevens, A. H.; Caldwell, B.; Hoffman, J.; Vadhavk, N.; Marquez, J.; Miller, M.; Squyres, S. W.; Lees, D. S.; Fong, T.; Cohen, T.; Smith, T.; Lee, G.; Frank, J.; Colaprete, A.

    2015-12-01

    This presentation will provide an overview of the BASALT (Biologic Analog Science Associated with Lava Terrains) program. BASALT research addresses Science, Science Operations, and Technology. Specifically, BASALT is focused on the investigation of terrestrial volcanic terrains and their habitability as analog environments for early and present-day Mars. Our scientific fieldwork is conducted under simulated Mars mission constraints to evaluate strategically selected concepts of operations (ConOps) and capabilities with respect to their anticipated value for the joint human and robotic exploration of Mars. a) Science: The BASALT science program is focused on understanding habitability conditions of early and present-day Mars in two relevant Mars-analog locations (the Southwest Rift Zone (SWRZ) and the East Rift Zone (ERZ) flows on the Big Island of Hawai'i and the eastern Snake River Plain (ESRP) in Idaho) to characterize and compare the physical and geochemical conditions of life in these environments and to learn how to seek, identify, and characterize life and life-related chemistry in basaltic environments representing these two epochs of martian history. b) Science Operations: The BASALT team will conduct real (non-simulated) biological and geological science at two high-fidelity Mars analogs, all within simulated Mars mission conditions (including communication latencies and bandwidth constraints) that are based on current architectural assumptions for Mars exploration missions. We will identify which human-robotic ConOps and supporting capabilities enable science return and discovery. c) Technology: BASALT will incorporate and evaluate technologies in to our field operations that are directly relevant to conducting the scientific investigations regarding life and life-related chemistry in Mars-analogous terrestrial environments. BASALT technologies include the use of mobile science platforms, extravehicular informatics, display technologies, communication

  9. Establishment of a Conditionally Immortalized Wilms Tumor Cell Line with a Homozygous WT1 Deletion within a Heterozygous 11p13 Deletion and UPD Limited to 11p15.

    Directory of Open Access Journals (Sweden)

    Artur Brandt

    Full Text Available We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD 3p21.3pter lead to the homozygous CTNNB1 mutation. The tumor cell line was immortalized using the catalytic subunit of human telomerase (hTERT in conjunction with a novel thermolabile mutant (U19dl89-97tsA58 of SV40 large T antigen (LT. This cell line is cytogenetically stable and can be grown indefinitely representing a valuable tool to study the effect of a complete lack of WT1 in tumor cells. The origin/fate of Wilms tumors with WT1 mutations is currently poorly defined. Here we studied the expression of several genes expressed in early kidney development, e.g. FOXD1, PAX3, SIX1, OSR1, OSR2 and MEIS1 and show that these are expressed at similar levels in the parental and the immortalized Wilms10 cells. In addition the limited potential for muscle/ osteogenic/ adipogenic differentiation similar to all other WT1 mutant cell lines is also observed in the Wilms10 tumor cell line and this is retained in the immortalized cells. In summary these Wilms10 cells are a valuable model system for functional studies of WT1 mutant cells.

  10. The role of natural analogs in the repository licensing process

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, W.M. [Center for Nuclear Waste Regulatory Analyses, San Antonio, TX (United States)

    1995-09-01

    The concept of a permanent geologic repository for high-level nuclear waste (NLW) is implicitly based on analogy to natural systems that have been stable for millions or billions of years. The time of radioactive and chemical toxicity of HLW exceeds the duration of human civilization, and it is impossible to demonstrate the accuracy of predictions of the behavior of engineered or social systems over such long periods.

  11. Fermilab accelerator control system: Analog monitoring facilities

    Energy Technology Data Exchange (ETDEWEB)

    Seino, K.; Anderson, L.; Smedinghoff, J.

    1987-10-01

    Thousands of analog signals are monitored in different areas of the Fermilab accelerator complex. For general purposes, analog signals are sent over coaxial or twinaxial cables with varying lengths, collected at fan-in boxes and digitized with 12 bit multiplexed ADCs. For higher resolution requirements, analog signals are digitized at sources and are serially sent to the control system. This paper surveys ADC subsystems that are used with the accelerator control systems and discusses practical problems and solutions, and it describes how analog data are presented on the console system.

  12. Robust hyperchaotic synchronization via analog transmission line

    Science.gov (United States)

    Sadoudi, S.; Tanougast, C.

    2016-02-01

    In this paper, a novel experimental chaotic synchronization technique via analog transmission is discussed. We demonstrate through Field-Programmable Gate Array (FPGA) implementation design the robust synchronization of two embedded hyperchaotic Lorenz generators interconnected with an analog transmission line. The basic idea of this work consists in combining a numerical generation of chaos and transmitting it with an analog signal. The numerical chaos allows to overcome the callback parameter mismatch problem and the analog transmission offers robust data security. As application, this technique can be applied to all families of chaotic systems including time-delayed chaotic systems.

  13. Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy.

    Science.gov (United States)

    Meng, Linyan; Donti, Taraka; Xia, Fan; Niu, Zhiyv; Al Shamsi, Aisha; Hertecant, Jozef; Al-Jasmi, Fatma; Gibson, James B; Nagakura, Honey; Zhang, Jing; He, Weimin; Eng, Christine; Yang, Yaping; Elsea, Sarah H

    2017-02-01

    Pyrroline-5-carboxylate reductase 2, encoded by PYCR2, is one of the three homologous enzymes that catalyze the last step of proline synthesis. Homozygous variants in PYCR2 have been reported in patients from multiple consanguineous families with hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420). Here, we report five additional patients from three families with homozygous nonsense or missense variants in PYCR2, identified through clinical exome sequencing. All patients presented with postnatally acquired microcephaly, moderate to profound global developmental delay, and failure to thrive. Brain MRI in these patients showed thin corpus callosum, delayed myelination, and generalized white-matter volume loss. Additional phenotypes that were less consistent among patients included seizures or seizure-like movements, spasticity and ataxic gait, recurrent vomiting, cortical blindness, dysmorphic features, joint contractures, and irritability. Exome sequencing identified homozygous variants in PYCR2 in the proband from each family: c.28C>T (p.(Glu10Ter)), c.796C>T (p.(Arg266Ter)), and c.577G>A (p.(Val193Met)). Subsequent targeted analyses demonstrated co-segregation of the disease with the variant in the family. Despite the metabolic role of PYCR2, routine serum metabolic test in these patients were normal. To further understand the disease etiology and functions of PYCR2, small molecule metabolomics profiling was performed in plasma from three severely affected patients. No significant changes were identified in proline biosynthesis pathway or related metabolites. Studying the clinical features and the metabolic profiles of the PYCR2-deficient patients provides a more comprehensive picture for this newly identified disorder and facilitates further research on the gene function and disease etiology. © 2016 Wiley Periodicals, Inc.

  14. A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

    Directory of Open Access Journals (Sweden)

    Celia Zazo Seco

    2017-02-01

    Full Text Available A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*, in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.

  15. A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

    DEFF Research Database (Denmark)

    Carvalho, Luciani R; Woods, Kathryn S; Mendonca, Berenice B

    2003-01-01

    The paired-like homeobox gene expressed in embryonic stem cells Hesx1/HESX1 encodes a developmental repressor and is expressed in early development in a region fated to form the forebrain, with subsequent localization to Rathke's pouch, the primordium of the anterior pituitary gland. Mutations...... within the gene have been associated with septo-optic dysplasia, a constellation of phenotypes including eye, forebrain, and pituitary abnormalities, or milder degrees of hypopituitarism. We identified a novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology...

  16. A Mechanical Analogy for the Photoelectric Effect

    Science.gov (United States)

    Kovacevic, Milan S.; Djordjevich, Alexandar

    2006-01-01

    Analogy is a potent tool in the teacher's repertoire. It has been particularly well recognized in the teaching of science. However, careful planning is required for its effective application to prevent documented drawbacks when analogies are stretched too far. Befitting the occasion of the World Year of Physics commemorating Albert Einstein's 1905…

  17. An Analog Computer for Electronic Engineering Education

    Science.gov (United States)

    Fitch, A. L.; Iu, H. H. C.; Lu, D. D. C.

    2011-01-01

    This paper describes a compact analog computer and proposes its use in electronic engineering teaching laboratories to develop student understanding of applications in analog electronics, electronic components, engineering mathematics, control engineering, safe laboratory and workshop practices, circuit construction, testing, and maintenance. The…

  18. An Analog Computer for Electronic Engineering Education

    Science.gov (United States)

    Fitch, A. L.; Iu, H. H. C.; Lu, D. D. C.

    2011-01-01

    This paper describes a compact analog computer and proposes its use in electronic engineering teaching laboratories to develop student understanding of applications in analog electronics, electronic components, engineering mathematics, control engineering, safe laboratory and workshop practices, circuit construction, testing, and maintenance. The…

  19. Analogies in high school Brazilian chemistry textbooks

    Directory of Open Access Journals (Sweden)

    Rosária Justi

    2000-05-01

    Full Text Available This paper presents and discusses an analysis of the analogies presented by Brazilian chemistry textbooks for the medium level. The main aim of the analysis is to discuss whether such analogies can be said good teaching models. From the results, some aspects concerning with teachers' role are discussed. Finally, some new research questions are emphasised.

  20. PEMETAAN ANALOGI PADA KONSEP ABSTRAK FISIKA

    Directory of Open Access Journals (Sweden)

    Nyoto Suseno

    2014-11-01

    Full Text Available The research of any where founded majority students have common difficulties in abstract physics concept. The result of observation, lecturers have problem  in teaching implementation of abstract concepts on physics learning. The objective of this research is to find out the ways how to overcome this problem. The research place of  physics education programs and senior high school. The data are colected by quetionere, observation and interview. The lecturer behavior to making out this case is use of analogy to make concrete a abstract concept. This action is true, because the analogies are dynamic tools that facilitate understanding, rather than representations of the correct and static explanations. Using analogies not only promoted profound understanding of abstract concept, but also helped students overcome their misconceptions. However used analogy in teaching not yet planed with seriousness, analogy used spontanously with the result that less optimal. By planing and selecting right analogy, the role of analogy can be achieved the optimal result. Therefore, it is important to maping analogies of abstract consepts on physics learning.

  1. Response Generation Norms for Verbal Analogies.

    Science.gov (United States)

    Ingram, Albert; Pellegrino, James W.

    Normative data were collected for the generation of responses to 150 incomplete verbal analogies. Two types of normative data are provided: (a) the probabilities associated with each response produced for each analogy base and (b) the probabilities that initial responses represented the appropriate semantic relationship, with a division of…

  2. Analogies in biology textbooks in zoology teaching

    Directory of Open Access Journals (Sweden)

    Saulo Cézar Seiffert Santos

    2011-05-01

    Full Text Available The biologic structures of living creatures are of difficult understanding for students, because they are usually unknown by those, in needs of strategic didactics in order to facilitate the student understanding. There are several strategies and methods for teaching, such as, analogies, metaphors, descriptions, among others. In this article we aim to identify, assess and classify the analogies used in the Higher School Biology textbooks, commonly used in Public State Schools of Manaus – AM, related to the zoology theme. The methodological procedure includes: a analysis of the whole zoological content of the most used textbooks in the public state network of Amazonas throughout the year; b three didactic textbooks have been specifically analyzed in order to specify the class taxon of “Fish” for the comparison of possible variations of types and quantities of analogies. The adopted classification of analogies was of Curtis & Reigeluth (1984 and the model of enriching analysis was according to the TWA Glynn model (Harrison & Treagust, 1993. It has been concluded that the use of analogies is greater in the content of invertebrates than that of vertebrates. Most Analogies are presented in a simple and direct manner, comparing structures, concrete to concrete, and of verbal mediation, almost nothing is presented in a diverse and heuristic manner of Zoology content on the LD. The development of limits of comparison and reflexion about the analogies was rare, only the presentation of the analogue and the target of analogy occurred.

  3. Verbal Analogical Reasoning in Children and Adolescents.

    Science.gov (United States)

    Nippold, Marilyn A.

    1986-01-01

    Verbal analogical reasoning tasks are described as potentially valuable in the assessment and management of subtle linguistic defects less easily detected by standardized language tests. Semantic and structural factors that should be considered in the development of verbal analogies as test items are cited, as well as adaptations for nonreaders.…

  4. The Multidimensionality of Verbal Analogy Items

    Science.gov (United States)

    Ullstadius, Eva; Carlstedt, Berit; Gustafsson, Jan-Eric

    2008-01-01

    The influence of general and verbal ability on each of 72 verbal analogy test items were investigated with new factor analytical techniques. The analogy items together with the Computerized Swedish Enlistment Battery (CAT-SEB) were given randomly to two samples of 18-year-old male conscripts (n = 8566 and n = 5289). Thirty-two of the 72 items had…

  5. Antibacterial and Antibiofilm Activities of Makaluvamine Analogs

    Directory of Open Access Journals (Sweden)

    Bhavitavya Nijampatnam

    2014-09-01

    Full Text Available Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their antibacterial activity against S. mutans and for their ability to inhibit S. mutans biofilm formation. All analogs contained the tricyclic pyrroloiminoquinone core of makaluvamines. The structural variations of the analogs are on the amino substituents at the 7-position of the ring and the inclusion of a tosyl group on the pyrrole ring N of the makaluvamine core. The makaluvamine analogs displayed biofilm inhibition with IC50 values ranging from 0.4 μM to 88 μM. Further, the observed bactericidal activity of the majority of the analogs was found to be consistent with the anti-biofilm activity, leading to the conclusion that the anti-biofilm activity of these analogs stems from their ability to kill S. mutans. However, three of the most potent N-tosyl analogs showed biofilm IC50 values at least an order of magnitude lower than that of bactericidal activity, indicating that the biofilm activity of these analogs is more selective and perhaps independent of bactericidal activity.

  6. Novel Analog For Muscle Deconditioning

    Science.gov (United States)

    Ploutz-Snyder, Lori; Ryder, Jeff; Buxton, Roxanne; Redd. Elizabeth; Scott-Pandorf, Melissa; Hackney, Kyle; Fiedler, James; Ploutz-Snyder, Robert; Bloomberg, Jacob

    2011-01-01

    Existing models (such as bed rest) of muscle deconditioning are cumbersome and expensive. We propose a new model utilizing a weighted suit to manipulate strength, power, or endurance (function) relative to body weight (BW). Methods: 20 subjects performed 7 occupational astronaut tasks while wearing a suit weighted with 0-120% of BW. Models of the full relationship between muscle function/BW and task completion time were developed using fractional polynomial regression and verified by the addition of pre-and postflightastronaut performance data for the same tasks. Splineregression was used to identify muscle function thresholds below which task performance was impaired. Results: Thresholds of performance decline were identified for each task. Seated egress & walk (most difficult task) showed thresholds of leg press (LP) isometric peak force/BW of 18 N/kg, LP power/BW of 18 W/kg, LP work/BW of 79 J/kg, isokineticknee extension (KE)/BW of 6 Nm/kg, and KE torque/BW of 1.9 Nm/kg.Conclusions: Laboratory manipulation of relative strength has promise as an appropriate analog for spaceflight-induced loss of muscle function, for predicting occupational task performance and establishing operationally relevant strength thresholds.

  7. Uncertainty Relations for Analog Signals

    CERN Document Server

    Eldar, Yonina C

    2008-01-01

    In the past several years there has been a surge of research investigating various aspects of sparse representations and compressed sensing. Most of this work has focused on the finite-dimensional setting in which the goal is to decompose a finite-length vector into a given finite dictionary. Underlying many of these results is the conceptual notion of an uncertainty principle: a signal cannot be sparsely represented in two different bases. Here, we extend these ideas and results to the analog, infinite-dimensional setting by considering signals that lie in a finitely-generated shift-invariant (SI) space. This class of signals is rich enough to include many interesting special cases such as multiband signals and splines. By adapting the notion of coherence defined for finite dictionaries to infinite SI representations, we develop an uncertainty principle similar in spirit to its finite counterpart. We demonstrate tightness of our bound by considering a bandlimited low-pass comb that achieves the uncertainty p...

  8. Compressed Sensing of Analog Signals

    CERN Document Server

    Eldar, Yonina C

    2008-01-01

    A traditional assumption underlying most data converters is that the signal should be sampled at a rate which exceeds twice the highest frequency. This statement is based on a worst-case scenario in which the signal occupies the entire available bandwidth. In practice, many signals posses a sparse structure so that a large part of the bandwidth is not exploited. In this paper, we consider a framework for utilizing this sparsity in order to sample such analog signals at a low rate. More specifically, we consider continuous-time signals that lie in a shift-invariant (SI) space generated by m kernels, so that any signal in the space can be expressed as an infinite linear combination of the shifted kernels. If the period of the underlying SI space is equal to T, then such signals can be perfectly reconstructed from samples at a rate of m/T. Here we treat the case in which only k out of the m generators are active, meaning that the signal actually lies in a lower dimensional space spanned by k generators. However,...

  9. An optical analog signal transmitter

    Energy Technology Data Exchange (ETDEWEB)

    Fudzita, K.; Itida, T.; Tanaka, Kh.

    1984-01-11

    An optical laser analog signal transmitter employing an amplitude modulated subcarrier is patented; this transmitter performs stable and high quality transmission of information signals over great distances. A feature of the proposed transmitter is a special transmitter operational mode in which the light emission reflected off the connection point to the fiber optic conduit is sent back to the laser diode in a transient period. As a result, the critical mode of the generated emission is not influenced by the reflected signal. The transmitter consists of a laser diode with biasing near the cutoff point, an amplitude modulator with a subcarrier frequency oscillator, a section of flexible fiber-optic cable of length L, which connects the laser diode to the primary optical fiber conduit, and the connector itself. The subcarrier frequency may vary over wide ranges to establish the necessary correlation between the length of the light conduit section L and the return propagation time of the reflected light signal from the connection point to the laser diode. The difference between the lasing time of the light signal and the return time to the laser diode of the signal reflected off the connector is determined by the relation tau equals 2nL/c - mtauc, where L is the length of the connecting section; n is the refractivity of the optical fiber; c is the velocity of light; tauc is the period of the high frequency subcarrier signal; and m is an integer.

  10. Demonstrative and non-demonstrative reasoning by analogy

    OpenAIRE

    Ippoliti, Emiliano

    2008-01-01

    The paper analizes a set of issues related to analogy and analogical reasoning, namely: 1) The problem of analogy and its duplicity; 2) The role of analogy in demonstrative reasoning; 3) The role of analogy in non-demonstrative reasoning; 4) The limits of analogy; 5) The convergence, particularly in multiple analogical reasoning, of these two apparently distinct aspects and its methodological and philosophical consequences. The paper, using example from number theory, argues for an heuristc c...

  11. Computational approaches to analogical reasoning current trends

    CERN Document Server

    Richard, Gilles

    2014-01-01

    Analogical reasoning is known as a powerful mode for drawing plausible conclusions and solving problems. It has been the topic of a huge number of works by philosophers, anthropologists, linguists, psychologists, and computer scientists. As such, it has been early studied in artificial intelligence, with a particular renewal of interest in the last decade. The present volume provides a structured view of current research trends on computational approaches to analogical reasoning. It starts with an overview of the field, with an extensive bibliography. The 14 collected contributions cover a large scope of issues. First, the use of analogical proportions and analogies is explained and discussed in various natural language processing problems, as well as in automated deduction. Then, different formal frameworks for handling analogies are presented, dealing with case-based reasoning, heuristic-driven theory projection, commonsense reasoning about incomplete rule bases, logical proportions induced by similarity an...

  12. Biosynthesis of sphinganine-analog mycotoxins.

    Science.gov (United States)

    Du, L; Zhu, X; Gerber, R; Huffman, J; Lou, L; Jorgenson, J; Yu, F; Zaleta-Rivera, K; Wang, Q

    2008-06-01

    Sphinganine-analog mycotoxins (SAMT) are polyketide-derived natural products produced by a number of plant pathogenic fungi and are among the most economically important mycotoxins. The toxins are structurally similar to sphinganine, a key intermediate in the biosynthesis of ceramides and sphingolipids, and competitive inhibitors for ceramide synthase. The inhibition of ceramide and sphingolipid biosynthesis is associated with several fatal diseases in domestic animals and esophageal cancer and neural tube defects in humans. SAMT contains a highly reduced, acyclic polyketide carbon backbone, which is assembled by a single module polyketide synthase. The biosynthesis of SAMT involves a unique polyketide chain-releasing mechanism, in which a pyridoxal 5'-phosphate-dependent enzyme catalyzes the termination, offloading and elongation of the polyketide chain. This leads to the introduction of a new carbon-carbon bond and an amino group to the polyketide chain. The mechanism is fundamentally different from the thioesterase/cyclase-catalyzed polyketide chain releasing found in bacterial and other fungal polyketide biosynthesis. Genetic data suggest that the ketosynthase domain of the polyketide synthase and the chain-releasing enzyme are important for controlling the final product structure. In addition, several post-polyketide modifications have to take place before SAMT become mature toxins.

  13. Cisplatin Analogs Confer Protection against Cyanide Poisoning.

    Science.gov (United States)

    Nath, Anjali K; Shi, Xu; Harrison, Devin L; Morningstar, Jordan E; Mahon, Sari; Chan, Adriano; Sips, Patrick; Lee, Jangwoen; MacRae, Calum A; Boss, Gerry R; Brenner, Matthew; Gerszten, Robert E; Peterson, Randall T

    2017-05-18

    Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cyanide kills organisms as diverse as insects, fish, and humans within seconds to hours. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro. We therefore screened a panel of diverse cisplatin analogs and identified compounds that conferred protection from cyanide poisoning in zebrafish, mice, and rabbits. Cumulatively, this discovery pipeline begins to establish the characteristics of platinum ligands that influence their solubility, toxicity, and efficacy, and provides proof of concept that platinum-based complexes are effective antidotes for cyanide poisoning. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Radiolabeled somatostatin analogs in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, M.L.; Kolan, H.; Li, J.; Wiaderkiewicz, R.; Pallela, V.R.; Duggaraju, R.; Schally, A.V

    1997-01-01

    Vapreotide (RC-160), a somatostatin analog, was labeled with {sup 99m}Tc by a direct method and also by using CPTA [1,4,8,11-tetraazacyclotetradecane] as a bifunctional chelating agent. The labeled compounds were evaluated in nude mice bearing experimental human prostate cancers. In these studies, {sup 111}In-DTPA-D-Phe-Octreotide ({sup 111}In-DTPA-octreotide) served as a standard and {sup 99m}Tc-oxytocin as a receptor-non-specific control. {sup 99m}Tc-octreotide was also used. The 24 htumor uptake of {sup 99m}Tc-RC-160 was nearly 400% higher, (p < 0.05), than that of {sup 111}In-DTPA-octreotide and diminished upon receptor blocking. In all tissues except the kidneys, the uptake of {sup 99m}Tc-RC-160 was also higher than that of {sup 111}In-DTPA-octreotide. The uptake of {sup 99m}Tc-RC-160 was influenced by the amount of peptide injected and the best tumor/muscle and tumor/blood ratios were obtained when only one {mu}g of the peptide (200 Ci/mmol) was administered.

  15. Homozygous missense mutation (G56R in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1 in two siblings with fasting chylomicronemia (MIM 144650

    Directory of Open Access Journals (Sweden)

    Hegele Robert A

    2007-09-01

    Full Text Available Abstract Background Mice with a deleted Gpihbp1 gene encoding glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1 develop severe chylomicronemia. We screened the coding regions of the human homologue – GPIHBP1 – from the genomic DNA of 160 unrelated adults with fasting chylomicronemia and plasma triglycerides >10 mmol/L, each of whom had normal sequence of the LPL and APOC2 genes. Results One patient with severe type 5 hyperlipoproteinemia (MIM 144650, fasting chylomicronemia and relapsing pancreatitis resistant to standard therapy was found to be homozygous for a novel GPIHBP1 missense variant, namely G56R. This mutation was absent from the genomes of 600 control subjects and 610 patients with hyperlipidemia. The GPIHBP1 G56 residue has been conserved throughout evolution and the G56R mutation was predicted to have compromised function. Her homozygous brother also had refractory chylomicronemia and relapsing pancreatitis together with early coronary heart disease. G56R heterozygotes in the family had fasting mild hypertriglyceridemia. Conclusion Thus, a very rare GPIHBP1 missense mutation appears to be associated with severe hypertriglyceridemia and chylomicronemia.

  16. Homozygous Wildtype of XPD K751Q Polymorphism Is Associated with Increased Risk of Nasopharyngeal Carcinoma in Malaysian Population.

    Directory of Open Access Journals (Sweden)

    Munn-Sann Lye

    Full Text Available The xeroderma pigmentosum group D (XPD gene encodes a DNA helicase, an important component in transcription factor IIH (TFIIH complex. XPD helicase plays a pivotal role in unwinding DNA at the damaged region during nucleotide excision repair (NER mechanism. Dysfunctional XPD helicase protein from polymorphic diversity may contribute to increased risk of developing cancers. This study aims to determine the association between XPD K751Q polymorphism (rs13181 and risk of nasopharyngeal carcinoma (NPC in the Malaysian population. In this hospital-based matched case-control study, 356 controls were matched by age, gender and ethnicity to 356 cases. RFLP-PCR was used to genotype the XPD K751Q polymorphism. A significant association was observed between XPD K751Q polymorphism and the risk of NPC using conditional logistic regression. Subjects with homozygous Lys/Lys (wildtype genotype have 1.58 times higher odds of developing NPC compared to subjects with recessive combination of heterozygous Lys/Gln and homozygous Gln/Gln genotypes (OR = 1.58, 95% CI = 1.05-2.38 p = 0.028 adjusted for cigarette smoking, alcohol and salted fish consumption. Our data suggests that Lys/Lys (wildtype of XPD K751Q contributes to increased risk of NPC in the Malaysian population.

  17. Homozygous mutation of focal adhesion kinase in embryonic stem cell derived neurons: normal electrophysiological and morphological properties in vitro

    Directory of Open Access Journals (Sweden)

    Komiyama NH

    2006-06-01

    Full Text Available Abstract Background Genetically manipulated embryonic stem (ES cell derived neurons (ESNs provide a powerful system with which to study the consequences of gene manipulation in mature, synaptically connected neurons in vitro. Here we report a study of focal adhesion kinase (FAK, which has been implicated in synapse formation and regulation of ion channels, using the ESN system to circumvent the embryonic lethality of homozygous FAK mutant mice. Results Mouse ES cells carrying homozygous null mutations (FAK-/- were generated and differentiated in vitro into neurons. FAK-/- ESNs extended axons and dendrites and formed morphologically and electrophysiologically intact synapses. A detailed study of NMDA receptor gated currents and voltage sensitive calcium currents revealed no difference in their magnitude, or modulation by tyrosine kinases. Conclusion FAK does not have an obligatory role in neuronal differentiation, synapse formation or the expression of NMDA receptor or voltage-gated calcium currents under the conditions used in this study. The use of genetically modified ESNs has great potential for rapidly and effectively examining the consequences of neuronal gene manipulation and is complementary to mouse studies.

  18. Patterns of bone diseases in transfusion-dependent homozygous thalassaemia major: predominance of osteoporosis and desferrioxamine-induced bone dysplasia

    Energy Technology Data Exchange (ETDEWEB)

    Chan, Yu-Leung; Pang, Lai-Man [Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, Shatin (Hong Kong); Chik, Ki-Wai; Li, Chi-Kong [Department of Paediatrics, Prince of Wales Hospital, Chinese University of Hong Kong (Hong Kong); Cheng, Jack C.Y. [Department Orthopaedics and Traumatology, Prince of Wales Hospital, Chinese University of Hong Kong (Hong Kong)

    2002-07-01

    Objective: To study the radiographic skeletal changes in transfusion-dependent homozygous {beta}-thalassaemia. Materials and methods: This was a retrospective review of radiographs of 41 homozygous {beta}-thalassaemic patients over 3 years. These included 55 left hand radiographs for bone age, 37 chest radiographs, 7 scanograms of lower limbs, 8 knee radiographs and 3 skull radiographs. The radiographs were evaluated for the skeletal changes owing to medullary expansion, as well as for the skeletal dysplasia related to desferrioxamine therapy. The combined cortical width of the mid shaft of the second metacarpal was measured on left hand radiographs to assess osteoporosis. Results: Sixteen patients had radiographic evidence of desferrioxamine-induced bone dysplasia. These included metaphyseal sclerosis in long bone (n=16), irregular sclerosis at the costochondral junction (n=3) and platyspondyly (n= 1). Two patients had radiographic evidence of medullary expansion with widening of medulla and marked thinning of cortex in the tubular bones. Osteoporosis, as indicated by thinning of metacarpal cortex, was noted in 17 patients (8 with and 9 without desferrioxamine-induced bone dysplasia). Conclusions: With provision of the modern regime of regular transfusion and desferrioxamine chelation, desferrioxamine-induced bone dysplasia was a much more frequently detected radiographic abnormality in {beta}-thalassaemia major than radiographic features owing to medullary expansion. Osteoporosis, as indicated by thinned metacarpal cortices, remained a frequent feature irrespective of the status of the skeletal dysplasia. (orig.)

  19. Homozygous Wildtype of XPD K751Q Polymorphism Is Associated with Increased Risk of Nasopharyngeal Carcinoma in Malaysian Population.

    Science.gov (United States)

    Lye, Munn-Sann; Visuvanathan, Shaneeta; Chong, Pei-Pei; Yap, Yoke-Yeow; Lim, Chin-Chye; Ban, Eng-Zhuan

    2015-01-01

    The xeroderma pigmentosum group D (XPD) gene encodes a DNA helicase, an important component in transcription factor IIH (TFIIH) complex. XPD helicase plays a pivotal role in unwinding DNA at the damaged region during nucleotide excision repair (NER) mechanism. Dysfunctional XPD helicase protein from polymorphic diversity may contribute to increased risk of developing cancers. This study aims to determine the association between XPD K751Q polymorphism (rs13181) and risk of nasopharyngeal carcinoma (NPC) in the Malaysian population. In this hospital-based matched case-control study, 356 controls were matched by age, gender and ethnicity to 356 cases. RFLP-PCR was used to genotype the XPD K751Q polymorphism. A significant association was observed between XPD K751Q polymorphism and the risk of NPC using conditional logistic regression. Subjects with homozygous Lys/Lys (wildtype) genotype have 1.58 times higher odds of developing NPC compared to subjects with recessive combination of heterozygous Lys/Gln and homozygous Gln/Gln genotypes (OR = 1.58, 95% CI = 1.05-2.38 p = 0.028) adjusted for cigarette smoking, alcohol and salted fish consumption. Our data suggests that Lys/Lys (wildtype) of XPD K751Q contributes to increased risk of NPC in the Malaysian population.

  20. A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia.

    Science.gov (United States)

    Roos, L; Fang, M; Dali, C; Jensen, H; Christoffersen, N; Wu, B; Zhang, J; Xu, R; Harris, P; Xu, X; Grønskov, K; Tümer, Z

    2014-09-01

    Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.

  1. An Analog Earth Climate Model

    Science.gov (United States)

    Varekamp, J. C.

    2010-12-01

    The earth climate is broadly governed by the radiative power of the sun as well as the heat retention and convective cooling of the atmosphere. I have constructed an analog earth model for an undergraduate climate class that simulates mean climate using these three parameters. The ‘earth’ is a hollow, black, bronze sphere (4 cm diameter) mounted on a thin insulated rod, and illuminated by two opposite optic fibers, with light focused on the sphere by a set of lenses. The sphere is encased in a large double-walled aluminum cylinder (34 cm diameter by 26 cm high) with separate water cooling jackets at the top, bottom, and sides. The cylinder can be filled with a gas of choice at a variety of pressures or can be run in vacuum. The exterior is cladded with insulation, and the temperature of the sphere, atmosphere and walls is monitored with thermocouples. The temperature and waterflow of the three cooling jackets can be monitored to establish the energy output of the whole system; the energy input is the energy yield of the two optic fibers. A small IR transmissive lens at the top provides the opportunity to hook up the fiber of a hyper spectrometer to monitor the emission spectrum of the black ‘earth’ sphere. A pressure gauge and gas inlet-outlet system for flushing of the cell completes it. The heat yield of the cooling water at the top is the sum of the radiative and convective components, whereas the bottom jacket only carries off the radiative heat of the sphere. Undergraduate E&ES students at Wesleyan University have run experiments with dry air, pure CO2, N2 and Ar at 1 atmosphere, and a low vacuum run was accomplished to calibrate the energy input. For each experiment, the lights are flipped on, the temperature acquisition routine is activated, and the sphere starts to warm up until an equilibrium temperature has been reached. The lights are then flipped off and the cooling sequence towards ambient is registered. The energy input is constant for a given

  2. Analog regulation of metabolic demand

    Directory of Open Access Journals (Sweden)

    Muskhelishvili Georgi

    2011-03-01

    Full Text Available Abstract Background The 3D structure of the chromosome of the model organism Escherichia coli is one key component of its gene regulatory machinery. This type of regulation mediated by topological transitions of the chromosomal DNA can be thought of as an analog control, complementing the digital control, i.e. the network of regulation mediated by dedicated transcription factors. It is known that alterations in the superhelical density of chromosomal DNA lead to a rich pattern of differential expressed genes. Using a network approach, we analyze these expression changes for wild type E. coli and mutants lacking nucleoid associated proteins (NAPs from a metabolic and transcriptional regulatory network perspective. Results We find a significantly higher correspondence between gene expression and metabolism for the wild type expression changes compared to mutants in NAPs, indicating that supercoiling induces meaningful metabolic adjustments. As soon as the underlying regulatory machinery is impeded (as for the NAP mutants, this coherence between expression changes and the metabolic network is substantially reduced. This effect is even more pronounced, when we compute a wild type metabolic flux distribution using flux balance analysis and restrict our analysis to active reactions. Furthermore, we are able to show that the regulatory control exhibited by DNA supercoiling is not mediated by the transcriptional regulatory network (TRN, as the consistency of the expression changes with the TRN logic of activation and suppression is strongly reduced in the wild type in comparison to the mutants. Conclusions So far, the rich patterns of gene expression changes induced by alterations of the superhelical density of chromosomal DNA have been difficult to interpret. Here we characterize the effective networks formed by supercoiling-induced gene expression changes mapped onto reconstructions of E. coli's metabolic and transcriptional regulatory network. Our

  3. Namibian Analogs To Titan Dunes

    Science.gov (United States)

    Wall, Stephen D.; Lopes, R.; Kirk, R.; Stofan, E.; Farr, T.; Van der Ploeg, P.; Lorenz, R.; Radebaugh, J.

    2009-09-01

    Titan's equatorial dunes, observed in Cassini SAR, have been described as longitudinal, similar to longitudinal dunes in the Namib sand sea in southern Africa. Their "Y” junctions and the way they divert around topography are used as evidence of equatorial wind flow direction. In two instances of such diversion they exhibit overlying or crosshatched patterns in two distinct directions that have been interpreted as a transition to transverse dunes. Here we describe field observations of the Namibian dunes and these comparisons, we present images of the dunes from terrestrial SAR missions, and we discuss implications to both the Titan dunes and the wind regime that created them. Selected portions of the Namibian dunes resemble Titan's dunes in peak-to-peak distance and length. They are morphologically similar to Titan, and specific superficial analogs are common, but they also differ. For example, when Titan dunes encounter topography they either terminate abruptly, "climb” the upslope, or divert around; only the latter behavior is seen in remote sensing images of Namibia. Namib linear dunes do transition to transverse as they divert, but at considerably smaller wavelength, while at Titan the wavelengths are of the same scale. Crosshatching of similar-wavelength dunes does occur in Namibia, but not near obstacles. Many additional aeolian features that are seen at Namibia such as star dunes, serpentine ridges and scours have not been detected on Titan, although they might be below the Cassini SAR's 300-m resolution. These similarities and differences allow us to explore mechanisms of Titan dune formation, in some cases giving us clues as to what larger scale evidence to look for in SAR images. Viewed at similar resolution, they provide interesting comparisons with the Titan dunes, both in likeness and differences. A part of this work was carried out at JPL under contract with NASA.

  4. Epistemic Function and Ontology of Analog and Digital Images

    Directory of Open Access Journals (Sweden)

    Aleksandra Łukaszewicz Alcaraz

    2016-01-01

    Full Text Available The important epistemic function of photographic images is their active role in construction and reconstruction of our beliefs concerning the world and human identity, since we often consider photographs as presenting reality or even the Real itself. Because photography can convince people of how different social and ethnic groups and even they themselves look, documentary projects and the dissemination of photographic practices supported the transition from disciplinary society to the present-day society of control. While both analog and digital images are formed from the same basic materia, the ways in which this matter appears are distinctive. In the case of analog photography, we deal with physical and chemical matter, whereas with digital images we face electronic matter. Because digital photography allows endless modification of the image, we can no longer believe in the truthfulness of digital images.

  5. Advances in Analog Circuit Design 2015

    CERN Document Server

    Baschirotto, Andrea; Harpe, Pieter

    2016-01-01

    This book is based on the 18 tutorials presented during the 24th workshop on Advances in Analog Circuit Design. Expert designers present readers with information about a variety of topics at the frontier of analog circuit design, including low-power and energy-efficient analog electronics, with specific contributions focusing on the design of efficient sensor interfaces and low-power RF systems. This book serves as a valuable reference to the state-of-the-art, for anyone involved in analog circuit research and development. ·         Provides a state-of-the-art reference in analog circuit design, written by experts from industry and academia; ·         Presents material in a tutorial-based format; ·         Includes coverage of high-performance analog-to-digital and digital to analog converters, integrated circuit design in scaled technologies, and time-domain signal processing.

  6. Analogies: Explanatory Tools in Web-Based Science Instruction

    Science.gov (United States)

    Glynn, Shawn M.; Taasoobshirazi, Gita; Fowler, Shawn

    2007-01-01

    This article helps designers of Web-based science instruction construct analogies that are as effective as those used in classrooms by exemplary science teachers. First, the authors explain what analogies are, how analogies foster learning, and what form analogies should take. Second, they discuss science teachers' use of analogies. Third, they…

  7. The use of analogs in the innovation process - A software engineering protocol analysis

    Science.gov (United States)

    Silverman, B. G.

    1985-01-01

    A human information processing account of how experienced practitioners utilize analogs in the innovation process is presented. The protocols of several practitioners are collected and analyzed. The problem behavior graphs, knowledge elements utilized, and operator elements applied are described, and a descriptive model of the innovation process is assembled. Implications for a production system, deviations from other models of the innovation process, and extensions to other models of the analogy procedure are explored.

  8. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function

    OpenAIRE

    Liu, Yaobin; Huang, Xiangao; He, Xian; Zhou, Yanqing; Jiang, Xiaogang; Chen-Kiang, Selina; Jaffrey, Samie R.; Xu, Guoqiang

    2015-01-01

    The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin-4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48-linked polyubiquitin chains a...

  9. Analog to Digital Conversion in Physical Measurements

    CERN Document Server

    Kapitaniak, T; Feudel, U; Grebogi, C

    1999-01-01

    There exist measuring devices where an analog input is converted into a digital output. Such converters can have a nonlinear internal dynamics. We show how measurements with such converting devices can be understood using concepts from symbolic dynamics. Our approach is based on a nonlinear one-to-one mapping between the analog input and the digital output of the device. We analyze the Bernoulli shift and the tent map which are realized in specific analog/digital converters. Furthermore, we discuss the sources of errors that are inevitable in physical realizations of such systems and suggest methods for error reduction.

  10. A computational model of analogical reasoning

    Institute of Scientific and Technical Information of China (English)

    李波; 赵沁平

    1997-01-01

    A computational model of analogical reasoning is presented, which divides analogical reasoning process into four subprocesses, i.e. reminding, elaboration, matching and transfer. For each subprocess, its role and the principles it follows are given. The model is discussed in detail, including salient feature-based reminding, relevance-directed elaboration, an improved matching model and a transfer model. And the advantages of this model are summarized based on the results of BHARS, which is an analogical reasoning system implemented by this model.

  11. Analogies in science education: contributions and challenges

    Directory of Open Access Journals (Sweden)

    Maria da Conceição Duarte

    2005-03-01

    Full Text Available An analogy is a comparison between domains of knowledge that have similarities at the levels of characteristics and relationships. Several authors highlight the importance of this tool in the teaching and learning of difficult scientific concepts. Nevertheless, some problems associated to the use of analogies have been found. This paper aims at contributing to a better understanding of the use of analogies in science education, by means of a review of the state of art regarding this matter. It will take into account its contribution to science education as well as the challenges to further research

  12. Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous Factor V Leiden carriers? A retrospective cohort study.

    Science.gov (United States)

    Perez Botero, J; Ormsby, W D; Ashrani, A A; McBane, R D; Wysokinski, W E; Patnaik, M M; Lewis, B R; Grill, D E; Pruthi, R K; Heit, J A

    2016-05-01

    While Factor V Leiden (F5 rs6025 A allele) is a known venous thromboembolism (VTE) risk factor, VTE risk among heterozygous vs. homozygous carriers is uncertain. In a retrospective cohort study of Mayo Clinic patients referred for genotyping between 1996 and 2013, we tested Factor V Leiden genotype as a risk factor for incident and recurrent VTE. Among heterozygous (n=268) and homozygous (n=111) carriers, the prevalence of VTE was 54% and 68%, respectively (p=0.016). While mean patient age at first VTE event (43.9 vs. 42.9years; p=0.70) did not differ significantly, median VTE-free survival was modestly shorter for homozygous carriers (56.8 vs 59.5 years; p=0.04). Sixty-nine (48%) and 31 (42%) heterozygous and homozygous carriers had ≥1 VTE recurrence (p=0.42). In a multivariable model, idiopathic incident VTE and a second thrombophilia were associated with increased and anticoagulation duration >6months with reduced hazards of VTE recurrence; Factor V Leiden genotype was not an independent predictor of recurrence. Aside from a higher VTE prevalence and modestly reduced VTE-free survival, VTE penetrance and phenotype severity did not differ significantly among homozygous vs. heterozygous carriers, suggesting that VTE prophylaxis and management should not differ by Factor V Leiden genotype. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  13. Homozygous hemoglobin S (HbSS) presenting with bilateral facial nerve palsy: a case report

    OpenAIRE

    Ogundunmade, Babatunde Gbolahan; Jasper, Unyime Sunday

    2014-01-01

    Background Bilateral facial nerve palsy is a relatively rare presentation and often points to a serious underlying medical condition. Several studies have reported presentation of bilateral facial nerve palsy in association with Lyme disease, Guillain-Barre syndrome, systemic lupus erythematosus, human immunodeficiency virus, sarcoidosis, diabetes and Hanson disease. While unilateral facial nerve palsy is sometimes associated with hemiplegia in sickle cell patients, no case of bilateral facia...

  14. Use of analogy in learning scientific concepts.

    Science.gov (United States)

    Donnelly, C M; McDaniel, M A

    1993-07-01

    Four experiments compared learning of scientific concepts as expressed in either traditional literal form or through an analogy. Comprehension of basic-level details and inferential implications was measured through multiple-choice testing. In Experiment 1, literal or analogical renditions were presented in textual form only. In Experiment 2, text was accompanied by a dynamic video. In Experiment 3, the video and text literal rendition was compared with a text-only analogical rendition. In Experiment 4, subjects read only about a familiar domain. Subjects consistently answered basic-level questions most accurately when concepts were expressed literally, but answered inferential questions most accurately when concepts were expressed analogically. Analysis of individual differences (Experiment 2) indicated that this interaction strongly characterized the conceptual learning of science novices. The results are discussed within the framework of schema induction.

  15. Efficient Image Transmission Through Analog Error Correction

    CERN Document Server

    Liu, Yang; Li,; Xie, Kai

    2011-01-01

    This paper presents a new paradigm for image transmission through analog error correction codes. Conventional schemes rely on digitizing images through quantization (which inevitably causes significant bandwidth expansion) and transmitting binary bit-streams through digital error correction codes (which do not automatically differentiate the different levels of significance among the bits). To strike a better overall performance in terms of transmission efficiency and quality, we propose to use a single analog error correction code in lieu of digital quantization, digital code and digital modulation. The key is to get analog coding right. We show that this can be achieved by cleverly exploiting an elegant "butterfly" property of chaotic systems. Specifically, we demonstrate a tail-biting triple-branch baker's map code and its maximum-likelihood decoding algorithm. Simulations show that the proposed analog code can actually outperform digital turbo code, one of the best codes known to date. The results and fin...

  16. Synthesis and Biological Activity of Philanthotoxin Analogs

    Institute of Scientific and Technical Information of China (English)

    Yong An ZHANG; Ke Zhong LIU; Deng Yuan WANG; Yu Zhu WANG; Liang Jian QU; Chang Jin ZHU

    2006-01-01

    The synthesis of four analogs of philanthotoxin is described. The preliminary bioassay showed that these compounds all had good insecticidal activities, and the compound 6a had the best killing effect.

  17. The Structure of Analogical Models in Science.

    Science.gov (United States)

    1980-07-01

    analogies cannot. 8. A Freudian defense might claim that the theory merely reflects the illogic of the unconscious. But a theory about an unclarified...an initial comparison. To illustrate the points, analogies of historical importance are analyzed. Although the focus is on theory , some empirical...feature-list theory , the structure-mapping approach makes a strong distinction between objects and their attributes, on the one hand, and relationships, on

  18. Learning Domain Theories via Analogical Transfer

    Science.gov (United States)

    2007-01-01

    Shive & Weber 1982). In the linear kinematics section of the textbook used for this study ( Giancoli 1991), there are eight worked out examples...is analogous to the dynamics of linear motion” (p. 197, Giancoli 1991). This is common practice in textbooks, and analogies between domains form the...and Worked Solution All problems and worked solutions used in this work were taken from the same physics textbook ( Giancoli 1991). Problems are

  19. Synthetic heparin-binding growth factor analogs

    Science.gov (United States)

    Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.

    2007-01-23

    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

  20. Analogical Learning and Automated Rule Constructions

    Institute of Scientific and Technical Information of China (English)

    周哈阳

    1991-01-01

    This paper describes some experiments of analogical learning and automated rule construction.The present investigation focuses on knowledge acquisition,learning by analyogy,and knowledge retention.The developed system initially learns from scratch,gradually acquires knowledge from its environment through trial-and-error interaction,incrementally augments its knowledge base,and analogically solves new tasks in a more efficient and direct manner.

  1. Analogy betwen dislocation creep and relativistic cosmology

    OpenAIRE

    J.A. Montemayor-Aldrete; J.D. Muñoz-Andrade; Mendoza-Allende, A.; Montemayor-Varela, A.

    2005-01-01

    A formal, physical analogy between plastic deformation, mainly dislocation creep, and Relativistic Cosmology is presented. The physical analogy between eight expressions for dislocation creep and Relativistic Cosmology have been obtained. By comparing the mathematical expressions and by using a physical analysis, two new equations have been obtained for dislocation creep. Also, four new expressions have been obtained for Relativistic Cosmology. From these four new equations, one may determine...

  2. Analog baseband circuits for sensor systems

    OpenAIRE

    2008-01-01

    This thesis is composed of six publications and an overview of the research topic, which also summarizes the work. The research presented in this thesis focuses on research into analog baseband circuits for sensor systems. The research is divided into three different topics: the integration of analog baseband circuits into a radio receiver for sensor applications; the integration of an ΔΣ modulator A/D converter into a GSM/WCDMA radio receiver for mobile phones, and the integration of algorit...

  3. Automated Integrated Analog Filter Design Issues

    OpenAIRE

    2015-01-01

    An analysis of modern automated integrated analog circuits design methods and their use in integrated filter design is done. Current modern analog circuits automated tools are based on optimization algorithms and/or new circuit generation methods. Most automated integrated filter design methods are only suited to gmC and switched current filter topologies. Here, an algorithm for an active RC integrated filter design is proposed, that can be used in automated filter designs. The algorithm is t...

  4. The analogy between stereo depth and brightness.

    Science.gov (United States)

    Brookes, A; Stevens, K A

    1989-01-01

    Apparent depth in stereograms exhibits various simultaneous-contrast and induction effects analogous to those reported in the luminance domain. This behavior suggests that stereo depth, like brightness, is reconstructed, ie recovered from higher-order spatial derivatives or differences of the original signal. The extent to which depth is analogous to brightness is examined. There are similarities in terms of contrast effects but dissimilarities in terms of the lateral inhibition effects traditionally attributed to underlying spatial-differentiation operators.

  5. Protein Structure Prediction with Visuospatial Analogy

    Science.gov (United States)

    Davies, Jim; Glasgow, Janice; Kuo, Tony

    We show that visuospatial representations and reasoning techniques can be used as a similarity metric for analogical protein structure prediction. Our system retrieves pairs of α-helices based on contact map similarity, then transfers and adapts the structure information to an unknown helix pair, showing that similar protein contact maps predict similar 3D protein structure. The success of this method provides support for the notion that changing representations can enable similarity metrics in analogy.

  6. AMiBA Wideband Analog Correlator

    CERN Document Server

    Li, Chao-Te; Wilson, Warwick; Lin, Kai-Yang; Chen, Ming-Tang; Ho, P T P; Chen, Chung-Cheng; Han, Chih-Chiang; Oshiro, Peter; Martin-Cocher, Pierre; Chang, Chia-Hao; Chang, Shu-Hao; Altamirano, Pablo; Jiang, Homin; Chiueh, Tzi-Dar; Lien, Chun-Hsien; Wang, Huei; Wei, Ray-Ming; Yang, Chia-Hsiang; Peterson, Jeffrey B; Chang, Su-Wei; Huang, Yau-De; Hwang, Yuh-Jing; Kesteven, Michael; Koch, Patrick; Liu, Guo-Chin; Nishioka, Hiroaki; Umetsu, Keiichi; Wei, Tashun; Wu, Jiun-Huei Proty

    2010-01-01

    A wideband analog correlator has been constructed for the Yuan-Tseh Lee Array for Microwave Background Anisotropy. Lag correlators using analog multipliers provide large bandwidth and moderate frequency resolution. Broadband IF distribution, backend signal processing and control are described. Operating conditions for optimum sensitivity and linearity are discussed. From observations, a large effective bandwidth of around 10 GHz has been shown to provide sufficient sensitivity for detecting cosmic microwave background variations.

  7. HAPS, a Handy Analog Programming System

    DEFF Research Database (Denmark)

    Højberg, Kristian Søe

    1975-01-01

    HAPS (Hybrid Analog Programming System) is an analog compiler that can be run on a minicomputer in an interactive mode. Essentially HAPS is written in FORTRAN. The equations to be programmed for an ana log computer are read in by using a FORTRAN-like notation. The input must contain maximum...... and emphasizes the limitations HAPS puts on equation structure, types of computing circuit, scaling, and static testing....

  8. Acute renal infarction associated with homozygous methylenetetrahydrofolate reductase mutation C677T and IgA beta-2-glycoprotein antibodies.

    Science.gov (United States)

    Vlachostergios, Panagiotis J; Dufresne, François

    2015-07-01

    Arterial thrombosis of the kidney(s) is a rare clinical entity usually presenting as a result of cardioembolic disease, though rare inherited hypercoagulable states have also been implicated. Within this context, both hyperhomocysteinemia triggered by a mutated methylenetetrahydrofolate reductase (MTHFR) gene product and the presence of antiphospholipid antibodies have been separately associated with arterial thrombotic events, including renal artery embolism. We present a case of combined homozygous MTHFR C677T mutation and IgA beta-2-glycoprotein antibody positivity resulting in acute renal infarction and previous silent myocardial infarction. An acute and otherwise unexplained thrombotic event of unusual location always warrants further investigation, which should include testing for hereditary thrombophilic disorders.

  9. Heterozygous beta-thalassemia and homozygous H63D hemochromatosis in a child: an 18-year follow-up.

    Science.gov (United States)

    Miniero, Roberto; Tardivo, Irene; Roetto, Antonella; De Gobbi, Marco

    2005-03-01

    At age of 3.2 years routine blood analysis showed the presence of a beta-thalassemic trait with unexpected high level of serum iron and high transferrin saturation. Hematological follow-up confirmed the moderate degree of anemia and persisting high levels of iron indices throughout the years with a progressive increase of serum ferritin. At the age of 19 years the patient was diagnosed homozygous for HC63D HFE. The patient referred by us confirm the possibility of precocious alteration of iron indices in patients with heterozygosity for beta-thalassemia inherited together with HFE mutations. This observation suggests that any children with thalassemic trait with increased transferrin saturation and/or serum ferritin might be investigated for the presence of the hemocromatosis genes in order to detect the disease before any clinical manifestation and even before organ iron loading.

  10. Valproate Treatment in an ALS Patient Carrying a c.194G>A Spastin Mutation and SMN2 Homozygous Deletion

    Directory of Open Access Journals (Sweden)

    Lucio Tremolizzo

    2014-01-01

    Full Text Available Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4 and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.

  11. Analog modelling of obduction processes

    Science.gov (United States)

    Agard, P.; Zuo, X.; Funiciello, F.; Bellahsen, N.; Faccenna, C.; Savva, D.

    2012-04-01

    Obduction corresponds to one of plate tectonics oddities, whereby dense, oceanic rocks (ophiolites) are presumably 'thrust' on top of light, continental ones, as for the short-lived, almost synchronous Peri-Arabic obduction (which took place along thousands of km from Turkey to Oman in c. 5-10 Ma). Analog modelling experiments were performed to study the mechanisms of obduction initiation and test various triggering hypotheses (i.e., plate acceleration, slab hitting the 660 km discontinuity, ridge subduction; Agard et al., 2007). The experimental setup comprises (1) an upper mantle, modelled as a low-viscosity transparent Newtonian glucose syrup filling a rigid Plexiglas tank and (2) high-viscosity silicone plates (Rhodrosil Gomme with PDMS iron fillers to reproduce densities of continental or oceanic plates), located at the centre of the tank above the syrup to simulate the subducting and the overriding plates - and avoid friction on the sides of the tank. Convergence is simulated by pushing on a piston at one end of the model with velocities comparable to those of plate tectonics (i.e., in the range 1-10 cm/yr). The reference set-up includes, from one end to the other (~60 cm): (i) the piston, (ii) a continental margin containing a transition zone to the adjacent oceanic plate, (iii) a weakness zone with variable resistance and dip (W), (iv) an oceanic plate - with or without a spreading ridge, (v) a subduction zone (S) dipping away from the piston and (vi) an upper, active continental margin, below which the oceanic plate is being subducted at the start of the experiment (as is known to have been the case in Oman). Several configurations were tested and over thirty different parametric tests were performed. Special emphasis was placed on comparing different types of weakness zone (W) and the extent of mechanical coupling across them, particularly when plates were accelerated. Displacements, together with along-strike and across-strike internal deformation in all

  12. Development of analogical problem-solving skill.

    Science.gov (United States)

    Holyoak, K J; Junn, E N; Billman, D O

    1984-12-01

    3 experiments were performed to assess children's ability to solve a problem by analogy to a superficially dissimilar situation. Preschoolers and fifth and sixth graders were asked to solve a problem that allowed multiple solutions. Some subjects were first read a story that included an analogous problem and its solution. When the mapping between the relations involved in the corresponding solutions was relatively simple, and the corresponding instruments were perceptually and functionally similar, even preschoolers were able to use the analogy to derive a solution to the transfer problem (Experiment 1). Furthermore, salient similarity of the instruments was neither sufficient (Experiment 2) nor necessary (Experiment 3) for success by preschool subjects. When the story analog mapped well onto the transfer problem, 4-year-olds were often able to generate a solution that required transformation of an object with little perceptual or semantic similarity to the instrument used in the base analog (Experiment 3). The older children used analogies in a manner qualitatively similar to that observed in comparable studies with adults (Experiment 1), whereas the younger children exhibited different limitations.

  13. Uniparental disomy of chromosome 2 resulting in lethal trifunctional protein deficiency due to homozygous alpha-subunit mutations.

    Science.gov (United States)

    Spiekerkoetter, Ute; Eeds, Angela; Yue, Zou; Haines, Jonathan; Strauss, Arnold W; Summar, Marshall

    2002-12-01

    The mitochondrial trifunctional protein (TFP) is an enzyme complex of the fatty acid beta-oxidation cycle composed of an alpha- and a beta-subunit. The two encoding genes are located in the same region on chromosome 2 (2p23). TFP deficiency due to either alpha- or beta-subunit mutations is characterized by mutational and phenotypic heterogeneity with severe, early-onset, cardiac forms and milder, later-onset, myopathic phenotypes. In two unrelated patients with lethal TFP deficiency, we delineated apparently homozygous alpha-subunit mutations that were present in heterozygous form in both mothers, but not in either biological father. We performed a microsatellite repeat analysis of both patients and their parents using seven chromosome 2-specific polymorphic DNA markers and four nonchromosome 2 markers. In both patients, two chromosome 2-specific markers demonstrated maternal isodisomy of chromosome 2. The other five chromosome 2-specific markers were noninformative in each patient. Inheritance of alleles from chromosomes 4, 5, and 7 was consistent with paternity. These results explain the apparently anomalous pattern of transmission. Six of our 12 known TFP-deficient patients with alpha-subunit mutations have disease due to homozygous changes and two of them via the mechanism of uniparental disomy (UPD) (16.7%). For very rare autosomal recessive diseases, UPD may represent a common mechanism. This study emphasizes the need to confirm mutations in parents whenever possible. TFP deficiency is another disorder that has become manifest due to isodisomy of chromosome 2. This information will impact genetic counseling for these families, reducing greatly the 25% risk normally used for recessive disorders.

  14. Efficient construction of homozygous diploid strains identifies genes required for the hyper-filamentous phenotype in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Kentaro Furukawa

    Full Text Available Yeast cells undergo diploid-specific developments such as spore formation via meiosis and pseudohyphal development under certain nutrient-limited conditions. Studies on these aspects require homozygous diploid mutants, which are generally constructed by crossing strains of opposite mating-type with the same genetic mutation. So far, there has been no direct way to generate and select diploids from haploid cells. Here, we developed a method for efficient construction of homozygous diploids using a PGAL1-HO gene (galactose-inducible mating-type switch and a PSTE18-URA3 gene (counter selection marker for diploids. Diploids are generated by transient induction of the HO endonuclease, which is followed by mating of part of the haploid population. Since the STE18 promoter is repressed in diploids, diploids carrying PSTE18-URA3 can be selected on 5-fluoroorotic acid (5-FOA plates where the uracil prototrophic haploids cannot grow. To demonstrate that this method is useful for genetic studies, we screened suppressor mutations of the complex colony morphology, strong agar invasion and/or hyper-filamentous growth caused by lack of the Hog1 MAPK in the diploid Σ1278b strain background. Following this approach, we identified 49 suppressor mutations. Those include well-known positive regulator genes for filamentous growth signaling pathways, genes involved in mitochondrial function, DNA damage checkpoint, chromatin remodeling, and cell cycle, and also previously uncharacterized genes. Our results indicate that combinatorial use of the PGAL1-HO and PSTE18-URA3 genes is suitable to efficiently construct and select diploids and that this approach is useful for genetic studies especially when combined with large-scale screening.

  15. Computational imaging analysis of fibrin matrices with the inclusion of erythrocytes from homozygous SS blood reveals agglomerated and amorphous structures.

    Science.gov (United States)

    Averett, Rodney D; Norton, David G; Fan, Natalie K; Platt, Manu O

    2017-01-01

    Sickle cell disease is a single point mutation disease that is known to alter the coagulation system, leading to hypercoagulable plasma conditions. These hypercoagulable conditions can lead to complications in the vasculature, caused by fibrin clots that form undesirably. There is a need to understand the morphology and structure of fibrin clots from patients with sickle cell disease, as this could lead to further discovery of treatments and life-saving therapies. In this work, a computational imaging analysis method is presented to evaluate fibrin agglomeration in the presence of erythrocytes (RBCs) homozygous for the sickle cell mutation (SS). Numerical algorithms were used to determine agglomeration of fibrin fibers within a matrix with SS RBCs to test the hypothesis that fibrin matrices with the inclusion of SS RBCs possess a more agglomerated structure than native fibrin matrices with AA RBCs. The numerical results showed that fibrin structures with SS RBCs displayed an overall higher degree of agglomeration as compared to native fibrin structures. The computational algorithm was also used to evaluate fibrin fiber overlap (aggregation) and anisotropy (orientation) in normal fibrin matrices compared to fibrin matrices polymerized around SS RBCs; however, there was no statistical difference. Ultrasound measurements of stiffness revealed rigid RBCs in the case of samples derived from homozygous SS blood, and densely evolving matrices, when compared to normal fibrin with the inclusion of AA RBCs. An agglomeration model is suggested to quantify the fibrin aggregation/clustering near RBCs for both normal fibrin matrices and for the altered structures. The results of this work are important in the sense that the understanding of aggregation and morphology in fibrin clots with incorporation of RBCs from persons living with sickle cell anemia may elucidate the complexities of comorbidities and other disease complications.

  16. An unusual presentation of Gaucher's disease: aortic valve fibrosis in a patient homozygous for a rare G377S mutation.

    Science.gov (United States)

    Perić, Zinaida; Kardum-Skelin, Ika; Puskarić, Biljana Jelić; Letilović, Tomislav; Vrhovac, Radovan; Jaksić, Branimir

    2010-03-01

    Gaucher's disease (GD) has variable presentations, but cardiac involvement is a generally uncommon clinical manifestation of the disease. In the past 25 years, the underlying genetic disorder in GD has been well characterized, with almost 300 mutations identified in the glucocerebrosidase gene (GBA). Nevertheless, clear genotype-phenotype correlations have been confirmed only for the most frequent mutations. We present a female patient, who was known to have aortic valve pathology from the age of 30. Despite medical follow up, at the age of 60 she presented with heart failure (NYHA III). At that time echocardiography showed severe fibrosed aortic valve stenosis. Valvuloplasty was planned, when thrombocytopenia, previously considered to be autoimmune, became severe. Anemia and leukopenia were also noted. Moderate splenomegaly and severe bone marrow infiltration were found on MRI. Bone marrow aspiration revealed typical Gaucher cells and the enzyme activity assay confirmed the diagnosis. DNA investigation showed that the patient is homozygous for the G377S mutation. To our knowledge, of all mutations identified so far, only homozygosity for the D409H mutation has been associated with cardiovascular valvular disease in patients with a rare type 3c GD. G377S, found in our patient, is a rare mutation, previously reported as a 'mild' mutation, because of the finding that homoallelic patients were essentialy asymptomatic or had mild disease. Our patient, also homozygous for G377S mutation, had a severe form of type 1 GD, with rare cardiac valve involvement, which is a previously unreported clinical presentation for this mutation. This case further proves that patients with the same genotypes can have different phenotypes, emphasizing the influence of other genetic and/or environmental factors.

  17. Correlation of liver density by magnetic resonance imaging and hepatic iron levels. A noninvasive means to exclude homozygous hemochromatosis.

    Science.gov (United States)

    Lawrence, S P; Caminer, S J; Yavorski, R T; Borosky, B D; Rak, K M; Merenich, J A; McDermott, M T; McNally, P R

    1996-09-01

    The diagnosis of hemochromatosis requires liver biopsy and the quantification of hepatic iron. Magnetic resonance imaging (MRI) of the liver shows a characteristic decrease in tissue signal intensity in iron overload states, but its role in the diagnosis of hemochromatosis has not been fully delineated. Forty-three patients (31 men and 12 women) were referred for the evaluation of hemochromatosis based upon a fasting transferrin saturation > 55% and/or a serum ferritin > 400 ng/ml in males or > 300 ng/ml in females. Each patient prospectively underwent MRI of the liver prior to percutaneous liver biopsy and quantitative hepatic iron determination. Homozygous hemochromatosis was diagnosed in 10 patients based upon an hepatic iron/age index > or = 2. MRI was performed with a 1.5 Tesla system using standard spin-echo sequences (T1; TR = 300-500 ms, TE = 13-17 ms, PD; TR = 2,000-2,600 ms, TE = 30 ms). Signal intensity values were blindly determined for regions of interest in liver and skeletal muscle at T1 and proton density. Ratios of liver to muscle (LM) for T1 and proton density (PD) calculated from these values showed a significant correlation with quantitative iron by multiple regression analysis. The LMPD ratio provided the best correlation with hepatic iron (r = -0.6946; p 0.5 had hepatic iron/age indices of < 2.0, thereby excluding homozygous hemochromatosis. These results suggest that LMPD ratios derived from MRI of the liver can accurately predict hepatic iron content. These ratios can be clinically useful in the evaluation of hemochromatosis among patients who either refuse or have contraindications to liver biopsy.

  18. Alu Sx repeat-induced homozygous deletion of the StAR gene causes lipoid congenital adrenal hyperplasia.

    Science.gov (United States)

    Eiden-Plach, Antje; Nguyen, Huy-Hoang; Schneider, Ursula; Hartmann, Michaela F; Bernhardt, Rita; Hannemann, Frank; Wudy, Stefan A

    2012-05-01

    Lipoid congenital adrenal hyperplasia (Lipoid CAH) is the most severe form of the autosomal recessive disorder CAH. A general loss of the steroid biosynthetic activity caused by defects in the StAR gene manifests as life-threatening primary adrenal insufficiency. We report a case of Lipoid CAH caused by a so far not described homozygous deletion of the complete StAR gene and provide diagnostic results based on a GC-MS steroid metabolomics and molecular genetic analysis. The patient presented with postnatal hypoglycemia, vomiting, adynamia, increasing pigmentation and hyponatremia. The constellation of urinary steroid metabolites suggested Lipoid CAH and ruled out all other forms of CAH or defects of aldosterone biosynthesis. After treatment with sodium supplementation, hydrocortisone and fludrocortisone the child fully recovered. Molecular genetic analysis demonstrated a homozygous 12.1 kb deletion in the StAR gene locus. The breakpoints of the deletion are embedded into two typical genomic repetitive Alu Sx elements upstream and downstream of the gene leading to the loss of all exons and regulatory elements. We established deletion-specific and intact allele-specific PCR methods and determined the StAR gene status of all available family members over three generations. This analysis revealed that one of the siblings, who died a few weeks after birth, carried the same genetic defect. Since several Alu repeats at the StAR gene locus increase the probability of deletions, patients with typical symptoms of lipoid CAH lacking evidence for the presence of both StAR alleles should be analyzed carefully for this kind of disorder.

  19. Homozygous Nonsense Mutation in SCHIP1/IQCJ-SCHIP1 Causes a Neurodevelopmental Brain Malformation Syndrome.

    Science.gov (United States)

    Elsaid, Mahmoud; Chalhoub, Nader; Ben-Omran, Tawfeg; Kamel, Hussein; Al Mureikhi, Mariam; Ibrahim, Khalid; Ross, M Elizabeth; Abdel Aleem, Alice

    2017-08-08

    We report a consanguineous Arab family with three affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain Magnetic Resonance Imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C-terminal region shared by the Schwanomin-Interacting Protein1 (SCHIP1) isoforms including the IQCJ-SCHIP1. The in-vitro expression of SCHIP1 and IQCJ-SCHIP1 truncated mutant isoforms (NM_001197109.1; p.R209* and NM_001197114.1; p.R501*, respectively) were markedly reduced as compared to their full-length versions suggesting protein stability/folding impairment. The pathogenic nature of this mutation is supported by a previously reported mouse knockout of Schip1 isoforms, which phenocopied the human axon guidance abnormality. This is the first report of a SCHIP1/IQCJ-SCHIP1 point mutation in humans associated with a neurological-developmental phenotype. This article is protected by copyright. All rights reserved.

  20. Differentiation of Keratinocytes Modulates Skin HPA Analog.

    Science.gov (United States)

    Wierzbicka, Justyna M; Żmijewski, Michał A; Antoniewicz, Jakub; Sobjanek, Michal; Slominski, Andrzej T

    2017-01-01

    It is well established, that epidermal keratinocytes express functional equivalent of hypothalamus-pituitary-adrenal axis (HPA) in order to respond to changing environment and maintain internal homeostasis. We are presenting data indicating that differentiation of primary neonatal human keratinocytes (HPEKp), induced by prolonged incubation or calcium is accompanied by significant changes in the expression of the elements of skin analog of HPA (sHPA). Expression of CRF, UCN1-3, POMC, ACTH, CRFR1, CRFR2, MC1R, MC2R, and GR (coded by NR3C1 gene) were observed on gene/protein levels along differentiation of keratinocytes in culture with similar pattern seen by immunohistochemistry on full thickness skin biopsies. Expression of CRF was more pronounced in less differentiated keratinocytes, which corresponded to the detection of CRF immunoreactivity preferentially in the stratum basale. POMC expression was enhanced in more differentiated keratinocytes, which corresponded to detection of ACTH immunoreactivity, predominantly in the stratum spinosum and stratum granulosum. Expression of urocortins was also affected by induction of HPEKp differentiation. Immunohistochemical studies showed high prevalence of CRFR1 in well differentiated keratinocytes, while smaller keratinocytes showed predominantly CRFR2 immunoreactivity. MC2R mRNA levels were elevated from days 4 to 8 of in vitro incubation, while MC2R immunoreactivity was the highest in the upper layers of epidermis. Similar changes in mRNA/protein levels of sHPA elements were observed in HPEKp keratinocytes treated with calcium. Summarizing, preferential expression of CRF and POMC (ACTH) by populations of keratinocytes on different stage of differentiation resembles organization of central HPA axis suggesting their distinct role in physiology and pathology of the epidermis. J. Cell. Physiol. 232: 154-166, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera–like disease

    Science.gov (United States)

    Akada, Hajime; Yan, Dongqing; Zou, Haiying; Fiering, Steven; Hutchison, Robert E.

    2010-01-01

    A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs. PMID:20197548

  2. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease.

    Science.gov (United States)

    Akada, Hajime; Yan, Dongqing; Zou, Haiying; Fiering, Steven; Hutchison, Robert E; Mohi, M Golam

    2010-04-29

    A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs.

  3. The First Synthesis and Anti-retroviral Activity of 5',5'-Difluoro-3'-Hydroxy-Apiosyl Nucleoside Cyclomonophosphonic Acid Analogs

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seyeon; Hong, Joon Hee [Chosun University, Gwangju (Korea, Republic of)

    2016-04-15

    The first synthesis of novel 5',5'-difluoro-30-hydroxy apiose nucleoside cyclomonophosphonic acid analogs was performed as potent anti-retroviral agents. Phosphonation was performed by direct displacement of a triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding(α, α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside cyclomonophosphonic acid analogs. The synthesized nucleoside analogs were subjected to anti-viral screening against the human immunodeficiency virus-1 (HIV-1). Cytosine analogs show significant anti-HIV activity.

  4. A Kolmogorov Complexity View of Analogy: From Logical Modeling to Experimentations

    Science.gov (United States)

    Bayoudh, Meriam; Prade, Henri; Richard, Gilles

    Analogical reasoning is considered as one of the main mechanisms underlying human intelligence and creativity, allowing the paradigm shift essential to a creative process. More specific is the notion of analogical proportion like "2 is to 4 as 5 is to 10" or "read is to reader as lecture is to lecturer": such statements can be precisely described within an algebraic framework. When the proportion holds between concepts as in "engine is to car as heart is to human" or "wine is to France as beer is to England", applying an algebraic framework is less straightforward and a new way to understand analogical proportions on the basis of Kolmogorov complexity theory may seem more appropriate. This viewpoint has been used to develop a classifier detecting analogies in natural language. Despite their apparent difference, it is quite clear that the two viewpoints should be strongly related. In this paper, we investigate the link between a purely abstract view of analogical proportions and a definition based on Kolmogorov complexity theory. This theory is used as a backbone to experiment a classifier of natural language analogies whose results are consistent with the abstract setting.

  5. Structure-activity relationships of strychnine analogs at glycine receptors.

    Science.gov (United States)

    Mohsen, Amal M Y; Heller, Eberhard; Holzgrabe, Ulrike; Jensen, Anders A; Zlotos, Darius P

    2014-08-01

    Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21) = C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine receptors. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

  6. Identification of Protein Substrates of Specific PARP Enzymes Using Analog-Sensitive PARP Mutants and a "Clickable" NAD(+) Analog.

    Science.gov (United States)

    Gibson, Bryan A; Kraus, W Lee

    2017-01-01

    The PARP family of ADP-ribosyl transferases contains 17 members in human cells, most of which catalyze the transfer of the ADP-ribose moiety of NAD(+) onto their target proteins. This posttranslational modification plays important roles in cellular signaling, especially during cellular stresses, such as heat shock, inflammation, unfolded protein responses, and DNA damage. Knowing the specific proteins that are substrates for individual PARPs, as well as the specific amino acid residues in a given target protein that are ADP-ribosylated, is a key step in understanding the biology of individual PARPs. Recently, we developed a robust NAD(+) analog-sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition ("click chemistry") reactions. When coupled with proteomics and mass spectrometry, the analog-sensitive PARP approach can be used to identify the specific amino acids that are ADP-ribosylated by individual PARP proteins. In this chapter, we describe the key facets of the experimental design and application of the analog-sensitive PARP methodology to identify site-specific modification of PARP target proteins.

  7. Use of Hawaii Analog Sites for Lunar Science and In-Situ Resource Utilization

    Science.gov (United States)

    Sanders, G. B.; Larson, W. E.; Picard, M.; Hamilton, J. C.

    2011-01-01

    In-Situ Resource Utilization (ISRU) and lunar science share similar objectives with respect to analyzing and characterizing the physical, mineral, and volatile materials and resources at sites of robotic and human exploration. To help mature and stress instruments, technologies, and hardware and to evaluate operations and procedures, space agencies have utilized demonstrations at analog sites on Earth before use in future missions. The US National Aeronautics and Space Administration (NASA), the Canadian Space Agency (CSA), and the German Space Agency (DLR) have utilized an analog site on the slope of Mauna Kea on the Big Island of Hawaii to test ISRU and lunar science hardware and operations in two previously held analog field tests. NASA and CSA are currently planning on a 3rd analog field test to be held in June, 2012 in Hawaii that will expand upon the successes from the previous two field tests.

  8. Potent anti-inflammatory activity of novel microtubule-modulating brominated noscapine analogs.

    Science.gov (United States)

    Zughaier, Susu; Karna, Prasanthi; Stephens, David; Aneja, Ritu

    2010-02-11

    Noscapine, a plant-derived, non-toxic, over-the-counter antitussive alkaloid has tubulin-binding properties. Based upon the structural resemblance of noscapine to colchicine, a tubulin-binding anti-inflammatory drug, noscapine and its semi-synthetic brominated analogs were examined for in vitro anti-inflammatory activity. Brominated noscapine analogs were found to inhibit cytokine and chemokine release from macrophage cell lines but did not affect cell viability. Brominated noscapine analogs demonstrated anti-inflammatory properties in both TLR- and non-TLR induced in vitro innate immune pathway inflammation models, mimicking septic and sterile infection respectively. In addition, electron microscopy and immunoblotting data indicated that these analogs induced robust autophagy in human macrophages. This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules.

  9. Potent anti-inflammatory activity of novel microtubule-modulating brominated noscapine analogs.

    Directory of Open Access Journals (Sweden)

    Susu Zughaier

    Full Text Available Noscapine, a plant-derived, non-toxic, over-the-counter antitussive alkaloid has tubulin-binding properties. Based upon the structural resemblance of noscapine to colchicine, a tubulin-binding anti-inflammatory drug, noscapine and its semi-synthetic brominated analogs were examined for in vitro anti-inflammatory activity. Brominated noscapine analogs were found to inhibit cytokine and chemokine release from macrophage cell lines but did not affect cell viability. Brominated noscapine analogs demonstrated anti-inflammatory properties in both TLR- and non-TLR induced in vitro innate immune pathway inflammation models, mimicking septic and sterile infection respectively. In addition, electron microscopy and immunoblotting data indicated that these analogs induced robust autophagy in human macrophages. This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules.

  10. Antigenic drift in H5N1 avian influenza virus in poultry is driven by mutations in major antigenic sites of the hemagglutinin molecule analogous to those for human influenza virus.

    Science.gov (United States)

    Cattoli, Giovanni; Milani, Adelaide; Temperton, Nigel; Zecchin, Bianca; Buratin, Alessandra; Molesti, Eleonora; Aly, Mona Meherez; Arafa, Abdel; Capua, Ilaria

    2011-09-01

    H5N1 highly pathogenic avian influenza virus has been endemic in poultry in Egypt since 2008, notwithstanding the implementation of mass vaccination and culling of infected birds. Extensive circulation of the virus has resulted in a progressive genetic evolution and an antigenic drift. In poultry, the occurrence of antigenic drift in avian influenza viruses is less well documented and the mechanisms remain to be clarified. To test the hypothesis that H5N1 antigenic drift is driven by mechanisms similar to type A influenza viruses in humans, we generated reassortant viruses, by reverse genetics, that harbored molecular changes identified in genetically divergent viruses circulating in the vaccinated population. Parental and reassortant phenotype viruses were antigenically analyzed by hemagglutination inhibition (HI) test and microneutralization (MN) assay. The results of the study indicate that the antigenic drift of H5N1 in poultry is driven by multiple mutations primarily occurring in major antigenic sites at the receptor binding subdomain, similarly to what has been described for human influenza H1 and H3 subtype viruses.

  11. Effect of a bispidinone analog on mitochondria‑mediated apoptosis in HeLa cells.

    Science.gov (United States)

    Yi, Myeongjin; Parthiban, Paramasivam; Hwang, Jiyoung; Zhang, Xin; Jeong, Hyunjin; Park, Dong Ho; Kim, Dong-Kyoo

    2014-01-01

    The present study was carried out to investigate the effect of 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonan-9-one (bispidinone) analogs on the in vitro growth of human cervical carcinoma (HeLa) cells. A series of 11 bispidinone analogs was synthesized with substituents, e.g., fluoro/methyl/ethyl/isopropyl/thiomethyl/methoxy groups, at various positions. These compounds were synthesized to identify which substituent and position induced the strongest cytotoxic effect in cancer cells. Among these synthetics, analog 9, which contains methoxy groups, had the most significant cytotoxic effect on HeLa cells, and its IC50 value was less than 13 µM. A WST-8 assay also showed that analog 9 inhibited the proliferation of HeLa cells. By using DNA content analysis, we found that analog 9 induced sub-G1 and G1 phase arrest in a time-dependent manner. A [3H]-thymidine incorporation assay suggested that analog 9 inhibited DNA replication in HeLa cells. On performing light microscopy, morphological changes such as cellular shrinkage and disruption, which are apoptotic features, were observed in HeLa cells. Annexin V/propidium iodide double staining and rhodamine-123 staining showed that analog 9 induced apoptosis and disrupted the intracellular mitochondrial membrane potential in HeLa cells. The western blot analysis results suggested that analog 9 induced mitochondria-mediated apoptosis. In addition, we have shown that analog 9 may play a role in the Fas signaling apoptotic pathway.

  12. The future of vitamin D analogs

    Directory of Open Access Journals (Sweden)

    Carlien eLeyssens

    2014-04-01

    Full Text Available The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (DaivonexR, which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Omics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 towards S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the

  13. Analogy, higher order thinking, and education.

    Science.gov (United States)

    Richland, Lindsey Engle; Simms, Nina

    2015-01-01

    Analogical reasoning, the ability to understand phenomena as systems of structured relationships that can be aligned, compared, and mapped together, plays a fundamental role in the technology rich, increasingly globalized educational climate of the 21st century. Flexible, conceptual thinking is prioritized in this view of education, and schools are emphasizing 'higher order thinking', rather than memorization of a cannon of key topics. The lack of a cognitively grounded definition for higher order thinking, however, has led to a field of research and practice with little coherence across domains or connection to the large body of cognitive science research on thinking. We review literature on analogy and disciplinary higher order thinking to propose that relational reasoning can be productively considered the cognitive underpinning of higher order thinking. We highlight the utility of this framework for developing insights into practice through a review of mathematics, science, and history educational contexts. In these disciplines, analogy is essential to developing expert-like disciplinary knowledge in which concepts are understood to be systems of relationships that can be connected and flexibly manipulated. At the same time, analogies in education require explicit support to ensure that learners notice the relevance of relational thinking, have adequate processing resources available to mentally hold and manipulate relations, and are able to recognize both the similarities and differences when drawing analogies between systems of relationships.

  14. Analog forecasting with dynamics-adapted kernels

    Science.gov (United States)

    Zhao, Zhizhen; Giannakis, Dimitrios

    2016-09-01

    Analog forecasting is a nonparametric technique introduced by Lorenz in 1969 which predicts the evolution of states of a dynamical system (or observables defined on the states) by following the evolution of the sample in a historical record of observations which most closely resembles the current initial data. Here, we introduce a suite of forecasting methods which improve traditional analog forecasting by combining ideas from kernel methods developed in harmonic analysis and machine learning and state-space reconstruction for dynamical systems. A key ingredient of our approach is to replace single-analog forecasting with weighted ensembles of analogs constructed using local similarity kernels. The kernels used here employ a number of dynamics-dependent features designed to improve forecast skill, including Takens’ delay-coordinate maps (to recover information in the initial data lost through partial observations) and a directional dependence on the dynamical vector field generating the data. Mathematically, our approach is closely related to kernel methods for out-of-sample extension of functions, and we discuss alternative strategies based on the Nyström method and the multiscale Laplacian pyramids technique. We illustrate these techniques in applications to forecasting in a low-order deterministic model for atmospheric dynamics with chaotic metastability, and interannual-scale forecasting in the North Pacific sector of a comprehensive climate model. We find that forecasts based on kernel-weighted ensembles have significantly higher skill than the conventional approach following a single analog.

  15. Magnetic activity of seismic solar analogs

    CERN Document Server

    Salabert, D

    2016-01-01

    We present our latest results on the solar-stellar connection by studying 18 solar analogs that we identified among the Kepler seismic sample (Salabert et al., 2016a). We measured their magnetic activity properties using observations collected by the Kepler satellite and the ground-based, high-resolution Hermes spectrograph. The photospheric (Sph) and chromospheric (S) magnetic activity proxies of these seismic solar analogs are compared in relation to solar activity. We show that the activity of the Sun is actually comparable to the activity of the seismic solar analogs. Furthermore, we report on the discovery of temporal variability in the acoustic frequencies of the young (1 Gyr-old) solar analog KIC10644253 with a modulation of about 1.5 years, which agrees with the derived photospheric activity (Salabert et al., 2016b). It could actually be the signature of the short-period modulation, or quasi-biennal oscillation, of its magnetic activity as observed in the Sun and the 1-Gyr-old solar analog HD30495. In...

  16. Not All Analogies Are Created Equal: Associative and Categorical Analogy Processing following Brain Damage

    Science.gov (United States)

    Schmidt, Gwenda L.; Cardillo, Eileen R.; Kranjec, Alexander; Lehet, Matthew; Widick, Page; Chatterjee, Anjan

    2012-01-01

    Current research on analogy processing assumes that different conceptual relations are treated similarly. However, just as words and concepts are related in distinct ways, different kinds of analogies may employ distinct types of relationships. An important distinction in how words are related is the difference between associative (dog-bone) and…

  17. Not All Analogies Are Created Equal: Associative and Categorical Analogy Processing following Brain Damage

    Science.gov (United States)

    Schmidt, Gwenda L.; Cardillo, Eileen R.; Kranjec, Alexander; Lehet, Matthew; Widick, Page; Chatterjee, Anjan

    2012-01-01

    Current research on analogy processing assumes that different conceptual relations are treated similarly. However, just as words and concepts are related in distinct ways, different kinds of analogies may employ distinct types of relationships. An important distinction in how words are related is the difference between associative (dog-bone) and…

  18. Analogy-Enhanced Instruction: Effects on Reasoning Skills in Science

    Science.gov (United States)

    Remigio, Krisette B.; Yangco, Rosanelia T.; Espinosa, Allen A.

    2014-01-01

    The study examined the reasoning skills of first year high school students after learning general science concepts through analogies. Two intact heterogeneous sections were randomly assigned to Analogy-Enhanced Instruction (AEI) group and Non Analogy-Enhanced (NAEI) group. Various analogies were incorporated in the lessons of the AEI group for…

  19. Value and Limitations of Analogs in Teaching Mathematics.

    Science.gov (United States)

    Halford, Graeme S.; Boulton-Lewis, Gillian M.

    Analogical reasoning is frequently used in acquisition of mathematical concepts. Concrete representations used to teach mathematics are essentially analogs of mathematical concepts, and it is argued that analogies enter into mathematical concept acquisition in numerous other ways as well. According to Gentner's theory, analogies entail a…

  20. Analog Module Placement Design Using Genetic Algorithm

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    This paper presents a novel genetic algorithm for analog module placement based on ageneralization of the two-dimensional bin packing problem. The genetic encoding and operators assure that allproblem constraints are always satisfied. Thus the potential problems of adding penalty terms to the costfunction are eliminated so that the search configuration space is drastically decreased. The dedicated costfunction is based on the special requirements of analog integrated circuits. A fractional factorial experimentwas conducted using an orthogonal array to study the algorithm parameters. A meta GA was applied todetermine the optimal parameter values. The algorithm was tested with several local benchmark circuits. Theexperimental results show that the algorithm has better performance than the simulated annealing approachwith satisfactory results comparable to manual placement. This study demonstrates the effectiveness of thegenetic algorithm in the analog module placement problem. The algorithm has been successfully used in alayout synthesis tool.

  1. Chemical synthesis of dinucleotide cap analogs.

    Science.gov (United States)

    Kore, Anilkumar R; Shanmugasundaram, Muthian

    2014-12-19

    This unit describes a reliable, efficient and general method for the synthesis of standard cap analog (mCAP), m(7)G[5']ppp[5']G, and anti-reverse cap analog (ARCA), m(7,3')(O)G[5']ppp[5']G. The synthesis of required intermediate m(7)GDP or m(2)(7,3'O)GDP has been achieved through regioselective methylation of the corresponding diphosphate using dimethyl sulfate under aqueous conditions. Then, the coupling reaction of m(7)GDP or m(2)(7,3'O)GDP with ImGMP using ZnCl(2)/DMF system affords the corresponding cap analog in good yields. Copyright © 2014 John Wiley & Sons, Inc.

  2. On Lovelock analogs of the Riemann tensor

    Energy Technology Data Exchange (ETDEWEB)

    Camanho, Xian O. [Albert-Einstein-Institut, Max-Planck-Institut fuer Gravitationsphysik, Golm (Germany); Dadhich, Naresh [Jamia Millia Islamia, Centre for Theoretical Physics, New Delhi (India); Inter-University Centre for Astronomy and Astrophysics, Pune (India)

    2016-03-15

    It is possible to define an analog of the Riemann tensor for Nth order Lovelock gravity, its characterizing property being that the trace of its Bianchi derivative yields the corresponding analog of the Einstein tensor. Interestingly there exist two parallel but distinct such analogs and the main purpose of this note is to reconcile both formulations. In addition we will introduce a simple tensor identity and use it to show that any pure Lovelock vacuum in odd d = 2N + 1 dimensions is Lovelock flat, i.e. any vacuum solution of the theory has vanishing Lovelock-Riemann tensor. Further, in the presence of cosmological constant it is the Lovelock-Weyl tensor that vanishes. (orig.)

  3. Formal analogies in physics teacher education

    DEFF Research Database (Denmark)

    Avelar Sotomaior Karam, Ricardo; Ricardo, Elio

    2012-01-01

    the relevance of the subject, formal analogies are rarely systematically approached in physics education. In order to discuss this issue with pre-service physics teachers, we planned a lecture and designed a questionnaire with the goal of encouraging them to think about some “coincidences” in well known......Reasoning by similarities, especially the ones associated with formal aspects, is one of the most valuable sources for the development of physical theories. The essential role of formal analogies in science can be highlighted by the fact that several equations for different physical situations have...... the exact same appearance. Coulomb’s law’s similarity with Newton’s, Maxwell’s application of fluid theory to electromagnetism and Hamilton’s optical mechanical analogy are some among many other examples. These cases illustrate the power of mathematics in providing unifying structures for physics. Despite...

  4. Analog Forecasting with Dynamics-Adapted Kernels

    CERN Document Server

    Zhao, Zhizhen

    2014-01-01

    Analog forecasting is a non-parametric technique introduced by Lorenz in 1969 which predicts the evolution of states of a dynamical system (or observables defined on the states) by following the evolution of the sample in a historical record of observations which most closely resembles the current initial data. Here, we introduce a suite of forecasting methods which improve traditional analog forecasting by combining ideas from state-space reconstruction for dynamical systems and kernel methods developed in harmonic analysis and machine learning. The first improvement is to augment the dimension of the initial data using Takens' delay-coordinate maps to recover information in the initial data lost through partial observations. Then, instead of using Euclidean distances between the states, weighted ensembles of analogs are constructed according to similarity kernels in delay-coordinate space, featuring an explicit dependence on the dynamical vector field generating the data. The eigenvalues and eigenfunctions ...

  5. Electronic devices for analog signal processing

    CERN Document Server

    Rybin, Yu K

    2012-01-01

    Electronic Devices for Analog Signal Processing is intended for engineers and post graduates and considers electronic devices applied to process analog signals in instrument making, automation, measurements, and other branches of technology. They perform various transformations of electrical signals: scaling, integration, logarithming, etc. The need in their deeper study is caused, on the one hand, by the extension of the forms of the input signal and increasing accuracy and performance of such devices, and on the other hand, new devices constantly emerge and are already widely used in practice, but no information about them are written in books on electronics. The basic approach of presenting the material in Electronic Devices for Analog Signal Processing can be formulated as follows: the study with help from self-education. While divided into seven chapters, each chapter contains theoretical material, examples of practical problems, questions and tests. The most difficult questions are marked by a diamon...

  6. Formal analogies in physics teacher education

    DEFF Research Database (Denmark)

    Avelar Sotomaior Karam, Ricardo; Ricardo, Elio

    2012-01-01

    the relevance of the subject, formal analogies are rarely systematically approached in physics education. In order to discuss this issue with pre-service physics teachers, we planned a lecture and designed a questionnaire with the goal of encouraging them to think about some “coincidences” in well known......Reasoning by similarities, especially the ones associated with formal aspects, is one of the most valuable sources for the development of physical theories. The essential role of formal analogies in science can be highlighted by the fact that several equations for different physical situations have...... the exact same appearance. Coulomb’s law’s similarity with Newton’s, Maxwell’s application of fluid theory to electromagnetism and Hamilton’s optical mechanical analogy are some among many other examples. These cases illustrate the power of mathematics in providing unifying structures for physics. Despite...

  7. Changes in analogical reasoning in adulthood.

    Science.gov (United States)

    Clark, E; Gardner, M K; Brown, G; Howell, R J

    1990-01-01

    This study sought to investigate adult intellectual development through an analysis of a particular type of cognitive ability, verbal analogical reasoning. The performance of 60 individuals between the ages of 20 and 79 was compared on 100 verbal analogies. The subjects consisted of six groups of ten individuals each (five males and five females), matched as a group for education and gender. Solution times and error rates served as the dependent measures. Results showed that there was a significant trend for the older subjects (60- and 70-year-olds) to be slower than the young subjects (20-, 30-, 40-, and 50-year-olds), but not necessarily more error prone. These data suggest that verbal analogical reasoning changes with age. Supplemental data demonstrated a change in other abilities as well (i.e., decline in perceptual-motor speed and spatial skill).

  8. SUPPLEMENTATION OF PATIENTS WITH HOMOZYGOUS SICKLE-CELL DISEASE WITH ZINC, ALPHA-TOCOPHEROL, VITAMIN-C, SOYBEAN OIL, AND FISH OIL

    NARCIS (Netherlands)

    MUSKIET, FAJ; MUSKIET, FD; MEIBORG, G; SCHERMER, JG

    1991-01-01

    Thirteen patients (aged 0.7-17.9 y) with homozygous sickle cell disease were supplemented with alpha-tocopherol, vitamin C, zinc, and soybean oil (suppl 1; for 8 mo) and alpha-tocopherol, vitamin C, and fish oil (suppl 2; for 7 mo). Urinary zinc (suppl 1), plasma vitamin C, plasma cholesterol ester

  9. Non-invasive detection of aortic and coronary atherosclerosis in homozygous familial hypercholesterolemia by 64 slice multi-detector row computed tomography angiography

    Science.gov (United States)

    Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by the early onset of atherosclerosis, often at the ostia of coronary arteries. In this study we document for the first time that aortic and coronary atherosclerosis can be detected using 64 slice multiple detector row ...

  10. Risk of Recurrent Venous Thrombosis in Homozygous Carriers and Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A

    NARCIS (Netherlands)

    Lijfering, Willem M.; Middeldorp, Saskia; Veeger, Nic J. G. M.; Hamulyak, Karly; Prins, Martin H.; Bueller, Harry R.; van der Meer, Jan

    2010-01-01

    Background-Homozygous or double heterozygous factor V Leiden and/or prothrombin G20210A is a rare inherited thrombophilic trait. Whether individuals with this genetic background have an increased risk of recurrent venous thrombosis is uncertain. Methods and Results-A case-control design within a lar

  11. A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

    DEFF Research Database (Denmark)

    Zazo Seco, Celia; Castells-Nobau, Anna; Joo, Seol-Hee

    2017-01-01

    A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous...

  12. Principles for Integrating Mars Analog Science, Operations, and Technology Research

    Science.gov (United States)

    Clancey, William J.

    2003-01-01

    During the Apollo program, the scientific community and NASA used terrestrial analog sites for understanding planetary features and for training astronauts to be scientists. Human factors studies (Harrison, Clearwater, & McKay 1991; Stuster 1996) have focused on the effects of isolation in extreme environments. More recently, with the advent of wireless computing, we have prototyped advanced EVA technologies for navigation, scheduling, and science data logging (Clancey 2002b; Clancey et al., in press). Combining these interests in a single expedition enables tremendous synergy and authenticity, as pioneered by Pascal Lee's Haughton-Mars Project (Lee 2001; Clancey 2000a) and the Mars Society s research stations on a crater rim on Devon Island in the High Canadian Arctic (Clancey 2000b; 2001b) and the Morrison Formation of southeast Utah (Clancey 2002a). Based on this experience, the following principles are proposed for conducting an integrated science, operations, and technology research program at analog sites: 1) Authentic work; 2) PI-based projects; 3) Unencumbered baseline studies; 4) Closed simulations; and 5) Observation and documentation. Following these principles, we have been integrating field science, operations research, and technology development at analog sites on Devon Island and in Utah over the past five years. Analytic methods include work practice simulation (Clancey 2002c; Sierhuis et a]., 2000a;b), by which the interaction of human behavior, facilities, geography, tools, and procedures are formalized in computer models. These models are then converted into the runtime EVA system we call mobile agents (Clancey 2002b; Clancey et al., in press). Furthermore, we have found that the Apollo Lunar Surface Journal (Jones, 1999) provides a vast repository or understanding astronaut and CapCom interactions, serving as a baseline for Mars operations and quickly highlighting opportunities for computer automation (Clancey, in press).

  13. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function.

    Science.gov (United States)

    Liu, Yaobin; Huang, Xiangao; He, Xian; Zhou, Yanqing; Jiang, Xiaogang; Chen-Kiang, Selina; Jaffrey, Samie R; Xu, Guoqiang

    2015-12-01

    The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin-4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48-linked polyubiquitin chains and that thalidomide blocks the formation of CRBN-ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 μM) and its structural analog lenalidomide (10 μM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins.

  14. Association between acquired uniparental disomy and homozygous mutations and HER2/ER/PR status in breast cancer.

    Directory of Open Access Journals (Sweden)

    Musaffe Tuna

    Full Text Available BACKGROUND: Genetic alterations in cellular signaling networks are a hallmark of cancer, however, effective methods to discover them are lacking. A novel form of abnormality called acquired uniparental disomy (aUPD was recently found to pinpoint the region of mutated genes in various cancers, thereby identifying the region for next-generation sequencing. METHODS/PRINCIPAL FINDINGS: We retrieved large genomic data sets from the Gene Expression Omnibus database to perform genome-wide analysis of aUPD in breast tumor samples and cell lines using approaches that can reliably detect aUPD. aUPD was identified in 52.29% of the tumor samples. The most frequent aUPD regions were located at chromosomes 2q, 3p, 5q, 9p, 9q, 10q, 11q, 13q, 14q and 17q. We evaluated the data for any correlation between the most frequent aUPD regions and HER2/neu, ER, and PR status, and found a statistically significant correlation between the recurrent regions of aUPD and triple negative (TN breast cancers. aUPD at chromosome 17q (VEZF1, WNT3, 3p (SUMF1, GRM7, 9p (MTAP, NFIB and 11q (CASP1, CASP4, CASP5 are predictors for TN. The frequency of aUPD was found to be significantly higher in TN breast cancer cases compared to HER2/neu-positive and/or ER or PR-positive cases. Furthermore, using previously published mutation data, we found TP53 homozygously mutated in cell lines having aUPD in that locus. CONCLUSIONS/SIGNIFICANCE: We conclude that aUPD is a common and non-random molecular feature of breast cancer that is most prominent in triple negative cases. As aUPD regions are different among the main pathological subtypes, specific aUPD regions may aid the sub-classification of breast cancer. In addition, we provide statistical support using TP53 as an example that identifying aUPD regions can be an effective approach in finding aberrant genes. We thus conclude that a genome-wide scale analysis of aUPD regions for homozygous sequence alterations can provide valuable insights

  15. Haematological values in homozygous sickle cell disease in steady state and haemoglobin phenotypes AA controls in Lagos, Nigeria

    Directory of Open Access Journals (Sweden)

    Akinbami Akinsegun

    2012-08-01

    Full Text Available Abstract Background Sickle cell disease is a genetic abnormality involving the haemoglobin. Although, it is primarily a red cell disorders, the white blood cells and platelets are also affected by the mutation. The consequent haemoglobin S causes polymerization of haemoglobin resulting in haemolysis and anaemia. This study aims to provide baseline haematological values in sickle cell disease patients in steady state and compare the deviation from haemoglobin phenotype AA control values. Methods A case–control study was conducted amongst homozygous sickle cell patients attending the sickle cell clinics of Lagos State University Teaching Hospital Ikeja and haemoglobin phenotype AA controls. About 4.5mls of blood sample was collected from each participant for full blood count analysis. All blood samples were screened for HIV and haemoglobin phenotypes confirmed using cellulose acetate haemoglobin electrophoresis at pH 8.6. Results A total of 103 cases and 98 controls were enrolled. The overall mean haemoglobin concentration for cases was 7.93 ± 1.47 g/dl, packed cell volume 24.44 ± 4.68%, mean cell volume 81.52 ± 7.89 fl, and mean cell haemoglobin 26.50 ± 3.20 pg. While for controls, mean haemoglobin concentration was 13.83 ± 1.32 g/dl, packed cell volume 43.07 ± 3.95%, mean cell volume 86.90 ± 4.69 fl, and mean cell haemoglobin 28.50 ± 1.34 pg. The overall mean white blood cell counts for the cases was 10.27 ± 3.94 *103/μl and platelet counts of 412.71 ± 145.09*103/μl. While white blood cell count for the controls was 5.67 ± 1.59*103/μl and platelet counts of 222.82 ± 57.62*103/μl. Conclusion Homozygous sickle cell disease patients have lower values of red cell parameters, but higher values of white cell and platelets counts compared to haemoglobin phenotype AA controls.

  16. Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

    Directory of Open Access Journals (Sweden)

    Eduardo Fernández-Martínez

    2016-10-01

    Full Text Available Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4 inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido-3-(3,4-dimethoxyphenyl-propanoate (4NO2PDPMe and methyl 3-(4-aminophthalimido-3-(3,4-dimethoxyphenyl-propanoate (4APDPMe and were compared to rolipram in functional studies of spontaneous phasic, K+-induced tonic, and Ca2+-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC, in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs. Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca2+-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively. Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05 and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

  17. Associative Pattern Recognition In Analog VLSI Circuits

    Science.gov (United States)

    Tawel, Raoul

    1995-01-01

    Winner-take-all circuit selects best-match stored pattern. Prototype cascadable very-large-scale integrated (VLSI) circuit chips built and tested to demonstrate concept of electronic associative pattern recognition. Based on low-power, sub-threshold analog complementary oxide/semiconductor (CMOS) VLSI circuitry, each chip can store 128 sets (vectors) of 16 analog values (vector components), vectors representing known patterns as diverse as spectra, histograms, graphs, or brightnesses of pixels in images. Chips exploit parallel nature of vector quantization architecture to implement highly parallel processing in relatively simple computational cells. Through collective action, cells classify input pattern in fraction of microsecond while consuming power of few microwatts.

  18. Analogy Mapping Development for Learning Programming

    Science.gov (United States)

    Sukamto, R. A.; Prabawa, H. W.; Kurniawati, S.

    2017-02-01

    Programming skill is an important skill for computer science students, whereas nowadays, there many computer science students are lack of skills and information technology knowledges in Indonesia. This is contrary with the implementation of the ASEAN Economic Community (AEC) since the end of 2015 which is the qualified worker needed. This study provided an effort for nailing programming skills by mapping program code to visual analogies as learning media. The developed media was based on state machine and compiler principle and was implemented in C programming language. The state of every basic condition in programming were successful determined as analogy visualization.

  19. Analogies between a Meniscus and a Cantilever

    Institute of Scientific and Technical Information of China (English)

    LIU Jian-Lin

    2009-01-01

    Systematic and quantitative analyses of exact analogies between a meniscus and an elastica are performed. It is shown that the two governing equations take the same style after coordinate translation and scale transformation. The morphologies of the liquid bridge and the cantilever are calculated in terms of elliptic integrations, which can be reduced to the same shape,after converting the boundary conditions. The present analyses can make us grasp the nature of this physical phenomenon deeply and show some inspiration for designing the analogy experiments. Moreover, the calculated results are helpful to engineering applications, such as design and fabrication of MEMS, and micro-manipulations in micro/nano- technology.

  20. Discrete analog computing with rotor-routers.

    Science.gov (United States)

    Propp, James

    2010-09-01

    Rotor-routing is a procedure for routing tokens through a network that can implement certain kinds of computation. These computations are inherently asynchronous (the order in which tokens are routed makes no difference) and distributed (information is spread throughout the system). It is also possible to efficiently check that a computation has been carried out correctly in less time than the computation itself required, provided one has a certificate that can itself be computed by the rotor-router network. Rotor-router networks can be viewed as both discrete analogs of continuous linear systems and deterministic analogs of stochastic processes.