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Sample records for aberrant mtorc1 signaling

  1. The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

    Melnik Bodo C

    2012-08-01

    Full Text Available Abstract Prostate cancer (PCa is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and

  2. The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

    Melnik Bodo C; John Swen; Carrera-Bastos Pedro; Cordain Loren

    2012-01-01

    Abstract Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for ...

  3. Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet.

    Melnik, Bodo

    2012-01-01

    The purpose of this paper is to highlight the endocrine signaling of Western diet, a fundamental environmental factor involved in the pathogenesis of epidemic acne. Western nutrition is characterized by high calorie uptake, high glycemic load, high fat and meat intake, as well as increased consumption of insulin- and IGF-1-level elevating dairy proteins. Metabolic signals of Western diet are sensed by the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), which integrates signals of cellular energy, growth factors (insulin, IGF-1) and protein-derived signals, predominantly leucine, provided in high amounts by milk proteins and meat. mTORC1 activates SREBP, the master transcription factor of lipogenesis. Leucine stimulates mTORC1-SREBP signaling and leucine is directly converted by sebocytes into fatty acids and sterols for sebaceous lipid synthesis. Over-activated mTORC1 increases androgen hormone secretion and most likely amplifies androgen-driven mTORC1 signaling of sebaceous follicles. Testosterone directly activates mTORC1. Future research should investigate the effects of isotretinoin on sebocyte mTORC1 activity. It is conceivable that isotretinoin may downregulate mTORC1 in sebocytes by upregulation of nuclear levels of FoxO1. The role of Western diet in acne can only be fully appreciated when all stimulatory inputs for maximal mTORC1 activation, i.e., glucose, insulin, IGF-1 and leucine, are adequately considered. Epidemic acne has to be recognized as an mTORC1-driven disease of civilization like obesity, type 2 diabetes, cancer and neurodegenerative diseases. These new insights into Western diet-mediated mTORC1-hyperactivity provide a rational basis for dietary intervention in acne by attenuating mTORC1 signaling by reducing (1) total energy intake, (2) hyperglycemic carbohydrates, (3) insulinotropic dairy proteins and (4) leucine-rich meat and dairy proteins. The necessary dietary changes are opposed to the evolution of

  4. Intrahippocampal Glutamine Administration Inhibits mTORC1 Signaling and Impairs Long-Term Memory

    Rozas, Natalia S.; Redell, John B.; Pita-Almenar, Juan D.; McKenna, James, III.; Moore, Anthony N.; Gambello, Michael J.; Dash, Pramod K.

    2015-01-01

    The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum- and amino…

  5. Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos.

    Gürke, Jacqueline; Schindler, Maria; Pendzialek, S Mareike; Thieme, René; Grybel, Katarzyna J; Heller, Regine; Spengler, Katrin; Fleming, Tom P; Fischer, Bernd; Navarrete Santos, Anne

    2016-05-01

    The mammalian target of rapamycin complex 1 (mTORC1) is known to be a central cellular nutrient sensor and master regulator of protein metabolism; therefore, it is indispensable for normal embryonic development. We showed previously in a diabetic pregnancy that embryonic mTORC1 phosphorylation is increased in case of maternal hyperglycaemia and hypoinsulinaemia. Further, the preimplantation embryo is exposed to increased L-leucine levels during a diabetic pregnancy. To understand how mTOR signalling is regulated in preimplantation embryos, we examined consequences of L-leucine and glucose stimulation on mTORC1 signalling and downstream targets in in vitro cultured preimplantation rabbit blastocysts and in vivo. High levels of L-leucine and glucose lead to higher phosphorylation of mTORC1 and its downstream target ribosomal S6 kinase 1 (S6K1) in these embryos. Further, L-leucine supplementation resulted in higher embryonic expression of genes involved in cell cycle (cyclin D1; CCND1), translation initiation (eukaryotic translation initiation factor 4E; EIF4E), amino acid transport (large neutral amino acid transporter 2; Lat2: gene SLC7A8) and proliferation (proliferating cell nuclear antigen; PCNA) in a mTORC1-dependent manner. Phosphorylation of S6K1 and expression patterns of CCND1 and EIF4E were increased in embryos from diabetic rabbits, while the expression of proliferation marker PCNA was decreased. In these embryos, protein synthesis was increased and autophagic activity was decreased. We conclude that mammalian preimplantation embryos sense changes in nutrient supply via mTORC1 signalling. Therefore, mTORC1 may be a decisive mediator of metabolic programming in a diabetic pregnancy. PMID:26836250

  6. Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis

    Fry Christopher S

    2011-03-01

    Full Text Available Abstract Background Sarcopenia, the loss of skeletal muscle mass during aging, increases the risk for falls and dependency. Resistance exercise (RE training is an effective treatment to improve muscle mass and strength in older adults, but aging is associated with a smaller amount of training-induced hypertrophy. This may be due in part to an inability to stimulate muscle-protein synthesis (MPS after an acute bout of RE. We hypothesized that older adults would have impaired mammalian target of rapamycin complex (mTORC1 signaling and MPS response compared with young adults after acute RE. Methods We measured intracellular signaling and MPS in 16 older (mean 70 ± 2 years and 16 younger (27 ± 2 years subjects. Muscle biopsies were sampled at baseline and at 3, 6 and 24 hr after exercise. Phosphorylation of regulatory signaling proteins and MPS were determined on successive muscle biopsies by immunoblotting and stable isotopic tracer techniques, respectively. Results Increased phosphorylation was seen only in the younger group (PP >0.05. After exercise, MPS increased from baseline only in the younger group (PP 0.05. Conclusions We conclude that aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. These age-related differences may contribute to the blunted hypertrophic response seen after resistance-exercise training in older adults, and highlight the mTORC1 pathway as a key therapeutic target to prevent sarcopenia.

  7. Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling

    Drummond, Micah J.; Dreyer, Hans C.; Fry, Christopher S.; Glynn, Erin L.; Rasmussen, Blake B.

    2009-01-01

    In this review we discuss current findings in the human skeletal muscle literature describing the acute influence of nutrients (leucine-enriched essential amino acids in particular) and resistance exercise on muscle protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling. We show that essential amino acids and an acute bout of resistance exercise independently stimulate human skeletal muscle protein synthesis. It also appears that ingestion of essential amino acids fo...

  8. De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy.

    Long, Pamela A; Zimmermann, Michael T; Kim, Maengjo; Evans, Jared M; Xu, Xiaolei; Olson, Timothy M

    2016-08-01

    Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder with variable age-dependent penetrance. We sought to identify the genetic underpinnings of syndromic, sporadic DCM in a newborn female diagnosed in utero. Postnatal evaluation revealed ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms. Comprehensive metabolic and genetic testing, including chromosomal microarray, mitochondrial DNA and targeted RASopathy gene sequencing, and clinical whole exome sequencing for known cardiomyopathy genes was non-diagnostic. Following exclusion of asymptomatic DCM in the parents, trio-based whole exome sequencing was carried out on a research basis, filtering for rare, predicted deleterious de novo and recessive variants. An unreported de novo S75Y mutation was discovered in RRAGC, encoding Ras-related GTP binding C, an essential GTPase in nutrient-activated mechanistic target of rapamycin complex 1 (mTORC1) signaling. In silico protein modeling and molecular dynamics simulation predicted the mutation to disrupt ligand interactions and increase the GDP-bound state. Overexpression of RagC(S75Y) rendered AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC. These findings implicate mTORC1 dysregulation through a gain-of-function mutation in RagC as a novel molecular basis for syndromic forms of pediatric heart failure, and expand genotype-phenotype correlation in RASopathy-related syndromes. PMID:27234373

  9. Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling

    Peng, Min; Yin, Na; Li, Ming O.

    2014-01-01

    Mechanistic target of rapamycin complex 1 (mTORC1) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. Here we show that Sestrins bind to the heterodimeric RagA/B-RagC/D GTPases, and function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B. Sestrin overexpression inhibits amino acid-induced...

  10. Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1

    Watson, Ailsa; Lipina, Christopher; McArdle, Harry J.; Taylor, Peter M.; Hundal, Harinder S.

    2016-01-01

    Iron is an indispensable micronutrient that regulates many aspects of cell function, including growth and proliferation. These processes are critically dependent upon signalling via the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Herein, we test whether iron depletion induced by cell incubation with the iron chelator, deferoxamine (DFO), mediates its effects on cell growth through mTORC1-directed signalling and protein synthesis. We have used Caco-2 cells, a well-established in vitro model of human intestinal epithelia. Iron depletion increased expression of iron-regulated proteins (TfR, transferrin receptor and DMT1, divalent metal transporter, as predicted, but it also promoted a marked reduction in growth and proliferation of Caco-2 cells. This was strongly associated with suppressed mTORC1 signalling, as judged by reduced phosphorylation of mTOR substrates, S6K1 and 4E-BP1, and diminished protein synthesis. The reduction in mTORC1 signalling was tightly coupled with increased expression and accumulation of REDD1 (regulated in DNA damage and development 1) and reduced phosphorylation of Akt and TSC2. The increase in REDD1 abundance was rapidly reversed upon iron repletion of cells but was also attenuated by inhibitors of gene transcription, protein phosphatase 2A (PP2A) and by REDD1 siRNA — strategies that also antagonised the loss in mTORC1 signalling associated with iron depletion. Our findings implicate REDD1 and PP2A as crucial regulators of mTORC1 activity in iron-depleted cells and indicate that their modulation may help mitigate atrophy of the intestinal mucosa that may occur in response to iron deficiency. PMID:26827808

  11. Regulation of mTORC1 signaling by Src kinase activity is Akt1-independent in RSV-transformed cells

    Vojtěchová, Martina; Turečková, Jolana; Kučerová, Dana; Šloncová, Eva; Vachtenheim, J.; Tuháčková, Zdena

    2008-01-01

    Roč. 10, č. 2 (2008), s. 99-107. ISSN 1522-8002 R&D Projects: GA ČR GA301/04/0550 Institutional research plan: CEZ:AV0Z50520514 Keywords : Akt/PKB * mTORC1 signaling pathway * Src Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.191, year: 2008

  12. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.

    Bermudez-Silva, Francisco J; Romero-Zerbo, Silvana Y; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases. PMID:26563389

  13. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice

    Francisco J. Bermudez-Silva

    2016-01-01

    Full Text Available The endocannabinoid system (ECS is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1 signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1 receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6 within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight, which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases.

  14. Selective Activation of mTORC1 Signaling Recapitulates Microcephaly, Tuberous Sclerosis, and Neurodegenerative Diseases

    Hidetoshi Kassai

    2014-06-01

    Full Text Available Mammalian target of rapamycin (mTOR has been implicated in human neurological diseases such as tuberous sclerosis complex (TSC, neurodegeneration, and autism. However, little is known about when and how mTOR is involved in the pathogenesis of these diseases, due to a lack of animal models that directly increase mTOR activity. Here, we generated transgenic mice expressing a gain-of-function mutant of mTOR in the forebrain in a temporally controlled manner. Selective activation of mTORC1 in embryonic stages induced cortical atrophy caused by prominent apoptosis of neuronal progenitors, associated with upregulation of HIF-1α. In striking contrast, activation of the mTORC1 pathway in adulthood resulted in cortical hypertrophy with fatal epileptic seizures, recapitulating human TSC. Activated mTORC1 in the adult cortex also promoted rapid accumulation of cytoplasmic inclusions and activation of microglial cells, indicative of progressive neurodegeneration. Our findings demonstrate that mTORC1 plays different roles in developmental and adult stages and contributes to human neurological diseases.

  15. The Pathogenic Role of Persistent Milk Signaling in mTORC1- and Milk-MicroRNA-Driven Type 2 Diabetes Mellitus

    Melnik, Bodo C

    2015-01-01

    Milk, the secretory product of the lactation genome, promotes growth of the newborn mammal. Milk delivers insulinotropic amino acids, thus maintains a molecular crosstalk with the pancreatic β-cell of the milk recipient. Homeostasis of β-cells and insulin production depend on the appropriate magnitude of mTORC1 signaling. mTORC1 is activated by branched-chain amino acids (BCAAs), glutamine, and palmitic acid, abundant nutrient signals of cow´s milk. Furthermore, milk delivers bioactive exosom...

  16. Amino Acids Attenuate Insulin Action on Gluconeogenesis and Promote Fatty Acid Biosynthesis via mTORC1 Signaling Pathway in trout Hepatocytes

    Weiwei Dai

    2015-06-01

    Full Text Available Background/Aims: Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs-induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway. Methods: We stimulated trout primary hepatocytes with different AA levels and employed acute administration of rapamycin to inhibit mTORC1 activation. Results: Increased AA levels enhanced the phosphorylation of ribosomal protein S6 kinase (S6K1, S6, and insulin receptor substrate 1 (IRS-1 on Ser302 but suppressed Akt and p38 phosphorylation; up-regulated the expression of genes related to gluconeogenesis and fatty acid biosynthesis. mTORC1 inhibition not only inhibited the phosphorylation of mTORC1 downstream targets, but also blunted IRS-1 Ser302 phosphorylation and restored excessive AAs-suppressed Akt phosphorylation. Rapamycin also inhibited fatty acid biosynthetic and gluconeogenic gene expression. Conclusion: High levels of AAs up-regulate hepatic fatty acid biosynthetic gene expression through an mTORC1-dependent manner, while attenuate insulin-mediated repression of gluconeogenesis through elevating IRS-1 Ser302 phosphorylation, which in turn impairs Akt activation and thereby weakening insulin action. We propose that p38 MAPK probably also involves in these AAs-induced metabolic changes.

  17. The pathogenic role of persistent milk signaling in mTORC1- and milk-microRNA-driven type 2 diabetes mellitus.

    Melnik, Bodo C

    2015-01-01

    Milk, the secretory product of the lactation genome, promotes growth of the newborn mammal. Milk delivers insulinotropic amino acids, thus maintains a molecular crosstalk with the pancreatic β-cell of the milk recipient. Homeostasis of β-cells and insulin production depend on the appropriate magnitude of mTORC1 signaling. mTORC1 is activated by branched-chain amino acids (BCAAs), glutamine, and palmitic acid, abundant nutrient signals of cow´s milk. Furthermore, milk delivers bioactive exosomal microRNAs. After milk consumption, bovine microRNA-29b, a member of the diabetogenic microRNA-29- family, reaches the systemic circulation and the cells of the milk consumer. MicroRNA-29b downregulates branchedchain α-ketoacid dehydrogenase, a potential explanation for increased BCAA serum levels, the metabolic signature of insulin resistance and type 2 diabetes mellitus (T2DM). In non-obese diabetic mice, microRNA-29b downregulates the antiapoptotic protein Mcl-1, which leads to early β-cell death. In all mammals except Neolithic humans, milk-driven mTORC1 signaling is physiologically restricted to the postnatal period. In contrast, chronic hyperactivated mTORC1 signaling has been associated with the development of age-related diseases of civilization including T2DM. Notably, chronic hyperactivation of mTORC1 enhances endoplasmic reticulum stress that promotes apoptosis. In fact, hyperactivated β-cell mTORC1 signaling induced early β-cell apoptosis in a mouse model. The EPIC-InterAct Study demonstrated an association between milk consumption and T2DM in France, Italy, United Kingdom, Germany, and Sweden. In contrast, fermented milk products and cheese exhibit an inverse correlation. Since the early 1950´s, refrigeration technology allowed widespread consumption of fresh pasteurized milk, which facilitates daily intake of bioactive bovine microRNAs. Persistent uptake of cow´s milk-derived microRNAs apparently transfers an overlooked epigenetic diabetogenic program

  18. mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress.

    Li, Jing; Shin, Sejeong; Sun, Yang; Yoon, Sang-Oh; Li, Chenggang; Zhang, Erik; Yu, Jane; Zhang, Jianming; Blenis, John

    2016-08-15

    mTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that coinhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816-27. ©2016 AACR. PMID:27197195

  19. Amino acids attenuate insulin action on gluconeogenesis and promote fatty acid biosynthesis via mTORC1 signaling pathway in trout hepatocytes

    Dai, Wei Wei; Panserat, Stephane; Plagnes- Juan, Elisabeth; Seiliez, Iban; Skiba-Cassy, Sandrine

    2015-01-01

    Background/Aims: Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs)-induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway. Methods: We stimulated trout primary hepatocytes with different AA levels and emplo...

  20. Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling

    Glazer, Hilary P.; Osipov, Robert M; Clements, Richard T.; Sellke, Frank W.; Bianchi, Cesario

    2009-01-01

    Nutritional excess and hyperlipidemia increase the heart’s susceptibility to ischemic injury. Mammalian target of rapamycin (mTOR) controls the cellular response to nutritional status and may play a role in ischemic injury. To explore the effect of hypercholesterolemia on cardiac mTOR signaling, we assessed mTOR signaling in hypercholesterolemic swine (HC) that are also susceptible to increased cardiac ischemia-reperfusion injury. Yucatan pigs were fed a high-fat/high-cholesterol diet for 4 w...

  1. Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling.

    Li, Chunying; Reif, Michaella M; Craige, Siobhan M; Kant, Shashi; Keaney, John F

    2016-05-01

    Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5-aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS-null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction. PMID:26989010

  2. The role of amino acid-induced mammalian target of rapamycin complex 1(mTORC1) signaling in insulin resistance.

    Yoon, Mee-Sup; Choi, Cheol Soo

    2016-01-01

    Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance. PMID:27534530

  3. n-3 polyunsaturated fatty acids abrogate mTORC1/2 signaling and inhibit adrenocortical carcinoma growth in vitro and in vivo.

    Liu, Jun; Xu, Meinian; Zhao, Yongbin; Ao, Chunping; Wu, Yukun; Chen, Zhenguo; Wang, Bangqi; Bai, Xiaochun; Li, Ming; Hu, Weilie

    2016-06-01

    n-3 polyunsaturated fatty acids (PUFAs) are essential for human health and have been reported to reduce the risk of cancer, inhibit the growth of various types of tumors both in vitro and in vivo, and affect adrenal function. However, their effects on adrenocortical carcinoma (ACC) are not known. In the present study, we demonstrated that docosahexenoic acid (DHA) inhibited ACC cell proliferation, colony formation and cell cycle progression, and promoted apoptosis. In addition, ectopic expression of fat-1, a desaturase that converts n-6 to n-3 PUFAs endogenously, also inhibited ACC cell proliferation. Moreover, supplementing n-3 PUFAs in the diet efficiently prevented ACC cell growth in xenograft models. Notably, implanted ACC cells were unable to grow in fat-1 transgenic severe combined immune deficiency mice. Further study revealed that exogenous and endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 signaling in ACC in vitro and in vivo. Taken together, our findings provide comprehensive preclinical evidence that n-3 PUFAs efficiently prevent ACC growth by inhibiting mTORC1/2, which may have important implications in the treatment of ACC. PMID:27035283

  4. Concurrent exercise incorporating high-intensity interval or continuous training modulates mTORC1 signaling and microRNA expression in human skeletal muscle.

    Fyfe, Jackson J; Bishop, David J; Zacharewicz, Evelyn; Russell, Aaron P; Stepto, Nigel K

    2016-06-01

    We compared the effects of concurrent exercise, incorporating either high-intensity interval training (HIT) or moderate-intensity continuous training (MICT), on mechanistic target of rapamycin complex 1 (mTORC1) signaling and microRNA expression in skeletal muscle, relative to resistance exercise (RE) alone. Eight males (mean ± SD: age, 27 ± 4 yr; V̇o2 peak , 45.7 ± 9 ml·kg(-1)·min(-1)) performed three experimental trials in a randomized order: 1) RE (8 × 5 leg press repetitions at 80% 1-repetition maximum) performed alone and RE preceded by either 2) HIT cycling [10 × 2 min at 120% lactate threshold (LT); HIT + RE] or 3) work-matched MICT cycling (30 min at 80% LT; MICT + RE). Vastus lateralis muscle biopsies were obtained immediately before RE, either without (REST) or with (POST) preceding endurance exercise and +1 h (RE + 1 h) and +3 h (RE + 3 h) after RE. Prior HIT and MICT similarly reduced muscle glycogen content and increased ACC(Ser79) and p70S6K(Thr389) phosphorylation before subsequent RE (i.e., at POST). Compared with MICT, HIT induced greater mTOR(Ser2448) and rps6(Ser235/236) phosphorylation at POST. RE-induced increases in p70S6K and rps6 phosphorylation were not influenced by prior HIT or MICT; however, mTOR phosphorylation was reduced at RE + 1 h for MICT + RE vs. both HIT + RE and RE. Expression of miR-133a, miR-378, and miR-486 was reduced at RE + 1 h for HIT + RE vs. both MICT + RE and RE. Postexercise mTORC1 signaling following RE is therefore not compromised by prior HIT or MICT, and concurrent exercise incorporating HIT, but not MICT, reduces postexercise expression of miRNAs implicated in skeletal muscle adaptation to RE. PMID:27101297

  5. Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism.

    Santini, Emanuela; Feyder, Michael; Gangarossa, Giuseppe; Bateup, Helen S; Greengard, Paul; Fisone, Gilberto

    2012-08-10

    Dyskinesia, a motor complication caused by prolonged administration of the antiparkinsonian drug l-3,4-dihydroxyphenylalanine (l-DOPA), is accompanied by activation of cAMP signaling and hyperphosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Here, we show that the abnormal phosphorylation of DARPP-32 occurs specifically in medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1R). Using mice in which DARPP-32 is selectively deleted in D1R-expressing MSNs, we demonstrate that this protein is required for l-DOPA-induced activation of the extracellular signal-regulated protein kinases 1 and 2 and the mammalian target of rapamycin complex 1 (mTORC1) pathways, which are implicated in dyskinesia. We also show that mutation of the phosphorylation site for cAMP-dependent protein kinase on DARPP-32 attenuates l-DOPA-induced dyskinesia and reduces the concomitant activations of ERK and mTORC1 signaling. These studies demonstrate that, in D1R-expressing MSNs, l-DOPA-induced activation of ERK and mTORC1 requires DARPP-32 and indicates the importance of the cAMP/DARPP-32 signaling cascade in dyskinesia. PMID:22753408

  6. Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism*

    Santini, Emanuela; Feyder, Michael; Gangarossa, Giuseppe; Bateup, Helen S.; Greengard, Paul; Fisone, Gilberto

    2012-01-01

    Dyskinesia, a motor complication caused by prolonged administration of the antiparkinsonian drug l-3,4-dihydroxyphenylalanine (l-DOPA), is accompanied by activation of cAMP signaling and hyperphosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Here, we show that the abnormal phosphorylation of DARPP-32 occurs specifically in medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1R). Using mice in which DARPP-32 is selectively deleted in D1R-expressing MSNs, we demonstrate that this protein is required for l-DOPA-induced activation of the extracellular signal-regulated protein kinases 1 and 2 and the mammalian target of rapamycin complex 1 (mTORC1) pathways, which are implicated in dyskinesia. We also show that mutation of the phosphorylation site for cAMP-dependent protein kinase on DARPP-32 attenuates l-DOPA-induced dyskinesia and reduces the concomitant activations of ERK and mTORC1 signaling. These studies demonstrate that, in D1R-expressing MSNs, l-DOPA-induced activation of ERK and mTORC1 requires DARPP-32 and indicates the importance of the cAMP/DARPP-32 signaling cascade in dyskinesia. PMID:22753408

  7. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth

    Melnik, Bodo C.; John, Swen Malte; Schmitz, Gerd

    2013-01-01

    Milk has been recognized to represent a functionally active nutrient system promoting neonatal growth of mammals. Cell growth is regulated by the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1). There is still a lack of information on the mechanisms of mTORC1 up-regulation by milk consumption. This review presents milk as a materno-neonatal relay system functioning by transfer of preferential amino acids, which increase plasma levels of glucose-dependent insulinot...

  8. PGE2-induced colon cancer growth is mediated by mTORC1

    Highlights: • PGE2 activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE2 induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE2 induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E2 (PGE2) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE2 directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE2-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE2 increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE2 EP4 receptor was responsible for transducing the signal to mTORC1. Moreover, PGE2 increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE2-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE2 increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE2 mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth

  9. The multifaceted role of mTORC1 in the control of lipid metabolism

    Ricoult, Stéphane J H; Manning, Brendan D.

    2012-01-01

    mTORC1 is emerging as a central regulator of lipid homeostasis. This review discusses the growing evidence for the functional importance of mTORC1 signalling in controlling mammalian lipid synthesis, oxidation, transport, storage and lipolysis, as well as adipocyte differentiation and function.

  10. Radix Astragali Improves Dysregulated Triglyceride Metabolism and Attenuates Macrophage Infiltration in Adipose Tissue in High-Fat Diet-Induced Obese Male Rats through Activating mTORC1-PPARγ Signaling Pathway

    Yang Long

    2014-01-01

    Full Text Available Increased levels of free fatty acids (FFAs and hypertriglyceridemia are important risk factors for cardiovascular disease. The effective fraction isolated from radix astragali (RA has been reported to alleviate hypertriglyceridemia. The mechanism of this triglyceride-lowering effect of RA is unclear. Here, we tested whether activation of the mTORC1-PPARγ signaling pathway is related to the triglyceride-lowering effect of RA. High-fat diet-induced obese (DIO rats were fed a high-fat diet (40% calories from fat for 9-10 weeks, and 4 g/kg/d RA was administered by gavage. RA treatment resulted in decreased fasting triglyceride levels, FFA concentrations, and adipocyte size. RA treated rats showed improved triglyceride clearance and fatty acid handling after olive oil overload. RA administration could also decrease macrophage infiltration and expression of MCP-1 and TNFα, but it may also increase the expression of PPARγ in epididymal adipose tissue from RA treated rats. Consistently, expressions of PPARγ and phospho-p70S6K were increased in differentiated 3T3-L1 adipocytes treated with RA. Moreover, RA couldnot upregulate the expression of PPARγ at the presence of rapamycin. In conclusion, the mTORC1-PPARγ signaling pathway is a potential mechanism through which RA exerts beneficial effects on the disturbance of triglyceride metabolism and dysfunction of adipose tissue in DIO rats.

  11. FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1

    Wu, Xiaochun; Zhao, Lingling; Chen, Zhi; Ji, Xin; Qiao, Xianfeng; Jin, Yaping; Liu, Wei

    2016-01-01

    The intracellular amino acid pool within lysosome is a signal that stimulates the nutrient-sensing mTORC1 signalling pathway. The signal transduction cascade has garnered much attention, but little is known about the sequestration of the signalling molecules within the lysosome. Using human HEK293 cells as a model, we found that suppression of the BHD syndrome gene FLCN reduced the leucine level in lysosome, which correlated with decreased mTORC1 activity. Both consequences could be reversed ...

  12. Milk—A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation

    Bodo C. Melnik

    2015-07-01

    Full Text Available Based on own translational research of the biochemical and hormonal effects of cow’s milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1, the pivotal regulator of translation. Milk, a mammary gland-derived secretory product, is required for species-specific gene-nutrient interactions that promote appropriate growth and development of the newborn mammal. This signaling system is highly conserved and tightly controlled by the lactation genome. Milk is sufficient to activate mTORC1, the crucial regulator of protein, lipid, and nucleotide synthesis orchestrating anabolism, cell growth and proliferation. To fulfill its mTORC1-activating function, milk delivers four key metabolic messengers: (1 essential branched-chain amino acids (BCAAs; (2 glutamine; (3 palmitic acid; and (4 bioactive exosomal microRNAs, which in a synergistical fashion promote mTORC1-dependent translation. In all mammals except Neolithic humans, postnatal activation of mTORC1 by milk intake is restricted to the postnatal lactation period. It is of critical concern that persistent hyperactivation of mTORC1 is associated with aging and the development of age-related disorders such as obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. Persistent mTORC1 activation promotes endoplasmic reticulum (ER stress and drives an aimless quasi-program, which promotes aging and age-related diseases.

  13. mTORC1 Controls PNS Myelination along the mTORC1-RXRγ-SREBP-Lipid Biosynthesis Axis in Schwann Cells

    Camilla Norrmén

    2014-10-01

    Full Text Available Myelin formation during peripheral nervous system (PNS development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1 and 2 (mTORC2, respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs. This course of action is mediated by the nuclear receptor RXRγ, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXRγ-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.

  14. PGE{sub 2}-induced colon cancer growth is mediated by mTORC1

    Dufour, Marc, E-mail: Marc.dufour@chuv.ch; Faes, Seraina, E-mail: Seraina.faes@chuv.ch; Dormond-Meuwly, Anne, E-mail: Anne.meuwly-Dormond@chuv.ch; Demartines, Nicolas, E-mail: Demartines@chuv.ch; Dormond, Olivier, E-mail: Olivier.dormond@chuv.ch

    2014-09-05

    Highlights: • PGE{sub 2} activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE{sub 2} induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE{sub 2} induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E{sub 2} (PGE{sub 2}) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE{sub 2} directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE{sub 2}-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE{sub 2} increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE{sub 2} EP{sub 4} receptor was responsible for transducing the signal to mTORC1. Moreover, PGE{sub 2} increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE{sub 2}-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE{sub 2} increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE{sub 2} mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.

  15. Deficiency in mTORC1-controlled C/EBP beta-mRNA translation improves metabolic health in mice

    Zidek, Laura M.; Ackermann, Tobias; Hartleben, Goetz; Eichwald, Sabrina; Kortman, Gertrud; Kiehntopf, Michael; Leutz, Achim; Sonenberg, Nahum; Wang, Zhao-Qi; von Maltzahn, Julia; Mueller, Christine; Calkhoven, Cornelis F.

    2015-01-01

    The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of physiological adaptations in response to changes in nutrient supply. Major downstream targets of mTORC1 signalling are the mRNA translation regulators p70 ribosomal protein S6 kinase 1 (S6K1p70) and the 4E-binding protein

  16. Sestrin2 inhibits mTORC1 through modulation of GATOR complexes.

    Kim, Jeong Sig; Ro, Seung-Hyun; Kim, Myungjin; Park, Hwan-Woo; Semple, Ian A; Park, Haeli; Cho, Uhn-Soo; Wang, Wei; Guan, Kun-Liang; Karin, Michael; Lee, Jun Hee

    2015-01-01

    Sestrins are stress-inducible metabolic regulators that suppress a wide range of age- and obesity-associated pathologies, many of which are due to mTORC1 overactivation. Upon various stresses, the Sestrins inhibit mTORC1 activity through an indirect mechanism that is still unclear. GATORs are recently identified protein complexes that regulate the activity of RagB, a small GTPase essential for mTORC1 activation. GATOR1 is a GTPase activating protein (GAP) for RagB whereas GATOR2 functions as an inhibitor of GATOR1. However, how the GATORs are physiologically regulated is unknown. Here we show that Sestrin2 binds to GATOR2, and liberates GATOR1 from GATOR2-mediated inhibition. Released GATOR1 subsequently binds to and inactivates RagB, ultimately resulting in mTORC1 suppression. Consistent with this biochemical mechanism, genetic ablation of GATOR1 nullifies the mTORC1-inhibiting effect of Sestrin2 in both cell culture and Drosophila models. Collectively, we elucidate a new signaling cascade composed of Sestrin2-GATOR2-GATOR1-RagB that mediates stress-dependent suppression of mTORC1 activity. PMID:25819761

  17. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin

    Kang, Seong A.; Pacold, Michael E.; Cervantes, Christopher L.; Lim, Daniel; Lou, Hua Jane; Ottina, Kathleen; Gray, Nathanael S.; Turk, Benjamin E.; Yaffe, Michael B.; Sabatini, David M.

    2013-01-01

    The mTOR Complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs lifespan in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals. PMID:23888043

  18. Aberrant Signaling Pathways in Glioma

    Nakada, Mitsutoshi, E-mail: nakada@ns.m.kanazawa-u.ac.jp; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Teng, Lei [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Department of Neurosurgery, The First Clinical College of Harbin Medical University, Nangang, Harbin 150001 (China); Pyko, Ilya V.; Hamada, Jun-Ichiro [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan)

    2011-08-10

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.

  19. Aberrant Signaling Pathways in Glioma

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  20. Aberrant Wnt Signaling in Leukemia.

    Staal, Frank J T; Famili, Farbod; Garcia Perez, Laura; Pike-Overzet, Karin

    2016-01-01

    The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the Wnt pathway for their self-renewal and proliferation. Here we review the multiple ways dysregulated Wnt signaling can contribute to leukemogenesis, both cell autonomously as well as by changes in the microenvironment. PMID:27571104

  1. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

    Pierre Sujobert

    2015-06-01

    Full Text Available AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.

  2. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia.

    Sujobert, Pierre; Poulain, Laury; Paubelle, Etienne; Zylbersztejn, Florence; Grenier, Adrien; Lambert, Mireille; Townsend, Elizabeth C; Brusq, Jean-Marie; Nicodeme, Edwige; Decrooqc, Justine; Nepstad, Ina; Green, Alexa S; Mondesir, Johanna; Hospital, Marie-Anne; Jacque, Nathalie; Christodoulou, Alexandra; Desouza, Tiffany A; Hermine, Olivier; Foretz, Marc; Viollet, Benoit; Lacombe, Catherine; Mayeux, Patrick; Weinstock, David M; Moura, Ivan C; Bouscary, Didier; Tamburini, Jerome

    2015-06-01

    AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. PMID:26004183

  3. The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes

    Highlights: ► p18 is a membrane adaptor that anchors mTORC1 to late endosomes/lysosomes. ► We examine the role of the p18-mTORC1 pathway in lysosome biogenesis. ► The loss of p18 causes accumulation of intact late endosomes by arresting lysosome maturation. ► Inhibition of mTORC1 activity with rapamycin phenocopies the defects of p18 loss. ► The p18-mTORC1 pathway plays crucial roles in the terminal maturation of lysosomes. -- Abstract: The late endosome/lysosome membrane adaptor p18 (or LAMTOR1) serves as an anchor for the mammalian target of rapamycin complex 1 (mTORC1) and is required for its activation on lysosomes. The loss of p18 causes severe defects in cell growth as well as endosome dynamics, including membrane protein transport and lysosome biogenesis. However, the mechanisms underlying these effects on lysosome biogenesis remain unknown. Here, we show that the p18-mTORC1 pathway is crucial for terminal maturation of lysosomes. The loss of p18 causes aberrant intracellular distribution and abnormal sizes of late endosomes/lysosomes and an accumulation of late endosome specific components, including Rab7, RagC, and LAMP1; this suggests that intact late endosomes accumulate in the absence of p18. These defects are phenocopied by inhibiting mTORC1 activity with rapamycin. Loss of p18 also suppresses the integration of late endosomes and lysosomes, resulting in the defective degradation of tracer proteins. These results suggest that the p18-mTORC1 pathway plays crucial roles in the late stages of lysosomal maturation, potentially in late endosome–lysosome fusion, which is required for processing of various macromolecules.

  4. The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes

    Takahashi, Yusuke; Nada, Shigeyuki; Mori, Shunsuke; Soma-Nagae, Taeko; Oneyama, Chitose [Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan); Okada, Masato, E-mail: okadam@biken.osaka-u.ac.jp [Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer p18 is a membrane adaptor that anchors mTORC1 to late endosomes/lysosomes. Black-Right-Pointing-Pointer We examine the role of the p18-mTORC1 pathway in lysosome biogenesis. Black-Right-Pointing-Pointer The loss of p18 causes accumulation of intact late endosomes by arresting lysosome maturation. Black-Right-Pointing-Pointer Inhibition of mTORC1 activity with rapamycin phenocopies the defects of p18 loss. Black-Right-Pointing-Pointer The p18-mTORC1 pathway plays crucial roles in the terminal maturation of lysosomes. -- Abstract: The late endosome/lysosome membrane adaptor p18 (or LAMTOR1) serves as an anchor for the mammalian target of rapamycin complex 1 (mTORC1) and is required for its activation on lysosomes. The loss of p18 causes severe defects in cell growth as well as endosome dynamics, including membrane protein transport and lysosome biogenesis. However, the mechanisms underlying these effects on lysosome biogenesis remain unknown. Here, we show that the p18-mTORC1 pathway is crucial for terminal maturation of lysosomes. The loss of p18 causes aberrant intracellular distribution and abnormal sizes of late endosomes/lysosomes and an accumulation of late endosome specific components, including Rab7, RagC, and LAMP1; this suggests that intact late endosomes accumulate in the absence of p18. These defects are phenocopied by inhibiting mTORC1 activity with rapamycin. Loss of p18 also suppresses the integration of late endosomes and lysosomes, resulting in the defective degradation of tracer proteins. These results suggest that the p18-mTORC1 pathway plays crucial roles in the late stages of lysosomal maturation, potentially in late endosome-lysosome fusion, which is required for processing of various macromolecules.

  5. Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning.

    Liu, Dianxin; Bordicchia, Marica; Zhang, Chaoying; Fang, Huafeng; Wei, Wan; Li, Jian-Liang; Guilherme, Adilson; Guntur, Kalyani; Czech, Michael P; Collins, Sheila

    2016-05-01

    A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through β-adrenergic receptor (βARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor or pharmacologic rapamycin treatment, were refractory to the well-known βAR-dependent increase of uncoupling protein UCP1 expression and expansion of beige/brite adipocytes (so-called browning) in white adipose tissue (WAT). Mechanistically, PKA directly phosphorylated mTOR and RAPTOR on unique serine residues, an effect that was independent of insulin/AKT signaling. Abrogation of the PKA site within RAPTOR disrupted βAR/mTORC1 activation of S6K1 without affecting mTORC1 activation by insulin. Conversely, a phosphomimetic RAPTOR augmented S6K1 activity. Together, these studies reveal a signaling pathway from βARs and PKA through mTORC1 that is required for adipose browning by catecholamines and provides potential therapeutic strategies to enhance energy expenditure and combat metabolic disease. PMID:27018708

  6. Adaptive and aberrant reward prediction signals in the human brain.

    Roiser, J.P.; Stephan, K.E.; Ouden, H.E.M. den; Friston, K.J.; Joyce, E.M.

    2010-01-01

    Theories of the positive symptoms of schizophrenia hypothesize a role for aberrant reinforcement signaling driven by dysregulated dopamine transmission. Recently, we provided evidence of aberrant reward learning in symptomatic, but not asymptomatic patients with schizophrenia, using a novel paradigm

  7. Antagonistic control of muscle cell size by AMPK and mTORC1.

    Mounier, Rémi; Lantier, Louise; Leclerc, Jocelyne; Sotiropoulos, Athanassia; Foretz, Marc; Viollet, Benoit

    2011-08-15

    Nutrition and physical activity have profound effects on skeletal muscle metabolism and growth. Regulation of muscle mass depends on a thin balance between growth-promoting and growth-suppressing factors. Over the past decade, the mammalian target of rapamycin (mTOR) kinase has emerged as an essential factor for muscle growth by mediating the anabolic response to nutrients, insulin, insulin-like growth factors and resistance exercise. As opposed to the mTOR signaling pathway, the AMP-activated protein kinase (AMPK) is switched on during starvation and endurance exercise to upregulate energy-conserving processes. Recent evidence indicates that mTORC1 (mTOR Complex 1) and AMPK represent two antagonistic forces governing muscle adaption to nutrition, starvation and growth stimulation. Animal knockout models with impaired mTORC1 signaling showed decreased muscle mass correlated with increased AMPK activation. Interestingly, AMPK inhibition in p70S6K-deficient muscle cells restores cell growth and sensitivity to nutrients. Conversely, muscle cells lacking AMPK have increased mTORC1 activation with increased cell size and protein synthesis rate. We also demonstrated that the hypertrophic action of MyrAkt is enhanced in AMPK-deficient muscle, indicating that AMPK acts as a negative feedback control to restrain muscle hypertrophy. Our recent results extend this notion by showing that AMPKα1, but not AMPKα2, regulates muscle cell size through the control of mTORC1 signaling. These results reveal the diverse functions of the two catalytic isoforms of AMPK, with AMPKα1 playing a predominant role in the control of muscle cell size and AMPKα2 mediating muscle metabolic adaptation. Thus, the crosstalk between AMPK and mTORC1 signaling is a highly regulated way to control changes in muscle growth and metabolic rate imposed by external cues. PMID:21799304

  8. Impact of mTORC1 Inhibition on Keratinocyte Proliferation During Skin Tumor Promotion in Wild-Type and BK5.AktWT Mice

    Rho, Okkyung; Kiguchi, Kaoru; Jiang, Guiyu; DiGiovanni, John

    2013-01-01

    In this study, we examined the impact of rapamycin on mTORC1 signaling during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocyte proliferation and skin tumor promotion in both wild-type (FVB/N) and BK5.AktWT mice. TPA activated mTORC1 signaling in a time-dependent manner in cultured primary mouse keratinocytes and a mouse keratinocyte cell line. Early activation (15–30 min) of mTORC1 signaling induced by TPA was mediated in part by PKC activation, whereas later activation (2–4 h)...

  9. Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice.

    Magdalon, Juliana; Chimin, Patricia; Belchior, Thiago; Neves, Rodrigo X; Vieira-Lara, Marcel A; Andrade, Maynara L; Farias, Talita S; Bolsoni-Lopes, Andressa; Paschoal, Vivian A; Yamashita, Alex S; Kowaltowski, Alicia J; Festuccia, William T

    2016-05-01

    Mechanistic target of rapamycin complex 1 (mTORC1) loss of function reduces adiposity whereas partial mTORC1 inhibition enhances fat deposition. Herein we evaluated how constitutive mTORC1 activation in adipocytes modulates adiposity in vivo. Mice with constitutive mTORC1 activation in adipocytes induced by tuberous sclerosis complex (Tsc)1 deletion and littermate controls were evaluated for body mass, energy expenditure, glucose and fatty acid metabolism, mitochondrial function, mRNA and protein contents. Adipocyte-specific Tsc1 deletion reduced visceral, but not subcutaneous, fat mass, as well as adipocyte number and diameter, phenotypes that were associated with increased lipolysis, UCP-1 content (browning) and mRNA levels of pro-browning transcriptional factors C/EBPβ and ERRα. Adipocyte Tsc1 deletion enhanced mitochondrial oxidative activity, fatty acid oxidation and the expression of PGC-1α and PPARα in both visceral and subcutaneous fat. In brown adipocytes, however, Tsc1 deletion did not affect UCP-1 content and basal respiration. Adipocyte Tsc1 deletion also reduced visceral adiposity and enhanced glucose tolerance, liver and muscle insulin signaling and adiponectin secretion in mice fed with purified low- or high-fat diet. In conclusion, adipocyte-specific Tsc1 deletion enhances mitochondrial activity, induces browning and reduces visceral adiposity in mice. PMID:26923434

  10. S6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1

    Vered Ben-Hur

    2013-01-01

    Full Text Available Ribosomal S6 kinase 1 (S6K1 is a major mTOR downstream signaling molecule that regulates cell size and translation efficiency. Here, we report that short isoforms of S6K1 are overproduced in breast cancer cell lines and tumors. Overexpression of S6K1 short isoforms induces transformation of human breast epithelial cells. The long S6K1 variant (Iso-1 induced opposite effects. It inhibits Ras-induced transformation and tumor formation, while its knockdown or knockout induces transformation, suggesting that Iso-1 has a tumor-suppressor activity. Furthermore, we found that S6K1 short isoforms bind and activate mTORC1, elevating 4E-BP1 phosphorylation, cap-dependent translation, and Mcl-1 protein levels. Both a phosphorylation-defective 4E-BP1 mutant and the mTORC1 inhibitor rapamycin partially blocked the oncogenic effects of S6K1 short isoforms, suggesting that these are mediated by mTORC1 and 4E-BP1. Thus, alternative splicing of S6K1 acts as a molecular switch in breast cancer cells, elevating oncogenic isoforms that activate mTORC1.

  11. Mouse hippocampal phosphorylation footprint induced by generalized seizures: Focus on ERK, mTORC1 and Akt/GSK-3 pathways.

    Gangarossa, Giuseppe; Sakkaki, Sophie; Lory, Philippe; Valjent, Emmanuel

    2015-12-17

    Exacerbated hippocampal activity has been associated to critical modifications of the intracellular signaling pathways. We have investigated rapid hippocampal adaptive responses induced by maximal electroshock seizure (MES). Here, we demonstrate that abnormal and exacerbated hippocampal activity induced by MES triggers specific and temporally distinct patterns of phosphorylation of extracellular signal-related kinase (ERK), mammalian target of rapamycin complex (mTORC) and Akt/glycogen synthase kinase-3 (Akt/GSK-3) pathways in the mouse hippocampus. While the ERK pathway is transiently activated, the mTORC1 cascade follows a rapid inhibition followed by a transient activation. This rebound of mTORC1 activity leads to the selective phosphorylation of p70S6K, which is accompanied by an enhanced phosphorylation of the ribosomal subunit S6. In contrast, the Akt/GSK-3 pathway is weakly altered. Finally, MES triggers a rapid upregulation of several plasticity-associated genes as a consequence exacerbated hippocampal activity. The results reported in the present study are reminiscent of the one observed in other models of generalized seizures, thus defining a common molecular footprint induced by intense and aberrant hippocampal activities. PMID:26545981

  12. Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells

    Thedieck, Kathrin; Holzwarth, Birgit; Prentzell, Mirja Tamara; Boehlke, Christopher; Klaesener, Kathrin; Ruf, Stefanie; Sonntag, Annika Gwendolin; Maerz, Lars; Grellscheid, Sushma-Nagaraja; Kremmer, Elisabeth; Nitschke, Roland; Kuehn, E. Wolfgang; Jonker, Johan W.; Groen, Albert K.; Reth, Michael; Hall, Michael N.; Baumeister, Ralf

    2013-01-01

    Mammalian target of rapamycin complex 1 (mTORC1) controls growth and survival in response to metabolic cues. Oxidative stress affects mTORC1 via inhibitory and stimulatory inputs. Whereas downregulation of TSC1-TSC2 activates mTORC1 upon oxidative stress, the molecular mechanism of mTORC1 inhibition

  13. Milk—A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation

    Melnik, Bodo C

    2015-01-01

    Based on own translational research of the biochemical and hormonal effects of cow’s milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the pivotal regulator of translation. Milk, a mammary gland-derived secretory product, is required for species-specific gene-nutrient interactions that promote appropriate growth and development of the newborn mammal...

  14. mTORC1 and SIRT1 Cooperate to Foster Expansion of Gut Adult Stem Cells during Calorie Restriction.

    Igarashi, Masaki; Guarente, Leonard

    2016-07-14

    Longevity-promoting caloric restriction is thought to trigger downregulation of mammalian target of rapamycin complex 1 (mTORC1) signaling and upregulation of SIRT1 activity with associated health benefits. Here, we show that mTORC1 signaling in intestinal stem cells (ISCs) is instead upregulated during calorie restriction (CR). SIRT1 deacetylates S6K1, thereby enhancing its phosphorylation by mTORC1, which leads to an increase in protein synthesis and an increase in ISC number. Paneth cells in the ISC niche secrete cyclic ADP ribose that triggers SIRT1 activity and mTORC1 signaling in neighboring ISCs. Notably, the mTOR inhibitor rapamycin, previously reported to mimic effects of CR, abolishes this expansion of ISCs. We suggest that Paneth cell signaling overrides any direct nutrient sensing in ISCs to sculpt the observed response to CR. Moreover, drugs that modulate pathways important in CR may exert opposing effects on different cell types. PMID:27345368

  15. In situ characterization of the mTORC1 during adipogenesis of human adult stem cells on chip.

    Wu, Xuanye; Schneider, Nils; Platen, Alina; Mitra, Indranil; Blazek, Matthias; Zengerle, Roland; Schüle, Roland; Meier, Matthias

    2016-07-19

    Mammalian target of rapamycin (mTOR) is a central kinase integrating nutrient, energy, and metabolite signals. The kinase forms two distinct complexes: mTORC1 and mTORC2. mTORC1 plays an essential but undefined regulatory function for regeneration of adipose tissue. Analysis of mTOR in general is hampered by the complexity of regulatory mechanisms, including protein interactions and/or phosphorylation, in an ever-changing cellular microenvironment. Here, we developed a microfluidic large-scale integration chip platform for culturing and differentiating human adipose-derived stem cells (hASCs) in 128 separated microchambers under standardized nutrient conditions over 3 wk. The progression of the stem cell differentiation was measured by determining the lipid accumulation rates in hASC cultures. For in situ protein analytics, we developed a multiplex in situ proximity ligation assay (mPLA) that can detect mTOR in its two complexes selectively in single cells and implemented it on the same chip. With this combined technology, it was possible to reveal that the mTORC1 is regulated in its abundance, phosphorylation state, and localization in coordination with lysosomes during adipogenesis. High-content image analysis and parameterization of the in situ PLA signals in over 1 million cells cultured on four individual chips showed that mTORC1 and lysosomes are temporally and spatially coordinated but not in its composition during adipogenesis. PMID:27382182

  16. Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade

    Juan F. Linares

    2015-08-01

    Full Text Available The mTORC1 complex is central to the cellular response to changes in nutrient availability. The signaling adaptor p62 contributes to mTORC1 activation in response to amino acids and interacts with TRAF6, which is required for the translocation of mTORC1 to the lysosome and the subsequent K63 polyubiquitination and activation of mTOR. However, the signal initiating these p62-driven processes was previously unknown. Here, we show that p62 is phosphorylated via a cascade that includes MEK3/6 and p38δ and is driven by the PB1-containing kinase MEKK3. This phosphorylation results in the recruitment of TRAF6 to p62, the ubiquitination and activation of mTOR, and the regulation of autophagy and cell proliferation. Genetic inactivation of MEKK3 or p38δ mimics that of p62 in that it leads to inhibited growth of PTEN-deficient prostate organoids. Analysis of human prostate cancer samples showed upregulation of these three components of the pathway, which correlated with enhanced mTORC1 activation.

  17. mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis

    Veronica Costa

    2016-04-01

    Full Text Available Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD, including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2+/− and TSC2−/− neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis.

  18. mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis.

    Costa, Veronica; Aigner, Stefan; Vukcevic, Mirko; Sauter, Evelyn; Behr, Katharina; Ebeling, Martin; Dunkley, Tom; Friedlein, Arno; Zoffmann, Sannah; Meyer, Claas A; Knoflach, Frédéric; Lugert, Sebastian; Patsch, Christoph; Fjeldskaar, Fatiha; Chicha-Gaudimier, Laurie; Kiialainen, Anna; Piraino, Paolo; Bedoucha, Marc; Graf, Martin; Jessberger, Sebastian; Ghosh, Anirvan; Bischofberger, Josef; Jagasia, Ravi

    2016-04-01

    Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2(+/-) and TSC2(-/-) neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis. PMID:27052171

  19. Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1.

    Fumin Dong

    Full Text Available ATP-binding cassette transporter A1 (ABCA1 plays an essential role in mediating cholesterol efflux to apolipoprotein A-I (apoA-I, a major housekeeping mechanism for cellular cholesterol homeostasis. After initial engagement with ABCA1, apoA-I directly interacts with the plasma membrane to acquire cholesterol. This apoA-I lipidation process is also known to require cellular signaling processes, presumably to support cholesterol trafficking to the plasma membrane. We report here that one of major signaling pathways in mammalian cells, Akt, is also involved. In several cell models that express ABCA1 including macrophages, pancreatic beta cells and hepatocytes, inhibition of Akt increases cholesterol efflux to apoA-I. Importantly, Akt inhibition has little effect on cells expressing non-functional mutant of ABCA1, implicating a specific role of Akt in ABCA1 function. Furthermore, we provide evidence that mTORC1, a major downstream target of Akt, is also a negative regulator of cholesterol efflux. In cells where mTORC1 is constitutively activated due to tuberous sclerosis complex 2 deletion, cholesterol efflux to apoA-I is no longer sensitive to Akt activity. This suggests that Akt suppresses cholesterol efflux through mTORC1 activation. Indeed, inhibition of mTORC1 by rapamycin or Torin-1 promotes cholesterol efflux. On the other hand, autophagy, one of the major pathways of cholesterol trafficking, is increased upon Akt inhibition. Furthermore, Akt inhibition disrupts lipid rafts, which is known to promote cholesterol efflux to apoA-I. We therefore conclude that Akt, through its downstream targets, mTORC1 and hence autophagy, negatively regulates cholesterol efflux to apoA-I.

  20. Glucose amplifies fatty acid-induced endoplasmic reticulum stress in pancreatic beta-cells via activation of mTORC1.

    Etti Bachar

    Full Text Available BACKGROUND: Palmitate is a potent inducer of endoplasmic reticulum (ER stress in beta-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic beta-cells, leading to beta-cell dysfunction and death. Why glucose exacerbates beta-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased beta-cell ER stress. PRINCIPAL FINDINGS: We found that glucose amplifies palmitate-induced ER stress by increasing IRE1alpha protein levels and activating the JNK pathway, leading to increased beta-cell apoptosis. Moreover, glucose increased mTORC1 activity and its inhibition by rapamycin decreased beta-cell apoptosis under conditions of glucolipotoxicity. Inhibition of mTORC1 by rapamycin did not affect proinsulin and total protein synthesis in beta-cells incubated at high glucose with palmitate. However, it decreased IRE1alpha expression and signaling and inhibited JNK pathway activation. In TSC2-deficient mouse embryonic fibroblasts, in which mTORC1 is constitutively active, mTORC1 regulated the stimulation of JNK by ER stressors, but not in response to anisomycin, which activates JNK independent of ER stress. Finally, we found that JNK inhibition decreased beta-cell apoptosis under conditions of glucolipotoxicity. CONCLUSIONS/SIGNIFICANCE: Collectively, our findings suggest that mTORC1 mediates glucose amplification of lipotoxicity, acting through activation of ER stress and JNK. Thus, mTORC1 is an important transducer of ER stress in beta-cell glucolipotoxicity. Moreover, in stressed beta-cells mTORC1 inhibition decreases IRE1alpha protein expression and JNK activity without affecting ER protein load, suggesting that mTORC1 regulates the beta-cell stress response to glucose and fatty acids by modulating the synthesis and activity of specific

  1. Glucose addiction of TSC-null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply

    Choo, Andrew Y.; Kim, Sang Gyun; Heiden, Matthew G. Vander; Mahoney, Sarah J.; Vu, Hieu; Yoon, Sang-Oh; Cantley, Lewis C.; Blenis, John

    2010-01-01

    Summary The mTORC1 signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply. PMID:20513425

  2. Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne.

    Melnik, Bodo C; Zouboulis, Christos C

    2013-05-01

    Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization. PMID:23614736

  3. Consequences of Aberrant Hedgehog Signaling During Zebrafish Development

    Koudijs, M.J.

    2007-01-01

    The Hedgehog signaling pathway is controlling proliferation, patterning and differentiation during development of vertebrates and invertebrates. Aberrant Hedgehog activity has been shown to be one of the underlying causes of a number of congenital disorders and multiple types of cancer. We investiga

  4. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.

    Okosun, Jessica; Wolfson, Rachel L; Wang, Jun; Araf, Shamzah; Wilkins, Lucy; Castellano, Brian M; Escudero-Ibarz, Leire; Al Seraihi, Ahad Fahad; Richter, Julia; Bernhart, Stephan H; Efeyan, Alejo; Iqbal, Sameena; Matthews, Janet; Clear, Andrew; Guerra-Assunção, José Afonso; Bödör, Csaba; Quentmeier, Hilmar; Mansbridge, Christopher; Johnson, Peter; Davies, Andrew; Strefford, Jonathan C; Packham, Graham; Barrans, Sharon; Jack, Andrew; Du, Ming-Qing; Calaminici, Maria; Lister, T Andrew; Auer, Rebecca; Montoto, Silvia; Gribben, John G; Siebert, Reiner; Chelala, Claude; Zoncu, Roberto; Sabatini, David M; Fitzgibbon, Jude

    2016-02-01

    Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting. PMID:26691987

  5. Turning acne on/off via mTORC1.

    Danby, F William

    2013-07-01

    Over the past 10 years, the increase in comprehension of the mechanisms behind acne has been truly exponential. Starting with the ethnological work of Cordain, accelerated by the epidemiological work of Adebamowo, supported by the clinical trials of Smith and Mann, Kwon, DiLandro and others, the interface of diet and acne is coming into focus. Melnik now presents an exceptional pair of papers that illustrate for dermatologists what translational research is all about. The Western diet, the role of dairy, FoxO1 and mTORC1, the interplay of agonists and antagonists, therapeutics present and future - the jigsaw puzzle is coming together. PMID:23800069

  6. ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma.

    Neil, Jayson; Shannon, Craig; Mohan, Avinash; Laurent, Dimitri; Murali, Raj; Jhanwar-Uniyal, Meena

    2016-03-01

    The PI3K-AKT-mTOR signaling axis is central to the transformed phenotype of glioblastoma (GBM) cells, due to frequent loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). The mechanistic target of rapamycin (mTOR) kinase is present in two cellular multi-protein complexes, mTORC1 and mTORC2, which have distinct subunit composition, substrates and mechanisms of action. Targeting the mTOR protein is a promising strategy for GBM therapy. However, neither of these complexes is fully inhibited by the allosteric inhibitor of mTOR, rapamycin or its analogs. Herein, we provide evidence that the combined inhibition of mTORC1/2, using the ATP-competitive binding inhibitor PP242, would effectively suppress GBM growth and dissemination as compared to an allosteric binding inhibitor of mTOR. GBM cells treated with PP242 demonstrated significantly decreased activation of mTORC1 and mTORC2, as shown by reduced phosphorylation of their substrate levels, p70 S6KThr389 and AKTSer473, respectively, in a dose-dependent manner. Furthermore, insulin induced activation of these kinases was abrogated by pretreatment with PP242 as compared with rapamycin. Unlike rapamycin, PP242 modestly activates extracellular regulated kinase (ERK1/2), as shown by expression of pERKThr202/Tyr204. Cell proliferation and S-phase entry of GBM cells was significantly suppressed by PP242, which was more pronounced compared to rapamycin treatment. Lastly, PP242 significantly suppressed the migration of GBM cells, which was associated with a change in cellular behavior rather than cytoskeleton loss. In conclusion, these results underscore the potential therapeutic use of the PP242, a novel ATP-competitive binding inhibitor of mTORC1/2 kinase, in suppression of GBM growth and dissemination. PMID:26719046

  7. Improvement of mTORC1-driven overproduction of apoB-containing triacylglyceride-rich lipoproteins by short-chain fatty acids, 4-phenylbutyric acid and (R)-α-lipoic acid, in human hepatocellular carcinoma cells.

    Roberts, Joseph L; He, Bo; Erickson, Anjeza; Moreau, Régis

    2016-03-01

    The activation of hepatic kinase mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the development of obesity-related metabolic disorders. This study investigated the metabolic sequelae of mTORC1 hyperactivation in human hepatoma cells and the lipid-regulating mechanisms of two short-chain fatty acids: 4-phenylbutyric acid (PBA) and (R)-α-lipoic acid (LA). We created three stable cell lines that exhibit low, normal, or high mTORC1 activity. mTORC1 hyperactivation induced the expression of lipogenic (DGAT1 and DGAT2) and lipoprotein assembly (MTP and APOB) genes, thereby raising cellular triacylglyceride (TG) and exacerbating secretion of apoB-containing TG-rich lipoproteins. LYS6K2, a specific inhibitor of the p70 S6 kinase branch of mTORC1 signaling, reversed these effects. PBA and LA decreased secreted TG through distinct mechanisms. PBA repressed apoB expression (both mRNA and protein) and lowered secreted TG without mitigation of mTORC1 hyperactivity or activation of AMPK. LA decreased cellular and secreted TG by attenuating mTORC1 signaling in an AMPK-independent manner. LA did not regulate apoB expression but led to the secretion of apoB-containing TG-poor lipoproteins by repressing the expression of lipogenic genes, FASN, DGAT1, and DGAT2. Our studies provide new mechanistic insight into the hypolipidemic activity of PBA and LA in the context of mTORC1 hyperactivation and suggest that the short-chain fatty acids may aid in the prevention and treatment of hypertriglyceridemia. PMID:26680362

  8. Sestrins Inhibit mTORC1 Kinase Activation through the GATOR Complex

    Anita Parmigiani

    2014-11-01

    Full Text Available The mechanistic target of rapamycin complex 1 (mTORC1 kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition.

  9. Aberrant WNT/β-catenin signaling in parathyroid carcinoma

    Åkerström Göran

    2010-11-01

    Full Text Available Abstract Background Parathyroid carcinoma (PC is a very rare malignancy with a high tendency to recur locally, and recurrent disease is difficult to eradicate. In most western European countries and United States, these malignant neoplasms cause less than 1% of the cases with primary hyperparathyroidism, whereas incidence as high as 5% have been reported from Italy, Japan, and India. The molecular etiology of PC is poorly understood. Results The APC (adenomatous polyposis coli tumor suppressor gene was inactivated by DNA methylation in five analyzed PCs, as determined by RT-PCR, Western blotting, and quantitative bisulfite pyrosequencing analyses. This was accompanied by accumulation of stabilized active nonphosphorylated β-catenin, strongly suggesting aberrant activation of the WNT/β-catenin signaling pathway in these tumors. Treatment of a primary PC cell culture with the DNA hypomethylating agent 5-aza-2'-deoxycytidine (decitabine, Dacogen(r induced APC expression, reduced active nonphosphorylated β-catenin, inhibited cell growth, and caused apoptosis. Conclusion Aberrant WNT/β-catenin signaling by lost expression and DNA methylation of APC, and accumulation of active nonphosphorylated β-catenin was observed in the analyzed PCs. We suggest that adjuvant epigenetic therapy should be considered as an additional option in the treatment of patients with recurrent or metastatic parathyroid carcinoma.

  10. Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

    Pollizzi Kristen

    2009-06-01

    Full Text Available Abstract Background Tuberous sclerosis (TSC is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235. Results Using ENU to enhance Tsc2+- kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week and NVP-BEZ235 (45 mg/kg PO QD had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation. Conclusion Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.

  11. mTORC1 inhibition in the nucleus accumbens 'protects' against the expression of drug seeking and 'relapse' and is associated with reductions in GluA1 AMPAR and CAMKIIα levels.

    James, Morgan H; Quinn, Rikki K; Ong, Lin Kooi; Levi, Emily M; Charnley, Janine L; Smith, Doug W; Dickson, Phillip W; Dayas, Christopher V

    2014-06-01

    The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca(2+)/Calmodulin-dependent kinase II alpha (CAMKIIα) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC1 signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an mTORC1 inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC1 in drug-related behaviors. Here, we examined mTORC1's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORC1 activity and assessing the effect of intra-cerebroventricular rapamycin on these behaviors in rats. We found that withdrawal from cocaine self-administration increased indices of mTORC1 activity in the nucleus accumbens (NAC). Intra-cerebroventricular rapamycin attenuated progressive ratio (PR) break points and reduced phospho-p70 ribosomal S6 kinase, GluA1 AMPAR, and CAMKIIα levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 μg/side/day for 5 days) during cocaine self-administration and then tracked the expression of addiction-relevant behaviors through to withdrawal and extinction. Rapamycin reduced drug seeking in signaled non-drug-available periods, PR responding, and cue-induced reinstatement, with these effects linked to reduced mTORC1 activity, total CAMKIIα, and GluA1 AMPAR levels in the NACsh. Together, these data highlight a role for mTORC1 in the neural processes that control the expression and maintenance of drug reward, including protracted relapse vulnerability. These effects appear to involve a role for mTORC1 in the regulation of GluA1 AMPARs and CAMKIIα in the NACsh. PMID:24469593

  12. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders

    Ryan M Smith

    2011-01-01

    Full Text Available Interactions between presynaptic and postsynaptic cellular adhesion molecules drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of cellular adhesion molecule RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins is associated with disrupted glutamatergic and gamma-aminobutyric acid signaling, resulting in loss of activity-dependent neuronal plasticity, and risk for developmental disorders, including autism. While the majority of genetic mutations currently linked to autism are rare variants that change the protein coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in numerous other diseases, accounting for an estimated 40-60% of general disease risk. Here, we review the relationship between aberrant RNA splicing of synapse-related genes and autism spectrum disorders.

  13. Impact of mTORC1 inhibition on keratinocyte proliferation during skin tumor promotion in wild-type and BK5.AktWT mice.

    Rho, Okkyung; Kiguchi, Kaoru; Jiang, Guiyu; DiGiovanni, John

    2014-11-01

    In this study, we examined the impact of rapamycin on mTORC1 signaling during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocyte proliferation and skin tumor promotion in both wild-type (FVB/N) and BK5.Akt(WT) mice. TPA activated mTORC1 signaling in a time-dependent manner in cultured primary mouse keratinocytes and a mouse keratinocyte cell line. Early activation (15-30 min) of mTORC1 signaling induced by TPA was mediated in part by PKC activation, whereas later activation (2-4 h) was mediated by activation of EGFR and Akt. BK5.Akt(WT) transgenic mice, where Akt1 is overexpressed in basal epidermis, are highly sensitive to TPA-induced epidermal proliferation and two-stage skin carcinogenesis. Targeting mTORC1 with rapamycin effectively inhibited TPA-induced epidermal hyperplasia and hyperproliferation as well as tumor promotion in a dose-dependent manner in both wild-type and BK5.Akt(WT) mice. A significant expansion (∼threefold) of the label retaining cell (LRC) population per hair follicle was observed in BK5.Akt(WT) mice compared to FVB/N mice. There was also a significant increase in K15 expressing cells in the hair follicle of transgenic mice that coincided with expression of phospho-Akt, phospho-S6K, and phospho-PRAS40, suggesting an important role of mTORC1 signaling in bulge-region keratinocyte stem cell (KSC) homeostasis. After 2 weeks of TPA treatment, LRCs had moved upward into the interfollicular epidermis from the bulge region of both wild-type and BK5.Akt(WT) mice. TPA-mediated LRC proliferation and migration was significantly inhibited by rapamycin. Collectively, the current data indicate that signaling through mTORC1 contributes significantly to the process of skin tumor promotion through effects on proliferation of the target cells for tumor development. PMID:24114993

  14. Regulation of bone formation by baicalein via the mTORC1 pathway

    Li SF

    2015-09-01

    Full Text Available Sheng-fa Li,1,2,* Jia-jun Tang,1,2,* Jian Chen,1–3,* Pei Zhang,4,* Ting Wang,5 Tian-yu Chen,1,2 Bo Yan,1,2 Bin Huang,1,2 Liang Wang,1,2 Min-jun Huang,1,2 Zhong-min Zhang,1,2 Da-di Jin1,21Academy of Orthopedics of Guangdong Province, Guangzhou, People’s Republic of China; 2Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Three Gorges Central Hospital of Chongqing, Chongqing, People’s Republic of China; 4School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 5Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workAbstract: Osteoporosis is a systemic skeletal disease that is characterized by low bone density and microarchitectural deterioration of bone tissue. The increasing prevalence of osteoporosis has attracted much attention. In this study, MC3T3-E1 pre-osteoblasts were treated with the natural compound, baicalein (0.1 µmol/L, 1 µmol/L, 10 µmol/L, to stimulate differentiation over a 14-day period. In addition, a canonical ovariectomized (OVX mouse model was used to investigate the effect of 3-month baicalein treatment (10 mg/kg per day in preventing postmenopausal osteoporosis. In vitro, we found that baicalein induced activation of alkaline phosphatase, stimulated the mammalian target of rapamycin complex 1 (mTORC1 signaling pathway, and induced expression of osteoblast differentiation markers, ie, osteocalcin, osterix, collagen Iα1, and runt-related transcription factor 2 (RUNX2, in osteoblasts. In vivo, several bone parameters, including trabecular thickness, trabecular bone mineral density, and trabecular number, in the distal femoral metaphysis were significantly increased in OVX mice treated intragastrically with baicalein for 3 months

  15. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex.

    Pema, Monika; Drusian, Luca; Chiaravalli, Marco; Castelli, Maddalena; Yao, Qin; Ricciardi, Sara; Somlo, Stefan; Qian, Feng; Biffo, Stefano; Boletta, Alessandra

    2016-01-01

    Previous studies report a cross-talk between the polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC) genes. mTOR signalling is upregulated in PKD and rapamycin slows cyst expansion, whereas renal inactivation of the Tsc genes causes cysts. Here we identify a new interplay between the PKD and TSC genes, with important implications for the pathophysiology of both diseases. Kidney-specific inactivation of either Pkd1 or Tsc1 using an identical Cre (KspCre) results in aggressive or very mild PKD, respectively. Unexpectedly, we find that mTORC1 negatively regulates the biogenesis of polycystin-1 (PC-1) and trafficking of the PC-1/2 complex to cilia. Genetic interaction studies reveal an important role for PC-1 downregulation by mTORC1 in the cystogenesis of Tsc1 mutants. Our data potentially explain the severe renal manifestations of the TSC/PKD contiguous gene syndrome and open new perspectives for the use of mTOR inhibitors in autosomal dominant PKD caused by hypomorphic or missense PKD1 mutations. PMID:26931735

  16. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2

    Lan eYe

    2012-09-01

    Full Text Available Rapamycin, an inhibitor of mTOR complex 1 (mTORC1, improves insulin sensitivity in acute studies in vitro and in vivo by disrupting a negative feedback loop mediated by S6 kinase. We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 hours. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Chronic rapamycin treatment may also impair insulin action via the inhibition of mTORC1-dependent mitochondrial biogenesis and activity, which could result in a buildup of lipid intermediates that are known to trigger insulin resistance. We confirmed that rapamycin inhibits expression of PGC-1α, a key mitochondrial transcription factor, and acutely reduces respiration rate in myotubes. However, rapamycin did not stimulate phosphorylation of PKCθ, a central mediator of lipid-induced insulin resistance. Instead, we found dramatic disruption of mTORC2, which coincided with the onset of insulin resistance. Selective inhibition of mTORC1 or mTORC2 by shRNA-mediated knockdown of specific components (Raptor and Rictor, respectively confirmed that mitochondrial effects of rapamycin are mTORC1-dependent, whereas insulin resistance was recapitulated only by knockdown of mTORC2. Thus, mTORC2 disruption, rather than inhibition of mitochondria, causes insulin resistance in rapamycin-treated myotubes, and this system may serve as a useful model to understand the effects of rapamycin on mTOR signaling in vivo.

  17. Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3

    Tsukumo, Yoshinori; Alain, Tommy; Fonseca, Bruno D.; Nadon, Robert; Sonenberg, Nahum

    2016-01-01

    Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1–3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer. PMID:27319316

  18. Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3.

    Tsukumo, Yoshinori; Alain, Tommy; Fonseca, Bruno D; Nadon, Robert; Sonenberg, Nahum

    2016-01-01

    Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1-3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer. PMID:27319316

  19. Caveat mTOR: aberrant signaling disrupts corticogenesis

    Osborne, Lucy R.

    2010-01-01

    The mammalian target of rapamycin (mTOR) signaling pathway is activated in several disorders associated with benign tumors and malformations of the cerebral cortex. In this issue of the JCI, Orlova et al. have now definitively added another disorder to this group by demonstrating that activation of mTOR signaling is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), which is characterized by severe intractable epilepsy and megalencephaly. PMSE is caused ...

  20. Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells.

    Ming Ming

    Full Text Available Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Here, we show that treatment of pancreatic ductal adenocarcinoma (PDAC cells (PANC-1, MiaPaCa-2 with the isoquinoline alkaloid berberine (0.3-6 µM inhibited DNA synthesis and proliferation of these cells and delay the progression of their cell cycle in G1. Berberine treatment also reduced (by 70% the growth of MiaPaCa-2 cell growth when implanted into the flanks of nu/nu mice. Mechanistic studies revealed that berberine decreased mitochondrial membrane potential and intracellular ATP levels and induced potent AMPK activation, as shown by phosphorylation of AMPK α subunit at Thr-172 and acetyl-CoA carboxylase (ACC at Ser79. Furthermore, berberine dose-dependently inhibited mTORC1 (phosphorylation of S6K at Thr389 and S6 at Ser240/244 and ERK activation in PDAC cells stimulated by insulin and neurotensin or fetal bovine serum. Knockdown of α1 and α2 catalytic subunit expression of AMPK reversed the inhibitory effect produced by treatment with low concentrations of berberine on mTORC1, ERK and DNA synthesis in PDAC cells. However, at higher concentrations, berberine inhibited mitogenic signaling (mTORC1 and ERK and DNA synthesis through an AMPK-independent mechanism. Similar results were obtained with metformin used at doses that induced either modest or pronounced reductions in intracellular ATP levels, which were virtually identical to the decreases in ATP levels obtained in response to berberine. We propose that berberine and metformin inhibit mitogenic signaling in PDAC cells through dose-dependent AMPK-dependent and independent pathways.

  1. Potentiation of Growth Inhibitory Responses of the mTOR Inhibitor Everolimus by Dual mTORC1/2 Inhibitors in Cultured Breast Cancer Cell Lines

    Leung, Euphemia Y.; Askarian-Amiri, Marjan; Finlay, Graeme J.; Rewcastle, Gordon W.; Baguley, Bruce C.

    2015-01-01

    The mammalian target of rapamycin (mTOR), a vital component of signaling pathways involving PI3K/AKT, is an attractive therapeutic target in breast cancer. Everolimus, an allosteric mTOR inhibitor that inhibits the mTOR functional complex mTORC1, is approved for treatment of estrogen receptor positive (ER+) breast cancer. Other mTOR inhibitors show interesting differences in target specificities: BEZ235 and GSK2126458 are ATP competitive mTOR inhibitors targeting both PI3K and mTORC1/2; AZD8055, AZD2014 and KU-0063794 are ATP competitive mTOR inhibitors targeting both mTORC1 and mTORC2; and GDC-0941 is a pan-PI3K inhibitor. We have addressed the question of whether mTOR inhibitors may be more effective in combination than singly in inhibiting the proliferation of breast cancer cells. We selected a panel of 30 human breast cancer cell lines that included ER and PR positive, HER2 over-expressing, and “triple negative” variants, and determined whether signaling pathway utilization was related to drug-induced inhibition of proliferation. A significant correlation (p = 0.005) was found between everolimus IC50 values and p70S6K phosphorylation, but not with AKT or ERK phosphorylation, consistent with the mTOR pathway being a principal target. We then carried out combination studies with four everolimus resistant triple-negative breast cancer cell lines, and found an unexpectedly high degree of synergy between everolimus and the other inhibitors tested. The level of potentiation of everolimus inhibitory activity (measured by IC50 values) was found to be cell line-specific for all the kinase inhibitors tested. The results suggest that judicious combination of mTOR inhibitors with different modes of action could have beneficial effects in the treatment of breast cancer. PMID:26148118

  2. Aberrant signaling pathways in medulloblastomas: a stem cell connection

    Carolina Oliveira Rodini

    2010-12-01

    Full Text Available Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

  3. Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo

    The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway

  4. Multi-organ abnormalities and mTORC1 activation in zebrafish model of multiple acyl-CoA dehydrogenase deficiency.

    Seok-Hyung Kim

    2013-06-01

    Full Text Available Multiple Acyl-CoA Dehydrogenase Deficiency (MADD is a severe mitochondrial disorder featuring multi-organ dysfunction. Mutations in either the ETFA, ETFB, and ETFDH genes can cause MADD but very little is known about disease specific mechanisms due to a paucity of animal models. We report a novel zebrafish mutant dark xavier (dxa(vu463 that has an inactivating mutation in the etfa gene. dxa(vu463 recapitulates numerous pathological and biochemical features seen in patients with MADD including brain, liver, and kidney disease. Similar to children with MADD, homozygote mutant dxa(vu463 zebrafish have a spectrum of phenotypes ranging from moderate to severe. Interestingly, excessive maternal feeding significantly exacerbated the phenotype. Homozygous mutant dxa(vu463 zebrafish have swollen and hyperplastic neural progenitor cells, hepatocytes and kidney tubule cells as well as elevations in triacylglycerol, cerebroside sulfate and cholesterol levels. Their mitochondria were also greatly enlarged, lacked normal cristae, and were dysfunctional. We also found increased signaling of the mechanistic target of rapamycin complex 1 (mTORC1 with enlarged cell size and proliferation. Treatment with rapamycin partially reversed these abnormalities. Our results indicate that etfa gene function is remarkably conserved in zebrafish as compared to humans with highly similar pathological, biochemical abnormalities to those reported in children with MADD. Altered mTORC1 signaling and maternal nutritional status may play critical roles in MADD disease progression and suggest novel treatment approaches that may ameliorate disease severity.

  5. Involvement of aberrant calcium signalling in herpetic neuralgia.

    Warwick, Rebekah A; Hanani, Menachem

    2016-03-01

    Alpha-herpesviruses, herpes simplex viruses (HSV) and varicella zoster virus (VZV), are pathogens of the peripheral nervous system. After primary infection, these viruses establish latency within sensory ganglia, while retaining the ability to reactivate. Reactivation of VZV results in herpes zoster, a condition characterized by skin lesions that leads to post-herpetic neuralgia. Recurrent reactivations of HSV, which cause mucocutaneous lesions, may also result in neuralgia. During reactivation of alpha-herpesviruses, satellite glial cells (SGCs), which surround neurons in sensory ganglia, become infected with the replicating virus. SGCs are known to contribute to neuropathic pain in a variety of animal pain models. Here we investigated how infection of short-term cultures of mouse trigeminal ganglia with HSV-1 affects communication between SGCs and neurons, and how this altered communication may increase neuronal excitability, thus contributing to herpetic neuralgia. Mechanical stimulation of single neurons or SGCs resulted in intercellular calcium waves, which were larger in cultures infected with HSV-1. Two differences were observed between control and HSV-1 infected cultures that could account for this augmentation. Firstly, HSV-1 infection induced cell fusion among SGCs and neurons, which would facilitate the spread of calcium signals over farther distances. Secondly, using calcium imaging and intracellular electrical recordings, we found that neurons in the HSV-1 infected cultures exhibited augmented influx of calcium upon depolarization. These virally induced changes may not only cause more neurons in the sensory ganglia to fire action potentials, but may also increase neurotransmitter release at the presynaptic terminals in the spinal cord. They are therefore likely to be contributing factors to herpetic neuralgia. PMID:26684187

  6. Aberrant Wnt/β-catenin signaling can induce chromosomal instability in colon cancer

    Hadjihannas, Michel V; Brückner, Martina; Jerchow, Boris; Birchmeier, Walter; Dietmaier, Wolfgang; Behrens, Jürgen

    2006-01-01

    Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/β-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here w...

  7. La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1)

    Fonseca, Bruno; Zakaria, Chadi; Jia, J J;

    2015-01-01

    -related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation...

  8. ULK1 regulates melanin levels in MNT-1 cells independently of mTORC1.

    Eyal Kalie

    Full Text Available Melanosomes are lysosome-related organelles that serve as specialized sites of melanin synthesis and storage in melanocytes. The progression of melanosomes through the different stages of their formation requires trafficking of specific proteins and membrane constituents in a sequential manner, which is likely to deploy ubiquitous cellular machinery along with melanocyte-specific proteins. Recent evidence revealed a connection between melanogenesis and the autophagy machinery, suggesting a novel role for members of the latter in melanocytes. Here we focused on ULK1, a key autophagy protein which is negatively regulated by mTORC1, to assess its potential role in melanogenesis in MNT-1 cells. We found that ULK1 depletion causes an increase in melanin levels, suggesting an inhibitory function for this protein in melanogenesis. Furthermore, this increase was accompanied by increased transcription of MITF (microphthalmia-associated transcription factor and tyrosinase and by elevated protein levels of tyrosinase, the rate-limiting factor in melanin biogenesis. We also provide evidence to show that ULK1 function in this context is independent of the canonical ULK1 autophagy partners, ATG13 and FIP200. Furthermore we show that regulation of melanogenesis by ULK1 is independent of mTORC1 inhibition. Our data thus provide intriguing insights regarding the involvement of the key regulatory autophagy machinery in melanogenesis.

  9. Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance.

    Bond, Peter

    2016-01-01

    The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) plays a pivotal role in the regulation of skeletal muscle protein synthesis. Activation of the complex leads to phosphorylation of two important sets of substrates, namely eIF4E binding proteins and ribosomal S6 kinases. Phosphorylation of these substrates then leads to an increase in protein synthesis, mainly by enhancing translation initiation. mTORC1 activity is regulated by several inputs, such as growth factors, energy status, amino acids and mechanical stimuli. Research in this field is rapidly evolving and unraveling how these inputs regulate the complex. Therefore this review attempts to provide a brief and up-to-date narrative on the regulation of this marvelous protein complex. Additionally, some sports supplements which have been shown to regulate mTORC1 activity are discussed. PMID:26937223

  10. Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1.

    Paulina Szymańska

    Full Text Available We constructed a mechanistic, computational model for regulation of (macroautophagy and protein synthesis (at the level of translation. The model was formulated to study the system-level consequences of interactions among the following proteins: two key components of MTOR complex 1 (MTORC1, namely the protein kinase MTOR (mechanistic target of rapamycin and the scaffold protein RPTOR; the autophagy-initiating protein kinase ULK1; and the multimeric energy-sensing AMP-activated protein kinase (AMPK. Inputs of the model include intrinsic AMPK kinase activity, which is taken as an adjustable surrogate parameter for cellular energy level or AMP:ATP ratio, and rapamycin dose, which controls MTORC1 activity. Outputs of the model include the phosphorylation level of the translational repressor EIF4EBP1, a substrate of MTORC1, and the phosphorylation level of AMBRA1 (activating molecule in BECN1-regulated autophagy, a substrate of ULK1 critical for autophagosome formation. The model incorporates reciprocal regulation of mTORC1 and ULK1 by AMPK, mutual inhibition of MTORC1 and ULK1, and ULK1-mediated negative feedback regulation of AMPK. Through analysis of the model, we find that these processes may be responsible, depending on conditions, for graded responses to stress inputs, for bistable switching between autophagy and protein synthesis, or relaxation oscillations, comprising alternating periods of autophagy and protein synthesis. A sensitivity analysis indicates that the prediction of oscillatory behavior is robust to changes of the parameter values of the model. The model provides testable predictions about the behavior of the AMPK-MTORC1-ULK1 network, which plays a central role in maintaining cellular energy and nutrient homeostasis.

  11. Mammalian target of rapamycin complex I (mTORC1 activity in ras homologue enriched in brain (Rheb-deficient mouse embryonic fibroblasts.

    Marlous J Groenewoud

    Full Text Available The Ras-like GTPase Rheb has been identified as a crucial activator of mTORC1. Activation most likely requires a direct interaction between Rheb and mTOR, but the exact mechanism remains unclear. Using a panel of Rheb-deficient mouse embryonic fibroblasts (MEFs, we show that Rheb is indeed essential for the rapid increase of mTORC1 activity following stimulation with insulin or amino acids. However, mTORC1 activity is less severely reduced in Rheb-deficient MEFs in the continuous presence of serum or upon stimulation with serum. This remaining mTORC1 activity is blocked by depleting the cells for amino acids or imposing energy stress. In addition, MEK inhibitors and the RSK-inhibitor BI-D1870 interfere in mTORC1 activity, suggesting that RSK acts as a bypass for Rheb in activating mTORC1. Finally, we show that this rapamycin-sensitive, Rheb-independent mTORC1 activity is important for cell cycle progression. In conclusion, whereas rapid adaptation in mTORC1 activity requires Rheb, a second Rheb-independent activation mechanism exists that contributes to cell cycle progression.

  12. A Novel mTORC1-Dependent, Akt-Independent Pathway Differentiates the Gut Tropism of Regulatory and Conventional CD4 T Cells.

    Chen, Leo C; Nicholson, Yawah T; Rosborough, Brian R; Thomson, Angus W; Raimondi, Giorgio

    2016-08-15

    The vitamin A metabolite all-trans retinoic acid (ATRA) induces a gut-homing phenotype in activated CD4(+) conventional T cells (Tconv) by upregulating the integrin α4β7 and the chemokine receptor CCR9. We report that, in contrast to mouse Tconv, only ∼50% of regulatory T cells (Treg) upregulate CCR9 when stimulated by physiological levels of ATRA, even though Tconv and Treg express similar levels of the retinoic acid receptor (RAR). The resulting bimodal CCR9 expression is not associated with differences in the extent of their proliferation, level of Foxp3 expression, or affiliation with naturally occurring Treg or induced Treg in the circulating Treg pool. Furthermore, we find that exposure of Treg to the mechanistic target of rapamycin (mTOR) inhibitor rapamycin suppresses upregulation of both CCR9 and α4β7, an effect that is not evident with Tconv. This suggests that in Treg, ATRA-induced upregulation of CCR9 and α4β7 is dependent on activation of a mTOR signaling pathway. The involvement of mTOR is independent of Akt activity, because specific inhibition of Akt, pyruvate dehydrogenase kinase-1, or its downstream target glycogen synthase kinase-3 did not prevent CCR9 expression. Additionally, Rictor (mTOR complex [mTORC]2)-deficient Treg showed unaltered ability to express CCR9, whereas Raptor (mTORC1)-deficient Treg were unable to upregulate CCR9, suggesting the selective participation of mTORC1. These findings reveal a novel difference between ATRA signaling and chemokine receptor induction in Treg versus Tconv and provide a framework via which the migratory behavior of Treg versus Tconv might be regulated differentially for therapeutic purposes. PMID:27402696

  13. Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion

    Jing Zhou; Shi-Hao Tan; Valérie Nicolas; Chantal Bauvy; Nai-Di Yang; Jianbin Zhang; Yuan Xue

    2013-01-01

    Lysosome is a key subcellular organelle in the execution of the autophagic process and at present little is known whether lysosomal function is controlled in the process of autophagy.In this study,we first found that suppression of mammalian target of rapamycin (mTOR) activity by starvation or two mTOR catalytic inhibitors (PP242 and Torinl),but not by an allosteric inhibitor (rapamycin),leads to activation of lysosomal function.Second,we provided evidence that activation of lysosomal function is associated with the suppression of mTOR complex 1 (mTORC1),but not mTORC2,and the mTORC1 localization to lysosomes is not directly correlated to its regulatory role in lysosomal function.Third,we examined the involvement of transcription factor EB (TFEB) and demonstrated that TFEB activation following mTORC1 suppression is necessary but not sufficient for lysosomal activation.Finally,Atg5 or Atg7deletion or blockage of the autophagosome-lysosome fusion process effectively diminished lysosomal activation,suggesting that lysosomal activation occurring in the course of autophagy is dependent on antophagosome-lysosome fusion.Taken together,this study demonstrates that in the course of autophagy,lysosomal function is upregulated via a dual mechanism involving mTORC1 suppression and autophagosome-lysosome fusion.

  14. Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.

    Shinya Tasaki

    Full Text Available BACKGROUND: Mutation of the epidermal growth factor receptor (EGFR results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling. METHODOLOGY/PRINCIPAL FINDINGS: Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992, one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics. CONCLUSIONS/SIGNIFICANCE: Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.

  15. Hypotaurine evokes a malignant phenotype in glioma through aberrant hypoxic signaling

    Nesvick, Cody L.; Feldman, Michael J.; Sizdahkhani, Saman; Liu, Huailei; Chu, Huiying; Yang, Fengxu; Tang, Ling; Tian, Jing; Zhao, Shiguang; Li, Guohui; Heiss, John D.; Liu, Yang; Zhuang, Zhengping; Xu, Guowang

    2016-01-01

    Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy. PMID:26934654

  16. Suppressors of hedgehog signaling: Linking aberrant development of neural progenitors and tumorigenesis.

    Di Marcotullio, Lucia; Ferretti, Elisabetta; De Smaele, Enrico; Screpanti, Isabella; Gulino, Alberto

    2006-12-01

    Subversion of signals that physiologically suppress Hedgehog pathway results in aberrant neural progenitor development and medulloblastoma, a malignancy of the cerebellum. The Hedgehog antagonist RENKCTD11 maps to chromosome 17p13.2 and is involved in the withdrawal of the Hedgehog signaling at the granule cell progenitor transition from the outer to the inner external germinal layers, thus promoting growth arrest and differentiation. Deletion of chromosome 17p, the most frequent genetic lesion observed in this tumor, is responsible for the loss of function of RENKCTD11, resulting in upregulated Hedgehog signaling and medulloblastoma. Persistence of signals that limit Hedgehog activity is also associated with malignancy. Hedgehog signaling- induced downregulation of ErbB4 receptor expression is attenuated in medulloblastoma subsets in which the extent of Hedgehog pathway activity is limited, thus favoring the accumulation of ErbB4 with imbalanced alternative splice CYT-1 isoform over the CYT-2. This is responsible for both Neuregulin ligand-induced CYT-1-dependent prosurvival activity and loss of CYT-2-mediated growth arrest. PMID:17308352

  17. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK

    Sinnett-Smith, James; Kisfalvi, Krisztina; Kui, Robert [Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, CA (United States); Rozengurt, Enrique, E-mail: erozengurt@mednet.ucla.edu [Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, CA (United States)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Metformin inhibits cancer cell growth but the mechanism(s) are not understood. Black-Right-Pointing-Pointer We show that the potency of metformin is sharply dependent on glucose in the medium. Black-Right-Pointing-Pointer AMPK activation was enhanced in cancer cells incubated in physiological glucose. Black-Right-Pointing-Pointer Reciprocally, metformin potently inhibited mTORC1, DNA synthesis and proliferation. Black-Right-Pointing-Pointer Metformin, at low concentrations, inhibited DNA synthesis through AMPK. -- Abstract: Metformin, a widely used anti-diabetic drug, is emerging as a potential anticancer agent but the mechanisms involved remain incompletely understood. Here, we demonstrate that the potency of metformin induced AMPK activation, as shown by the phosphorylation of its substrates acetyl-CoA carboxylase (ACC) at Ser{sup 79} and Raptor at Ser{sup 792}, was dramatically enhanced in human pancreatic ductal adenocarcinoma (PDAC) cells PANC-1 and MiaPaCa-2 cultured in medium containing physiological concentrations of glucose (5 mM), as compared with parallel cultures in medium with glucose at 25 mM. In physiological glucose, metformin inhibited mTORC1 activation, DNA synthesis and proliferation of PDAC cells stimulated by crosstalk between G protein-coupled receptors and insulin/IGF signaling systems, at concentrations (0.05-0.1 mM) that were 10-100-fold lower than those used in most previous reports. Using siRNA-mediated knockdown of the {alpha}{sub 1} and {alpha}{sub 2} catalytic subunits of AMPK, we demonstrated that metformin, at low concentrations, inhibited DNA synthesis through an AMPK-dependent mechanism. Our results emphasize the importance of using medium containing physiological concentrations of glucose to elucidate the anticancer mechanism of action of metformin in pancreatic cancer cells and other cancer cell types.

  18. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK

    Highlights: ► Metformin inhibits cancer cell growth but the mechanism(s) are not understood. ► We show that the potency of metformin is sharply dependent on glucose in the medium. ► AMPK activation was enhanced in cancer cells incubated in physiological glucose. ► Reciprocally, metformin potently inhibited mTORC1, DNA synthesis and proliferation. ► Metformin, at low concentrations, inhibited DNA synthesis through AMPK. -- Abstract: Metformin, a widely used anti-diabetic drug, is emerging as a potential anticancer agent but the mechanisms involved remain incompletely understood. Here, we demonstrate that the potency of metformin induced AMPK activation, as shown by the phosphorylation of its substrates acetyl-CoA carboxylase (ACC) at Ser79 and Raptor at Ser792, was dramatically enhanced in human pancreatic ductal adenocarcinoma (PDAC) cells PANC-1 and MiaPaCa-2 cultured in medium containing physiological concentrations of glucose (5 mM), as compared with parallel cultures in medium with glucose at 25 mM. In physiological glucose, metformin inhibited mTORC1 activation, DNA synthesis and proliferation of PDAC cells stimulated by crosstalk between G protein-coupled receptors and insulin/IGF signaling systems, at concentrations (0.05–0.1 mM) that were 10–100-fold lower than those used in most previous reports. Using siRNA-mediated knockdown of the α1 and α2 catalytic subunits of AMPK, we demonstrated that metformin, at low concentrations, inhibited DNA synthesis through an AMPK-dependent mechanism. Our results emphasize the importance of using medium containing physiological concentrations of glucose to elucidate the anticancer mechanism of action of metformin in pancreatic cancer cells and other cancer cell types.

  19. Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma

    Blix Egil S

    2012-10-01

    -induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.

  20. The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability

    Chung, Jacky; Bauer, Daniel E.; Ghamari, Alireza; Nizzi, Christopher P.; Deck, Kathryn M.; Kingsley, Paul D.; Yien, Yvette Y.; Huston, Nicholas C.; Chen, Caiyong; Schultz, Iman J.; Dalton, Arthur J.; Wittig, Johannes G.; Palis, James; Orkin, Stuart H.; Lodish, Harvey F.; Eisenstein, Richard S.; Cantor, Alan B.; Paw, Barry H.

    2015-01-01

    In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. Here, we found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mechanistic target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine. PMID:25872869

  1. Regulation of MYC gene expression by aberrant Wnt/β-catenin signaling in colorectal cancer

    Sherri; Rennoll; Gregory; Yochum

    2015-01-01

    The Wnt/β-catenin signaling pathway controls intestinal homeostasis and mutations in components of this pathway are prevalent in human colorectal cancers(CRCs).These mutations lead to inappropriate expression of genes controlled by Wnt responsive DNA elements(WREs). T-cell factor/Lymphoid enhancer factor transcription factors bind WREs and recruit the β-catenin transcriptional co-activator to activate target gene expression. Deregulated expression of the c-MYC proto-oncogene(MYC) by aberrant Wnt/β-catenin signaling drives colorectal carcinogenesis. In this review,we discuss the current literature pertaining to the identification and characterization of WREs that control oncogenic MYC expression in CRCs. A common theme has emerged whereby these WREs often map distally to the MYC genomic locus and control MYC gene expression through long-range chromatin loops with the MYC proximal promoter. We propose that by determining which of these WREs is critical for CRC pathogenesis,novel strategies can be developed to treat individuals suffering from this disease.

  2. Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells

    Marzec, Michal; Liu, Xiaobin; Wysocka, Maria; Rook, Alain H; Ødum, Niels; Wasik, Mariusz A

    2011-01-01

    mTOR kinase forms the mTORC1 complex by associating with raptor and other proteins and affects a number of key cell functions. mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein 1 (4E-BP1). In turn, p70S6K1 phosphorylates a S6 protein of the 40S ribosomal subunit (S6rp) and 4E...

  3. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    Bartkova, J; Hamerlik, P; Stockhausen, Marie;

    2010-01-01

    brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low...... and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.......Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA...

  4. RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes.

    Weinberg, Mark A

    2016-07-01

    RES-529 (previously named Palomid 529, P529) is a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway inhibitor that interferes with the pathway through both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) dissociation. This compound is currently being developed in oncology and ophthalmology. The oncology focus is for the treatment of glioblastoma, where it has received orphan designation by the US Food and Drug Administration, and prostate cancer. We present a review of the PI3K/AKT/mTOR pathway, its role in tumorigenesis, and the potential of RES-529 in cancer treatment. RES-529 inhibits mTORC1/mTORC2 activity in various cancer cell lines, as noted by decreased phosphorylation of substrates including ribosomal protein S6, 4E-BP1, and AKT, leading to cell growth inhibition and death, with activity generally in the range of 5-15 μmol/l. In animal tumor models where the PI3K/AKT/mTOR pathway is abnormally activated (i.e. glioblastoma, prostate cancer, and breast cancer), RES-529 reduces tumor growth by as much as 78%. RES-529 treatment is synergistic with radiation therapy, chemotherapy, and hormonal therapy in reducing tumor growth, potentially by preventing PI3K/AKT/mTOR pathway activation associated with these treatments. Furthermore, this compound has shown antiangiogenic activity in several animal models. mTORC1 and mTORC2 have redundant and distinct activities that contribute toward oncogenesis. Current inhibitors of this pathway have primarily targeted mTORC1, but have shown limited clinical efficacy. Inhibitors of mTORC1 and mTORC2 such as RES-529 may therefore have the potential to overcome the deficiencies found in targeting only mTORC1. PMID:26918392

  5. Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.

    Huynh, Hung; Hao, Huai-Xiang; Chan, Stephen L; Chen, David; Ong, Richard; Soo, Khee Chee; Pochanard, Panisa; Yang, David; Ruddy, David; Liu, Manway; Derti, Adnan; Balak, Marissa N; Palmer, Michael R; Wang, Yan; Lee, Benjamin H; Sellami, Dalila; Zhu, Andrew X; Schlegel, Robert; Huang, Alan

    2015-05-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. PMID:25724664

  6. Aberrant activation of Wnt/β-catenin signaling pathway contributes to the sequential progression of DMBA-induced HBP carcinomas.

    Vidya Priyadarsini, Ramamurthi; Senthil Murugan, Ramalingam; Nagini, Siddavaram

    2012-01-01

    Wnt signaling pathway mediated via interactions between β-catenin and members of the TCF/LEF-1 family of transcription factors plays a central role in the regulation of epithelial cell proliferation, apoptosis, differentiation, adhesion, epithelial-mesenchymal transition, and invasion. Aberrant activation of the Wnt/β-catenin signaling pathway with overexpression of Wnt and Fz, mutations of APC, β-catenin, and axin 1, and cytoplasmic accumulation of β-catenin have been frequently reported in a broad spectrum of human malignancies including oral squamous cell carcinomas (OSCCs). However, changes in the components of the Wnt signaling pathway have not been documented during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis, a paradigm for oral oncogenesis and chemointervention. In this study, we evaluated the role of β-catenin accumulation and Wnt ligands, Wnt signaling members (Fz, Dvl, APC, GSK-3β, axin, and WIF) and the downstream targets of Wnt (cyclin D1, MMP-2, and MMP-9) during the sequential progression of DMBA-induced HBP carcinomas by semi-quantitative RT-PCR and western blot analyses. Our data reveal a correlation between β-catenin accumulation and activation of Wnt signaling, and its downstream effector molecules during the sequential development of HBP carcinomas from hyperplasia to invasive carcinoma through dysplasia. Our data also support a pivotal role for β-catenin in the malignant transition of the HBP. Aberrant Wnt signaling may be a hallmark of progression to malignancy during DMBA-induced HBP carcinogenesis and could be a potential preventive and therapeutic target for suppression of OSCC. PMID:21924667

  7. Dual mTORC1/2 inhibition by INK-128 results in antitumor activity in preclinical models of osteosarcoma.

    Jiang, Haibin; Zeng, Zhiyuan

    Existing evidence has shown that mammalian target of rapamycin (mTOR) overactivation is an important contributor of osteosarcoma (OS) progression. Here, we studied the potential anti-OS activity of a potent mTOR kinase inhibitor: INK-128 (MLN0128). We demonstrated that INK-128 induced potent cytotoxic effects against several human OS cell lines (U2OS, MG-63 and SaOs-2), yet same INK-128 treatment was safe (non-cytotoxic) to OB-6 human osteoblastic cells and MLO-Y4 human osteocytic cells. INK-128 induced caspase-dependent apoptosis in OS cells, but not in MLO-Y4/OB-6 cells. The caspase-3 specific inhibitor (z-DVED-fmk) or the pan caspase inhibitor (z-VAD-fmk) dramatically attenuated INK-128-exerted cytotoxicity against OS cells. Molecularly, INK-128 inhibited activation of mTORC1 (S6K1 and S6 phosphorylations) and mTORC2 (AKT Ser-473 phosphorylation), without affecting AKT Thr-308 phosphorylation in U2OS cells. Significantly, AKT inhibition by MK-2206 (an AKT inhibitor), or AKT1/2 stable knockdown by targeted-shRNA, remarkably sensitized INK-128-induced activity in OS cells. In vivo, oral administration of INK-128 potently inhibited U2OS xenograft growth in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation in xenograft tumors was also suppressed with INK-128 administration. In summary, we show that INK-128 exerts potent anti-OS activity in vitro and in vivo. INK-128 might be further investigated as a novel anti-OS agent. PMID:26514724

  8. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

    Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

    2015-08-15

    Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. PMID:26074264

  9. Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington's Disease.

    Dallérac, Glenn M; Cummings, Damian M; Hirst, Mark C; Milnerwood, Austen J; Murphy, Kerry P S J

    2016-03-01

    Altered dopamine receptor labelling has been demonstrated in presymptomatic and symptomatic Huntington's disease (HD) gene carriers, indicating that alterations in dopaminergic signalling are an early event in HD. We have previously described early alterations in synaptic transmission and plasticity in both the cortex and hippocampus of the R6/1 mouse model of Huntington's disease. Deficits in cortical synaptic plasticity were associated with altered dopaminergic signalling and could be reversed by D1- or D2-like dopamine receptor activation. In light of these findings we here investigated whether defects in dopamine signalling could also contribute to the marked alteration in hippocampal synaptic function. To this end we performed dopamine receptor labelling and pharmacology in the R6/1 hippocampus and report a marked, age-dependent elevation of hippocampal D1 and D2 receptor labelling in R6/1 hippocampal subfields. Yet, pharmacological inhibition or activation of D1- or D2-like receptors did not modify the aberrant synaptic plasticity observed in R6/1 mice. These findings demonstrate that global perturbations to dopamine receptor expression do occur in HD transgenic mice, similarly in HD gene carriers and patients. However, the direction of change and the lack of effect of dopaminergic pharmacological agents on synaptic function demonstrate that the perturbations are heterogeneous and region-specific, a finding that may explain the mixed results of dopamine therapy in HD. PMID:26782175

  10. Leucine signaling in the pathogenesis of type 2 diabetes and obesity

    Bodo C Melnik

    2012-01-01

    Full Text Available Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D. This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1. mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response to glucose, energy, growth factors and amino acids. Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of β-cells. Moreover, leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis, thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis. Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects. Furthermore, bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids. Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine

  11. Aberrant Activation of the RANK Signaling Receptor Induces Murine Salivary Gland Tumors.

    Maria M Szwarc

    Full Text Available Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis and treatment of aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management of malignant salivary gland cancers is undercut by our limited knowledge concerning the key molecular signals that underpin the etiopathogenesis of this rare and heterogeneous head and neck cancer. Without knowledge of the critical signals that drive salivary gland tumorigenesis, tumor vulnerabilities cannot be exploited that allow for targeted molecular therapies. This knowledge insufficiency is further exacerbated by a paucity of preclinical mouse models (as compared to other cancer fields with which to both study salivary gland pathobiology and test novel intervention strategies. Using a mouse transgenic approach, we demonstrate that deregulation of the Receptor Activator of NFkB Ligand (RANKL/RANK signaling axis results in rapid tumor development in all three major salivary glands. In line with its established role in other exocrine gland cancers (i.e., breast cancer, the RANKL/RANK signaling axis elicits an aggressive salivary gland tumor phenotype both at the histologic and molecular level. Despite the ability of this cytokine signaling axis to drive advanced stage disease within a short latency period, early blockade of RANKL/RANK signaling markedly attenuates the development of malignant salivary gland neoplasms. Together, our findings have uncovered a tumorigenic role for RANKL/RANK in the salivary gland and suggest that targeting this pathway may represent a novel therapeutic intervention approach in the prevention and/or treatment of this understudied head and neck cancer.

  12. Antagonistic control of muscle cell size by AMPK and mTORC1.

    Mounier, Rémi; Lantier, Louise; Leclerc, Jocelyne; Sotiropoulos, Athanassia; Foretz, Marc; Viollet, Benoit

    2011-01-01

    Nutrition and physical activity have profound effects on skeletal muscle metabolism and growth. Regulation of muscle mass depends on a thin balance between growth-promoting and growth-suppressing factors. Over the past decade, the mammalian target of rapamycin (mTOR) kinase has emerged as an essential factor for muscle growth by mediating the anabolic response to nutrients, insulin, insulin-like growth factors and resistance exercise. As opposed to the mTOR signaling pathway, the AMP-activate...

  13. A matter of energy stress:p38β meets mTORC1

    Adem Kalender; Anand Selvaraj; George Thomas

    2011-01-01

    @@ Throughout evolution, cells have developed sophisticated signaling mechanisms to balance the production and expenditure of energy to maintain energy homeostasis.During an energy crisis, cells suppress energy consuming anabolic processes and up-regulate basic catabolic routes to maintain the energy currency of the cell, Adenosine Triphosphate (ATP).The main paths of ATP generation are through glycolysis in the cytoplasm and oxidative phosphorylation in mitochondria.

  14. Differential regulation of protein synthesis in skeletal muscle and liver of neonatal pigs by leucine through an mTORC1-dependent pathway.

    Suryawan, Agus; Nguyen, Hanh V; Almonaci, Rosemarie D; Davis, Teresa A

    2012-02-28

    Neonatal growth is characterized by a high protein synthesis rate that is largely due to an enhanced sensitivity to the postprandial rise in insulin and amino acids, especially leucine. The mechanism of leucine's action in vivo is not well understood. In this study, we investigated the effect of leucine infusion on protein synthesis in skeletal muscle and liver of neonatal pigs. To evaluate the mode of action of leucine, we used rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) complex-1 (mTORC1). Overnight-fasted 7-day-old piglets were treated with rapamycin for 1 hour and then infused with leucine (400 μmol·kg(-1)·h(-1)) for 1 hour. Leucine infusion increased the rate of protein synthesis, and ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein-1 (4E-BP1) phosphorylation in gastrocnemius and masseter muscles (P liver. The leucine-induced stimulation of protein synthesis and S6K1 and 4E-BP1 phosphorylation were completely blocked by rapamycin, suggesting that leucine action is by an mTORC1-dependent mechanism. Neither leucine nor rapamycin had any effect on the activation of the upstream mTORC1 regulators, AMP-activated protein kinase and protein kinase B, in skeletal muscle or liver. The activation of eIF2α and elongation factor 2 was not affected by leucine or rapamycin, indicating that these two pathways are not limiting steps of leucine-induced protein synthesis. These results suggest that leucine stimulates muscle protein synthesis in neonatal pigs by inducing the activation of mTORC1 and its downstream pathway leading to mRNA translation. PMID:22675606

  15. Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model.

    Lamming, Dudley W; Cummings, Nicole E; Rastelli, Antonella L; Gao, Feng; Cava, Edda; Bertozzi, Beatrice; Spelta, Francesco; Pili, Roberto; Fontana, Luigi

    2015-10-13

    Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. In this study we compared the effects of PR and IF on tumor growth in a xenograft mouse model of breast cancer. We also investigated the effects of PR and IF on the mechanistic Target Of Rapamycin (mTOR) pathway, inhibition of which extends lifespan in model organisms including mice. The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo. We found that both PR and IF inhibit tumor growth and mTORC1 phosphorylation in tumor xenografts. In somatic tissues, we found that PR, but not IF, selectively inhibits the activity of the amino acid sensitive mTORC1, while the activity of the second mTOR complex, mTORC2, was relatively unaffected by PR. In contrast, IF resulted in increased S6 phosphorylation in multiple metabolic tissues. Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases. PMID:26378060

  16. NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling

    Stančíková, Jitka; Krausová, Michaela; Kolář, Michal; Fafílek, Bohumil; Švec, Jiří; Sedláček, Radislav; Neroldová, M.; Dobeš, Jan; Horázná, Monika; Janečková, Lucie; Vojtěchová, Martina; Oliverius, M.; Jirsa, M.; Kořínek, Vladimír

    2015-01-01

    Roč. 27, č. 2 (2015), s. 245-256. ISSN 1873-3913 R&D Projects: GA ČR GAP305/11/1780; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LM2011032 Institutional support: RVO:68378050 Keywords : Wnt signaling * NKD 1 * Intestine * Liver * Colorectal cancer * Hepatocellular carcinoma Subject RIV: EB - Genetics ; Molecular Biology

  17. Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells.

    Choi, Dongwon; Ramu, Swapnika; Park, Eunkyung; Jung, Eunson; Yang, Sara; Jung, Wonhyeuk; Choi, Inho; Lee, Sunju; Kim, Kyu Eui; Seong, Young Jin; Hong, Mingu; Daghlian, George; Kim, Daniel; Shin, Eugene; Seo, Jung In; Khatchadourian, Vicken; Zou, Mengchen; Li, Wei; De Filippo, Roger; Kokorowski, Paul; Chang, Andy; Kim, Steve; Bertoni, Ana; Furlanetto, Tania Weber; Shin, Sung; Li, Meng; Chen, Yibu; Wong, Alex; Koh, Chester; Geliebter, Jan; Hong, Young-Kwon

    2016-02-01

    Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression. PMID:26609053

  18. Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer's disease

    Riise, Jesper; Plath, Niels; Pakkenberg, Bente;

    2015-01-01

    hippocampus exhibiting most pronounced changes. Furthermore, the Wnt pathway constituents Wnt7b and Tcf7l1/Tcf3 showed overlapping gene expression alterations across both medial temporal lobe structures, while β-catenin was inversely expressed between brain regions. We also identified total protein......-targeted hyperphosphorylation at specific tau epitope in soluble pretangles and prominent tau aggregation exclusively in insoluble neurofibrillary tangles of AD subjects. The Wnt pathway-focused approach confirms altered Wnt signaling in the neurodegenerative AD brain and highlights the potential role of the pathway as a...

  19. Renal Hypodysplasia Associates with a Wnt4 Variant that Causes Aberrant Canonical Wnt Signaling

    Vivante, Asaf; Mark-Danieli, Michal; Davidovits, Miriam; Harari-Steinberg, Orit; Omer, Dorit; Gnatek, Yehudit; Cleper, Roxana; Landau, Daniel; Kovalski, Yael; Weissman, Irit; Eisenstein, Israel; Soudack, Michalle; Wolf, Haike Reznik; Issler, Naomi; Lotan, Danny; Anikster, Yair

    2013-01-01

    Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/β-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia. PMID:23520208

  20. Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men

    Fry, Christopher S.; Glynn, Erin L.; Drummond, Micah J.; Timmerman, Kyle L.; Fujita, Satoshi; Abe, Takashi; Dhanani, Shaheen; Volpi, Elena; Rasmussen, Blake B.

    2010-01-01

    The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, low-intensity RE, combined with blood flow restriction (BFR), has been shown to stimulate mammalian targ...

  1. TGF-{beta}-stimulated aberrant expression of class III {beta}-tubulin via the ERK signaling pathway in cultured retinal pigment epithelial cells

    Chung, Eun Jee [Department of Ophthalmology, National Health Insurance Corporation Ilsan Hospital, Gyeonggi-do (Korea, Republic of); Chun, Ji Na; Jung, Sun-Ah [Konyang University Myunggok Medical Research Institute, Kim' s Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of); Cho, Jin Won [Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Lee, Joon H., E-mail: joonhlee@konyang.ac.kr [Konyang University Myunggok Medical Research Institute, Kim' s Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer TGF-{beta} induces aberrant expression of {beta}III in RPE cells via the ERK pathway. Black-Right-Pointing-Pointer TGF-{beta} increases O-GlcNAc modification of {beta}III in RPE cells. Black-Right-Pointing-Pointer Mature RPE cells have the capacity to express a neuron-associated gene by TGF-{beta}. -- Abstract: The class III {beta}-tubulin isotype ({beta}{sub III}) is expressed exclusively by neurons within the normal human retina and is not present in normal retinal pigment epithelial (RPE) cells in situ or in the early phase of primary cultures. However, aberrant expression of class III {beta}-tubulin has been observed in passaged RPE cells and RPE cells with dedifferentiated morphology in pathologic epiretinal membranes from idiopathic macular pucker, proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Transforming growth factor-{beta} (TGF-{beta}) has been implicated in dedifferentiation of RPE cells and has a critical role in the development of proliferative vitreoretinal diseases. Here, we investigated the potential effects of TGF-{beta} on the aberrant expression of class III {beta}-tubulin and the intracellular signaling pathway mediating these changes. TGF-{beta}-induced aberrant expression and O-linked-{beta}-N-acetylglucosamine (O-GlcNac) modification of class III {beta}-tubulin in cultured RPE cells as determined using Western blotting, RT-PCR and immunocytochemistry. TGF-{beta} also stimulated phosphorylation of ERK. TGF-{beta}-induced aberrant expression of class III {beta}-tubulin was significantly reduced by pretreatment with U0126, an inhibitor of ERK phosphorylation. Our findings indicate that TGF-{beta} stimulated aberrant expression of class III {beta}-tubulin via activation of the ERK signaling pathway. These data demonstrate that mature RPE cells have the capacity to express a neuron-associated gene in response to TGF-{beta} stimulation and provide useful information

  2. TGF-β-stimulated aberrant expression of class III β-tubulin via the ERK signaling pathway in cultured retinal pigment epithelial cells

    Highlights: ► TGF-β induces aberrant expression of βIII in RPE cells via the ERK pathway. ► TGF-β increases O-GlcNAc modification of βIII in RPE cells. ► Mature RPE cells have the capacity to express a neuron-associated gene by TGF-β. -- Abstract: The class III β-tubulin isotype (βIII) is expressed exclusively by neurons within the normal human retina and is not present in normal retinal pigment epithelial (RPE) cells in situ or in the early phase of primary cultures. However, aberrant expression of class III β-tubulin has been observed in passaged RPE cells and RPE cells with dedifferentiated morphology in pathologic epiretinal membranes from idiopathic macular pucker, proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Transforming growth factor-β (TGF-β) has been implicated in dedifferentiation of RPE cells and has a critical role in the development of proliferative vitreoretinal diseases. Here, we investigated the potential effects of TGF-β on the aberrant expression of class III β-tubulin and the intracellular signaling pathway mediating these changes. TGF-β-induced aberrant expression and O-linked-β-N-acetylglucosamine (O-GlcNac) modification of class III β-tubulin in cultured RPE cells as determined using Western blotting, RT-PCR and immunocytochemistry. TGF-β also stimulated phosphorylation of ERK. TGF-β-induced aberrant expression of class III β-tubulin was significantly reduced by pretreatment with U0126, an inhibitor of ERK phosphorylation. Our findings indicate that TGF-β stimulated aberrant expression of class III β-tubulin via activation of the ERK signaling pathway. These data demonstrate that mature RPE cells have the capacity to express a neuron-associated gene in response to TGF-β stimulation and provide useful information towards understanding the pathogenesis of proliferative vitreoretinal diseases.

  3. The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro

    Li, Qiang; Song, Xin-mao; Ji, Yang-yang; Jiang, Hui; Xu, Lin-gen, E-mail: drlingenxu@126.com

    2013-11-01

    Highlights: •AZD8055 induces significant cytotoxic effects in cultured HNSCC cells. •AZD8055 blocks mTORC1 and mTORC2 activation in cultured HNSCC cells. •JNK activation is required for AZD8055-induced HNSCC cell death. •AZD8055 inhibits Hep-2 cell growth in vivo, and was more efficient than rapamycin. -- Abstract: The serine/threonine kinase mammalian target of rapamycin (mTOR) promotes cell survival and proliferation, and is constitutively activated in head and neck squamous cell carcinoma (HNSCC). Thus mTOR is an important target for drug development in this disease. Here we tested the anti-tumor ability of AZD8055, the novel mTOR inhibitor, in HNSCC cells. AZD8055 induced dramatic cell death of HNSCC lines (Hep-2 and SCC-9) through autophagy. AZD8055 blocked both mTOR complex (mTORC) 1 and mTORC2 activation without affecting Erk in cultured HNSCC cells. Meanwhile, AZD8055 induced significant c-Jun N-terminal kinase (JNK) activation, which was also required for cancer cell death. JNK inhibition by its inhibitors (SP 600125 and JNK-IN-8), or by RNA interference (RNAi) alleviated AZD8055-induced cell death. Finally, AZD8055 markedly increased the survival of Hep-2 transplanted mice through a significant reduction of tumor growth, without apparent toxicity, and its anti-tumor ability was more potent than rapamycin. Meanwhile, AZD8055 administration activated JNK while blocking mTORC1/2 in Hep-2 tumor engrafts. Our current results strongly suggest that AZD8055 may be further investigated for HNSCC treatment in clinical trials.

  4. Chromosomal aberration

    Chromosomal aberrations are classified into two types, chromosome-type and chromatid-type. Chromosom-type aberrations include terminal deletion, dicentric, ring and interstitial deletion, and chromatid-type aberrations include achromatic lesion, chromatid deletion, isochromatid deletion and chromatid exchange. Clastogens which induce chromosomal aberration are divided into ''S-dependent'' agents and ''S-independent''. It might mean whether they can induce double strand breaks independent of the S phase or not. Double strand breaks may be the ultimate lesions to induce chromosomal aberrations. Caffeine added even in the G2 phase appeared to modify the frequency of chromatid aberrations induced by X-rays and mitomycin C. Those might suggest that the G2 phase involves in the chromatid aberration formation. The double strand breaks might be repaired by ''G2 repair system'', the error of which might yield breakage types of chromatid aberrations and the by-pass of which might yield chromatid exchanges. Chromosome-type aberrations might be formed in the G1 phase. (author)

  5. Inhibitions of mTORC1 and 4EBP-1 are key events orchestrated by Rottlerin in SK-Mel-28 cell killing.

    Daveri, E; Maellaro, E; Valacchi, G; Ietta, F; Muscettola, M; Maioli, E

    2016-09-28

    Earlier studies demonstrated that Rottlerin exerts a time- and dose-dependent antiproliferative effect on SK-Mel-28 melanoma cells during 24 h of treatment, but cytotoxicity due to cell death began only after a 48 h exposure. In the current study, in order to identify the type of cell death in this cell line, which is notoriously refractory to most anticancer therapies, and to clarify the underlying mechanisms of this delayed outcome, we searched for apoptotic, necrotic/necroptotic and autophagic traits in Rottlerin-exposed cells. Although SK-Mel-28 cells are both apoptosis and autophagy competent, Western blotting analysis, caspase activity assay, nuclear imaging and the effects of autophagy, apoptosis and necroptosis inhibitors, indicated that Rottlerin cytotoxicity was due to none of the aforementioned death mechanisms. Nevertheless, in growth arrested cells, the death did occur after a prolonged treatment and most likely ensued from the observed blockage of protein synthesis that reached levels expected to be incompatible with cell survival. From a mechanistic point of view, we ascribed this effect to the documented inhibition of mTORC1 activity; mTORC1 inhibition on the one hand led to a not deadly, rather protective autophagic response but, on the other hand caused a near complete arrest of protein synthesis. Interestingly, no cytotoxicity was found towards normal skin fibroblasts, which only resulted mildly growth arrested by the drug. PMID:27343979

  6. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells

    Lou, Hai-zhou [Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016 (China); Weng, Xiao-chuan [Department of Anesthesiology, Hangzhou Xia-sha Hospital, Hangzhou 310018 (China); Pan, Hong-ming; Pan, Qin [Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016 (China); Sun, Peng [Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060 (China); Liu, Li-li [Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016 (China); Chen, Bin, E-mail: chenbinhangzhou126@126.com [Department of Hepatopancreatobiliary Surgery, First People’s Hospital of Hangzhou, Hangzhou 310006 (China)

    2014-07-25

    Highlights: • INK-128 inhibits the survival and growth of human pancreatic cancer cells. • INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. • INK-128 blocks mTORC1/2 activation simultaneously in pancreatic cancer cells. • INK-128 down-regulates cyclin D1 and causes pancreatic cancer cell cycle arrest. • INK-128 significantly increases sensitivity of pancreatic cancer cells to gemcitabine. - Abstract: Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment.

  7. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells

    Highlights: • INK-128 inhibits the survival and growth of human pancreatic cancer cells. • INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. • INK-128 blocks mTORC1/2 activation simultaneously in pancreatic cancer cells. • INK-128 down-regulates cyclin D1 and causes pancreatic cancer cell cycle arrest. • INK-128 significantly increases sensitivity of pancreatic cancer cells to gemcitabine. - Abstract: Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment

  8. Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis.

    Yu, Xinlei; Long, Yun Chau

    2016-01-01

    Although essential amino acids regulate mechanistic target of rapamycin complex 1 (mTORC1) and the integrated stress response (ISR), the role of cysteine is unknown. We found that in hepatoma HepG2 cells, cystine (oxidized form of cysteine) activated mTORC1 and suppressed the ISR. Cystine deprivation induced GSH efflux and extracellular degradation, which aimed to restore cellular cysteine. Inhibition of γ-glutamyl transpeptidase (GGT) impaired the ability of GSH or cell-permeable GSH to restore mTORC1 signaling and the ISR, suggesting that the capacity of GSH to release cysteine, but not GSH per se, regulated the signaling networks. Inhibition of protein translation restored both mTORC1 signaling and the ISR during cystine starvation, suggesting the bulk of cellular cysteine was committed to the biosynthetic process. Cellular cysteine and GSH displayed overlapping protective roles in the suppression of ferroptosis, further supporting their cooperation in the regulation of cell signaling. Thus, cellular cysteine and its derivative GSH cooperate to regulate mTORC1 pathway, the ISR and ferroptosis. PMID:27425006

  9. Up-regulation of miRNA-221 inhibits hypoxia/reoxygenation-induced autophagy through the DDIT4/mTORC1 and Tp53inp1/p62 pathways.

    Chen, Qiying; Zhou, Yue; Richards, A Mark; Wang, Peipei

    2016-05-20

    Timely reperfusion in acute myocardial infarction has improved clinical outcomes but the benefits are partially offset by ischemia-reperfusion injury (I/R). MiRNA regulates mRNA of multiple effectors within injury and survival cell signaling pathways. We have previously reported the protective effects of miRNA-221 in I/R injury. The purpose of this study was to explore the mechanisms underlying cardioprotection of miR-221. Myoblast H9c2 and neonatal rat ventricular myocytes (NRVM) were subjected to 0.2% O2 hypoxia followed by 2 h of re-oxygenation (H/R). In gain-and-loss function studies through transfections of miR-221 mimic (miR-221) and inhibitor (miR-221-i), the protective effects of miR-221 were confirmed as assessed by increased cell metabolic activity (WST-1) and decreased LDH release. Autophagy was assessed by GFP-LC3 labeling of autophagosome formation, LC3 and p62 measurements. Co-immuno-precipitation and specific gene cloning and function were used to identify the pathways underpinning miR-221 effects. MiR-221 significantly reduced H/R injury in association with inhibition of autophagy. Underlying mechanisms include (1) down-regulation of Ddit4 (disinhibiting the mTORC1/p-4EBP1 pathway) which inhibits autophagosome formation (2) down-regulation of Tp53inp1 (with reduced Tp53inp1/p62 complex formation) which inhibits autophagosome degradation. In conclusion, miRNA-221 exerts cytoprotective effects in hypoxia-reoxygenation injury in association with alterations in autophagic cell injury. Mir-221 may constitute is a novel therapeutic target in the treatment of cardiac I/R injury. PMID:27105917

  10. Excessive Leucine-mTORC1-Signalling of Cow Milk-Based Infant Formula: The Missing Link to Understand Early Childhood Obesity

    Bodo C. Melnik

    2012-01-01

    Full Text Available Increased protein supply by feeding cow-milk-based infant formula in comparison to lower protein content of human milk is a well-recognized major risk factor of childhood obesity. However, there is yet no conclusive biochemical concept explaining the mechanisms of formula-induced childhood obesity. It is the intention of this article to provide the biochemical link between leucine-mediated signalling of mammalian milk proteins and adipogenesis as well as early adipogenic programming. Leucine has been identified as the predominant signal transducer of mammalian milk, which stimulates the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1. Leucine thus functions as a maternal-neonatal relay for mTORC1-dependent neonatal β-cell proliferation and insulin secretion. The mTORC1 target S6K1 plays a pivotal role in stimulation of mesenchymal stem cells to differentiate into adipocytes and to induce insulin resistance. It is of most critical concern that infant formulas provide higher amounts of leucine in comparison to human milk. Exaggerated leucine-mediated mTORC1-S6K1 signalling induced by infant formulas may thus explain increased adipogenesis and generation of lifelong elevated adipocyte numbers. Attenuation of mTORC1 signalling of infant formula by leucine restriction to physiologic lower levels of human milk offers a great chance for the prevention of childhood obesity and obesity-related metabolic diseases.

  11. Aberrant expression of Notch1/numb/snail signaling, an epithelial mesenchymal transition related pathway, in adenomyosis

    Qi, Shasha; Zhao, Xingbo; Li, Mingjiang; Zhang, Xiaohui; Lu, Zhenzhen; Yang, Chunrun; Zhang, Chunhua; Zhang, Hui; Zhang, Na

    2015-01-01

    Background Epithelial mesenchymal transition (EMT) is involved in the pathogenesis of adenomyosis, and Notch signaling is crucial to EMT. The objective of this study was to explore Notch1/Numb/Snail signaling in adenomyosis. Methods The expression levels of the members of the Notch1/Numb/Snail signaling cascade in normal endometria (proliferative phase: n = 15; secretory phase: n = 15; postmenopausal phase: n = 15) and adenomyotic endometria (proliferative phase: n = 15; secretory phase: n = ...

  12. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice.

    Kishi, Noriyuki; MacDonald, Jessica L; Ye, Julia; Molyneaux, Bradley J; Azim, Eiman; Macklis, Jeffrey D

    2016-01-01

    Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

  13. mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration.

    Deng, Zhili; Lei, Xiaohua; Zhang, Xudong; Zhang, Huishan; Liu, Shuang; Chen, Qi; Hu, Huimin; Wang, Xinyue; Ning, Lina; Cao, Yujing; Zhao, Tongbiao; Zhou, Jiaxi; Chen, Ting; Duan, Enkui

    2015-02-01

    Hair follicles (HFs) undergo cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) phases. Anagen begins when the hair follicle stem cells (HFSCs) obtain sufficient activation cues to overcome suppressive signals, mainly the BMP pathway, from their niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSC activation at the telogen-to-anagen transition. By using both an inducible conditional gene targeting strategy and a pharmacological inhibition method to ablate or inhibit mTOR signaling in adult skin epithelium before anagen initiation, we demonstrate that HFs that cannot respond to mTOR signaling display significantly delayed HFSC activation and extended telogen. Unexpectedly, BMP signaling activity is dramatically prolonged in mTOR signaling-deficient HFs. Through both gain- and loss-of-function studies in vitro, we show that mTORC1 signaling negatively affects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitates HFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-null skin. Our findings reveal a critical role for mTOR signaling in regulating stem cell activation through counterbalancing BMP-mediated repression during hair regeneration. PMID:25609845

  14. Differential regulation of protein synthesis in skeletal muscle and liver of neonatal pigs by leucine through an mTORC1-dependent pathway

    Suryawan Agus

    2012-02-01

    Full Text Available Abstract Neonatal growth is characterized by a high protein synthesis rate that is largely due to an enhanced sensitivity to the postprandial rise in insulin and amino acids, especially leucine. The mechanism of leucine's action in vivo is not well understood. In this study, we investigated the effect of leucine infusion on protein synthesis in skeletal muscle and liver of neonatal pigs. To evaluate the mode of action of leucine, we used rapamycin, an inhibitor of mammalian target of rapamycin (mTOR complex-1 (mTORC1. Overnight-fasted 7-day-old piglets were treated with rapamycin for 1 hour and then infused with leucine (400 μmol·kg-1·h-1 for 1 hour. Leucine infusion increased the rate of protein synthesis, and ribosomal protein S6 kinase 1 (S6K1 and eukaryotic initiation factor (eIF 4E-binding protein-1 (4E-BP1 phosphorylation in gastrocnemius and masseter muscles (P

  15. Optical Aberrations and Wavefront

    Nihat Polat

    2014-08-01

    Full Text Available The deviation of light to create normal retinal image in the optical system is called aberration. Aberrations are divided two subgroup: low-order aberrations (defocus: spherical and cylindrical refractive errors and high-order aberrations (coma, spherical, trefoil, tetrafoil, quadrifoil, pentafoil, secondary astigmatism. Aberrations increase with aging. Spherical aberrations are compensated by positive corneal and negative lenticular spherical aberrations in youth. Total aberrations are elevated by positive corneal and positive lenticular spherical aberrations in elderly. In this study, we aimed to analyze the basic terms regarding optic aberrations which have gained significance recently. (Turk J Ophthalmol 2014; 44: 306-11

  16. Leucine signaling in the pathogenesis of type 2 diabetes and obesity

    Melnik, Bodo C.

    2012-01-01

    Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D). This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response t...

  17. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    Bartkova, J; Hamerlik, P; Stockhausen, Marie;

    2010-01-01

    damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that...... brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low......-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis...

  18. Adipocytes from New Zealand Obese Mice Exhibit Aberrant Proinflammatory Reactivity to the Stress Signal Heat Shock Protein 60

    Tina Märker

    2014-01-01

    Full Text Available Adipocytes release immune mediators that contribute to diabetes-associated inflammatory processes. As the stress protein heat shock protein 60 (Hsp60 induces proinflammatory adipocyte activities, we hypothesized that adipocytes of diabetes-predisposed mice exhibit an increased proinflammatory reactivity to Hsp60. Preadipocytes and mature adipocytes from nonobese diabetic (NOD, New Zealand obese (NZO, and C57BL/6J mice were analyzed for Hsp60 binding, Hsp60-activated signaling pathways, and Hsp60-induced release of the chemokine CXCL-1 (KC, interleukin 6 (IL-6, and macrophage chemoattractant protein-1 (MCP-1. Hsp60 showed specific binding to (pre-adipocytes of NOD, NZO, and C57BL/6J mice. Hsp60 binding involved conserved binding structure(s and Hsp60 epitopes and was strongest to NZO mouse-derived mature adipocytes. Hsp60 exposure induced KC, IL-6, and MCP-1 release from (pre-adipocytes of all mouse strains with a pronounced increase of IL-6 release from NZO mouse-derived adipocytes. Compared to NOD and C57BL/6J mouse derived cells, Hsp60-induced formation of IL-6, KC, and MCP-1 from NZO mouse-derived (pre-adipocytes strongly depended on NFκB-activation. Increased Hsp60 binding and Hsp60-induced IL-6 release by mature adipocytes of NZO mice suggest that enhanced adipocyte reactivity to the stress signal Hsp60 contributes to inflammatory processes underlying diabetes associated with obesity and insulin resistance.

  19. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States); Oakley, Gregory G.; Wahl, James K. [Department of Oral Biology, University of Nebraska College of Dentistry, Lincoln, NE 68588 (United States); Simpson, Melanie A., E-mail: msimpson2@unl.edu [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States); Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

    2011-05-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and {beta}-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  20. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and β-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  1. Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function.

    Wang, Weihuan; Zimmerman, Grant; Huang, Xiaoran; Yu, Shuiliang; Myers, Jay; Wang, Yiwei; Moreton, Stephen; Nthale, Joseph; Awadallah, Amad; Beck, Rose; Xin, Wei; Wald, David; Huang, Alex Y; Zhou, Lan

    2016-03-15

    More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. PMID:26801976

  2. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

    Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Rosenfelt, Cory; Gertner, Michael J.; Campbell, Sean R.; Emerson, Danielle; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Chambers, Daniel B.; Langer, Steven; Sust, Steven; Malik, Aatika; Terlizzi, Allison M.; Liebelt, David A.; Ferreiro, David; Sharma, Ali; Koenigsberg, Eric; Choi, Richard J.; Louneva, Natalia; Arnold, Steven E.; Featherstone, Robert E.; Siegel, Steven J.; Zukin, R. Suzanne; McDonald, Thomas V.; Bolduc, Francois V.; Jongens, Thomas A.; McBride, Sean M. J.

    2016-01-01

    Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. PMID:27445731

  3. mTOR信号通路与支气管肺发育不良%mTOR signaling pathway and bronchopulmonary dysplasia

    邹冬梅(综述); 王少华(审校)

    2016-01-01

    mTOR信号通路是在进化上高度保守的细胞内信号通路,参与多条信号通路的传导,主要包括 PI3K/AKT/mTOR 通路、AKT/TSC1-TSC2/Rheb/mTOR 通路、LKB1-AMPK-TSC-mTOR 通路和 FGF-10-Spry2-mTORC1-STAT3/HIF-1α-VEGF-A通路。该信号通路从多个水平多个方面参与肺发育及肺部多种疾病的调控过程,可能与支气管肺发育不良( bronchopulmonary dysplasia,BPD)有关。 BPD是早产儿十分常见的一种慢性肺疾病( chronic lung disease,CLD),是各种理化因素对发育不成熟肺造成急性肺损伤及损伤后异常修复、肺纤维化的过程。该文总结了mTOR信号通路与肺发育、急性肺损伤及肺纤维化可能存在的关系,探索mTOR信号通路在BPD形成过程中的作用,以期为BPD的防治提供新的切入点。%mTOR signaling pathway is a highly conserved intracellular signaling pathway,which partici-pates in several signaling pathways, such as PI3K/AKT/mTOR, AKT/TSC1-TSC2/Rheb/mTOR, LKB1-AMPK-TSC-mTOR and FGF-10-Spry2-mTORC1-STAT3/HIF-1α-VEGF-A. mTOR signaling implicate in the regulation of the development of lung and many pulmonary diseases in many aspects,may be connected to bron-chopulmonary dysplasia. Bronchopulmonary dysplasia is one of the very common chronic lung diseases in pre-term,physical and chemical factors have been shown to induce acute lung injury, aberrant wound healing and lung fibrosis in the immature lung. This review summarizes relationship of mTOR signaling among lung develop-ment,acute lung injury and lung fibrosis,to explore the role of mTOR signaling in the development of bronchop-ulmonary dysplasia,in hope of providing novel method in the prevention and treatment of bronchopulmonary dysplasia.

  4. Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne

    Melnik, Bodo C; Zouboulis, Christos C.

    2013-01-01

    Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed...

  5. Aberration Corrected Emittance Exchange

    Nanni, Emilio A

    2015-01-01

    Full exploitation of emittance exchange (EEX) requires aberration-free performance of a complex imaging system including active radio-frequency (RF) elements which can add temporal distortions. We investigate the performance of an EEX line where the exchange occurs between two dimensions with normalized emittances which differ by orders of magnitude. The transverse emittance is exchanged into the longitudinal dimension using a double dog-leg emittance exchange setup with a 5 cell RF deflector cavity. Aberration correction is performed on the four most dominant aberrations. These include temporal aberrations that are corrected with higher order magnetic optical elements located where longitudinal and transverse emittance are coupled. We demonstrate aberration-free performance of emittances differing by 4 orders of magnitude, i.e. an initial transverse emittance of $\\epsilon_x=1$ pm-rad is exchanged with a longitudinal emittance of $\\epsilon_z=10$ nm-rad.

  6. Photothermal Lens Aberration Effects in Two Laser Thermal Lens Spectrometry

    Bialkowski, Stephen E.

    1985-01-01

    A comparison of theories describing two laser photothermal lens signals is given. The aberrant nature of this lens is accounted for in a theory which treats the propagation of a monitor laser in terms of a phase shift in this laser beam wave front. The difference between theories are discussed in terms of the predicted signal strengths and temporal behavior. The aberrant theory results in smaller theoretical signal strengths and different functional relationships between signal and analyte le...

  7. Protein supplementation does not alter intramuscular anabolic signaling or endocrine response after resistance exercise in trained men.

    Gonzalez, Adam M; Hoffman, Jay R; Jajtner, Adam R; Townsend, Jeremy R; Boone, Carleigh H; Beyer, Kyle S; Baker, Kayla M; Wells, Adam J; Church, David D; Mangine, Gerald T; Oliveira, Leonardo P; Moon, Jordan R; Fukuda, David H; Stout, Jeffrey R

    2015-11-01

    The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway appears to be the primary regulator of muscle protein synthesis. A variety of stimuli including resistance exercise, amino acids, and hormonal signals activate mTORC1 signaling. The purpose of this study was to investigate the effect of a protein supplement on mTORC1 signaling following a resistance exercise protocol designed to promote elevations in circulating hormone concentrations. We hypothesized that the protein supplement would augment the intramuscular anabolic signaling response. Ten resistance-trained men (age, 24.7 ± 3.4 years; weight, 90.1 ± 11.3 kg; height, 176.0 ± 4.9 cm) received either a placebo or a supplement containing 20 g protein, 6 g carbohydrates, and 1 g fat after high-volume, short-rest lower-body resistance exercise. Blood samples were obtained at baseline, immediately, 30 minutes, 1 hour, 2 hours, and 5 hours after exercise. Fine-needle muscle biopsies were completed at baseline, 1 hour, and 5 hours after exercise. Myoglobin, lactate dehydrogenase, and lactate concentrations were significantly elevated after resistance exercise (P exercise also elicited a significant insulin, growth hormone, and cortisol response (P testosterone, growth hormone, or cortisol. Intramuscular anabolic signaling analysis revealed significant elevations in RPS6 phosphorylation after resistance exercise (P = .001); however, no differences were observed between trials for signaling proteins including Akt, mTOR, p70S6k, and RPS6. The endocrine response and phosphorylation status of signaling proteins within the mTORC1 pathway did not appear to be altered by ingestion of supplement after resistance exercise in resistance-trained men. PMID:26428621

  8. Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic β cells.

    Wang, Jing; Yang, Xin; Zhang, Jingjing

    2016-08-01

    Pancreatic β cell dysfunction, i.e., failure to provide insulin in concentrations sufficient to control blood sugar, is central to the etiology of all types of diabetes. Current evidence implicates mitochondrial oxidative stress and endoplasmic reticulum (ER) stress in pancreatic β cell loss and impaired insulin secretion. Oxidative and ER stress are interconnected so that misfolded proteins induce reactive oxygen species (ROS) production; likewise, oxidative stress disturbs the ER redox state thereby disrupting correct disulfide bond formation and proper protein folding. mTOR signaling regulates many metabolic processes including protein synthesis, cell growth, survival and proliferation. Oxidative stress inhibits mTORC1, which is considered an important suppressor of mitochondrial oxidative stress in β cells, and ultimately, controls cell survival. The interplay between ER stress and mTORC1 is complicated, since the unfolded protein response (UPR) activation can occur upstream or downstream of mTORC1. Persistent activation of mTORC1 initiates protein synthesis and UPR activation, while in the later phase induces ER stress. Chronic activation of ER stress inhibits Akt/mTORC1 pathway, while under particular settings, acute activation of UPR activates Akt-mTOR signaling. Thus, modulating mitochondrial oxidative stress and ER stress via mTOR signaling may be an approach that will effectively suppress obesity- or glucolipotoxicity-induced metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM). In this review, we focus on the regulations between mTOR signaling and mitochondrial oxidative or ER stress in pancreatic β cells. PMID:27185188

  9. PARP-1 modulation of mTOR signaling in response to a DNA alkylating agent.

    Chantal Ethier

    Full Text Available Poly(ADP-ribose polymerase-1 (PARP-1 is widely involved in cell death responses. Depending on the degree of injury and on cell type, PARP activation may lead to autophagy, apoptosis or necrosis. In HEK293 cells exposed to the alkylating agent N-methyl-N'-nitro-N'-nitrosoguanine (MNNG, we show that PARP-1 activation triggers a necrotic cell death response. The massive poly(ADP-ribose (PAR synthesis following PARP-1 activation leads to the modulation of mTORC1 pathway. Shortly after MNNG exposure, NAD⁺ and ATP levels decrease, while AMP levels drastically increase. We characterized at the molecular level the consequences of these altered nucleotide levels. First, AMP-activated protein kinase (AMPK is activated and the mTORC1 pathway is inhibited by the phosphorylation of Raptor, in an attempt to preserve cellular energy. Phosphorylation of the mTORC1 target S6 is decreased as well as the phosphorylation of the mTORC2 component Rictor on Thr1135. Finally, Akt phosphorylation on Ser473 is lost and then, cell death by necrosis occurs. Inhibition of PARP-1 with the potent PARP inhibitor AG14361 prevents all of these events. Moreover, the antioxidant N-acetyl-L-cysteine (NAC can also abrogate all the signaling events caused by MNNG exposure suggesting that reactive oxygen species (ROS production is involved in PARP-1 activation and modulation of mTOR signaling. In this study, we show that PARP-1 activation and PAR synthesis affect the energetic status of cells, inhibit the mTORC1 signaling pathway and possibly modulate the mTORC2 complex affecting cell fate. These results provide new evidence that cell death by necrosis is orchestrated by the balance between several signaling pathways, and that PARP-1 and PAR take part in these events.

  10. Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/β-catenin signalling

    Fang, Lishan; Cai, Junchao; Chen, Baixue; Wu, Shanshan; Li, Rong; Xu, Xiaonan; Yang, Yi; Guan, Hongyu; Zhu, Xun; Zhang, Le; Yuan, Jie; Wu, Jueheng; Li, Mengfeng

    2015-01-01

    Cancer stem cells (CSCs) are involved in tumorigenesis, tumour recurrence and therapy resistance and Wnt signalling is essential for the development of the biological traits of CSCs. In non-small cell lung carcinoma (NSCLC), unlike in colon cancer, mutations in β-catenin and APC genes are uncommon; thus, the mechanism underlying the constitutive activation of Wnt signalling in NSCLC remains unclear. Here we report that miR-582-3p expression correlates with the overall- and recurrence-free-sur...

  11. Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/β-catenin signalling.

    Fang, Lishan; Cai, Junchao; Chen, Baixue; Wu, Shanshan; Li, Rong; Xu, Xiaonan; Yang, Yi; Guan, Hongyu; Zhu, Xun; Zhang, Le; Yuan, Jie; Wu, Jueheng; Li, Mengfeng

    2015-01-01

    Cancer stem cells (CSCs) are involved in tumorigenesis, tumour recurrence and therapy resistance and Wnt signalling is essential for the development of the biological traits of CSCs. In non-small cell lung carcinoma (NSCLC), unlike in colon cancer, mutations in β-catenin and APC genes are uncommon; thus, the mechanism underlying the constitutive activation of Wnt signalling in NSCLC remains unclear. Here we report that miR-582-3p expression correlates with the overall- and recurrence-free-survival of NSCLC patients, and miR-582-3p has an activating effect on Wnt/β-catenin signalling. miR-582-3p overexpression simultaneously targets multiple negative regulators of the Wnt/β-catenin pathway, namely, AXIN2, DKK3 and SFRP1. Consequently, miR-582-3p promotes CSC traits of NSCLC cells in vitro and tumorigenesis and tumour recurrence in vivo. Antagonizing miR-582-3p potently inhibits tumour initiation and progression in xenografted animal models. These findings suggest that miR-582-3p mediates the constitutive activation of Wnt/β-catenin signalling, likely serving as a potential therapeutic target for NSCLC. PMID:26468775

  12. The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease.

    Atwood, Craig S; Bowen, Richard L

    2015-11-01

    This article is part of a Special Issue "SBN 2014". Sex hormones are physiological factors that promote neurogenesis during embryonic and fetal development. During childhood and adulthood these hormones support the maintenance of brain structure and function via neurogenesis and the formation of dendritic spines, axons and synapses required for the capture, processing and retrieval of information (memories). Not surprisingly, changes in these reproductive hormones that occur with menopause and during andropause are strongly correlated with neurodegeneration and cognitive decline. In this connection, much evidence now indicates that Alzheimer's disease (AD) involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Intriguingly, a recent animal study has demonstrated that induction of adult neurogenesis results in the loss of previously encoded memories while decreasing neurogenesis after memory formation during infancy mitigated forgetting. Here we review the biochemical, epidemiological and clinical evidence that alterations in sex hormone signaling associated with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle that leads to neurite retraction, neuron dysfunction and neuron death. When the reproductive axis is in balance, gonadotropins such as luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the LH:sex steroid ratio as driving aberrant mitotic events. These include the upregulation of tumor necrosis factor; amyloid-β precursor protein processing towards the production of mitogenic Aβ; and

  13. Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis.

    Melnik, Bodo C

    2012-05-01

    Recent evidence underlines the role of Western diet in the pathogenesis of acne. Acne is absent in populations consuming Palaeolithic diets with low glycaemic load and no consumption of milk or dairy products. Two randomized controlled studies, one of which is presented in this issue of Acta Dermato-Venereologica, have provided evidence for the beneficial therapeutic effects of low glycaemic load diets in acne. Epidemiological evidence confirms that milk consumption has an acne-promoting or acne-aggravating effect. Recent progress in understanding the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1) allows a new view of nutrient signalling in acne by both high glycaemic load and increased insulin-, IGF-1-, and leucine signalling due to milk protein consumption. Acne should be regarded as an mTORC1-driven disease of civilization, like obesity, type 2 diabetes and cancer induced by Western diet. Early dietary counselling of teenage acne patients is thus a great opportunity for dermatology, which will not only help to improve acne but may reduce the long-term adverse effects of Western diet on more serious mTORC1-driven diseases of civilization. PMID:22419445

  14. Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells

    Pan, Jing-Xuan; Ding, Ke; Wang, Cheng-Yan

    2012-01-01

    Niclosamide, an oral antihelminthic drug, has been used to treat tapeworm infection for about 50 years. Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs. Recently, several groups have independently discovered that niclosamide is also active against cancer cells, but its precise mechanism of antitumor action is not fully understood. Evidence supports that niclosamide targets multiple signaling pathways (NF-κB, Wnt/β-catenin, Notch, ROS, mTORC1,...

  15. A Multi-Lineage Screen Reveals mTORC1 Inhibition Enhances Human Pluripotent Stem Cell Mesendoderm and Blood Progenitor Production

    Emanuel Joseph Paul Nazareth

    2016-05-01

    Full Text Available Human pluripotent stem cells (hPSCs exist in heterogeneous micro-environments with multiple subpopulations, convoluting fate-regulation analysis. We patterned hPSCs into engineered micro-environments and screened responses to 400 small-molecule kinase inhibitors, measuring yield and purity outputs of undifferentiated, neuroectoderm, mesendoderm, and extra-embryonic populations. Enrichment analysis revealed mammalian target of rapamycin (mTOR inhibition as a strong inducer of mesendoderm. Dose responses of mTOR inhibitors such as rapamycin synergized with Bone Morphogenetic protein 4 (BMP4 and activin A to enhance the yield and purity of BRACHYURY-expressing cells. Mechanistically, small interfering RNA knockdown of RAPTOR, a component of mTOR complex 1, phenocopied the mesendoderm-enhancing effects of rapamycin. Functional analysis during mesoderm and endoderm differentiation revealed that mTOR inhibition increased the output of hemogenic endothelial cells 3-fold, with a concomitant enhancement of blood colony-forming cells. These data demonstrate the power of our multi-lineage screening approach and identify mTOR signaling as a node in hPSC differentiation to mesendoderm and its derivatives.

  16. A Multi-Lineage Screen Reveals mTORC1 Inhibition Enhances Human Pluripotent Stem Cell Mesendoderm and Blood Progenitor Production.

    Nazareth, Emanuel Joseph Paul; Rahman, Nafees; Yin, Ting; Zandstra, Peter William

    2016-05-10

    Human pluripotent stem cells (hPSCs) exist in heterogeneous micro-environments with multiple subpopulations, convoluting fate-regulation analysis. We patterned hPSCs into engineered micro-environments and screened responses to 400 small-molecule kinase inhibitors, measuring yield and purity outputs of undifferentiated, neuroectoderm, mesendoderm, and extra-embryonic populations. Enrichment analysis revealed mammalian target of rapamycin (mTOR) inhibition as a strong inducer of mesendoderm. Dose responses of mTOR inhibitors such as rapamycin synergized with Bone Morphogenetic protein 4 (BMP4) and activin A to enhance the yield and purity of BRACHYURY-expressing cells. Mechanistically, small interfering RNA knockdown of RAPTOR, a component of mTOR complex 1, phenocopied the mesendoderm-enhancing effects of rapamycin. Functional analysis during mesoderm and endoderm differentiation revealed that mTOR inhibition increased the output of hemogenic endothelial cells 3-fold, with a concomitant enhancement of blood colony-forming cells. These data demonstrate the power of our multi-lineage screening approach and identify mTOR signaling as a node in hPSC differentiation to mesendoderm and its derivatives. PMID:27132889

  17. Aging Reduces the Activation of the mTORC1 Pathway after Resistance Exercise and Protein Intake in Human Skeletal Muscle: Potential Role of REDD1 and Impaired Anabolic Sensitivity

    Marc Francaux

    2016-01-01

    Full Text Available This study was designed to better understand the molecular mechanisms involved in the anabolic resistance observed in elderly people. Nine young (22 ± 0.1 years and 10 older (69 ± 1.7 years volunteers performed a one-leg extension exercise consisting of 10 × 10 repetitions at 70% of their 3-RM, immediately after which they ingested 30 g of whey protein. Muscle biopsies were taken from the vastus lateralis at rest in the fasted state and 30 min after protein ingestion in the non-exercised (Pro and exercised (Pro+ex legs. Plasma insulin levels were determined at the same time points. No age difference was measured in fasting insulin levels but the older subjects had a 50% higher concentration than the young subjects in the fed state (p < 0.05. While no difference was observed in the fasted state, in response to exercise and protein ingestion, the phosphorylation state of PKB (p < 0.05 in Pro and Pro+ex and S6K1 (p = 0.059 in Pro; p = 0.066 in Pro+ex was lower in the older subjects compared with the young subjects. After Pro+ex, REDD1 expression tended to be higher (p = 0.087 in the older group while AMPK phosphorylation was not modified by any condition. In conclusion, we show that the activation of the mTORC1 pathway is reduced in skeletal muscle of older subjects after resistance exercise and protein ingestion compared with young subjects, which could be partially due to an increased expression of REDD1 and an impaired anabolic sensitivity.

  18. Fine-Tuning of PI3K/AKT Signalling by the Tumour Suppressor PTEN Is Required for Maintenance of Flight Muscle Function and Mitochondrial Integrity in Ageing Adult Drosophila melanogaster.

    Lawrence B Mensah

    Full Text Available Insulin/insulin-like growth factor signalling (IIS, acting primarily through the PI3-kinase (PI3K/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. The dysfunction of this pathway has been linked to several age-related human diseases including cancer, Type 2 diabetes and neurodegenerative disorders. However, it remains unclear whether minor defects in IIS can independently induce the age-dependent functional decline in cells that accompany some of these diseases or whether IIS alters the sensitivity to other aberrant signalling. We identified a novel hypomorphic allele of PI3K's direct antagonist, Phosphatase and tensin homologue on chromosome 10 (Pten, in the fruit fly, Drosophila melanogaster. Adults carrying combinations of this allele, Pten5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. We show that the phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1 pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. Our data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight

  19. [Regulative mechanisms of mammalian target of rapamycin signaling pathway in glomerular hypertrophy in diabetic nephropathy and interventional effects of Chinese herbal medicine].

    Yang, Jing-Jing; Huang, Yan-ru; Wan, Yi-gang; Shen, Shan-mei; Mao, Zhi-min; Wu, Wei; Yao, Jian

    2015-08-01

    Glomerular hypertrophy is the main pathological characteristic in the early stage of diabetic nephropathy (DN), and its regulatory mechanism is closely related to mammalian target of rapamycin (mTOR) signaling pathway activity. mTOR includes mTOR complex 1 (mTORC1) and mTOR complex 2(mTORC2), in which, the upstream pathway of mTORC1 is phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase(Akt)/adenosine monophosphate activated protein kinase(AMPK), and the representative signaling molecules in the downstream pathway of mTORC1 are 4E-binding proteins(4EBP) and phosphoprotein 70 S6Kinase(p70S6K). Some Chinese herbal extracts could improve cell proliferation via intervening the expressions of the key molecules in the upstream or downstream of PIK/Akt/mTOR signaling pathway in vivo. As for glomerular mesangial cells(MC) and podocyte, mTOR plays an important role in regulating glomerular inherent cells, including adjusting cell cycle, energy metabolism and matrix protein synthesis. Rapamycin, the inhibitor of mTOR, could suppress glomerular inherent cell hypertrophy, cell proliferation, glomerular basement membrane (GBM) thickening and mesangial matrix deposition in model rats with DN. Some Chinese herbal extracts could alleviate glomerular lesions by intervening mTOR signaling pathway activity in renal tissue of DN animal models or in renal inherent cells in vivo and in vitro. PMID:26790279

  20. TNF-{alpha} promotes human retinal pigment epithelial (RPE) cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression through activation of Akt/mTORC1 signaling

    Wang, Cheng-hu; Cao, Guo-Fan [The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029 (China); Jiang, Qin, E-mail: Jqin710@vip.sina.com [The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029 (China); Yao, Jin, E-mail: dryaojin@yahoo.com [The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029 (China)

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer TNF-{alpha} induces MMP-9 expression and secretion to promote RPE cell migration. Black-Right-Pointing-Pointer MAPK activation is not critical for TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer Akt and mTORC1 signaling mediate TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer SIN1 knockdown showed no significant effect on MMP-9 expression by TNF-{alpha}. -- Abstract: Tumor necrosis factor-alpha (TNF-{alpha}) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-{alpha} promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-{alpha}-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-{alpha}-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-{alpha} promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.

  1. TNF-α promotes human retinal pigment epithelial (RPE) cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression through activation of Akt/mTORC1 signaling

    Highlights: ► TNF-α induces MMP-9 expression and secretion to promote RPE cell migration. ► MAPK activation is not critical for TNF-α-induced MMP-9 expression. ► Akt and mTORC1 signaling mediate TNF-α-induced MMP-9 expression. ► SIN1 knockdown showed no significant effect on MMP-9 expression by TNF-α. -- Abstract: Tumor necrosis factor-alpha (TNF-α) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-α promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-α-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-α-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-α promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.

  2. Aberrations in asymmetrical electron lenses

    Starting from well established knowledge in light-optics we explore the question if electron-optical aberration can be improved in asymmetrical electron lenses. We show that spherical as well as chromatic aberration coefficients are reduced in asymmetric electrostatic einzel lenses when the center electrode is moved away from the center position towards the entrance electrode. Relative improvements up to 40% for both the chromatic and the spherical aberration coefficients can be obtained. We use analytical and numerical calculations to confirm this result for exemplary cases of a lens with fixed length and working distance. The agreement of the two calculation methods is very good. We then derive an estimate for the electron-optical aberration coefficients from light-optics. The derived expressions for chromatic and spherical aberrations are somewhat simpler than the ones derived from electron-optics as they involve integrals only over the electrostatic potential, not over the electron paths. The estimated formulas still agree well with the electron optical calculations. Overall, we are tempted to suggest that the enormous knowledge base of light optics can provide considerable guidance for electron-optical applications. -- Highlights: ► Develops the analogy between light and electron optics in aberration calculations. ► Optimized spherical and chromatic aberrations for an electrostatic einzel lens. ► Comparison between analytic and numerical aberration calculations.

  3. Aberrant splicing and drug resistance in AML.

    de Necochea-Campion, Rosalia; Shouse, Geoffrey P; Zhou, Qi; Mirshahidi, Saied; Chen, Chien-Shing

    2016-01-01

    The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets. PMID:27613060

  4. Reactive oxygen species and PI3K/Akt signaling in cancer.

    Jin, Seo Yeon; Lee, Hye Sun; Kim, Eun Kyoung; Ha, Jung Min; Kim, Young Whan; Bae, SunSik

    2014-10-01

    Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen and associates with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. In the present study, we showed that Insulin-like growth factor-1(IGF-1) modulates SKOV-3 ovarian cancer cell by regulation of generation of ROS. Akt mediates cellular signaling pathways in association with mammalian target of rapamycin complex (mTOR) and Rac small G protein. Insulin-like growth factor-1 (IGF-1)-induced generation of ROS was completely abolished by phosphatidylinositol 3-kinase (PI3K) (LY294002, 10?µM) or Akt inhibitors (SH-5, 50?µM), whereas inhibition of extracellular-regulated kinase by an ERK inhibitor (PD98059, 10?µM) or inhibition of mammalian target of rapamycin complex 1 (mTORC1) by an mTORC1 inhibitor (Rapamycin, 100?nM) did not affect IGF-1-induced generation of ROS. Inactivation of mTORC2 by silencing Rapamycin-insensitive companion of mTOR (Rictor), abolished IGF-1-induced SKOV-3 cell migration as well as activation of Akt. However, inactivation of mTORC1 by silencing of Raptor had no effect. Silencing of Akt1 but not Akt2 attenuated IGF-1-induced generation of ROS. Expression of PIP3-dependent Rac exchanger1 (P-Rex1), a Rac guanosine exchange factor and a component of the mTOR complex. Silencing of P-Rex1 abolished IGF-1-induced generation of ROS. Finally, inhibition of NADPH oxidase system completely blunted IGF-1-induced generation of ROS, whereas inhibition of xanthine oxiase,cyclooxygenase, and mitochondrial respiratory chain complex was not effective. Given these results, we suggest that IGF-1 induces ROS generation through the PI3K/Akt/ mTOR2/NADPH oxidase signaling axis. PMID:26461347

  5. Aberrations in asymmetrical electron lenses.

    Fitzgerald, J P S; Word, R C; Könenkamp, R

    2012-08-01

    Starting from well established knowledge in light-optics we explore the question if electron-optical aberration can be improved in asymmetrical electron lenses. We show that spherical as well as chromatic aberration coefficients are reduced in asymmetric electrostatic einzel lenses when the center electrode is moved away from the center position towards the entrance electrode. Relative improvements up to 40% for both the chromatic and the spherical aberration coefficients can be obtained. We use analytical and numerical calculations to confirm this result for exemplary cases of a lens with fixed length and working distance. The agreement of the two calculation methods is very good. We then derive an estimate for the electron-optical aberration coefficients from light-optics. The derived expressions for chromatic and spherical aberrations are somewhat simpler than the ones derived from electron-optics as they involve integrals only over the electrostatic potential, not over the electron paths. The estimated formulas still agree well with the electron optical calculations. Overall, we are tempted to suggest that the enormous knowledge base of light optics can provide considerable guidance for electron-optical applications. PMID:22206603

  6. Aberrations of diffracted wave fields.

    Harvey, J E; Shack, R V

    1978-09-15

    This paper is an attempt to provide new insight into the behavior of near-field scalar diffraction phenomena by showing that the Rayleigh-Sommerfeld diffraction integral is equivalent to the Fourier transform integral of a generalized pupil function which includes a term that represents phase errors in the aperture. This term can be interpreted as describing a conventional wavefront aberration function. The resulting aberration coefficients are calculated and expressed in terms of the aperture diameter, observation distance, and appropriate field parameter for several different geometrical configurations of incident beam and observation space. These aberrations, which are inherently associated with the diffraction process, are precisely the effects ignored when making the usual Fresnel and Fraunhofer approximations. PMID:20203910

  7. Chromosome Aberrations by Heavy Ions

    Ballarini, Francesca; Ottolenghi, Andrea

    It is well known that mammalian cells exposed to ionizing radiation can show different types of chromosome aberrations (CAs) including dicentrics, translocations, rings, deletions and complex exchanges. Chromosome aberrations are a particularly relevant endpoint in radiobiology, because they play a fundamental role in the pathways leading either to cell death, or to cell conversion to malignancy. In particular, reciprocal translocations involving pairs of specific genes are strongly correlated (and probably also causally-related) with specific tumour types; a typical example is the BCR-ABL translocation for Chronic Myeloid Leukaemia. Furthermore, aberrations can be used for applications in biodosimetry and more generally as biomarkers of exposure and risk, that is the case for cancer patients monitored during Carbon-ion therapy and astronauts exposed to space radiation. Indeed hadron therapy and astronauts' exposure to space radiation represent two of the few scenarios where human beings can be exposed to heavy ions. After a brief introduction on the main general features of chromosome aberrations, in this work we will address key aspects of the current knowledge on chromosome aberration induction, both from an experimental and from a theoretical point of view. More specifically, in vitro data will be summarized and discussed, outlining important issues such as the role of interphase death/mitotic delay and that of complex-exchange scoring. Some available in vivo data on cancer patients and astronauts will be also reported, together with possible interpretation problems. Finally, two of the few available models of chromosome aberration induction by ionizing radiation (including heavy ions) will be described and compared, focusing on the different assumptions adopted by the authors and on how these models can deal with heavy ions.

  8. Immunohistochemical analysis of the mechanistic target of rapamycin and hypoxia signalling pathways in basal cell carcinoma and trichoepithelioma.

    Tjinta Brinkhuizen

    Full Text Available BACKGROUND: Basal cell carcinoma (BCC is the most common cancer in Caucasians. Trichoepithelioma (TE is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1 and mechanistic/mammalian target of rapamycin (mTOR are key players in these pathways. OBJECTIVES: To determine whether HIF1/mTOR signalling is involved in BCC and TE. METHODS: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45 and TE (n = 35 samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, 80%. RESULTS: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3, 73% and 75% (CAIX, 79% and 86% (GLUT1, 50% and 19% (HIF1α, 89% and 88% (pAKT, 55% and 61% (pS6, 15% and 25% (pMTOR, 44% and 63% (PHD2 and 44% and 49% (VEGF-A. CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included. CONCLUSIONS: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE.

  9. Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise: Implications for Muscle Hypertrophy.

    Gonzalez, Adam M; Hoffman, Jay R; Stout, Jeffrey R; Fukuda, David H; Willoughby, Darryn S

    2016-05-01

    Maintaining skeletal muscle mass and function is critical for disease prevention, mobility and quality of life, and whole-body metabolism. Resistance exercise is known to be a major regulator for promoting muscle protein synthesis and muscle mass accretion. Manipulation of exercise intensity, volume, and rest elicit specific muscular adaptations that can maximize the magnitude of muscle growth. The stimulus of muscle contraction that occurs during differing intensities of resistance exercise results in varying biochemical responses regulating the rate of protein synthesis, known as mechanotransduction. At the cellular level, skeletal muscle adaptation appears to be the result of the cumulative effects of transient changes in gene expression following acute bouts of exercise. Thus, maximizing the resistance exercise-induced anabolic response produces the greatest potential for hypertrophic adaptation with training. The mechanisms involved in converting mechanical signals into the molecular events that control muscle growth are not completely understood; however, skeletal muscle protein synthesis appears to be regulated by the multi-protein phosphorylation cascade, mTORC1 (mammalian/mechanistic target of rapamycin complex 1). The purpose of this review is to examine the physiological response to resistance exercise, with particular emphasis on the endocrine response and intramuscular anabolic signaling through mTORC1. It appears that resistance exercise protocols that maximize muscle fiber recruitment, time-under-tension, and metabolic stress will contribute to maximizing intramuscular anabolic signaling; however, the resistance exercise parameters for maximizing the anabolic response remain unclear. PMID:26666743

  10. Distortion of ultrashort pulses caused by aberrations

    Horváth, Z. L.; Kovács, A. P.; Bor, Zs.

    The effect of the primary wave aberrations (spherical aberration, astigmatism and coma) on ultrashort pulses is studied by the Nijboer-Zernike theory. The results of the geometrical and the wave optical treatments are compared.

  11. The mTOR Signalling Pathway in Human Cancer

    Paula Soares

    2012-02-01

    Full Text Available The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin, a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

  12. Baseline chromosome aberrations in children

    Merlo, D.F.; Ceppi, M.; Stagi, E.; Bocchini, V.; Šrám, Radim; Rössner st., Pavel

    2007-01-01

    Roč. 172, - (2007), s. 60-67. ISSN 0378-4274 Grant ostatní: EU(EU) 2002-02198; EU(EU) 2005-016320 Institutional research plan: CEZ:AV0Z50390512 Source of funding: R - rámcový projekt EK ; R - rámcový projekt EK Keywords : chromosome aberrations * children * molecular epidemiology Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.826, year: 2007

  13. Aberrant methylation patterns in cancer

    Hudler, Petra; Videtič, Alja

    2016-01-01

    Epigenetic mechanisms, such as DNA methylation, DNA hydroxymethylation, post-translational modifications (PTMs) of histone proteins affecting nucleosome remodelling, and regulation by small and large non-coding RNAs (ncRNAs) work in concert with cis and trans acting elements to drive appropriate gene expression. Advances in detection methods and development of dedicated platforms and methylation arrays resulted in an explo - sion of information on aberrantly methylated sequences linking devia...

  14. Metabotropic Glutamate Receptor-dependent Long-term Depression is Impaired Due to Elevated ERK Signaling in the ΔRG Mouse Model of Tuberous Sclerosis Complex

    Chévere-Torres, Itzamarie; Kaphzan, Hanoch; Bhattacharya, Aditi; Kang, Areum; Maki, Jordan M.; Michael J Gambello; Arbiser, Jack L.; Santini, Emanuela; Klann, Eric

    2011-01-01

    Tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) are caused by mutations in negative regulators of translation. FXS model mice exhibit enhanced metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Therefore, we hypothesized that a mouse model of TSC, ΔRG transgenic mice, also would exhibit enhanced mGluR-LTD. We measured the impact of TSC2-GAP mutations on the mTORC1 and ERK signaling pathways and protein synthesis-dependent hippocampal synaptic plasticity ...

  15. Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration

    Elena Rainero

    2015-01-01

    Full Text Available Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 integrin undergoes tensin-dependent centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged α5β1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged α5β1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.

  16. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.

    Wander, Seth A

    2011-04-01

    Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

  17. Chromosomal aberrations and bone marrow toxicity.

    Heddle, J A; Salamone, M F

    1981-01-01

    The importance of chromosomal aberrations as a proximate cause of bone marrow toxicity is discussed. Since chemicals that can cause nondisjunction are rare, numerical aberrations (aneuploidy, polyploidy) are not ordinarily important. Many structural aberrations, however, can lead directly to cell death and so are proximate causes of toxicity when they occur. The micronucleus test which utilizes the polychromatic erythrocyte is capable of detecting agents (clastogens) that can cause such struc...

  18. Chromosomal aberrations in ore miners of Slovakia

    A pilot study was performed in which the incidence of chromosomal aberrations in lymphocytes of miners in ore mines located in Central Slovakia was monitored and related to lifetime underground radon exposure and to lifetime smoking. The conclusions drawn from the results of the study were as follows: the counts of chromosomal aberrations in lymphocytes of miners were significantly higher than in an age matched control group of white-collar staff; the higher counts of chromosomal aberrations could be ascribed to underground exposure of miners and to smoking; a dependence of chromosomal aberration counts on the exposure to radon could not be assessed. (A.K.)

  19. Non-Gaussianity and CMB aberration and Doppler

    The peculiar motion of an observer with respect to the CMB rest frame induces a deflection in the arrival direction of the observed photons (also known as CMB aberration) and a Doppler shift in the measured photon frequencies. As a consequence, aberration and Doppler effects induce non trivial correlations between the harmonic coefficients of the observed CMB temperature maps. In this paper we investigate whether these correlations generate a bias on non-Gaussianity estimators fNL. We perform this analysis simulating a large number of temperature maps with Planck-like resolution (lmax = 2000) as different realizations of the same cosmological fiducial model (WMAP7yr). We then add to these maps aberration and Doppler effects employing a modified version of the HEALPix code. We finally evaluate a generalization of the Komatsu, Spergel and Wandelt non-Gaussianity estimator for all the simulated maps, both when peculiar velocity effects have been considered and when these phenomena have been neglected. Using the value v/c = 1.23 × 10−3 for our peculiar velocity, we found that the aberration/Doppler induced non-Gaussian signal is at most of about half of the cosmic variance σ for fNL both in a full-sky and in a cut-sky experimental configuration, for local, equilateral and orthogonal estimators. We conclude therefore that when estimating fNL it is safe to ignore aberration and Doppler effects if the primordial map is already Gaussian. More work is necessary however to assess whether a map which contains non-Gaussianity can be significantly distorted by a peculiar velocity

  20. Hypoxia induces a phase transition within a kinase signaling network in cancer cells.

    Wei, Wei; Shi, Qihui; Remacle, Francoise; Qin, Lidong; Shackelford, David B; Shin, Young Shik; Mischel, Paul S; Levine, R D; Heath, James R

    2013-04-01

    Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)--a critical component of hypoxic signaling and a compelling cancer drug target--is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier's principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles. PMID:23530221

  1. Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production.

    Titchenell, Paul M; Quinn, William J; Lu, Mingjian; Chu, Qingwei; Lu, Wenyun; Li, Changhong; Chen, Helen; Monks, Bobby R; Chen, Julia; Rabinowitz, Joshua D; Birnbaum, Morris J

    2016-06-14

    During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed "selective insulin resistance" to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic insulin signaling is likely to be intact in insulin-resistant states. Moreover, cell-nonautonomous suppression of HGP by insulin depends on a reduction of adipocyte lipolysis and serum FFAs but is independent of vagal efferents or glucagon signaling. These data are consistent with a model in which, during T2DM, intact liver insulin signaling drives enhanced lipogenesis while excess circulating FFAs become a dominant inducer of nonsuppressible HGP. PMID:27238637

  2. Calculation of aberration coefficients by ray tracing

    Oral, Martin; Lencová, Bohumila

    2009-01-01

    Roč. 109, č. 11 (2009), s. 1365-1373. ISSN 0304-3991 R&D Projects: GA AV ČR IAA100650805 Institutional research plan: CEZ:AV0Z20650511 Keywords : Aberrations * Aberration coefficients * Ray tracing * Regression * Fitting Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering Impact factor: 2.067, year: 2009

  3. Optimum aberration coefficients for recording high-resolution off-axis holograms in a Cs-corrected TEM

    Linck, Martin, E-mail: linck@ceos-gmbh.de [CEOS GmbH, Englerstr. 28, D-69126 Heidelberg (Germany)

    2013-01-15

    Amongst the impressive improvements in high-resolution electron microscopy, the Cs-corrector also has significantly enhanced the capabilities of off-axis electron holography. Recently, it has been shown that the signal above noise in the reconstructable phase can be significantly improved by combining holography and hardware aberration correction. Additionally, with a spherical aberration close to zero, the traditional optimum focus for recording high-resolution holograms ('Lichte's defocus') has become less stringent and both, defocus and spherical aberration, can be selected freely within a certain range. This new degree of freedom can be used to improve the signal resolution in the holographically reconstructed object wave locally, e.g. at the atomic positions. A brute force simulation study for an aberration corrected 200 kV TEM is performed to determine optimum values for defocus and spherical aberration for best possible signal to noise in the reconstructed atomic phase signals. Compared to the optimum aberrations for conventional phase contrast imaging (NCSI), which produce 'bright atoms' in the image intensity, the resulting optimum values of defocus and spherical aberration for off-axis holography enable 'black atom contrast' in the hologram. However, they can significantly enhance the local signal resolution at the atomic positions. At the same time, the benefits of hardware aberration correction for high-resolution off-axis holography are preserved. It turns out that the optimum is depending on the object and its thickness and therefore not universal. -- Highlights: Black-Right-Pointing-Pointer Optimized aberration parameters for high-resolution off-axis holography. Black-Right-Pointing-Pointer Simulation and analysis of noise in high-resolution off-axis holograms. Black-Right-Pointing-Pointer Improving signal resolution in the holographically reconstructed phase shift. Black-Right-Pointing-Pointer Comparison of &apos

  4. Nodal aberration theory applied to freeform surfaces

    Fuerschbach, Kyle; Rolland, Jannick P.; Thompson, Kevin P.

    2014-12-01

    When new three-dimensional packages are developed for imaging optical systems, the rotational symmetry of the optical system is often broken, changing its imaging behavior and making the optical performance worse. A method to restore the performance is to use freeform optical surfaces that compensate directly the aberrations introduced from tilting and decentering the optical surfaces. In order to effectively optimize the shape of a freeform surface to restore optical functionality, it is helpful to understand the aberration effect the surface may induce. Using nodal aberration theory the aberration fields induced by a freeform surface in an optical system are explored. These theoretical predications are experimentally validated with the design and implementation of an aberration generating telescope.

  5. Aberration compensation in charged particle projection lithography

    Projection systems offer the opportunity to increase the throughput for charged particle lithography, because such systems image a large area of a mask directly on to a wafer as a single shot. Shots have to be imaged over a certain range of off-axis distances at the wafer to increase the writing speed, because shot sizes are limited to about 0.25x0.25 mm2 due to aberrations. In a projection system with only lenses, however, the aberrations for off-axis shots are still very large, and some aberration compensation elements need to be introduced. In this paper, three aberration compensation elements (deflectors, stigmators and dynamic focus lenses) are first discussed, a suite of newly developed software, called PROJECTION, based on this principle and our unified aberration theory is then described, and an illustrative example computed with the software is finally given

  6. Higher-Order Aberrations in Myopic Eyes

    Farid Karimian

    2010-01-01

    Full Text Available Purpose: To evaluate the correlation between refractive error and higher-order aberrations (HOAs in patients with myopic astigmatism. Methods: HOAs were measured using the Zywave II aberrometer over a 6 mm pupil. Correlations between HOAs and myopia, astigmatism, and age were analyzed. Results: One hundred and twenty-six eyes of 63 subjects with mean age of 26.4±5.9 years were studied. Mean spherical equivalent refractive error and refractive astigmatism were -4.94±1.63 D and 0.96±1.06 D, respectively. The most common higher-order aberration was primary horizontal trefoil with mean value of 0.069±0.152 μm followed by spherical aberration (-0.064±0.130 μm and primary vertical coma (-0.038±0.148 μm. As the order of aberration increased from third to fifth, its contribution to total HOA decreased: 53.9% for third order, 31.9% for fourth order, and 14.2% for fifth order aberrations. Significant correlations were observed between spherical equivalent refractive error and primary horizontal coma (R=0.231, P=0.022, and root mean square (RMS of spherical aberration (R=0.213, P=0.031; between astigmatism and RMS of total HOA (R=0.251, P=0.032, RMS of fourth order aberration (R=0.35, P<0.001, and primary horizontal coma (R=0.314, P=0.004. Spherical aberration (R=0.214, P=0.034 and secondary vertical coma (R=0.203, P=0.031 significantly increased with age. Conclusion: Primary horizontal trefoil, spherical aberration and primary vertical coma are the predominant higher-order aberrations in eyes with myopic astigmatism.

  7. ROLE OF PI3K-AKT-mTOR AND Wnt SIGNALING PATHWAYS IN G1-S TRANSITION OF CELL CYCLE IN CANCER CELLS

    LAKSHMIPATHI eVADLAKONDA

    2013-04-01

    Full Text Available The PI3K–Akt pathway together with one of its downstream targets, the mechanistic target of rapamycin (mTOR is a highly deregulated pathway in cancers. There is a reciprocal relation between the Akt phosphorylation and mTOR complexes. Akt phosphorylated at T308 activates mTORC1 by inhibition of the tuberous sclerosis complex (TSC1/2, where as mTORC2 is recognized as the kinase that phosphorylates Akt at S473. Recent developments in the research on regulatory mechanisms of autophagy places mTORC1 mediated inhibition of autophagy at the central position in activation of proliferation and survival pathways in cells. Autophagy is a negative regulator of Wnt signaling pathway and the downstream effectors of Wnt signaling pathway, cyclin D1 and the c-Myc, are the key players in initiation of cell cycle and regulation of the G1-S transition in cancer cells. Production of reaction oxygen species (ROS, a common feature of a cancer cell metabolism, activates several downstream targets like the transcription factors FoxO, which play key roles in promoting the progression of cell cycle. A model is presented on the role of PI3K -Akt - mTOR and Wnt pathways in regulation of the progression of cell cycle through Go-G1-and S phases.

  8. Chromosome aberration assays in Allium

    Grant, W.F.

    1982-01-01

    The common onion (Allium cepa) is an excellent plant for the assay of chromosome aberrations after chemical treatment. Other species of Allium (A. cepa var. proliferum, A. carinatum, A. fistulosum and A. sativum) have also been used but to a much lesser extent. Protocols have been given for using root tips from either bulbs or seeds of Allium cepa to study the cytological end-points, such as chromosome breaks and exchanges, which follow the testing of chemicals in somatic cells. It is considered that both mitotic and meiotic end-points should be used to a greater extent in assaying the cytogenetic effects of a chemical. From a literature survey, 148 chemicals are tabulated that have been assayed in 164 Allium tests for their clastogenic effect. Of the 164 assays which have been carried out, 75 are reported as giving a positive reaction, 49 positive and with a dose response, 1 positive and temperature-related, 9 borderline positive, and 30 negative; 76% of the chemicals gave a definite positive response. It is proposed that the Allium test be included among those tests routinely used for assessing chromosomal damage induced by chemicals.

  9. Adaptive optics full-field OCT: a resolution almost insensitive to aberrations (Conference Presentation)

    Xiao, Peng; Fink, Mathias; Boccara, A. Claude

    2016-03-01

    A Full-Field OCT (FFOCT) setup coupled to a compact transmissive liquid crystal spatial light modulator (LCSLM) is used to induce or correct aberrations and simulate eye examinations. To reduce the system complexity, strict pupil conjugation was abandoned. During our work on quantifying the effect of geometrical aberrations on FFOCT images, we found that the image resolution is almost insensitive to aberrations. Indeed if the object channel PSF is distorted, its interference with the reference channel conserves the main feature of an unperturbed PSF with only a reduction of the signal level. This unique behavior is specific to the use of a spatially incoherent illumination. Based on this, the FFOCT image intensity was used as the metric for our wavefront sensorless correction. Aberration correction was first conducted on an USAF resolution target with the LSCLM as both aberration generator and corrector. A random aberration mask was induced, and the low-order Zernike Modes were corrected sequentially according to the intensity metric function optimization. A Ficus leaf and a fixed mouse brain tissue slice were also imaged to demonstrate the correction of sample self-induced wavefront distortions. After optimization, more structured information appears for the leaf imaging. And the high-signal fiber-like myelin fiber structures were resolved much more clearly after the whole correction process for mouse brain imaging. Our experiment shows the potential of this compact AO-FFOCT system for aberration correction imaging. This preliminary approach that simulates eyes aberrations correction also opens the path to a simple implementation of FFOCT adaptive optics for retinal examinations.

  10. Effect of aberrations in vortex spatial filtering

    Sharma, Manoj Kumar; Joseph, Joby; Senthilkumaran, P.

    2012-11-01

    Edge enhancement is a very important operation in image processing and a spiral phase plate can be used as a radial Hilbert mask for isotropic edge enhancement. In this paper we analyze the effect of various Seidel aberrations on the performance of radial Hilbert mask or the vortex phase mask. The aberrated vortex phase mask is implemented optically with the help of a high resolution, spatial light modulator (SLM). It has also been shown that out of various aberrations astigmatism can introduce anisotropy in the Hilbert mask which causes selective edge enhancement.

  11. Aberrant 3H in Ehrlich mouse ascites tumor cell nucleotides after in vivo labeling with myo-[2-3H]- and L -myo-[1-3H]inositol: implications for measuring inositol phosphate signaling

    Christensen, Søren C.; Jensen, Annelie Kolbjørn; Simonsen, L.O.

    2003-01-01

    After in vivo radiolabeling of Ehrlich cells for 24 h with conventional myo-[2-3H]inositol we previously demonstrated an aberrant 3H-labeling of ATP that interfered in the HPLC analysis of inositol trisphosphates. This aberrant 3H-labeling was accounted for by the extensive kidney catabolism of m......]Inositol appears nevertheless to be a preferable alternative to myo-[2-3H]inositol for tracing the intact myo-inositol molecule after in vivo labeling, with minimized interference from aberrant 3H-labeling of nucleotides....

  12. Spatially incoherent illumination interferometry: a PSF almost insensitive to aberrations

    Xiao, Peng; Boccara, A Claude

    2016-01-01

    We show that with spatially incoherent illumination, the point spread function width of an imaging interferometer like that used in full-field optical coherence tomography (FFOCT) is almost insensitive to aberrations that mostly induce a reduction of the signal level without broadening. This is demonstrated by comparison with traditional scanning OCT and wide-field OCT with spatially coherent illuminations. Theoretical analysis, numerical calculation as well as experimental results are provided to show this specific merit of incoherent illumination in full-field OCT. To the best of our knowledge, this is the first time that such result has been demonstrated.

  13. Aberration corrected Lorentz scanning transmission electron microscopy

    We present results from an aberration corrected scanning transmission electron microscope which has been customised for high resolution quantitative Lorentz microscopy with the sample located in a magnetic field free or low field environment. We discuss the innovations in microscope instrumentation and additional hardware that underpin the imaging improvements in resolution and detection with a focus on developments in differential phase contrast microscopy. Examples from materials possessing nanometre scale variations in magnetisation illustrate the potential for aberration corrected Lorentz imaging as a tool to further our understanding of magnetism on this lengthscale. - Highlights: • Demonstration of nanometre scale resolution in magnetic field free environment using aberration correction in the scanning transmission electron microscope (STEM). • Implementation of differential phase contrast mode of Lorentz microscopy in aberration corrected STEM with improved sensitivity. • Quantitative imaging of magnetic induction of nanostructures in amorphous and cross-section samples

  14. Aberration features in directional dark matter detection

    Bozorgnia, Nassim; Gondolo, Paolo

    2012-01-01

    The motion of the Earth around the Sun causes an annual change in the magnitude and direction of the arrival velocity of dark matter particles on Earth, in a way analogous to aberration of stellar light. In directional detectors, aberration of weakly interacting massive particles (WIMPs) modulates the pattern of nuclear recoil directions in a way that depends on the orbital velocity of the Earth and the local galactic distribution of WIMP velocities. Knowing the former, WIMP aberration can give information on the latter, besides being a curious way of confirming the revolution of the Earth and the extraterrestrial provenance of WIMPs. While observing the full aberration pattern requires extremely large exposures, we claim that the annual variation of the mean recoil direction or of the event counts over specific solid angles may be detectable with moderately large exposures. For example, integrated counts over galactic hemispheres separated by planes perpendicular to Earth's orbit would modulate annually, res...

  15. Catadioptric aberration correction in cathode lens microscopy

    Tromp, R.M. [IBM T.J. Watson Research Center, PO Box 218, Yorktown Heights, NY 10598 (United States); Kamerlingh Onnes Laboratory, Leiden Institute of Physics, Niels Bohrweg 2, 2333 CA Leiden (Netherlands)

    2015-04-15

    In this paper I briefly review the use of electrostatic electron mirrors to correct the aberrations of the cathode lens objective lens in low energy electron microscope (LEEM) and photo electron emission microscope (PEEM) instruments. These catadioptric systems, combining electrostatic lens elements with a reflecting mirror, offer a compact solution, allowing simultaneous and independent correction of both spherical and chromatic aberrations. A comparison with catadioptric systems in light optics informs our understanding of the working principles behind aberration correction with electron mirrors, and may point the way to further improvements in the latter. With additional developments in detector technology, 1 nm spatial resolution in LEEM appears to be within reach. - Highlights: • The use of electron mirrors for aberration correction in LEEM/PEEM is reviewed. • A comparison is made with similar systems in light optics. • Conditions for 1 nm spatial resolution are discussed.

  16. Catadioptric aberration correction in cathode lens microscopy

    In this paper I briefly review the use of electrostatic electron mirrors to correct the aberrations of the cathode lens objective lens in low energy electron microscope (LEEM) and photo electron emission microscope (PEEM) instruments. These catadioptric systems, combining electrostatic lens elements with a reflecting mirror, offer a compact solution, allowing simultaneous and independent correction of both spherical and chromatic aberrations. A comparison with catadioptric systems in light optics informs our understanding of the working principles behind aberration correction with electron mirrors, and may point the way to further improvements in the latter. With additional developments in detector technology, 1 nm spatial resolution in LEEM appears to be within reach. - Highlights: • The use of electron mirrors for aberration correction in LEEM/PEEM is reviewed. • A comparison is made with similar systems in light optics. • Conditions for 1 nm spatial resolution are discussed

  17. Sensing Phase Aberrations behind Lyot Coronagraphs

    Sivaramakrishnan, Anand; Soummer, Rémi; Pueyo, Laurent; Wallace, J. Kent; Shao, Michael

    2008-11-01

    Direct detection of young extrasolar planets orbiting nearby stars can be accomplished from the ground with extreme adaptive optics and coronagraphy in the near-infrared, as long as this combination can provide an image with a dynamic range of 107 after the data are processed. Slowly varying speckles due to residual phase aberrations that are not measured by the primary wave-front sensor are the primary obstacle to achieving such a dynamic range. In particular, non-common optical path aberrations occurring between the wave-front sensor and the coronagraphic occulting spot degrade performance the most. We analyze the passage of both low and high spatial frequency phase ripples, as well as low-order Zernike aberrations, through an apodized pupil Lyot coronagraph in order to demonstrate the way coronagraphic filtering affects various aberrations. We derive the coronagraphically induced cutoff frequency of the filtering and estimate coronagraphic contrast losses due to low-order Zernike aberrations: tilt, astigmatism, defocus, coma, and spherical aberration. Such slowly varying path errors can be measured behind a coronagraph and corrected by a slowly updated optical path delay precompensation or offset asserted on the wave front by the adaptive optics (AO) system. We suggest ways of measuring and correcting all but the lowest spatial frequency aberrations using Lyot plane wave-front data, in spite of the complex interaction between the coronagraph and those mid-spatial frequency aberrations that cause image plane speckles near the coronagraphic focal plane mask occulter's edge. This investigation provides guidance for next-generation coronagraphic instruments currently under construction.

  18. Aberrant right hepatic artery; A case report

    We present a rare case of aberrant hepatic artery in a 40-year-old male with a history of chronic cholecystitis. During laparoscopic surgery, the artery found to pass anterior to the body the gallbladder and bifurcating anterior to the gallbladder body. The surgery was un eventful. We present this anomaly of the rare condition of aberrant right hepatic artery which should be in mind during laparoscopic cholecystectomy, because inadverant injury could lead to massive bleeding and increase co morbidities. (author)

  19. Turning acne on/off via mTORC1

    Danby, F. William

    2013-01-01

    Over the past 10 years, the increase in comprehension of the mechanisms behind acne has been truly exponential. Starting with the ethnological work of Cordain, accelerated by the epidemiological work of Adebamowo, supported by the clinical trials of Smith and Mann, Kwon, DiLandro and others, the interface of diet and acne is coming into focus. Melnik now presents an exceptional pair of papers that illustrate for dermatologists what translational research is all about. The Western diet, the ro...

  20. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders

    Ryan M Smith; Wolfgang eSadee

    2011-01-01

    Interactions between presynaptic and postsynaptic cellular adhesion molecules drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of cellular adhesion molecule RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic ...

  1. Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders

    Smith, Ryan M; Sadee, Wolfgang

    2011-01-01

    Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of CAM RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins i...

  2. The ATM kinase signaling induced by the low-energy {beta}-particles emitted by {sup 33}P is essential for the suppression of chromosome aberrations and is greater than that induced by the energetic {beta}-particles emitted by {sup 32}P

    White, Jason S.; Yue Ning [Department of Radiation Oncology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 (United States); Hu Jing [Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 (United States); Bakkenist, Christopher J., E-mail: bakkenistcj@upmc.edu [Department of Radiation Oncology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 (United States); Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 (United States)

    2011-03-15

    Ataxia-telangiectasia mutated (ATM) encodes a nuclear serine/threonine protein kinase whose activity is increased in cells exposed to low doses of ionizing radiation (IR). Here we examine ATM kinase activation in cells exposed to either {sup 32}P- or {sup 33}P-orthophosphate under conditions typically employed in metabolic labelling experiments. We calculate that the absorbed dose of IR delivered to a 5 cm x 5 cm monolayer of cells incubated in 2 ml media containing 1 mCi of the high-energy (1.70 MeV) {beta}-particle emitter {sup 32}P-orthophosphate for 30 min is {approx}1 Gy IR. The absorbed dose of IR following an otherwise identical exposure to the low-energy (0.24 MeV) {beta}-particle emitter {sup 33}P-orthophosphate is {approx}0.18 Gy IR. We show that low-energy {beta}-particles emitted by {sup 33}P induce a greater number of ionizing radiation-induced foci (IRIF) and greater ATM kinase signaling than energetic {beta}-particles emitted by {sup 32}P. Hence, we demonstrate that it is inappropriate to use {sup 33}P-orthophosphate as a negative control for {sup 32}P-orthophosphate in experiments investigating DNA damage responses to DNA double-strand breaks (DSBs). Significantly, we show that ATM accumulates in the chromatin fraction when ATM kinase activity is inhibited during exposure to either radionuclide. Finally, we also show that chromosome aberrations accumulate in cells when ATM kinase activity is inhibited during exposure to {approx}0.36 Gy {beta}-particles emitted by {sup 33}P. We therefore propose that direct cellular exposure to {sup 33}P-orthophosphate is an excellent means to induce and label the IR-induced, ATM kinase-dependent phosphoproteome.

  3. Mouse Skeletal Muscle Fiber-Type-Specific Macroautophagy and Muscle Wasting Are Regulated by a Fyn/STAT3/Vps34 Signaling Pathway

    Eijiro Yamada

    2012-05-01

    Full Text Available Skeletal muscle atrophy induced by aging (sarcopenia, inactivity, and prolonged fasting states (starvation is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1 signaling complex, it also induced marked atrophy of glycolytic fibers with relatively less effect on oxidative muscle fibers. This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1. Physiologically, in the fed state endogenous Fyn kinase activity was increased in glycolytic but not oxidative skeletal muscle. In parallel, Y705-STAT3 phosphorylation increased with decreased Vps34 protein levels. Moreover, fed/starved regulation of Y705-STAT3 phosphorylation and Vps34 protein levels was prevented in skeletal muscle of Fyn null mice. These data demonstrate a Fyn/STAT3/Vps34 pathway that is responsible for fiber-type-specific regulation of macroautophagy and skeletal muscle atrophy.

  4. Genomic and molecular aberrations in malignant peripheral nerve sheath tumor and their roles in personalized target therapy.

    Yang, Jilong; Du, Xiaoling

    2013-09-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors with a high rate of local recurrence and a significant tendency to metastasize. Its dismal outcome points to the urgent need to establish better therapeutic strategies for patients harboring MPNSTs. The investigations of genomic and molecular aberrations in MPNSTs which detect many chromosomal aberrations, pathway abnormalities, and specific molecular aberrant events would supply multiple potential therapy targets and contribute to achievement of personalized medicine. The involved genes in the significant gains aberrations include BIRC5, CCNE2, DAB2, DDX15, EGFR, DAB2, MSH2, CDK6, HGF, ITGB4, KCNK12, LAMA3, LOXL2, MET, and PDGFRA. The involved genes in the significant deletion aberrations include CDH1, GLTSCR2, EGR1, CTSB, GATA3, SULT2A1, GLTSCR2, HMMR/RHAMM, LICAM2, MMP13, p16/INK4a, RASSF2, NM-23H1, and TP53. These genetic aberrations involve in several important signaling pathways such as TFF, EGFR, ARF, IGF1R signaling pathways. The genomic and molecular aberrations of EGFR, IGF1R, SOX9, EYA4, TOP2A, ETV4, and BIRC5 exhibit great promise as personalized therapeutic targets for MPNST patients. PMID:23830351

  5. Modelling the formation of polycentric chromosome aberrations

    Sachs, R.K.; Tarver, J. (California Univ., Berkeley, CA (United States). Dept. of Mathematics); Yates, B.L.; Morgan, W.F. (California Univ., San Francisco, CA (United States))

    1992-10-01

    Exchange-type chromosome aberrations produced by ionizing radiation or restriction enzymes are believed to result from pairwise interaction of DNA double-strand breaks (dsb). In addition to dicentrics, such aberrations may include higher-order polycentries (tricentries, tetracentrics, etc.). The authors have developed computer programs that calculate the probability of the various polycentrics for a given average number of pairwise interactions. Two models are used. Model I incorporates kinetic competition between restitution, complete exchanges (illegitimate recombination events), and incomplete exchanges. Model II allows unrestituted breaks even if there is no recombination. The models were applied to experimental observations of aberrations produced in G[sub 1] Chinese hamster ovary cells after electroporation with the restriction enzyme PvuII, which produces blunt-end dsb. (author).

  6. Modelling the formation of polycentric chromosome aberrations

    Exchange-type chromosome aberrations produced by ionizing radiation or restriction enzymes are believed to result from pairwise interaction of DNA double-strand breaks (dsb). In addition to dicentrics, such aberrations may include higher-order polycentries (tricentries, tetracentrics, etc.). The authors have developed computer programs that calculate the probability of the various polycentrics for a given average number of pairwise interactions. Two models are used. Model I incorporates kinetic competition between restitution, complete exchanges (illegitimate recombination events), and incomplete exchanges. Model II allows unrestituted breaks even if there is no recombination. The models were applied to experimental observations of aberrations produced in G1 Chinese hamster ovary cells after electroporation with the restriction enzyme PvuII, which produces blunt-end dsb. (author)

  7. Chromosomal aberrations induced by alpha particles

    The chromosomal aberrations produced by the ionizing radiation are commonly used when it is necessary to establish the exposure dose of an individual, it is a study that is used like complement of the traditional physical systems and its application is only in cases in that there is doubt about what indicates the conventional dosimetry. The biological dosimetry is based on the frequency of aberrations in the chromosomes of the lymphocytes of the individual in study and the dose is calculated taking like reference to the dose-response curves previously generated In vitro. A case of apparent over-exposure to alpha particles to which is practiced analysis of chromosomal aberrations to settle down if in fact there was exposure and as much as possible, to determine the presumed dose is presented. (Author)

  8. Estimation of dose from chromosome aberration rate

    The methods and skills of evaluating dose from correctly scored shromsome aberration rate are presented, and supplemented with corresponding BASIC computer code. The possibility and preventive measures of excessive probability of missing score of the aberrations in some of the current routine score methods are discussed. The use of dose-effect relationship with exposure time correction factor G in evaluating doses and their confidence intervals, dose estimation in mixed n-γ exposure, and identification of high by nonuniform acute exposure to low LET radiation and its dose estimation are discussed in more detail. The difference of estimated dose due to whether the interaction between subleisoms produced by n and γ have been taken into account is examined. In fitting the standard dose-aberration rate curve, proper weighing of experiment points and comparison with commonly accepted values are emphasised, and the coefficient of variation σy√y of the aberration rate y as a function of dose and exposure time is given. In appendix I and II, the dose-aberration rate formula is derived from dual action theory, and the time variation of subleisom is illustrated and in appendix III, the estimation of dose from scores of two different types of aberrations (of other related score) is illustrated. Two computer codes are given in appendix IV, one is a simple code, the other a complete code, including the fitting of standard curve. the skills of using compressed data storage, and the production of simulated 'data ' for testing the curve fitting procedure are also given

  9. Transmissive liquid-crystal device correcting primary coma aberration and astigmatism in laser scanning microscopy

    Tanabe, Ayano; Hibi, Terumasa; Ipponjima, Sari; Matsumoto, Kenji; Yokoyama, Masafumi; Kurihara, Makoto; Hashimoto, Nobuyuki; Nemoto, Tomomi

    2016-03-01

    Laser scanning microscopy allows 3D cross-sectional imaging inside biospecimens. However, certain aberrations produced can degrade the quality of the resulting images. We previously reported a transmissive liquid-crystal device that could compensate for the predominant spherical aberrations during the observations, particularly in deep regions of the samples. The device, inserted between the objective lens and the microscope revolver, improved the image quality of fixed-mouse-brain slices that were observed using two-photon excitation laser scanning microscopy, which was originally degraded by spherical aberration. In this study, we developed a transmissive device that corrects primary coma aberration and astigmatism, motivated by the fact that these asymmetric aberrations can also often considerably deteriorate image quality, even near the sample surface. The device's performance was evaluated by observing fluorescent beads using single-photon excitation laser scanning microscopy. The fluorescence intensity in the image of the bead under a cover slip tilted in the y-direction was increased by 1.5 times after correction by the device. Furthermore, the y- and z-widths of the imaged bead were reduced to 66% and 65%, respectively. On the other hand, for the imaged bead sucked into a glass capillary in the longitudinal x-direction, correction with the device increased the fluorescence intensity by 2.2 times compared to that of the aberrated image. In addition, the x-, y-, and z-widths of the bead image were reduced to 75%, 53%, and 40%, respectively. Our device successfully corrected several asymmetric aberrations to improve the fluorescent signal and spatial resolution, and might be useful for observing various biospecimens.

  10. SURF imaging beams in an aberrative medium: generation and post-processing enhancement

    Nasholm, Sven Peter; 10.1109/TUFFC.2012.2494

    2013-01-01

    This paper presents numerical simulations of dual-frequency second-order ultrasound field (SURF) reverberation suppression transmit-pulse complexes. Such propagation was previously studied in a homogeneous medium. Here instead the propagation path includes a strongly aberrating body-wall modeled by a sequence of delay-screens. The applied SURF transmit pulse complexes each consist of a high-frequency imaging 3.5 MHz pulse combined with a low-frequency 0.5 MHz sound speed manipulation pulse. Furthermore, the feasibility of two signal post-processing methods are investigated using the aberrated transmit SURF beams. These methods are previously shown to adjust the depth of maximum SURF reverberation suppression within a homogeneous medium. The request of the study arises because imaging situations where reverberation suppression is useful are also likely to produce pulse wave-front distortion (aberration). Such distortions could potentially produce time-delays that cancel the accumulated propagation time-delay n...

  11. The correction of electron lens aberrations

    Hawkes, P.W., E-mail: peter.hawkes@cemes.fr

    2015-09-15

    The progress of electron lens aberration correction from about 1990 onwards is chronicled. Reasonably complete lists of publications on this and related topics are appended. A present for Max Haider and Ondrej Krivanek in the year of their 65th birthdays. By a happy coincidence, this review was completed in the year that both Max Haider and Ondrej Krivanek reached the age of 65. It is a pleasure to dedicate it to the two leading actors in the saga of aberration corrector design and construction. They would both wish to associate their colleagues with such a tribute but it is the names of Haider and Krivanek (not forgetting Joachim Zach) that will remain in the annals of electron optics, next to that of Harald Rose. I am proud to know that both regard me as a friend as well as a colleague. - Highlights: • Geometrical aberration correction. • Chromatic aberration correction. • 50 pm resolution. • High-resolution electron energy-loss spectroscopy. • Extensive bibliographies.

  12. Aberration features in directional dark matter detection

    The motion of the Earth around the Sun causes an annual change in the magnitude and direction of the arrival velocity of dark matter particles on Earth, in a way analogous to aberration of stellar light. In directional detectors, aberration of weakly interacting massive particles (WIMPs) modulates the pattern of nuclear recoil directions in a way that depends on the orbital velocity of the Earth and the local galactic distribution of WIMP velocities. Knowing the former, WIMP aberration can give information on the latter, besides being a curious way of confirming the revolution of the Earth and the extraterrestrial provenance of WIMPs. While observing the full aberration pattern requires extremely large exposures, we claim that the annual variation of the mean recoil direction or of the event counts over specific solid angles may be detectable with moderately large exposures. For example, integrated counts over Galactic hemispheres separated by planes perpendicular to Earth's orbit would modulate annually, resulting in Galactic Hemisphere Annual Modulations (GHAM) with amplitudes larger than the usual non-directional annual modulation

  13. Prenatal hydronephrosis caused by aberrant renal vessels

    Lenz, K; Thorup, Jørgen Mogens; Rabol, A;

    1996-01-01

    With routine use of obstetric ultrasonography, fetal low-grade hydronephrosis is commonly detected, but may resolve spontaneously after birth. Two cases are presented to illustrate that in some cases such findings can express intermittent hydronephrosis caused by aberrant renal vessels. Renal det...

  14. The correction of electron lens aberrations

    The progress of electron lens aberration correction from about 1990 onwards is chronicled. Reasonably complete lists of publications on this and related topics are appended. A present for Max Haider and Ondrej Krivanek in the year of their 65th birthdays. By a happy coincidence, this review was completed in the year that both Max Haider and Ondrej Krivanek reached the age of 65. It is a pleasure to dedicate it to the two leading actors in the saga of aberration corrector design and construction. They would both wish to associate their colleagues with such a tribute but it is the names of Haider and Krivanek (not forgetting Joachim Zach) that will remain in the annals of electron optics, next to that of Harald Rose. I am proud to know that both regard me as a friend as well as a colleague. - Highlights: • Geometrical aberration correction. • Chromatic aberration correction. • 50 pm resolution. • High-resolution electron energy-loss spectroscopy. • Extensive bibliographies

  15. Optical advantages of astigmatic aberration corrected heliostats

    van Rooyen, De Wet; Schöttl, Peter; Bern, Gregor; Heimsath, Anna; Nitz, Peter

    2016-05-01

    Astigmatic aberration corrected heliostats adapt their shape in dependence of the incidence angle of the sun on the heliostat. Simulations show that this optical correction leads to a higher concentration ratio at the target and thus in a decrease in required receiver aperture in particular for smaller heliostat fields.

  16. Anti-forensics of chromatic aberration

    Mayer, Owen; Stamm, Matthew C.

    2015-03-01

    Over the past decade, a number of information forensic techniques have been developed to identify digital image manipulation and falsification. Recent research has shown, however, that an intelligent forger can use anti-forensic countermeasures to disguise their forgeries. In this paper, an anti-forensic technique is proposed to falsify the lateral chromatic aberration present in a digital image. Lateral chromatic aberration corresponds to the relative contraction or expansion between an image's color channels that occurs due to a lens's inability to focus all wavelengths of light on the same point. Previous work has used localized inconsistencies in an image's chromatic aberration to expose cut-and-paste image forgeries. The anti-forensic technique presented in this paper operates by estimating the expected lateral chromatic aberration at an image location, then removing deviations from this estimate caused by tampering or falsification. Experimental results are presented that demonstrate that our anti-forensic technique can be used to effectively disguise evidence of an image forgery.

  17. Cosmological parameter estimation: impact of CMB aberration

    The peculiar motion of an observer with respect to the CMB rest frame induces an apparent deflection of the observed CMB photons, i.e. aberration, and a shift in their frequency, i.e. Doppler effect. Both effects distort the temperature multipoles alm's via a mixing matrix at any l. The common lore when performing a CMB based cosmological parameter estimation is to consider that Doppler affects only the l = 1 multipole, and neglect any other corrections. In this paper we reconsider the validity of this assumption, showing that it is actually not robust when sky cuts are included to model CMB foreground contaminations. Assuming a simple fiducial cosmological model with five parameters, we simulated CMB temperature maps of the sky in a WMAP-like and in a Planck-like experiment and added aberration and Doppler effects to the maps. We then analyzed with a MCMC in a Bayesian framework the maps with and without aberration and Doppler effects in order to assess the ability of reconstructing the parameters of the fiducial model. We find that, depending on the specific realization of the simulated data, the parameters can be biased up to one standard deviation for WMAP and almost two standard deviations for Planck. Therefore we conclude that in general it is not a solid assumption to neglect aberration in a CMB based cosmological parameter estimation

  18. An emerging role for the mammalian Target of Rapamycin (mTOR in 'pathological' protein translation: relevance to cocaine addiction

    Christopher V Dayas

    2012-02-01

    Full Text Available Complex neuroadaptations within key nodes of the brain’s ‘reward circuitry’ are thought to underpin long-term vulnerability to relapse. A more comprehensive understanding of the molecular and cellular signalling events that subserve relapse vulnerability may lead to pharmacological treatments that could improve treatment outcomes for psychostimulant-addicted individuals. Recent advances in this regard include findings that drug-induced perturbations to neurotrophin, metabotropic glutamate receptor and dopamine receptor signalling pathways perpetuate plasticity impairments at excitatory glutamatergic synapses on ventral tegmental area (VTA and nucleus accumbens (NAC neurons. In the context of addiction, much previous work, in terms of downstream effectors to these receptor systems, has centered on the extracellular-regulated MAP kinase (ERK signalling pathway. The purpose of the present review is to highlight the evidence of an emerging role for another downstream effector of these addiction-relevant receptor systems - the mammalian target of rapamycin complex 1 (mTORC1. mTORC1 functions to regulate synaptic protein translation and is a potential critical link in our understanding of the neurobiological processes that drive addiction and relapse behavior. The precise cellular and molecular changes that are regulated by mTORC1 and contribute to relapse vulnerability are only just coming to light. Therefore, we aim to highlight evidence that mTORC1 signalling may be dysregulated by drug-exposure and that these changes may contribute to aberrant translation of synaptic proteins that appear critical to increased relapse vulnerability, including AMPARs. The importance of understanding the role of this signalling pathway in the development of addiction vulnerability is underscored by the fact that the mTORC1 inhibitor rapamycin reduces drug-seeking in preclinical models and preliminary evidence indicating that rapamycin suppresses drug craving in

  19. An Emerging Role for the Mammalian Target of Rapamycin in “Pathological” Protein Translation: Relevance to Cocaine Addiction

    Dayas, Christopher V.; Smith, Doug W.; Dunkley, Peter R.

    2011-01-01

    Complex neuroadaptations within key nodes of the brain’s “reward circuitry” are thought to underpin long-term vulnerability to relapse. A more comprehensive understanding of the molecular and cellular signaling events that subserve relapse vulnerability may lead to pharmacological treatments that could improve treatment outcomes for psychostimulant-addicted individuals. Recent advances in this regard include findings that drug-induced perturbations to neurotrophin, metabotropic glutamate receptor, and dopamine receptor signaling pathways perpetuate plasticity impairments at excitatory glutamatergic synapses on ventral tegmental area and nucleus accumbens neurons. In the context of addiction, much previous work, in terms of downstream effectors to these receptor systems, has centered on the extracellular-regulated MAP kinase signaling pathway. The purpose of the present review is to highlight the evidence of an emerging role for another downstream effector of these addiction-relevant receptor systems – the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 functions to regulate synaptic protein translation and is a potential critical link in our understanding of the neurobiological processes that drive addiction and relapse behavior. The precise cellular and molecular changes that are regulated by mTORC1 and contribute to relapse vulnerability are only just coming to light. Therefore, we aim to highlight evidence that mTORC1 signaling may be dysregulated by drug exposure and that these changes may contribute to aberrant translation of synaptic proteins that appear critical to increased relapse vulnerability, including AMPARs. The importance of understanding the role of this signaling pathway in the development of addiction vulnerability is underscored by the fact that the mTORC1 inhibitor rapamycin reduces drug-seeking in pre-clinical models and preliminary evidence indicating that rapamycin suppresses drug craving in humans. PMID:22347189

  20. Aberrantly methylated DNA as a biomarker in breast cancer

    Kristiansen, Søren; Jørgensen, Lars Mønster; Guldberg, Per;

    2013-01-01

    hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients......Aberrant DNA hypermethylation at gene promoters is a frequent event in human breast cancer. Recent genome-wide studies have identified hundreds of genes that exhibit differential methylation between breast cancer cells and normal breast tissue. Due to the tumor-specific nature of DNA...... occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients into...

  1. Primary aberrations in focused radially polarized vortex beams

    Biss, David P.; Brown, T. G.

    2004-02-01

    We study the effect of primary aberrations on the 3-D polarization of the electric field in a focused lowest order radially polarized beam. A full vector diffraction treatment of the focused beams is used. Attention is given to the effects of primary spherical, astigmatic, and comatic aberrations on the local polarization, Strehl ratio, and aberration induced degradation of the longitudinal field at focus

  2. The correction of electron lens aberrations.

    Hawkes, P W

    2015-09-01

    The progress of electron lens aberration correction from about 1990 onwards is chronicled. Reasonably complete lists of publications on this and related topics are appended. A present for Max Haider and Ondrej Krivanek in the year of their 65th birthdays. By a happy coincidence, this review was completed in the year that both Max Haider and Ondrej Krivanek reached the age of 65. It is a pleasure to dedicate it to the two leading actors in the saga of aberration corrector design and construction. They would both wish to associate their colleagues with such a tribute but it is the names of Haider and Krivanek (not forgetting Joachim Zach) that will remain in the annals of electron optics, next to that of Harald Rose. I am proud to know that both regard me as a friend as well as a colleague. PMID:26025209

  3. Do patients with schizophrenia exhibit aberrant salience?

    Roiser, J. P.; Stephan, K E; den Ouden, H. E. M.; Barnes, T. R. E.; Friston, K.J.; Joyce, E. M.

    2009-01-01

    BACKGROUND: It has been suggested that some psychotic symptoms reflect ‘aberrant salience’, related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulusreinforcement associations in the presence of distracting task-irrelevant cues. METHODS: We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, ...

  4. Tailored displays to compensate for visual aberrations

    Pamplona, Vitor F.; Oliveira, Manuel M.; Aliaga, Daniel G.; Raskar, Ramesh

    2012-01-01

    We introduce tailored displays that enhance visual acuity by decomposing virtual objects and placing the resulting anisotropic pieces into the subject's focal range. The goal is to free the viewer from needing wearable optical corrections when looking at displays. Our tailoring process uses aberration and scattering maps to account for refractive errors and cataracts. It splits an object's light field into multiple instances that are each in-focus for a given eye sub-aperture. Their integrati...

  5. Assessing the construct validity of aberrant salience

    Kristin Schmidt

    2009-12-01

    Full Text Available We sought to validate the psychometric properties of a recently developed paradigm that aims to measure salience attribution processes proposed to contribute to positive psychotic symptoms, the Salience Attribution Test (SAT. The “aberrant salience” measure from the SAT showed good face validity in previous results, with elevated scores both in high-schizotypy individuals, and in patients with schizophrenia suffering from delusions. Exploring the construct validity of salience attribution variables derived from the SAT is important, since other factors, including latent inhibition/learned irrelevance, attention, probabilistic reward learning, sensitivity to probability, general cognitive ability and working memory could influence these measures. Fifty healthy participants completed schizotypy scales, the SAT, a learned irrelevance task, and a number of other cognitive tasks tapping into potentially confounding processes. Behavioural measures of interest from each task were entered into a principal components analysis, which yielded a five-factor structure accounting for ~75% percent of the variance in behaviour. Implicit aberrant salience was found to load onto its own factor, which was associated with elevated “Introvertive Anhedonia” schizotypy, replicating our previous finding. Learned irrelevance loaded onto a separate factor, which also included implicit adaptive salience, but was not associated with schizotypy. Explicit adaptive and aberrant salience, along with a measure of probabilistic learning, loaded onto a further factor, though this also did not correlate with schizotypy. These results suggest that the measures of learned irrelevance and implicit adaptive salience might be based on similar underlying processes, which are dissociable both from implicit aberrant salience and explicit measures of salience.

  6. DNA Repair Defects and Chromosomal Aberrations

    Hada, Megumi; George, K. A.; Huff, J. L.; Pluth, J. M.; Cucinotta, F. A.

    2009-01-01

    Yields of chromosome aberrations were assessed in cells deficient in DNA doublestrand break (DSB) repair, after exposure to acute or to low-dose-rate (0.018 Gy/hr) gamma rays or acute high LET iron nuclei. We studied several cell lines including fibroblasts deficient in ATM (ataxia telangiectasia mutated; product of the gene that is mutated in ataxia telangiectasia patients) or NBS (nibrin; product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase (DNA-PK) activity. Chromosomes were analyzed using the fluorescence in situ hybridization (FISH) chromosome painting method in cells at the first division post irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). Gamma irradiation induced greater yields of both simple and complex exchanges in the DSB repair-defective cells than in the normal cells. The quadratic dose-response terms for both simple and complex chromosome exchanges were significantly higher for the ATM- and NBS-deficient lines than for normal fibroblasts. However, in the NBS cells the linear dose-response term was significantly higher only for simple exchanges. The large increases in the quadratic dose-response terms in these repair-defective cell lines points the importance of the functions of ATM and NBS in chromatin modifications to facilitate correct DSB repair and minimize the formation of aberrations. The differences found between ATM- and NBS-deficient cells at low doses suggest that important questions should with regard to applying observations of radiation sensitivity at high dose to low-dose exposures. For aberrations induced by iron nuclei, regression models preferred purely linear dose responses for simple exchanges and quadratic dose responses for complex exchanges. Relative biological effectiveness (RBE) factors of all of

  7. Radiotherapeutical chromosomal aberrations in laryngeal cancer patients

    Stošić-Divjak Svetlana L.

    2009-01-01

    Full Text Available Introduction. The authors present the results of cytogenetic analysis of 21 patients with laryngeal carcinomas diagnosed and treated in the period 1995-2000 at the Institute of Otorhinolaryngology and Maxillofacial Surgery, Clinical Center of Serbia and Clinical Center of Novi Sad. Material and methods. The patients were specially monitored and the material was analyzed at the Institute of Human Genetics of the School of Medicine in Belgrade as well as in the Laboratory for Radiological Protection of the Institute of Occupational and Radiological Health 'Dr Dragomir Karajovic' in Belgrade. Results. The incidence of chromosomal aberrations and incidence of exchange of material between sister chromatids were observed in the preparation of the metaphasic lymphocyte chromosomes of the peripheral blood obtained in the culture. Structural aberrations were found on the chromosomes in the form of breakups, rings, translocations and dicentrics as early as after a single exposure of patients to tumor radiation dose of 2 Gy in the field sized 5x7. Out of the total number of 35 cultivated blood samples obtained from 13 patients, 21 were successfully cultivated and they were proved to contain chromosomal aberrations. Some of the peripheral blood samples failed to show cell growth in vitro due to the lethal cell damages in vivo. Discussion.. We have consluded that the number of structural aberrations cannot be used as a biological measure of the absorbed ionizing radiation dose. The presence of aberrations per se is indicative of the mutagenic effect of the ionizing radiation, which was also confirmed in our series on the original model by cultivation of the peripheral blood lymphocytes in the culture of the cells of the volunteer donors upon in vitro radiation. Using the method of bromdeoxyuridylreductase, the increased incidence of SCE as a mutagenic effect was registered. Conclusion. It has been concluded that the increase of absorbed radiation dose in

  8. Chromatic variation of aberration: the role of induced aberrations and raytrace direction

    Berner, A.; Nobis, T.; Shafer, D.; Gross, H.

    2015-09-01

    The design and optimization process of an optical system contains several first order steps. The definition of the appropriate lens type and the fixation of the raytrace direction are some of them. The latter can be understood as a hidden assumption rather than an aware design step. This is usually followed by the determination of the paraxial lens layout calculated for the primary wavelength. It is obvious, that for this primary wavelength the paraxial calculations are independent of raytrace direction. Today, most of the lens designs are specified not to work only for one wavelength, but in a certain wavelength range. Considering such rays of other wavelengths, one can observe that depending on the direction there will already occur differences in the first order chromatic aberrations and additionally in the chromatic variation of the third-order aberrations. The reason for this effect are induced aberrations emerging from one surface to the following surfaces by perturbed ray heights and ray angles. It can be shown, that the total amount of surface-resolved first order chromatic aberrations and the chromatic variation of the five primary aberrations can be split into an intrinsic part and an induced part. The intrinsic part is independent of the raytrace direction whereas the induced part is not.

  9. Block of gap junctions eliminates aberrant activity and restores light responses during retinal degeneration.

    Toychiev, Abduqodir H; Ivanova, Elena; Yee, Christopher W; Sagdullaev, Botir T

    2013-08-28

    Retinal degeneration leads to progressive photoreceptor cell death, resulting in vision loss. Subsequently, inner retinal neurons develop aberrant synaptic activity, compounding visual impairment. In retinal ganglion cells, light responses driven by surviving photoreceptors are obscured by elevated levels of aberrant spiking activity. Here, we demonstrate in rd10 mice that targeting disruptive neuronal circuitry with a gap junction antagonist can significantly reduce excessive spiking. This treatment increases the sensitivity of the degenerated retina to light stimuli driven by residual photoreceptors. Additionally, this enhances signal transmission from inner retinal neurons to ganglion cells, potentially allowing the retinal network to preserve the fidelity of signals either from prosthetic electronic devices, or from cells optogenetically modified to transduce light. Thus, targeting maladaptive changes to the retina allows for treatments to use existing neuronal tissue to restore light sensitivity, and to augment existing strategies to replace lost photoreceptors. PMID:23986234

  10. Expression and aberrant promoter methylation of Wnt inhibitory factor-1 in human astrocytomas

    Wu Jun; Liu Jinfang; Chen Fenghua; Fang Jiasheng; Wang Ying; Yang Zhuanyi; Wang Yanjin

    2010-01-01

    Abstract Background Wnt inhibitory factor-1(WIF-1) acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas. Methods The tissue samples consisted of 53 astrocytomas and 6 normal brain tissues. The expression levels of WIF-1 were det...

  11. Activation of a metabolic gene regulatory network downstream of mTOR complex 1

    Düvel, Katrin; Yecies, Jessica L.; Menon, Suchithra; Raman, Pichai; Lipovsky, Alex I.; Souza, Amanda L.; Triantafellow, Ellen; Ma, Qicheng; Gorski, Regina; Cleaver, Stephen; Heiden, Matthew G. Vander; MacKeigan, Jeffrey P.; Finan, Peter M.; Clish, Clary B; Murphy, Leon O.

    2010-01-01

    Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidati...

  12. Chromosomal aberrations in ISS crew members

    Johannes, Christian; Goedecke, Wolfgang; Antonopoulos, Alexandra

    2012-07-01

    High energy radiation is a major risk factor in manned space missions. Astronauts and cosmonauts are exposed to ionising radiations of cosmic and solar origin, while on the Earth's surface people are well protected by the atmosphere and a deflecting magnetic field. There are now data available describing the dose and the quality of ionising radiation on-board of the International Space Station (ISS). Nonetheless, the effect of increased radiation dose on mutation rates of ISS crew members are hard to predict. Therefore, direct measurements of mutation rates are required in order to better estimate the radiation risk for longer duration missions. The analysis of chromosomal aberrations in peripheral blood lymphocytes is a well established method to measure radiation-induced mutations. We present data of chromosome aberration analyses from lymphocyte metaphase spreads of ISS crew members participating in short term (10-14 days) or long term (around 6 months) missions. From each subject we received two blood samples. The first sample was drawn about 10 days before launch and a second one within 3 days after return from flight. From lymphocyte cultures metaphase plates were prepared on glass slides. Giemsa stained and in situ hybridised metaphases were scored for chromosome changes in pre-flight and post-flight blood samples and the mutation rates were compared. Results obtained in chromosomal studies on long-term flight crew members showed pronounced inter-individual differences in the response to elevated radiation levels. Overall slight but significant elevations of typical radiation induced aberrations, i.e., dicentric chromosomes and reciprocal translocations have been observed. Our data indicate no elevation of mutation rates due to short term stays on-board the ISS.

  13. Clinicopathological significance of aberrant Notch receptors in intrahepatic cholangiocarcinoma

    Wu, Wen-Rui; Shi, Xiang-De; Zhang, Rui; Zhu, Man-Sheng; Xu, Lei-Bo; Yu, Xian-Huan; Zeng, Hong; Wang, Jie; Liu, Chao

    2014-01-01

    Notch signaling has been reported to be activated to promote biliary epithelial cell differentiation and tubulogenesis during bile duct development. In this study, clinicopathological significance of aberrant expression of Notch receptors in intrahepatic cholangiocarcinoma (ICC) was investigated. Thus, forty-one ICC specimens were examined by immunohistochemistry using anti-Notch1-4 antibodies, respectively. Expression of Notch receptors was scored by percentage of positive tumor cells and intensity of immunostaining. Clinicopathological parameters and survival data were compared with the expression of Notch receptors, respectively. Expression of Notch receptors was identified in cancer cells, as well as in non-neoplastic cells. Compared with adjacent non-tumor liver tissues, Notch1 and 4 were up regulated, and Notch2 and 3 were relatively weaker. Positive immunostaining of Notch1 in ICC cells was detected in 34 cases (82.9%), Notch2 in 23 (56.1%), Notch3 in 16 (39.0%) and Notch4 in 14 (34.1%). Notch1 was overexpressed in cases with tumor size > 5 cm (P = 0.036). Expression of Notch2 was correlated inversely with histological grade (P = 0.016). Overexpression of Notch4 was more common in cases with serum CA125 > 35 U/ml than cases with CA125 ≤ 35 U/ml (P = 0.048). Expression of Notch3 was not correlated with any other clinicopathological parameters. Moreover, Notch4 was related to poor survival (P < 0.001). To conclude, this study reveals that aberrant expression of Notch receptors 1 and 4 might play important roles during ICC progression. PMID:25031748

  14. Phospholipase D regulates the size of skeletal muscle cells through the activation of mTOR signaling.

    Jaafar, Rami; De Larichaudy, Joffrey; Chanon, Stéphanie; Euthine, Vanessa; Durand, Christine; Naro, Fabio; Bertolino, Philippe; Vidal, Hubert; Lefai, Etienne; Némoz, Georges

    2013-01-01

    mTOR is a major actor of skeletal muscle mass regulation in situations of atrophy or hypertrophy. It is established that Phospholipase D (PLD) activates mTOR signaling, through the binding of its product phosphatidic acid (PA) to mTOR protein. An influence of PLD on muscle cell size could thus be suspected. We explored the consequences of altered expression and activity of PLD isoforms in differentiated L6 myotubes. Inhibition or down-regulation of the PLD1 isoform markedly decreased myotube size and muscle specific protein content. Conversely, PLD1 overexpression induced muscle cell hypertrophy, both in vitro in myotubes and in vivo in mouse gastrocnemius. In the presence of atrophy-promoting dexamethasone, PLD1 overexpression or addition of exogenous PA protected myotubes against atrophy. Similarly, exogenous PA protected myotubes against TNFα-induced atrophy. Moreover, the modulation of PLD expression or activity in myotubes showed that PLD1 negatively regulates the expression of factors involved in muscle protein degradation, such as the E3-ubiquitin ligases Murf1 and Atrogin-1, and the Foxo3 transcription factor. Inhibition of mTOR by PP242 abolished the positive effects of PLD1 on myotubes, whereas modulating PLD influenced the phosphorylation of both S6K1 and Akt, which are respectively substrates of mTORC1 and mTORC2 complexes. These observations suggest that PLD1 acts through the activation of both mTORC1 and mTORC2 to induce positive trophic effects on muscle cells. This pathway may offer interesting therapeutic potentialities in the treatment of muscle wasting. PMID:23915343

  15. Aberrations in Fresnel Lenses and Mirrors

    Gregory, Don

    1999-01-01

    The NASA/MSFC Shooting Star program revealed a number of technical problems that must be solved before solar thermal propulsion can become a reality. The fundamental problem of interest here is the collection of solar energy. This is the first step in the propulsion process and indeed the most important. Everything else depends on the efficiency and focusing ability of the collection lens or mirror. An initial model of Fresnel lens behavior using a wave optics approach has been completed and the results were encouraging enough to warrant an experimental investigation. This experimental investigation confirmed some of the effects predicted and produced invaluable photographic evidence of coherence based diffraction and aberration.

  16. A proposal for the holographic correction of incoherent aberrations by tilted reference waves.

    Röder, Falk; Lubk, Axel

    2015-05-01

    The recently derived general transfer theory for off-axis electron holography provides a new approach for reconstructing the electron wave beyond the conventional sideband information limit. Limited ensemble coherence of the electron beam between object and reference area leads to an attenuation of spatial frequencies of the object exit wave in the presence of aberrations of the objective lens. Concerted tilts of the reference wave under the condition of an invariant object exit wave are proposed to diminish the aberration impact on spatial frequencies even beyond the sideband information limit allowing its transfer with maximum possible contrast. In addition to the theoretical considerations outlined in detail, an experimental proof-of-principle is presented. A fully controlled tilt of the reference wave, however, remains as a promising task for the future. The use of a hologram series with varying reference wave tilt is considered for linearly synthesizing an effective aperture for the transfer into the sideband with broader bandwidth compared to conventional off-axis electron holography allowing us to correct the incoherent aberrations in transmission electron microscopy. Furthermore, tilting a reference wave with respect to a plane wave is expected to be an alternative way for measuring the coherent and incoherent aberrations of a transmission electron microscope. The capability of tilting the reference wave is expected to be beneficial for improving the signal-to-noise ratio in dark-field off-axis electron holography as well. PMID:25680104

  17. Assessment of radial image distortion and spherical aberration on 3D synthetic aperture PIV measurements

    This paper presents a study of the effects of radial image distortion and spherical aberration on reconstruction quality of synthetic aperture particle image velocimetry (SAPIV). A simulated SAPIV system is used to image a synthetic particle volume. An idealized pinhole camera model is used for image formation with distortion and spherical aberration being added on with a polynomial model and a Fourier waveform model, respectively. Images from a simulated 5 × 5 camera array are taken, distorted or aberrated, realigned and averaged to form synthetic aperture images at a set of depths within the seeded volume. These images are thresholded to recover three-dimensional (3D) particle locations and a reconstructed 3D intensity field is formed. This reconstructed field is then evaluated according to intensity data and a signal-to-noise ratio (SNR) as well as standard and rank correlation metrics. Results show that even small amounts of image distortion and spherical aberration can lead to lower correlation values, degradation of the SNR and information loss. Use of rank correlation increases the ability to match elements between the synthetic and reconstructed volumes relative to standard correlation. (paper)

  18. Role of Nutrient-Sensing Signals in the Pathogenesis of Diabetic Nephropathy

    Shinji Kume

    2014-01-01

    Full Text Available Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. The multipronged drug approach still fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to improve the prognosis of diabetic nephropathy is urgently required. Nutrient-sensing signals and their related intracellular machinery have evolved to combat prolonged periods of starvation in mammals; and these systems are conserved in the kidney. Recent studies have suggested that the activity of three nutrient-sensing signals, mTORC1, AMPK, and Sirt1, is altered in the diabetic kidney. Furthermore, autophagy activity, which is regulated by the above-mentioned nutrient-sensing signals, is also altered in both podocytes and proximal tubular cells under diabetic conditions. Under diabetic conditions, an altered nutritional state owing to nutrient excess may disturb cellular homeostasis regulated by nutrient-responsible systems, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing relationships between nutrient-sensing signals, autophagy, and diabetic nephropathy and suggest the therapeutic potential of nutrient-sensing signals in diabetic nephropathy.

  19. Sensitivity of singular beams in the presence of Zernike aberrations

    Dixit, Awakash; Mishra, Sanjay Kumar; Gupta, Arun Kumar

    2015-08-01

    Singular beams in the presence of Zernike aberrations create an opportunity for various applications such as trapping and manipulation of micro-particles, atomic optics and atmospheric optics. In the milieu of importance of the role of aberrations, sensitivity of singular beams with Zernike aberrations is studied. In this paper, the effect of various Zernike aberrations on a singular beam is reported in terms of its Point Spread Function (PSF) deformations. The intensity distributions around the focal plane, i.e. PSF, of the singular beam of various topological charges and in the presence of different strengths of Zernike aberrations are theoretically estimated by the Huygens-Fresnel diffraction integral. Experimentally, the singular beams have been generated and known strengths of Zernike aberration introduced in the beam by a phase-only Spatial Light Modulator. Metric Ensquared Energy is used to analyze the PSF of the corresponding intensity distributions of the singular beams. The experimental results have been validated with numerical simulation.

  20. Calculation of aberration of electron gun in color picture tubes

    In a color picture tube, aberration is an important factor influencing the electron beam spot on the screen. This paper discusses a new method which is used to calculate the aberration of an electron gun in a CPT. In this method, electron trajectories are simulated directly in the cathode and the pre-focus lens. In the main lens, the asymptotic aberration is calculated to decide the size of the image. Some results of the calculation are shown in this paper. (orig.)

  1. Monitoring of chromosomal aberrations in natural populations of Pinus pallasiana

    V. P. Koba

    2012-01-01

    This paper presents the results of monitoring research of the chromosome aberrations at the stage of anaphase-telophase. The statistical characteristics of dynamics of chromosomal aberrations in populations of Pinus pallasiana D. Don across the high-altitude zones of the Mountain Crimea is given. It is established that on the southern macroslope of the Crimean Main Ridge the frequency of chromosomal aberrations in the P. pallasiana stands is higher in the lower zone in comparison with the mid...

  2. Aberrations caused by mechanical misalignments in electrostatic quadrupole lens systems

    Baranova, L. A.; Read, F. H.

    Image aberrations resulting from small misalignments in quadrupole lenses multiplets have been analysed. Analytical formulas for the coefficients of the beam displacement, astigmatism and coma associated with misalignments in a general quadrupole lens system have been derived. Numerical computations of systems of three and four quadrupole lenses have also been carried out. The aberration figures obtained for systems with and without a mechanical defect are compared. The aberration coefficients that have been obtained can be used for estimating tolerance limits for lens misalignments.

  3. Chromosomal aberrations in children exposed to diagnostic x-rays

    Among children who have received high x-ray doses congenital dislocation of the hip joint is the predominating diagnosis. In a series of 9 children who had received high x-ray doses (8 with luxation of the hip joint and one with achondroplasia) a significant increase of chromosomal aberrations was found. The increase concerned mainly chromosome type aberrations. The shorter the time since the last x-ray investigation the higher was the frequency of chromosome type aberrations. (author)

  4. Hydronephrosis by an Aberrant Renal Artery: A Case Report

    Park, Byoung Seok; Jeong, Taek Kyun; Ma, Seong Kwon; Kim, Soo Wan; Kim, Nam Ho; Choi, Ki Chul; Jeong, Yong Yeon

    2003-01-01

    Ureteropelvic junction obstruction is usually intrinsic and is most common in children. Aberrant renal arteries are present in about 30% of individuals. Aberrant renal arteries to the inferior pole cross anteriorly to the ureter and may cause hydronephrosis. To the best of our knowledge, although there are some papers about aberrant renal arteries producing ureteropelvic junction obstruction, there is no report of a case which is diagnosed by the new modalities, such as computed tomography an...

  5. Pattern of Chromosomal Aberrations in Patients from North East Iran

    Saeedeh Ghazaey; Farzaneh Mirzaei; Mitra Ahadian; Fatemeh Keifi; Semiramis Tootian; Mohammad Reza Abbaszadegan

    2013-01-01

    Objective: Chromosomal aberrations are common causes of multiple anomaly syndromes. Recurrent chromosomal aberrations have been identified by conventional cytogenetic methods used widely as one of the most important clinical diagnostic techniques. Materials and Methods: In this retrospective study, the incidences of chromosomal aberrations were evaluated in a six year period from 2005 to 2011 in Pardis Clinical and Genetics Laboratory on patients referred to from Mashhad and other cities in K...

  6. Chromosome aberration analysis for biological dosimetry: a review

    Among various biological dosimetry techniques, dicentric chromosome aberration method appears to be the method of choice in analysing accidental radiation exposure in most of the laboratories. The major advantage of this method is its sensitivity as the number of dicentric chromosomes present in control population is too small and more importantly radiation induces mainly dicentric chromosome aberration among unstable aberration. This report brings out the historical development of various cytogenetic methods, the basic structure of DNA, chromosomes and different forms of chromosome aberrations. It also highlights the construction of dose-response curve for dicentric chromosome and its use in the estimation of radiation dose. (author)

  7. Cellular origin of prognostic chromosomal aberrations in AML patients

    Mora-Jensen, H.; Jendholm, J.; Rapin, N.;

    2015-01-01

    these aberrations occur in normal hematopoietic stem and progenitor cells (HSCs/HPCs) before definitive leukemic transformation through additional acquisition of a few (that is, mostly 1 or 2) leukemia-promoting driver aberrations. NGS studies on sorted bone marrow (BM) populations of AML patients with...... molecular aberrations that were present in the fully transformed committed HPCs together with the prognostic driver aberration. Adding to this vast heterogeneity and complexity of AML genomes and their clonal evolution, a recent study of a murine AML model demonstrated that t(9;11) AML originating from HSCs...

  8. Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival

    Maia, Sara; Pelletier, Marc; Ding, Jixin; Hsu, Yen-Ming; Rao, Sambasiva P.; Cardoso, Angelo A.; Sallan, Stephen Earl; Nadler, Lee Marshall

    2011-01-01

    Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies. We observed that primary leukemia B-cell precursors aberrantly express recept...

  9. A proposal for the holographic correction of incoherent aberrations by tilted reference waves

    Röder, Falk, E-mail: Falk.Roeder@Triebenberg.de; Lubk, Axel

    2015-05-15

    The recently derived general transfer theory for off-axis electron holography provides a new approach for reconstructing the electron wave beyond the conventional sideband information limit. Limited ensemble coherence of the electron beam between object and reference area leads to an attenuation of spatial frequencies of the object exit wave in the presence of aberrations of the objective lens. Concerted tilts of the reference wave under the condition of an invariant object exit wave are proposed to diminish the aberration impact on spatial frequencies even beyond the sideband information limit allowing its transfer with maximum possible contrast. In addition to the theoretical considerations outlined in detail, an experimental proof-of-principle is presented. A fully controlled tilt of the reference wave, however, remains as a promising task for the future. The use of a hologram series with varying reference wave tilt is considered for linearly synthesizing an effective aperture for the transfer into the sideband with broader bandwidth compared to conventional off-axis electron holography allowing us to correct the incoherent aberrations in transmission electron microscopy. Furthermore, tilting a reference wave with respect to a plane wave is expected to be an alternative way for measuring the coherent and incoherent aberrations of a transmission electron microscope. The capability of tilting the reference wave is expected to be beneficial for improving the signal-to-noise ratio in dark-field off-axis electron holography as well. - Highlights: • We examine the use of tilted reference waves in off-axis electron holography. • Generalized holographic transfer theory reveals a selective filtering effect. • We propose the correction of incoherent aberrations by series acquisitions. • For a proof-of-principle, we employ a crystal for tilting the reference wave.

  10. A proposal for the holographic correction of incoherent aberrations by tilted reference waves

    The recently derived general transfer theory for off-axis electron holography provides a new approach for reconstructing the electron wave beyond the conventional sideband information limit. Limited ensemble coherence of the electron beam between object and reference area leads to an attenuation of spatial frequencies of the object exit wave in the presence of aberrations of the objective lens. Concerted tilts of the reference wave under the condition of an invariant object exit wave are proposed to diminish the aberration impact on spatial frequencies even beyond the sideband information limit allowing its transfer with maximum possible contrast. In addition to the theoretical considerations outlined in detail, an experimental proof-of-principle is presented. A fully controlled tilt of the reference wave, however, remains as a promising task for the future. The use of a hologram series with varying reference wave tilt is considered for linearly synthesizing an effective aperture for the transfer into the sideband with broader bandwidth compared to conventional off-axis electron holography allowing us to correct the incoherent aberrations in transmission electron microscopy. Furthermore, tilting a reference wave with respect to a plane wave is expected to be an alternative way for measuring the coherent and incoherent aberrations of a transmission electron microscope. The capability of tilting the reference wave is expected to be beneficial for improving the signal-to-noise ratio in dark-field off-axis electron holography as well. - Highlights: • We examine the use of tilted reference waves in off-axis electron holography. • Generalized holographic transfer theory reveals a selective filtering effect. • We propose the correction of incoherent aberrations by series acquisitions. • For a proof-of-principle, we employ a crystal for tilting the reference wave

  11. mTOR signaling pathway genes in focal epilepsies.

    Baulac, S

    2016-01-01

    Focal epilepsies, where seizures initiate in spatially limited networks, are the most frequent epilepsy type, accounting for two-thirds of patients. Focal epilepsies have long been thought to be acquired disorders; several focal epilepsy syndromes are now proven to be (genetically heterogeneous) monogenic disorders. While earlier genetic studies have demonstrated a strong contribution of ion channel and neurotransmitter receptor genes, or synaptic secreted protein genes, later work has revealed a new class of genes encoding components of the mechanistic target of rapamycin (mTOR) signal transduction pathway. The mTOR pathway controls a myriad of biological processes among which cell growth and protein synthesis in response to several extracellular and intracellular. Recently, germline mutations have been found in genes encoding the components of the GATOR1 complex (DEPDC5, NPRL2, NPRL3), a repressor of mTORC1. These mutations are increasingly recognized as causing a wide and yet evolving spectrum of focal epilepsy syndromes, with and without cortical structural abnormalities (usually focal cortical dysplasia). Brain somatic mutations in the gene encoding mTOR (MTOR) have recently been linked to focal cortical dysplasia and other associated brain pathologies including hemimegalencephaly. This chapter reviews the genetics and neurobiology of DEPDC5, NPRL2, and NPRL3, and summarizes the clinical and molecular spectrum of GATOR1-related epilepsies. PMID:27323939

  12. Periostin Responds to Mechanical Stress and Tension by Activating the MTOR Signaling Pathway

    Rosselli-Murai, Luciana K.; Galindo-Moreno, Pablo; Padial-Molina, Miguel; Volk, Sarah L.; Murai, Marcelo J.; Rios, Hector F.; Squarize, Cristiane H.; Castilho, Rogerio M.

    2013-01-01

    Current knowledge about Periostin biology has expanded from its recognized functions in embryogenesis and bone metabolism to its roles in tissue repair and remodeling and its clinical implications in cancer. Emerging evidence suggests that Periostin plays a critical role in the mechanism of wound healing; however, the paracrine effect of Periostin in epithelial cell biology is still poorly understood. We found that epithelial cells are capable of producing endogenous Periostin that, unlike mesenchymal cell, cannot be secreted. Epithelial cells responded to Periostin paracrine stimuli by enhancing cellular migration and proliferation and by activating the mTOR signaling pathway. Interestingly, biomechanical stimulation of epithelial cells, which simulates tension forces that occur during initial steps of tissue healing, induced Periostin production and mTOR activation. The molecular association of Periostin and mTOR signaling was further dissected by administering rapamycin, a selective pharmacological inhibitor of mTOR, and by disruption of Raptor and Rictor scaffold proteins implicated in the regulation of mTORC1 and mTORC2 complex assembly. Both strategies resulted in ablation of Periostin-induced mitogenic and migratory activity. These results indicate that Periostin-induced epithelial migration and proliferation requires mTOR signaling. Collectively, our findings identify Periostin as a mechanical stress responsive molecule that is primarily secreted by fibroblasts during wound healing and expressed endogenously in epithelial cells resulting in the control of cellular physiology through a mechanism mediated by the mTOR signaling cascade. PMID:24349533

  13. Periostin responds to mechanical stress and tension by activating the MTOR signaling pathway.

    Luciana K Rosselli-Murai

    Full Text Available Current knowledge about Periostin biology has expanded from its recognized functions in embryogenesis and bone metabolism to its roles in tissue repair and remodeling and its clinical implications in cancer. Emerging evidence suggests that Periostin plays a critical role in the mechanism of wound healing; however, the paracrine effect of Periostin in epithelial cell biology is still poorly understood. We found that epithelial cells are capable of producing endogenous Periostin that, unlike mesenchymal cell, cannot be secreted. Epithelial cells responded to Periostin paracrine stimuli by enhancing cellular migration and proliferation and by activating the mTOR signaling pathway. Interestingly, biomechanical stimulation of epithelial cells, which simulates tension forces that occur during initial steps of tissue healing, induced Periostin production and mTOR activation. The molecular association of Periostin and mTOR signaling was further dissected by administering rapamycin, a selective pharmacological inhibitor of mTOR, and by disruption of Raptor and Rictor scaffold proteins implicated in the regulation of mTORC1 and mTORC2 complex assembly. Both strategies resulted in ablation of Periostin-induced mitogenic and migratory activity. These results indicate that Periostin-induced epithelial migration and proliferation requires mTOR signaling. Collectively, our findings identify Periostin as a mechanical stress responsive molecule that is primarily secreted by fibroblasts during wound healing and expressed endogenously in epithelial cells resulting in the control of cellular physiology through a mechanism mediated by the mTOR signaling cascade.

  14. Aberrant angiogenesis: The gateway to diabetic complications

    Sunil K Kota

    2012-01-01

    Full Text Available Diabetes Mellitus is a metabolic cum vascular syndrome with resultant abnormalities in both micro- and macrovasculature. The adverse long-term effects of diabetes mellitus have been described to involve many organ systems. Apart from hyperglycemia, abnormalities of angiogenesis may cause or contribute toward many of the clinical manifestations of diabetes. These are implicated in the pathogenesis of vascular abnormalities of the retina, kidneys, and fetus, impaired wound healing, increased risk of rejection of transplanted organs, and impaired formation of coronary collaterals. A perplexing feature of the aberrant angiogenesis is that excessive and insufficient angiogenesis can occur in different organs in the same individual. The current article hereby reviews the molecular mechanisms including abnormalities in growth factors, cytokines, and metabolic derangements, clinical implications, and therapeutic options of dealing with abnormal angiogenesis in diabetes.

  15. Using nodal aberration theory to understand the aberrations of multiple unobscured three mirror anastigmatic (TMA) telescopes

    Thompson, Kevin P.; Fuerschbach, Kyle; Schmid, Tobias; Rolland, Jannick P.

    2009-08-01

    The alignment of three mirror anastigmatic (TMA) telescopes has been studied since their invention in the 60s. Recently, Thompson et al.1 reported that other than the conventional uniform coma over the field caused by misalignment, TMA telescopes display only one other misalignment induced aberration, field-asymmetric, field-linear astigmatism. Currently, an instrument with three TMAs is under development as the primary spectrometer on the James Webb Space Telescope. This paper will report on the application of Nodal Aberration Theory (NAT) to understanding the optical design of an optical system with multiple TMAs as a first step towards investigating and potentially independently analyzing the sensitivities to alignment of this key instrument.

  16. Wnt signaling in liver physiology and pathology

    Satdarshan P. Singh Monga

    2009-01-01

    @@ 1 Wnt/β-catenin signaling This signaling pathway is known to play key roles during development and in maintaining homeostasis in many adult tissues. Its aberrant activation is associated with cancers in many tissues such as breast, colon, pancreas, skin and liver.

  17. Expressions for third-order aberration theory for holographic images

    S K Tripathy; S Ananda Rao

    2003-01-01

    Expressions for third-order aberration in the reconstructed wave front of point objects are established by Meier. But Smith, Neil Mohon, Sweatt independently reported that their results differ from that of Meier. We found that coefficients for spherical aberration, astigmatism, tally with Meier’s while coefficients for distortion and coma differ.

  18. Fifth-order aberrations in magnetic quadrupole-octupole systems

    Explicit integral expressions are given for the fifth-order geometrical aberration coefficients in rectilinear magnetic quadrupole-octupole systems used for the transport of nonrelativistic charged particle beams. The numerical values of the fifth-order geometrical aberration coefficients for a rare earth cobalt (REC) quadrupole doublet are given as an example. 26 refs., 5 figs., 4 tabs

  19. Aberration analysis calculations for synchrotron radiation beamline design

    The application of ray deviation calculations based on aberration coefficients for a single optical surface for the design of beamline optical systems is reviewed. A systematic development is presented which allows insight into which aberration may be causing the rays to deviate from perfect focus. A new development allowing analytical calculation of line shape is presented

  20. Statistical virtual eye model based on wavefront aberration

    Wang, Jie-Mei; Liu, Chun-Ling; Luo, Yi-Ning; Liu, Yi-Guang; Hu, Bing-Jie

    2012-01-01

    Wavefront aberration affects the quality of retinal image directly. This paper reviews the representation and reconstruction of wavefront aberration, as well as the construction of virtual eye model based on Zernike polynomial coefficients. In addition, the promising prospect of virtual eye model is emphasized.

  1. Exact solutions in the scalar diffraction theory of aberrations.

    Budgor, A B

    1980-05-15

    A simple exact method is presented for evaluating the circularly symmetric Fresnel-Kirchhoff diffraction integral in the presence of Seidel aberrations, all orders of spherical aberration, and all orders of linear coma. The resultant formulas involve a simple quadrature over a single special function of mathematics. PMID:20221084

  2. Exact solutions in the scalar diffraction theory of aberrations

    A simple exact method is presented for evaluating the circularly symmetric Fresnel-Kirchhoff diffraction integral in the presence of Seidel aberrations, all orders of spherical aberration, and all orders of linear coma. The resultant formulas involve a simple quadrature over a single special function of mathematics

  3. Bone sonometry: reducing phase aberration to improve estimates of broadband ultrasonic attenuation.

    Bauer, Adam Q; Anderson, Christian C; Holland, Mark R; Miller, James G

    2009-01-01

    Previous studies suggest that phase cancellation at the receiving transducer can result in the overestimation of the frequency dependent ultrasonic attenuation of bone, a quantity that has been shown to correlate with bone mineral density and ultimately with osteoporotic fracture risk. Evidence supporting this interpretation is provided by phase insensitive processing of the data, which appear to reduce the apparent overestimates of attenuation. The present study was designed to clarify the components underlying phase aberration artifacts in such through-transmission measurements by conducting systematic studies of the simplest possible test objects capable of introducing phase aberration. Experimental results are presented for a Lexan phantom over the frequency range 300-700 kHz and a Plexiglas phantom over the 3-7 MHz range. Both phantoms were flat and parallel plates featuring a step discontinuity milled into one of their initially flat sides. The through-transmitted signals were received by a 0.6 mm diameter membrane hydrophone that was raster scanned over a grid coaxial with the transmitting transducer. Signals received by the pseudoarray were processed offline to emulate phase sensitive and phase insensitive receivers with different aperture diameters. The data processed phase sensitively were focused to demonstrate the results of planar, geometrical, and correlation-based aberration correction methods. Results are presented illustrating the relative roles of interference in the ultrasonic field and phase cancellation at the receiving transducer in producing phase aberration artifacts. It was found that artifacts due to phase cancellation or interference can only be minimized with phase insensitive summation techniques by choosing an appropriately large receiving aperture. Data also suggest the potentially confounding role of time-and frequency-domain artifacts on ultrasonic measurements and illustrate the advantages of two-dimensional receiving arrays in

  4. Brown's transport up to third order aberration by artificial intelligence

    Brown's TRANSPORT is a first and second order matrix multiplication computer program intended for the design of accelerator beam transport systems, neglecting the third order aberration. Recently a new method was developed to derive analytically any order aberration coefficients of general charged particle optic system, applicable to any practical systems, such as accelerators, electron microscopes, lithographs, including those unknown systems yet to be invented. An artificial intelligence program in Turbo Prolog was implemented on IBM-PC 286 or 386 machine to generate automatically the analytical expression of any order aberration coefficients of general charged particle optic system. Based on this new method and technique, Brown's TRANSPORT is extended beyond the second order aberration effect by artificial intelligence, outputting automatically all the analytical expressions up to the third order aberration coefficients

  5. Chromosome aberration analysis based on a beta-binomial distribution

    Analyses carried out here generalized on earlier studies of chromosomal aberrations in the populations of Hiroshima and Nagasaki, by allowing extra-binomial variation in aberrant cell counts corresponding to within-subject correlations in cell aberrations. Strong within-subject correlations were detected with corresponding standard errors for the average number of aberrant cells that were often substantially larger than was previously assumed. The extra-binomial variation is accomodated in the analysis in the present report, as described in the section on dose-response models, by using a beta-binomial (B-B) variance structure. It is emphasized that we have generally satisfactory agreement between the observed and the B-B fitted frequencies by city-dose category. The chromosomal aberration data considered here are not extensive enough to allow a precise discrimination between competing dose-response models. A quadratic gamma ray and linear neutron model, however, most closely fits the chromosome data. (author)

  6. Brown's TRANSPORT up to third order aberration by artificial intelligence

    Brown's TRANSPORT is a first and second order matrix multiplication computer program intended for the design of accelerator beam transport systems, neglecting the third order aberration. Recently a new method was developed to derive analytically any order aberration coefficients of general charged particle optic system, applicable to any practical systems, such as accelerators, electron microscopes, lithographs, etc., including those unknown systems yet to be invented. An artificial intelligence program in Turbo Prolog was implemented on IBM-PC 286 or 386 machine to generate automatically the analytical expression of any order aberration coefficients of general charged particle optic system. Based on this new method and technique, Brown's TRANSPORT is extended beyond the second order aberration effects by artificial intelligence, outputing automatically all the analytical expressions up to the third order aberration coefficients

  7. Aberrations of the cathode objective lens up to fifth order.

    Tromp, R M; Wan, W; Schramm, S M

    2012-08-01

    In this paper we discuss a topic that was close to Prof. Gertrude Rempfer s interests for many years. On this occasion of her 100th birthday, we remember and honor Gertrude for her many outstanding contributions, and for the inspiring example that she set. We derive theoretical expressions for the aberration coefficients of the uniform electrostatic field up to 5th order and compare these with raytracing calculations for the cathode lens used in Low Energy Electron Microscopy and Photo Electron Emission Microscopy experiments. These higher order aberration coefficients are of interest for aberration corrected experiments in which chromatic (C(c)) and spherical (C₃) aberrations of the microscope are set to zero. The theoretical predictions are in good agreement with the results of raytracing. Calculations of image resolution using the Contrast Transfer Function method show that sub-nanometer resolution is achievable in an aberration corrected LEEM system. PMID:22188906

  8. Aberrant repair and fibrosis development in skeletal muscle

    Mann Christopher J

    2011-05-01

    Full Text Available Abstract The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair.

  9. Insulin signaling and skeletal muscle atrophy and autophagy in transition dairy cows either overfed energy or fed a controlled energy diet prepartum.

    Mann, S; Abuelo, A; Nydam, D V; Leal Yepes, F A; Overton, T R; Wakshlag, J J

    2016-05-01

    During periods of negative energy balance, mobilization of muscle is a physiologic process providing energy and amino acids. This is important in transition dairy cows experiencing negative energy and protein balance postpartum. Overconsumption of energy during late pregnancy affects resting glucose and insulin concentrations peripartum and increases the risk for hyperketonemia postpartum, but the effects on muscle tissue are not fully understood. Skeletal muscle accounts for the majority of insulin-dependent glucose utilization in ruminants. Our objective was to study peripartal skeletal muscle insulin signaling as well as muscle accretion and atrophy in cows with excess energy consumption prepartum. Skeletal muscle biopsies were obtained 28 and 10 days prepartum, as well as 4 and 21 days postpartum from 24 Holstein cows. Biopsies were taken immediately before and 60 min after intravenous glucose challenge causing endogenous release of insulin. Gene expression of IGF-1, myostatin, and atrogin-1, as well as immunoblot analysis of atrogin-1, muRF1, ubiquitinated proteins, LC3, and phosphorylation of AKT, ERK and mTORC1 substrate 4EBP1 was performed. Excess energy consumption in late pregnancy did not lead to changes in insulin-dependent molecular regulation of muscle accretion or atrophy compared with the controlled energy group. In both groups, phosphorylation of AKT and mTORC1 substrate was significantly decreased postpartum whereas proteasome activity and macroautopagy were upregulated. This study showed that in addition to the proteasome pathway of muscle atrophy, macroautophagy is upregulated in postpartum negative energy and protein balance regardless of dietary energy strategy prepartum and was higher in cows overfed energy throughout the study period. PMID:26920795

  10. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes

    Choudhary, Chuna Ram; Olsen, Jesper V; Brandts, Christian;

    2009-01-01

    Inappropriate activation of oncogenic kinases at intracellular locations is frequently observed in human cancers, but its effects on global signaling are incompletely understood. Here, we show that the oncogenic mutant of Flt3 (Flt3-ITD), when localized at the endoplasmic reticulum (ER), aberrant...... patterns of the receptor itself. Thus, intracellular activation of RTKs by oncogenic mutations in the biosynthetic route may exploit cellular architecture to initiate aberrant signaling cascades, thus evading negative regulation....

  11. Aberrations of the cathode objective lens up to fifth order

    Tromp, R.M., E-mail: rtromp@us.ibm.com [Thomas J. Watson Research Center, IBM Research Division, 1101 Kitchawan Road, P.O. Box 218, Yorktown Heights, NY 10598 (United States); Leiden University, Kamerlingh Onnes Laboratorium, P.O. Box 9504, NL-2300 RA Leiden (Netherlands); Wan, W. [Ernest Orlando Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 80R0114, Berkeley, CA 94720 (United States); Schramm, S.M. [Leiden University, Kamerlingh Onnes Laboratorium, P.O. Box 9504, NL-2300 RA Leiden (Netherlands)

    2012-08-15

    In this paper we discuss a topic that was close to Prof. Gertrude Rempfer s interests for many years. On this occasion of her 100th birthday, we remember and honor Gertrude for her many outstanding contributions, and for the inspiring example that she set. We derive theoretical expressions for the aberration coefficients of the uniform electrostatic field up to 5th order and compare these with raytracing calculations for the cathode lens used in Low Energy Electron Microscopy and Photo Electron Emission Microscopy experiments. These higher order aberration coefficients are of interest for aberration corrected experiments in which chromatic (C{sub c}) and spherical (C{sub 3}) aberrations of the microscope are set to zero. The theoretical predictions are in good agreement with the results of raytracing. Calculations of image resolution using the Contrast Transfer Function method show that sub-nanometer resolution is achievable in an aberration corrected LEEM system. -- Highlights: Black-Right-Pointing-Pointer A theory is presented for the aberrations of the uniform electrostatic field up to fifth order. Black-Right-Pointing-Pointer Such aberrations are important for advanced LEEM and PEEM instruments. Black-Right-Pointing-Pointer Good agreement between theory and raytracing results for a full cathode objective lens. Black-Right-Pointing-Pointer Contrast Transfer Function calculations predict that spatial resolution below 1 nm is achievable.

  12. Chromosome aberrations in solid tumors have a stochastic nature

    Castro, Mauro A.A. [Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-anexo, Porto Alegre 90035-003 (Brazil) and Departamento de Medicina Interna, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Porto Alegre 90035-903 (Brazil) and Instituto de Fisica, Universidade Federal do Rio Grande do Sul, Av. Bento Goncalves 9500, Porto Alegre 91501-970 (Brazil) and Universidade Luterana do Brasil, Rua Miguel Tostes 101, Canoas 92420-280 (Brazil)]. E-mail: mauro@ufrgs.br; Onsten, Tor G.H. [Departamento de Medicina Interna, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Porto Alegre 90035-903 (Brazil); Universidade Luterana do Brasil, Rua Miguel Tostes 101, Canoas 92420-280 (Brazil); Moreira, Jose C.F. [Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-anexo, Porto Alegre 90035-003 (Brazil); Almeida, Rita M.C. de [Instituto de Fisica, Universidade Federal do Rio Grande do Sul, Av. Bento Goncalves 9500, Porto Alegre 91501-970 (Brazil)

    2006-08-30

    An important question nowadays is whether chromosome aberrations are random events or arise from an internal deterministic mechanism, which leads to the delicate task of quantifying the degree of randomness. For this purpose, we have defined several Shannon information functions to evaluate disorder inside a tumor and between tumors of the same kind. We have considered 79 different kinds of solid tumors with 30 or more karyotypes retrieved from the Mitelman Database of Chromosome Aberrations in Cancer. The Kaplan-Meier cumulative survival was also obtained for each solid tumor type in order to correlate data with tumor malignance. The results here show that aberration spread is specific for each tumor type, with high degree of diversity for those tumor types with worst survival indices. Those tumor types with preferential variants (e.g. high proportion of a given karyotype) have shown better survival statistics, indicating that aberration recurrence is a good prognosis. Indeed, global spread of both numerical and structural abnormalities demonstrates the stochastic nature of chromosome aberrations by setting a signature of randomness associated to the production of disorder. These results also indicate that tumor malignancy correlates not only with karyotypic diversity taken from different tumor types but also taken from single tumors. Therefore, by quantifying aberration spread, we could confront diverse models and verify which of them points to the most likely outcome. Our results suggest that the generating process of chromosome aberrations is neither deterministic nor totally random, but produces variations that are distributed between these two boundaries.

  13. Aberrant DNA methylation in cloned ovine embryos

    LIU Lei; HOU Jian; LEI TingHua; BAI JiaHua; GUAN Hong; AN XiaoRong

    2008-01-01

    By using the approach of immunofluorescence staining with an antibody against 5-methylcytosine (5MeC), the present study detected the DNA methylation patterns of cloned ovine embryos. The em-bryos derived from in vitro fertilization were also examined for reference purpose. The results showed that: (1) during the pre-implantation development, cloned embryos displayed a similar demethylation profile to the fertilized embryos; that is, the methylation level decreased to the lowest at 8-cell stage, and then increased again at morulae stage. However, methylation level was obviously higher in cloned embryos than in stage-matched fertilized embryos, especially at 8-cell stage and afterwards; (2) at blastocyst stage, the methylation pattern in cloned embryos was different from that in fertilized em-bryos. In cloned blastocyst, inner cell mass (ICM) exhibited a comparable level to trophectoderm cells (TE), while in in-vitro fertilized blastocyst the methylation level of ICM was lower than that of TE, which is not consistent with that reported by other authors. These results indicate that DNA methylation is abnormally reprogrammed in cloned embryos, implying that aberrant DNA methylation reprogramming may be one of the factors causing cloned embryos developmental failure.

  14. Aberrant glycosylation associated with enzymes as cancer biomarkers

    Meany Danni L

    2011-06-01

    Full Text Available Abstract Background One of the new roles for enzymes in personalized medicine builds on a rational approach to cancer biomarker discovery using enzyme-associated aberrant glycosylation. A hallmark of cancer, aberrant glycosylation is associated with differential expressions of enzymes such as glycosyltransferase and glycosidases. The aberrant expressions of the enzymes in turn cause cancer cells to produce glycoproteins with specific cancer-associated aberrations in glycan structures. Content In this review we provide examples of cancer biomarker discovery using aberrant glycosylation in three areas. First, changes in glycosylation machinery such as glycosyltransferases/glycosidases could be used as cancer biomarkers. Second, most of the clinically useful cancer biomarkers are glycoproteins. Discovery of specific cancer-associated aberrations in glycan structures of these existing biomarkers could improve their cancer specificity, such as the discovery of AFP-L3, fucosylated glycoforms of AFP. Third, cancer-associated aberrations in glycan structures provide a compelling rationale for discovering new biomarkers using glycomic and glycoproteomic technologies. Summary As a hallmark of cancer, aberrant glycosylation allows for the rational design of biomarker discovery efforts. But more important, we need to translate these biomarkers from discovery to clinical diagnostics using good strategies, such as the lessons learned from translating the biomarkers discovered using proteomic technologies to OVA 1, the first FDA-cleared In Vitro Diagnostic Multivariate Index Assay (IVDMIA. These lessons, providing important guidance in current efforts in biomarker discovery and translation, are applicable to the discovery of aberrant glycosylation associated with enzymes as cancer biomarkers as well.

  15. Automatic Compensation of Total Phase Aberrations in Digital Holographic Biological Imaging

    ZHANG Yi-Zhuo; WANG Da-Yong; WANG Yun-Xin; TAO Shi-Quan

    2011-01-01

    Digital holographic microscopy has been a powerful metrological technique for phase-contrast imaging. However inherent phase aberrations always exist and degrade the quality of the phase-contrast images. A surface fitting method based on an improved mathematic model is proposed, which can be used to remove the phase aberrations without any pre-knowledge of the setup or manual operation. The improved mathematic model includes not only the usual terms but also the cross terms and the high order terms to describe the phase aberrations with high accuracy. Meanwhile, a non-iterative algorithm is used to solve the parametersand thus less computational load is imposed. The proposed method is applied to the live imaging of cells. The experimental results verify its validity.%Digital holographic microscopy has been a powerful metrological technique for phase-contrast imaging.However inherent phase aberrations always exist and degrade the quality of the phase-contrast images.A surface fitting method based on an improved mathematic model is proposed,which can be used to remove the phase aberrations without any pre-knowledge of the setup or manual operation.The improved mathematic model includes not only the usual terms but also the cross terms and the high order terms to describe the phase aberrations with high accuracy.Meanwhile,a non-iterative algorithm is used to solve the parametersand thus less computational load is imposed.The proposed method is applied to the live imaging of cells.The experimental results verify its validity.Digital holographic microscopy (DHM) has been a powerful metrological technique which permits realtime quantitative phase-contrast imaging.The hologram is recorded by a CCD or a CMOS camera while the reconstruction is performed numerically.Many digital signal processing techniques have been introduced to enhance DHM for speckle removal,[1,2] aperture truncation,[3] phase unwrapping[4,5] etc.It has been widely used in biomedical optics for

  16. Interpreting the CMB aberration and Doppler measurements: boost or intrinsic dipole?

    Roldan, Omar; Notari, Alessio; Quartin, Miguel

    2016-06-01

    The aberration and Doppler coupling effects of the Cosmic Microwave Background (CMB) were recently measured by the Planck satellite. The most straightforward interpretation leads to a direct detection of our peculiar velocity β, consistent with the measurement of the well-known dipole. In this paper we discuss the assumptions behind such interpretation. We show that Doppler-like couplings appear from two effects: our peculiar velocity and a second order large-scale effect due to the dipolar part of the gravitational potential. We find that the two effects are exactly degenerate but only if we assume second-order initial conditions from single-field Inflation. Thus, detecting a discrepancy in the value of β from the dipole and the Doppler couplings implies the presence of a primordial non-Gaussianity. We also show that aberration-like signals likewise arise from two independent effects: our peculiar velocity and lensing due to a first order large-scale dipolar gravitational potential, independently on Gaussianity of the initial conditions. In general such effects are not degenerate and so a discrepancy between the measured β from the dipole and aberration could be accounted for by a dipolar gravitational potential. Only through a fine-tuning of the radial profile of the potential it is possible to have a complete degeneracy with a boost effect. Finally we discuss that we also expect other signatures due to integrated second order terms, which may be further used to disentangle this scenario from a simple boost.

  17. Differential algebraic method for aberration analysis of typical electrostatic lenses

    In this paper up to fifth-order geometric and third-order chromatic aberration coefficients of typical electrostatic lenses are calculated by means of the charged particle optics code, COSY INFINITY, based on the differential algebraic (DA) method. A two-tube immersion lens and a symmetric einzel lens have been chosen as two examples, whose axial potential distributions are numerically calculated by a FORTRAN program using the finite difference method. The DA results are in good agreement with those evaluated by the aberration integrals in electron optics. The DA method presented here can easily be extended to aberration analysis of other numerically computed electron lenses, including magnetic lenses

  18. Aberrations of Genetic Material as Biomarkers of Ionizing Radiation Effects

    Milacic, S.

    2004-07-01

    Ionizing radiation is the most powerful mutagen in environmental and working conditions. The result of genotoxic effect of radiation is the development of chromosome aberrations. The structural chromosome aberrations in peripheral blood lymphocytes are dicentric, ring, acentric fragment. The observation of chromosome aberration frequency in lymphocyte karyotype is the conclusive method to assess the absorbed dose of ionizing radiation. Our study compared the incidence of chromosome aberrations in occupationally exposed healthy medical workers and in non-exposed healthy population. We analyzed the effect of working place, dose by thermo luminescence personal dosimeter (TLD), duration of occupational exposure (DOE) and age to the sum of aberrant cells and aberrations. four-year study included 462 subjects, mean-aged 42.3 years, who were occupational exposed to ionizing radiation and 95 subjects, mean-aged 35,2 years, who were not exposed to ionizing radiation, during the same time period and from the same territory. All of them possess thermo luminescence personal dosimeter (TLD) which is read by scanner for thermo luminescence dosimeters. Modified Moorheard's micro method for peripheral blood lymphocytes and conventional cytogenetic technique of chromosome aberration analysis were used for analysis of chromosome aberrations. Stained preparations (Giemsa) are observed in immersion by light microscope. The karyotype of 200 lymphocytes in metaphase is analyzed the most characteristic aberration: dicentric, then the ring and acentric fragments. The increased incidence of chromosome aberrations was found to tbe 21.6% in the exposed group and 2.1% in the controls, while the findings within the limits (non-specific chromosome lesions-gaps breaks, elongations, and exchanges) were equal in both groups (22%). Among occupationally exposed medical workers, the highest incidence was found in nuclear medicine workers (42.6%), then in orthopedists (27.08%). There is highly

  19. High order aberration and straylight evaluation after cataract surgery with implantation of an aspheric,aberration correcting monofocal intraocular lens

    Florian; T; A; Kretz; Tamer; Tandogan; Ramin; Khoramnia; Gerd; U; Auffarth

    2015-01-01

    ·AIM: To evaluate the quality of vision in respect to high order aberrations and straylight perception after implantation of an aspheric, aberration correcting,monofocal intraocular lens(IOL).·METHODS: Twenty-one patients(34 eyes) aged 50 to83 y underwent cataract surgery with implantation of an aspheric, aberration correcting IOL(Tecnis ZCB00,Abbott Medical Optics). Three months after surgery they were examined for uncorrected(UDVA) and corrected distance visual acuity(CDVA), contrast sensitivity(CS)under photopic and mesopic conditions with and without glare source, ocular high order aberrations(HOA, Zywave II) and retinal straylight(C-Quant).· RESULTS: Postoperatively, patients achieved a postoperative CDVA of 0.0 log MAR or better in 97.1% of eyes. Mean values of high order abberations were +0.02±0.27(primary coma components) and-0.04 ±0.16(spherical aberration term). Straylight values of the C-Quant were 1.35±0.44 log which is within normal range of age matched phakic patients. The CS measurements under mesopic and photopic conditions in combination with and without glare did not show any statistical significance in the patient group observed(P ≥0.28).· CONCLUSION: The implantation of an aspherical aberration correcting monofocal IOL after cataractsurgery resulted in very low residual higher order aberration(HOA) and normal straylight.

  20. Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli

    Suen, KinMan

    2013-05-01

    Control mechanisms that prevent aberrant signaling are necessary to maintain cellular homeostasis. We describe a new mechanism by which the adaptor protein Shc directly binds the MAP kinase Erk, thus preventing its activation in the absence of extracellular stimuli. The Shc-Erk complex restricts Erk nuclear translocation, restraining Erk-dependent transcription of genes, including those responsible for oncogenic growth. The complex forms through unique binding sites on both the Shc PTB domain and the N-terminal lobe of Erk. Upon receptor tyrosine kinase stimulation, a conformational change within Shc - induced through interaction with the phosphorylated receptor - releases Erk, allowing it to fulfill its role in signaling. Thus, in addition to its established role in promoting MAP kinase signaling in stimulated cells, Shc negatively regulates Erk activation in the absence of growth factors and thus could be considered a tumor suppressor in human cells. © 2013 Nature America, Inc. All rights reserved.

  1. Vascular endothelial growth factor signaling in acute myeloid leukemia

    Kampen, Kim R.; ter Elst, Arja; de Bont, Eveline S. J. M.

    2013-01-01

    This review is designed to provide an overview of the current literature concerning vascular endothelial growth factor signaling (VEGF) in acute myeloid leukemia (AML). Aberrant VEGF signaling operates in the bone marrow of AML patients and is related to a poor prognosis. The altered signaling pathw

  2. Chromosome aberrations in pesticide-exposed greenhouse workers

    Lander, B F; Knudsen, Lisbeth E.; Gamborg, M O;

    2000-01-01

    OBJECTIVES: The aim of this study was to investigate the possibility of subtoxic exposure to pesticides causing chromosome aberrations in greenhouse workers. METHODS: In a cross-sectional and prospective study design chromosome aberration frequencies in cultured lymphocytes were examined for 116...... greenhouse workers exposed to a complex mixture of almost 50 insecticides, fungicides, and growth regulators and also for 29 nonsmoking, nonpesticide-exposed referents. RESULTS: The preseason frequencies of chromosome aberrations were slightly but not statistically significantly elevated for the greenhouse...... workers when they were compared with the referents. After a summer season of pesticide spraying in the greenhouses, the total frequencies of cells with chromosome aberrations were significantly higher than in the preseason samples (P=0.02) and also higher than for the referents (P=0.05). This finding was...

  3. Electron Optics for Biologists: Physical Origins of Spherical Aberrations

    Geissler, Peter; Zadunaisky, Jose

    1974-01-01

    Reports on the physical origins of spherical aberrations in axially symmetric electrostatic lenses to convey the essentials of electon optics to those who must think critically about the resolution of the electron microscope. (GS)

  4. CT of ruptured aneurysm of aberrant right subclavian artery.

    Vega, A; Ortíz, A; Longo, J M; Pagola, M A

    1987-01-01

    This paper presents the first description of a ruptured aneurysm of an aberrant right subclavian artery. CT clearly demonstrated the vascular malformation as well as the existence of a bilateral hemothorax. PMID:3102065

  5. Lymphocyte chromosome aberrations in partial-body fractionated radiation therapy

    a relationship between lymphocyte chromosome aberration yields which occur in partial-body fractionated radiation therapy and those yields measured in vitro is derived. These calculations are applied to the case of patients undergoing radiation therapy for mammary carcinoma. (author)

  6. Lymphocyte chromosome aberrations in partial-body fractionated radiation therapy

    Ekstrand, K.E.; Dixon, R.L. (Wake Forest Univ., Winston-Salem, NC (USA))

    1982-03-01

    a relationship between lymphocyte chromosome aberration yields which occur in partial-body fractionated radiation therapy and those yields measured in vitro is derived. These calculations are applied to the case of patients undergoing radiation therapy for mammary carcinoma.

  7. Lens aberration measurement and analysis using a novel pattern

    Nam, Byung-Ho; Cho, Byeong-Ho; Park, Jong O.; Kim, Dong-Seok; Baek, SungJin; Jeong, JongHo; Nam, ByungSub; Hwang, Young J.; Song, Young Jin

    2001-09-01

    Lens aberration of the exposure tool causes pattern deformation and position shift. As design rule shrinks, the ratio of printed feature size to applied wavelength for optical lithography is driven inexorably toward resolution limit. In this study, we devised an efficient method to evaluate lens aberration using multi-ring pattern on an attenuated phase-shift mask. Adoption of multi-ring pattern can cut down measurement time and improve measurement repeatability. These patterns are uniformly distributed through entire field in 7 by 7 manner. Lens aberration was evaluated by multi-ring pattern array under conventional or off-axis illumination with KrF stepper of NA 0.65. Multi-ring critical dimension (CD) data was discussed together with the issue of lens aberration such as coma, astigmatism, field curvature, etc. We can apply this new measurement technique to select better lens system efficiently. multi-ring, field size, pattern deformation

  8. Optimizing chromatic aberration calibration using a novel genetic algorithm

    Fang, Yi-Chin; Liu, Tung-Kuan; MacDonald, John; Chou, Jyh-Horng; Wu, Bo-Wen; Tsai, Hsien-Lin; Chang, En-Hao

    2006-10-01

    Advances in digitalized image optics has increased the importance of chromatic aberration. The axial and lateral chromatic aberrations of an optical lens depends on the choice of optical glass. Based on statistics from glass companies worldwide, more than 300 optical glasses have been developed for commercial purposes. However, the complexity of optical systems makes it extremely difficult to obtain the right solution to eliminate small chromatic aberration. Even the damped least-squares technique, which is a ray-tracing-based method, is limited owing to its inability to identify an enhanced optical system configuration. Alternatively, this study instead attempts to eliminate even negligible axial and lateral colour aberration by using algorithms involving the theories of geometric optics in triplet lens, binary and real encoding, multiple dynamic crossover and random gene mutation techniques.

  9. Aberrant internal carotid artery in the middle ear

    The knowledge about the aberrant internal carotid artery (ICA) in the middle ear is essential for clinicians, because a misdiagnosis of the aberrant ICA could have serious consequences such as excessive aural bleeding during a middle ear surgery. A 38-year-old woman presented with tinnitus and hearing difficulties of the left ear that had started 5 years ago. During otoscopy, an anteroinferior bluish mass was seen in the tympanic space. Computed tomography and magnetic resonance imaging demonstrated a left-side aberrant ICA with bony dehiscence of the carotid canal in the middle ear and a reduced diameter of the tympanic ICA. Herein we report a case of an aberrant ICA in the middle ear. We also review the literature regarding this important vascular anomaly of the temporal bone which may lead to disastrous surgical complications.

  10. Aberrant internal carotid artery in the middle ear

    Roh, Keun Tak; Kang, Hyun Koo [Dept. of Radiology, Seoul Veterans Hospital, Seoul (Korea, Republic of)

    2014-10-15

    The knowledge about the aberrant internal carotid artery (ICA) in the middle ear is essential for clinicians, because a misdiagnosis of the aberrant ICA could have serious consequences such as excessive aural bleeding during a middle ear surgery. A 38-year-old woman presented with tinnitus and hearing difficulties of the left ear that had started 5 years ago. During otoscopy, an anteroinferior bluish mass was seen in the tympanic space. Computed tomography and magnetic resonance imaging demonstrated a left-side aberrant ICA with bony dehiscence of the carotid canal in the middle ear and a reduced diameter of the tympanic ICA. Herein we report a case of an aberrant ICA in the middle ear. We also review the literature regarding this important vascular anomaly of the temporal bone which may lead to disastrous surgical complications.

  11. Isoplanatic patch size for aberration correction in ultrasonic imaging

    Pilkington, Wayne C.

    Methods and experimental results are described for determination of the region size in an aberrating medium over which a single set of aberration estimates can achieve satisfactory b-scan resolution ( i.e., the isoplanatic patch) using time-shift compensation for aberration correction of ultrasonic transmit and receive beams. Based on twenty percent allowable increases in the -12 dB width of the receive or transmit beam focus using cross-correction compared to self-correction, the isoplanatic patch sizes were found to between 3 and 5 millimeters laterally for a linearly-scanned transducer, and at least 12 millimeters axially for a target distance of 55 millimeters and aberration comparable to human abdominal wall. These sizes depend on the aberration severity, reference site axial position, and allowable resolution degradation with cross-correction. The lateral isoplanatic patch size of a linearly scanned image can be more than doubled to match that of a beam-steered acquisition using aberration estimate position matching relative to the tissue surface. Further expansion of the lateral isoplanatic patch size by an additional 50 to 100 percent for both scanning methods is also shown through propagation path matched cross-correction mapping of aberration estimates. The specific mapping required to achieve the best propagation path match depends on the axial distribution of the aberrating structures, the focal depth being imaged, and the cross-correction distance. The effectiveness of alternate methods to derive propagation path matching maps with and without a priori knowledge of aberrator spatial distribution are contrasted; and a means to dynamically adjust correction maps to maximize isoplanatic patch sizes is proposed and verified. Lateral cross-correction mapping and the map changes required for each cross-correction distance can all be implemented with simple shifting of aberration estimates within the transducer aperture. Therefore, use of optimally mapped

  12. Moment aberrations in magneto-electrostatic plasma lenses (computer simulation)

    Butenko, V I

    2001-01-01

    In this work moment aberrations in the plasma magneto-electrostatic lenses are considered in more detail with the use of the computer modeling. For solution of the problem we have developed a special computer code - the model of plasma optical focusing device, allowing to display the main parameters and operations of experimental sample of a lens, to simulate the moment and geometrical aberrations and give recommendations on their elimination.

  13. Study of the wavefront aberrations in children with amblyopia

    ZHAO Peng-fei; ZHOU Yue-hua; WANG Ning-li; ZHANG Jing

    2010-01-01

    Background Amblyopia is a common ophthalmological condition and the wavefront aberrometer is a relatively new diagnostic tool used globally to measure optical characteristics of human eyes as well as to study refractive errors in amblyopic eyes. We studied the wavefront aberration of the amblyopic children's eyes and analyzed the mechanism of the wavefront aberration in the formation of the amblyopia, try to investigate the new evidence of the treatment of the amblyopia, especially in the refractory amblyopia.Methods The WaveScan Wavefront System (VISX, USA) aberrometer was used to investigate four groups of children under dark accommodation and cilliary muscle paralysis. There were 45 cases in the metropic group, 87 in the amblyopic group, 92 in the corrected-amblyopic group and 38 in the refractory amblyopic group. One-way analysis of variance (ANOVA), t-test and multivariate linear regression were used to analyze all the data.Results Third order to 6th order aberrations showed a decreasing trend whereas in the higher order aberrations the main ones were 3rd order coma (Z3-1-Z31), trefoil (Z3-3-Z33) and 4th order aberration (Z40); and 3rd order coma represented the highest percentage of all three main aberrations. Within 3rd order coma, vertical coma (Z3-1) accounted for a greater percentage than horizontal coma (Z31). Significant differences of vertical coma were found among all clinical groups of children: vertical coma in the amblyopic group (0.17±0.15) was significantly higher than in the metropic group (0.11±0.13, P0.05).Conclusions Although lower order aberrations such as defocus (myopia and hyperopia) and astigmatism are major factors determining the quality of the retinal image, higher order aberrations also need to be considered in amblyopic eyes as their effects are significant.

  14. Minimum $G_2$-aberration for nonregular fractional factorial designs

    Tang, Boxin; Deng, Lih-Yuan

    1999-01-01

    Deng and Tang proposed generalized resolution and minimum aberration criteria for comparing and assessing nonregular fractional factorials, of which Plackett–Burman designs are special cases.A relaxed variant of generalized aberration is proposed and studied in this paper.We show that a best design according to this criterion minimizes the contamination of nonnegligible interactions on the estimation of main effects in the order of importance given by the hierarchical assump...

  15. Sharpness changes of gaussian beams induced by spherically aberrated lenses

    Piquero, G.; Mejías, P. M.; Martínez-Herrero, R.

    1994-04-01

    Sharpness changes of the spatial profile of a gaussian beam induced by spherically aberrated lenses are investigated in terms of the so-called kurtosis parameter. It is shown both theoretically and experimentally that, after a single aberrated lens, it is possible to get flatter and sharper beam intensity distributions than the input gaussian beam depending on the plane where the field is observed. Agreement between analytical and experimental results is discussed.

  16. Pattern of Chromosomal Aberrations in Patients from North East Iran

    Saeedeh Ghazaey

    2013-01-01

    Full Text Available Objective: Chromosomal aberrations are common causes of multiple anomaly syndromes. Recurrent chromosomal aberrations have been identified by conventional cytogenetic methods used widely as one of the most important clinical diagnostic techniques.Materials and Methods: In this retrospective study, the incidences of chromosomal aberrations were evaluated in a six year period from 2005 to 2011 in Pardis Clinical and Genetics Laboratory on patients referred to from Mashhad and other cities in Khorasan province. Karyotyping was performed on 3728 patients suspected of having chromosomal abnormalities.Results: The frequencies of the different types of chromosomal abnormalities were determined, and the relative frequencies were calculated in each group. Among these patients, 83.3% had normal karyotypes with no aberrations. The overall incidences of chromosomal abnormalities were 16.7% including sex and autosomal chromosomal anomalies. Of those, 75.1 % showed autosomal chromosomal aberrations. Down syndrome (DS was the most prevalent autosomal aberration in the patients (77.1%. Pericentric inversion of chromosome 9 was seen in 5% of patients. This inversion was prevalent in patients with recurrent spontaneous abortion (RSA. Sex chromosomal aberrations were observed in 24.9% of abnormal patients of which 61% had Turner’s syndrome and 33.5% had Klinefelter’s syndrome.Conclusion: According to the current study, the pattern of chromosomal aberrations in North East of Iran demonstrates the importance of cytogenetic evaluation in patients who show clinical abnormalities. These findings provide a reason for preparing a local cytogenetic data bank to enhance genetic counseling of families who require this service.

  17. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB

    Settembre C; Zoncu R; Medina DL; Vetrini F; Erdin S; Huynh T; Ferron M; Karsenty G; Vellard MC; Facchinetti V; Sabatini DM; Ballabio A.

    2012-01-01

    The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activ...

  18. Lens customization method to minimize aberration in integral imaging

    Miranda, Matheus; Kim, Jonghyun; Hong, Keehoon; Lee, Byoungho

    2015-10-01

    Conventionally the elemental lenses of the lens-array used in integral imaging have spherical surface profiles, thus they suffer from intrinsic lens aberrations such as spherical aberration and astigmatism. Aberrations affect the ability of the lens to focus light in a single point, or to collimate light from a point source. In integral imaging, this results in a loss of image quality of the reconstructed image due to distortions. The viewing characteristics of the integral imaging system, such as viewing angle and image resolution, are also affected by aberrations. We propose the use of a custom made aspherical lens-array which was specifically designed to minimize distortions due to aberrations and hence improve the reconstructed image quality. Ray optics calculations are used in order to analyze the aberrations and find the initial lens surface profile. Lens optimization is performed with the aid of numerical simulation software. The designed lens-array is compared to a conventional spherical lens-array of same properties. The design, optimization, and fabrication processes are described and the experiments are presented and compared with the computer simulations.

  19. Ocular aberrations after wavefront optimized LASIK for myopia

    Padmanabhan Prema

    2010-01-01

    Full Text Available Purpose: To study the change in ocular aberrations after wavefront optimized (WFO laser in situ keratomileusis ( Lasik for correction of myopia and to analyze causative factors that may influence them. Materials and Methods: This was a prospective case series. WFO Lasik was performed for the correction of myopia, using the hansatome (Bausch and Lomb microkeratome to create the flap and the Allegretto laser (Wavelight Technologie to perform the ablation. The Allegretto wave analyser (Tscherning-type measured the ocular aberrations prior to Lasik , one month and six months postoperatively. Results: The mean age of the 59 patients included in the study was 25±5.64 years and the mean spherical equivalent of the 117 eyes that underwent Lasik0 was -5.33±1.22 preoperatively and -0.21±0.38 postoperatively. Hundred and two eyes of 117 (87% achieved uncorrected visual acuity (UCVA of 20/20 or better after WFO Lasik and 104 of 117 eyes (89% were within ±0.5D of the attempted refractive correction. There was a 1.96-fold increase in total root-mean-square of higher order aberrations. Induced changes in seven of the 22 higher order Zernike terms showed a significant linear correlation with the refractive correction attempted. Larger ablation zones induced less spherical aberration. Conclusion: In spite of an excellent visual outcome, WFO Lasik induces significant higher order aberrations. Large ablation zones reduce the induction of spherical aberration.

  20. Null vector fields in spaces with affine connections and metrics. Doppler's effect, Hubble's effect, and aberration's effect

    Manoff, Sawa

    2003-01-01

    The notion of null (isotropic) vector field is considered in spaces with affine connections and metrics as models of space or space-time. On its basis the propagation of signals in space-time is considered. The Doppler effect is generalized for these types of spaces. The notions of standard (longitudinal) Doppler effect and transversal Doppler effect are introduced. On their grounds, the Hubble effect and the aberration effect appear as Doppler effects with explicit forms of the centrifugal (...

  1. Transcranial phase aberration correction using beam simulations and MR-ARFI

    Purpose: Transcranial magnetic resonance-guided focused ultrasound surgery is a noninvasive technique for causing selective tissue necrosis. Variations in density, thickness, and shape of the skull cause aberrations in the location and shape of the focal zone. In this paper, the authors propose a hybrid simulation-MR-ARFI technique to achieve aberration correction for transcranial MR-guided focused ultrasound surgery. The technique uses ultrasound beam propagation simulations with MR Acoustic Radiation Force Imaging (MR-ARFI) to correct skull-caused phase aberrations. Methods: Skull-based numerical aberrations were obtained from a MR-guided focused ultrasound patient treatment and were added to all elements of the InSightec conformal bone focused ultrasound surgery transducer during transmission. In the first experiment, the 1024 aberrations derived from a human skull were condensed into 16 aberrations by averaging over the transducer area of 64 elements. In the second experiment, all 1024 aberrations were applied to the transducer. The aberrated MR-ARFI images were used in the hybrid simulation-MR-ARFI technique to find 16 estimated aberrations. These estimated aberrations were subtracted from the original aberrations to result in the corrected images. Each aberration experiment (16-aberration and 1024-aberration) was repeated three times. Results: The corrected MR-ARFI image was compared to the aberrated image and the ideal image (image with zero aberrations) for each experiment. The hybrid simulation-MR-ARFI technique resulted in an average increase in focal MR-ARFI phase of 44% for the 16-aberration case and 52% for the 1024-aberration case, and recovered 83% and 39% of the ideal MR-ARFI phase for the 16-aberrations and 1024-aberration case, respectively. Conclusions: Using one MR-ARFI image and noa priori information about the applied phase aberrations, the hybrid simulation-MR-ARFI technique improved the maximum MR-ARFI phase of the beam's focus

  2. Transcranial phase aberration correction using beam simulations and MR-ARFI

    Vyas, Urvi, E-mail: urvi.vyas@gmail.com; Kaye, Elena; Pauly, Kim Butts [Department of Radiology, Stanford University, Stanford, California 94305 (United States)

    2014-03-15

    Purpose: Transcranial magnetic resonance-guided focused ultrasound surgery is a noninvasive technique for causing selective tissue necrosis. Variations in density, thickness, and shape of the skull cause aberrations in the location and shape of the focal zone. In this paper, the authors propose a hybrid simulation-MR-ARFI technique to achieve aberration correction for transcranial MR-guided focused ultrasound surgery. The technique uses ultrasound beam propagation simulations with MR Acoustic Radiation Force Imaging (MR-ARFI) to correct skull-caused phase aberrations. Methods: Skull-based numerical aberrations were obtained from a MR-guided focused ultrasound patient treatment and were added to all elements of the InSightec conformal bone focused ultrasound surgery transducer during transmission. In the first experiment, the 1024 aberrations derived from a human skull were condensed into 16 aberrations by averaging over the transducer area of 64 elements. In the second experiment, all 1024 aberrations were applied to the transducer. The aberrated MR-ARFI images were used in the hybrid simulation-MR-ARFI technique to find 16 estimated aberrations. These estimated aberrations were subtracted from the original aberrations to result in the corrected images. Each aberration experiment (16-aberration and 1024-aberration) was repeated three times. Results: The corrected MR-ARFI image was compared to the aberrated image and the ideal image (image with zero aberrations) for each experiment. The hybrid simulation-MR-ARFI technique resulted in an average increase in focal MR-ARFI phase of 44% for the 16-aberration case and 52% for the 1024-aberration case, and recovered 83% and 39% of the ideal MR-ARFI phase for the 16-aberrations and 1024-aberration case, respectively. Conclusions: Using one MR-ARFI image and noa priori information about the applied phase aberrations, the hybrid simulation-MR-ARFI technique improved the maximum MR-ARFI phase of the beam's focus.

  3. Modelling of multi-conjugate adaptive optics for spatially variant aberrations in microscopy

    Adaptive optics has been implemented in a range of high-resolution microscopes in order to overcome the problems of specimen-induced aberrations. Most implementations have used a single aberration correction across the imaged field. It is known, however, that aberrations often vary across the field of view, so a single correction setting cannot compensate all aberrations. Multi-conjugate adaptive optics (MCAO) has been suggested as a possible method for correction of these spatially variant aberrations. MCAO is modelled to simulate the correction of aberrations, both for simple model specimens and using real aberration data from a biological specimen. (special issue article)

  4. Induction of chromosomal aberrations in human lymphocytes by fission neutrons

    Chromosome aberrations induced by sparsely ionizing radiation (low-LET) are well known and cytogenetic analyses of irradiated human lymphocytes have been widely applied to biological dosimetry. However, much less is known about chromosome aberrations induced by densely ionizing radiation (high LET), such as that of alpha particles or neutrons. Such particles induce DNA strand breaks, as well as chromosome breakage and rearrangements of high complexity. This damage is more localized and less efficiently repaired than after X- or γ-ray irradiation. This preferential production of complex aberrations by densely ionizing radiation is related to the unique energy deposition patterns, which produces highly localized multiple DNA damage at the chromosomal level. A better knowledge of the interactions between different types of radiation and cellular DNA is of importance, not only from the radiobiological viewpoint but also for dosimetric and therapeutic purposes. The objective of the present study was to analyse the cytogenetic effects of fission neutrons on peripheral blood lymphocytes in order to evaluate structural and numerical aberrations and number of cells in the different mitotic cycles. So, blood samples from five healthy donors, 22-25 years old, of both sexes, were irradiated in the Research Reactor IEA-R1 of our Institute (IPEN/CNEN-SP) with thermal and fast neutrons at doses of 0.2; 0.3; 0.5 and 1.0 Gy. The γ contribution to the total absorbed dose was about 30%. These doses were monitored by thermoluminescent dosemeters: LiF-600 (for neutrons) and LiF-700 (for γ-rays). The data concerning structural aberrations were evaluated with regard to three parameters: percentage of cells with aberrations, number of aberrations/cell and number of dicentric/cell. The cytogenetic results showed an increase in the three parameters after irradiation with neutrons, as a function of radiation dose. Apparently, there was no influence of neutrons on the kinetics of cellular

  5. Reduction of chromatic aberration influences in vertical scanning white-light interferometry

    Vertical scanning white-light interferometry (SWLI) is a well-established method that is widely used in high precision surface topography measurement. However, SWLI results show characteristic slope-dependent errors due to dispersion effects and lateral chromatic aberrations of the optical imaging system. In this paper, we present methods to characterize these systematic errors related to dispersion and lateral colour. Lateral colour leads to field-dependent systematic discrepancies of the topography data obtained from the envelope position of a low-coherence interference signal and the data resulting from its interference phase. Hence, an erroneous fringe order obtained from the envelope position leads to a 2π phase jump and thus to a so-called ghost step in the measured topography. Our first approach to solve this problem is based on the measurement of a surface standard of well-known geometry. By comparison of measurement results related to the envelope position and the phase of SWLI signals, the systematic error is estimated and a numerical error compensation method is proposed. Both experimental and simulation results confirm the validity of this numerical method. In addition, using an improved design of a white-light Michelson interferometer we demonstrate experimentally that lateral chromatic aberrations and dispersion influences can be reduced also in a physical way. In this context, a conventional long working distance microscope objective is used which was not originally designed for a Michelson interference microscope. (paper)

  6. HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes.

    Tan, Hayden Weng Siong; Sim, Arthur Yi Loong; Huang, Su Ling; Leng, Ying; Long, Yun Chau

    2015-12-01

    Exercise enhances numerous signalling pathways and activates substrate metabolism in skeletal muscle. Small molecule compounds that activate these cellular responses have been shown to recapitulate the metabolic benefits of exercise. In this study, a histone deacetylase (HDAC) inhibitor, HC toxin, was investigated as a small molecule compound that activates exercise-induced adaptations. In C2C12 myotubes, HC toxin treatment activated two exercise-stimulated pathways: AMP-activated protein kinase (AMPK) and Akt pathways. HC toxin increased the protein content and phosphorylation of insulin receptor substrate 1 as well as the activation of downstream Akt signalling. The effects of HC toxin on IRS1-Akt signalling were PI3K-dependent as wortmannin abolishes its effects on IRS1 protein accumulation and Akt phosphorylation. HC toxin-induced Akt activation was sufficient to enhance downstream mTOR complex 1 (mTORC1) signalling including p70S6K and S6, which were consistently abolished by PI3K inhibition. Insulin-stimulated glucose uptake, glycolysis, mitochondrial respiration and fatty acid oxidation were also enhanced in HC toxin-treated myotubes. When myotubes were challenged with serum starvation for the induction of atrophy, HC toxin treatment prevented the induction of genes that are involved in autophagy and proteasomal proteolysis. Conversely, IRS1-Akt signalling was not induced by HC toxin in several hepatoma cell lines, providing evidence for a favourable safety profile of this small molecule. These data highlight the potential of HDAC inhibitors as a novel class of small molecules for the induction of exercise-like signalling pathways and metabolism. PMID:26373795

  7. Antimutagenic potential of curcumin on chromosomal aberrations in Allium cepa

    RAGUNATHAN Irulappan; PANNEERSELVAM Natarajan

    2007-01-01

    Turmeric has long been used as a spice and food colouring agent in Asia. In the present investigation, the antimutagenic potential of curcumin was evaluated in Allium cepa root meristem cells. So far there is no report on the biological properties of curcumin in plant test systems. The root tip cells were treated with sodium azide at 200 and 300 μg/ml for 3 h and curcumin was given at 5, 10 and 20 μg/ml for 16 h, prior to sodium azide treatment. The tips were squashed after colchicine treatment and the cells were analyzed for chromosome aberration and mitotic index. Curcumin induces chromosomal aberration in Allium cepa root tip cells in an insignificant manner, when compared with untreated control. Sodium azide alone induces chromosomal aberrations significantly with increasing concentrations. The total number of aberrations was significantly reduced in root tip cells pretreated with curcumin. The study reveals that curcumin has antimutagenic potential against sodium azide induced chromosomal aberrations in Allium cepa root meristem cells. In addition, it showed mild cytotoxicity by reducing the percentage of mitotic index in all curcumin treated groups, but the mechanism of action remains unknown. The antimutagenic potential of curcumin is effective at 5 μg/ml in Allium cepa root meristem cells.

  8. Metaphase chromosome aberrations as markers of radiation exposure and dose

    Chromosome aberration frequency provides the most reliable biological marker of dose for detecting acute accidental radiation exposure. Significant radiation-induced changes in the frequency of chromosome aberrations can be detected at very low doses. Our paper provides information on using molecular chromosome probes ''paints'' to score chromosome damage and illustrates how technical advances make it possible to understand mechanisms involved during formation of chromosome aberrations. In animal studies chromosome aberrations provide a method to relate cellular damage to cellular dose. Using an In vivo/In vitro approach aberrations provided a biological marker of dose from radon progeny exposure which was used to convert WLM to dose in rat tracheal epithelial cells. Injection of Chinese hamsters with 144Ce which produced a low dose rate exposure of bone marrow to either low-LET radiation increased the sensitivity of the cells to subsequent external exposure to 60Co. These studies demonstrated the usefulness of chromosome damage as a biological marker of dose and cellular responsiveness

  9. Split-plot fractional designs: Is minimum aberration enough?

    Kulahci, Murat; Ramirez, Jose; Tobias, Randy

    2006-01-01

    Split-plot experiments are commonly used in industry for product and process improvement. Recent articles on designing split-plot experiments concentrate on minimum aberration as the design criterion. Minimum aberration has been criticized as a design criterion for completely randomized fractional...... factorial design and alternative criteria, such as the maximum number of clear two-factor interactions, are suggested (Wu and Hamada (2000)). The need for alternatives to minimum aberration is even more acute for split-plot designs. In a standard split-plot design, there are several types of two...... completely randomized designs. Consequently, we provide a modified version of the maximum number of clear two-factor interactions design criterion to be used for split-plot designs....

  10. Biological dosimetry: chromosomal aberration analysis for dose assessment

    In view of the growing importance of chromosomal aberration analysis as a biological dosimeter, the present report provides a concise summary of the scientific background of the subject and a comprehensive source of information at the technical level. After a review of the basic principles of radiation dosimetry and radiation biology basic information on the biology of lymphocytes, the structure of chromosomes and the classification of chromosomal aberrations are presented. This is followed by a presentation of techniques for collecting blood, storing, transporting, culturing, making chromosomal preparations and scaring of aberrations. The physical and statistical parameters involved in dose assessment are discussed and examples of actual dose assessments taken from the scientific literature are given

  11. Measurement of the atmospheric primary aberrations by 4-aperture DIMM

    Shomali, Ramin; Darudi, Ahmad

    2011-01-01

    The present paper investigates and discusses the ability of the Hartmann test with 4-aperture DIMM to measure the atmospheric primary aberrations which, in turn, can be used for calculation of the atmospheric coherence time. Through performing numerical simulations, we show that the 4-aperture DIMM is able to measure the defocus and astigmatism terms correctly while its results are not reliable for the coma. The most important limitation in the measurement of the primary aberrations by 4-aperture DIMM is the centroid displacements of the spots which are caused by the higher order aberrations. This effect is negligible in calculating of the defocus and astigmatisms, while, it cannot be ignored in the calculation of the coma.

  12. Correcting the Chromatic Aberration in Barrel Distortion of Endoscopic Images

    Y. M. Harry Ng

    2003-04-01

    Full Text Available Modern endoscopes offer physicians a wide-angle field of view (FOV for minimally invasive therapies. However, the high level of barrel distortion may prevent accurate perception of image. Fortunately, this kind of distortion may be corrected by digital image processing. In this paper we investigate the chromatic aberrations in the barrel distortion of endoscopic images. In the past, chromatic aberration in endoscopes is corrected by achromatic lenses or active lens control. In contrast, we take a computational approach by modifying the concept of image warping and the existing barrel distortion correction algorithm to tackle the chromatic aberration problem. In addition, an error function for the determination of the level of centroid coincidence is proposed. Simulation and experimental results confirm the effectiveness of our method.

  13. Screening for aberrant behavior in the nuclear industry

    This paper attempts to promote a fuller understanding of how psychological assessment procedures can be used to reduce the threat from aberrant behavior in the nuclear industry. It begins with a discussion of the scientifically based methods that are used by psychologists in constructing, scoring, and interpreting these procedures. This discussion includes an emphasis on the concepts of validity and reliability and their central importance when one is choosing specific psychological screening tools. Criteria for selecting and using psychological assessment procedures when screening for aberrant behavior are also provided. Some commonly used assessment procedures that satisfy these criteria are discussed. A number a psychological assessment procedures specifically recommended for use in screening for aberrant behavior in the nuclear industry are described

  14. On-line correction of aberrations in particle spectrographs

    A new method is presented that allows the reconstruction of trajectories and the on-line correction of residual aberrations that limit the resolution of particle spectrographs. Using a computed or fitted high order transfer map that describes the uncorrected aberrations of the spectrograph under consideration, it is possible to determine a pseudo transfer map that allows the computation of the corrected data of interest as well as the reconstructed trajectories in terms of position measurements in two planes near the focal plane. The technique is only limited by the accuracy of the position measurements and the accuracy of the transfer map. In practice the method can be expressed as an inversion of a pseudo transfer map and implemented in the differential algebraic framework. The method will be used to correct residual high aberrations in the S800 spectrograph which is under construction at the National Superconducting Cyclotron Laboratory at Michigan State University

  15. Subwavelength-grating-induced wavefront aberrations: a case study

    Crabtree, Karlton; Chipman, Russell A.

    2007-07-01

    The on-axis wavefront aberrations of a one-dimensional subwavelength-grating antireflection coating on an f/1.7 lens surface are shown to be small with noticeable contributions of defocus, astigmatism, and piston. The astigmatism is 0.02 wave, and the magnitude of the piston approaches one wave peak-to-valley. The difference in aberrations between orthogonally polarized wavefronts, or the retardance aberration, shows 0.01 wave of astigmatismlike variation and more than 0.01 wave of retardance-induced defocuslike variation. A small coupling between polarization states occurs in the form of the familiar Maltese cross, yielding a maximum of 3% coupling in the four diagonal edges of the pupil.

  16. Non-Gaussianity and CMB aberration and Doppler

    Catena, Riccardo; Notari, Alessio; Renzi, Alessandro

    2013-01-01

    The peculiar motion of an observer with respect to the CMB rest frame induces a deflection in the arrival direction of the observed photons (also known as CMB aberration) and a Doppler shift in the measured photon frequencies. As a consequence, aberration and Doppler effects induce non trivial correlations between the harmonic coefficients of the observed CMB temperature maps. In this paper we investigate whether these correlations generate a bias on Non-Gaussianity estimators $f_{NL}$. We perform this analysis simulating a large number of temperature maps with Planck-like resolution (lmax $= 2000$) as different realizations of the same cosmological fiducial model (WMAP7yr). We then add to these maps aberration and Doppler effects employing a modified version of the HEALPix code. We finally evaluate a generalization of the Komatsu, Spergel and Wandelt Non-Gaussianity estimator for all the simulated maps, both when peculiar velocity effects have been considered and when these phenomena have been neglected. Usi...

  17. Radiation-induced chromosome aberrations in human lymphocytes

    Dose-response relationships for unstable chromosome exchange aberrations were obtained after irradiation with 200 kV X-rays and 60Co gamma rays, the doses ranging within 0.05-3.0 Gy. The data points were fitted to the linear quadratic model Y = C + αD + βD2, and after the chromosome hits leading to two-break unstable aberrations were estimated, to the model average x = C +kD. The results fitted the latter model particularly well, the index of determination being 0.988 for gamma rays and 0.997 for X-rays. The RBE of 200 kV X-rays as compared with 60Co gamma radiation was 1.6, when primary chromosome breaks leading to dicentric and centric ring aberrations were used as the biological endpoint. (author)

  18. Split-plot fractional designs: Is minimum aberration enough?

    Kulahci, Murat; Ramirez, Jose; Tobias, Randy

    2006-01-01

    Split-plot experiments are commonly used in industry for product and process improvement. Recent articles on designing split-plot experiments concentrate on minimum aberration as the design criterion. Minimum aberration has been criticized as a design criterion for completely randomized fractional...... factorial design and alternative criteria, such as the maximum number of clear two-factor interactions, are suggested (Wu and Hamada (2000)). The need for alternatives to minimum aberration is even more acute for split-plot designs. In a standard split-plot design, there are several types of two...... for completely randomized designs. Consequently, we provide a modified version of the maximum number of clear two-factor interactions design criterion to be used for split-plot designs....

  19. Stability of chromosome aberrations with post-irradiation time. Implications in retrospective biodosimetry. Chromosome aberration analysis in retrospective biodosimetry

    The aim of the present study was to evaluate the persistence chromosome aberrations induced by three doses of X-rays. For this purpose fluorescence in situ hybridisation (FISH) painting and multiplex FISH (mFISH) techniques have been applied to a long-term culture of irradiated cells. By painting, at 2 Gy the frequency of apparently simple translocations remained almost invariable during all the culture, whereas at 4 Gy a rapid decline was observed between the first and the second sample, followed by a slight decrease until the end of the culture. Apparently simple dicentrics and complex aberrations disappeared after the first sample at 2 and 4 Gy. When simple aberrations analysed by mFISH are considered, at 2 Gy the frequency of complete plus one-way translocations remained invariable between the first and last sample, but at 4 Gy a 60% decline was observed. True incomplete simple translocations disappeared at 2 and 4 Gy. The analysis by mFISH showed that the frequency of complex aberrations and their complexity increased with dose and tends to disappear in the last sample. Our results indicate that the dose influence on the decrease of the frequency of simple translocations with post-irradiation time cannot be fully explained by the disappearance of true incomplete translocations and complex aberrations. (author)

  20. Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway.

    Quaresma, Alexandre Jose Christino; Sievert, Rachel; Nickerson, Jeffrey A

    2013-04-01

    UAP56, ALY/REF, and NXF1 are mRNA export factors that sequentially bind at the 5' end of a nuclear mRNA but are also reported to associate with the exon junction complex (EJC). To screen for signal transduction pathways regulating mRNA export complex assembly, we used fluorescence recovery after photobleaching to measure the binding of mRNA export and EJC core proteins in nuclear complexes. The fraction of UAP56, ALY/REF, and NXF1 tightly bound in complexes was reduced by drug inhibition of the phosphatidylinositide 3-kinase (PI3 kinase)/AKT pathway, as was the tightly bound fraction of the core EJC proteins eIF4A3, MAGOH, and Y14. Inhibition of the mTOR mTORC1 pathway decreased the tight binding of MAGOH. Inhibition of the PI3 kinase/AKT pathway increased the export of poly(A) RNA and of a subset of candidate mRNAs. A similar effect of PI3 kinase/AKT inhibition was observed for mRNAs from both intron-containing and intronless histone genes. However, the nuclear export of mRNAs coding for proteins targeted to the endoplasmic reticulum or to mitochondria was not affected by the PI3 kinase/AKT pathway. These results show that the active PI3 kinase/AKT pathway can regulate mRNA export and promote the nuclear retention of some mRNAs. PMID:23427269

  1. Use of Chromosome Aberration Frequencies for Biological Dosimetry in Man

    The vast amount of work on chromosome aberrations induced by radiation exposure under defined biological and physical conditions, has shown that there exist strict relationships between aberration frequencies, radiation quality and absorbed dose in a variety of cell systems. These relationships are such that in many irradiated plant and animal systems the frequency of induced chromosome aberrations has been used to give reliable estimates of the radiation dose to which the system was exposed. A similar extrapolation from induced aberration frequency to absorbed dose can be made with human peripheral blood lymphocytes, if such cells are exposed and cultured in vitro under well defined conditions. Moreover, since aberrations induced in lymphocytes following an in vivo exposure can be detected in the cells when subsequently cultured in vitro, the peripheral blood leucocyte system has been utilized for biological dosimetry in cases where individuals have been accidentally exposed to radiations. In the case of uniform whole-body exposure of an individual, and under defined conditions of in vitro culture, the system may be expected to fulfil most of the requirements for a sensitive and accurate biological measure of absorbed dose. In this context biological variations between individuals may be of importance and the influence of such factors as age and genotype on the radiation response are considered. In cases of partial body exposure, there are a variety of biological factors that may have a considerable influence on the yields of aberrations measured in cells removed from the body shortly after exposure. Factors that are important include: the proportions of lymphocytes located in or passing through the radiation field at the time of exposure; the distribution and mobility of lymphocytes between peripheral blood and the lymphoid systems; differences in the radiation response of lymphocytes of differing types, and differences in the capacities of irradiated and non

  2. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

    Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

  3. Aberration corrected STEM of iron rhodium nanoislands

    McLaren, M. J.; Hage, F. S.; Loving, M.; Ramasse, Q. M.; Lewis, L. H.; Marrows, C. H.; Brydson, R. M. D.

    2014-06-01

    Iron-rhodium (FeRh) nanoislands of equiatomic composition have been analysed using scanning transmission electron microscopy (STEM) electron energy loss spec-troscopy(EELS) and high angle annular dark field (HAADF) techniques. Previous magne-tometry results have lead to a hypothesis that at room temperature the core of the islands are antiferromagnetic while the shell has a small ferromagnetic signal. The causes of this effect are most likely to be a difference in composition at the edges or a strain on the island that stretches the lattice and forces the ferromagnetic transition. The results find, at the film-substrate interface, an iron-rich layer ~ 5 Å thick that could play a key role in affecting the magnetostructural transition around the interfacial region and account for the room temperature ferromagnetism.

  4. A study on optical aberrations in parabolic neutron guides

    Wang, Yu; Wang, Hongli; Liu, Yuntao [Neutron Scattering Laboratory, China Institute of Atomic Energy, Beijing 102413 (China); Zu, Yong [China International Engineering Consulting Corporation, Beijing 100048 (China); He, Linfeng; Wei, Guohai; Sun, Kai [Neutron Scattering Laboratory, China Institute of Atomic Energy, Beijing 102413 (China); Han, Songbai, E-mail: hansb@ciae.ac.cn [Neutron Scattering Laboratory, China Institute of Atomic Energy, Beijing 102413 (China); Chen, Dongfeng, E-mail: dongfeng@ciae.ac.cn [Neutron Scattering Laboratory, China Institute of Atomic Energy, Beijing 102413 (China)

    2015-06-21

    It is widely believed that a neutron beam can be focused to a small spot using a parabolic guide, which will significantly improve the flux. However, researchers have also noted challenges for the neutron inhomogeneous phase space distribution in parabolic focusing guide systems. In this paper, the sources of most prominent optical aberrations, such as an inhomogeneous phase space distribution and irregular divergence distribution, are discussed, and an optimization solution is also proposed. We indicate that optimizing the parabolic guide geometrical configuration removes almost all of the aberrations and yields a considerable intensity gain factor.

  5. Aberrations of the point spread function of a multimode fiber

    Descloux, Adrien; Pinkse, Pepijn W H

    2016-01-01

    We investigate the point spread function of a multimode fiber. The distortion of the focal spot created on the fiber output facet is studied for a variety of the parameters. We develop a theoretical model of wavefront shaping through a multimode fiber and use it to confirm our experimental results and analyze the nature of the focal distortions. We show that aberration-free imaging with a large field of view can be achieved by using an appropriate number of segments on the spatial light modulator during the wavefront-shaping procedure. The results describe aberration limits for imaging with multimode fibers as in, e.g., microendoscopy.

  6. Investigation of spherical aberration effects on coherent lidar performance

    Hu, Qi; Rodrigo, Peter John; Iversen, Theis Faber Quist;

    2013-01-01

    different telescope configurations using a hard target. It is experimentally and numerically proven that the SA has a significant impact on lidar antenna efficiency and optimal beam truncation ratio. Furthermore, we demonstrate that both effective probing range and spatial resolution of the system are......In this paper we demonstrate experimentally the performance of a monostatic coherent lidar system under the influence of phase aberrations, especially the typically predominant spherical aberration (SA). The performance is evaluated by probing the spatial weighting function of the lidar system with...

  7. Optical imaging and aberrations, p.2 wave diffraction optics

    Mahajan, Virendra N

    2011-01-01

    Ten years have passed since the publication of the first edition of this classic text in April 2001. Considerable new material amounting to 100 pages has been added in this second edition. Each chapter now contains a Summary section at the end. The new material in Chapter 4 consists of a detailed comparison of Gaussian apodization with a corresponding beam, determination of the optimum value of the Gaussian radius relative to that of the pupil to yield maximum focal-point irradiance, detailed discussion of standard deviation, aberration balancing, and Strehl ratio for primary aberrations, deri

  8. The interplay between the hippocampus and the amygdala in regulating aberrant hippocampal neurogenesis during protracted abstinence from alcohol dependence

    Chitra D Mandyam

    2013-06-01

    Full Text Available The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems (e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal [HPA] hormonal levels, altered corticotropin-releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis.

  9. Mutation in SHOC2 promotes aberrant protein N-myristoylation and underlies Noonan-like syndrome with loose anagen hair

    Cordeddu, Viviana; Di Schiavi, Elia; Pennacchio, Len A.; Ma'ayan, Avi; Sarkozy, Anna; Fodale, Valentina; Cecchetti, Serena; Cardinale, Alessio; Martin, Joel; Schackwitz, Wendy; Lipzen, Anna; Zampino, Giuseppe; Mazzanti, Laura; Digilio, Maria C.; Martinelli, Simone; Flex, Elisabetta; Lepri, Francesca; Bartholdi, Deborah; Kutsche, Kerstin; Ferrero, Giovanni B.; Anichini, Cecilia; Selicorni, Angelo; Rossi, Cesare; Tenconi, Romano; Zenker, Martin; Merlo, Daniela; Dallapiccola, Bruno; Iyengar, Ravi; Bazzicalupo, Paolo; Gelb, Bruce D.; Tartaglia, Marco

    2009-01-01

    N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue.1,2 We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow,3–6 underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair [OMIM 607721]7 shared the 4A>G missense change (Ser2Gly) in SHOC2 that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2S2G in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease. PMID:19684605

  10. Dysregulation of Wnt/β-catenin Signaling in Gastrointestinal Cancers

    White, Bryan D.; Chien, Andy J.; Dawson, David W.

    2011-01-01

    Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal (GI) tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, APC (adenomatous polyposis coli), and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including crosstalk with other altered signaling pathways. A more complex view of Wnt...

  11. Aberration of a negative ion beam caused by space charge effect

    Aberrations are inevitable when the charged particle beams are extracted, accelerated, transmitted, and focused with electrostatic and magnetic fields. In this study, we investigate the aberration of a negative ion accelerator for a neutral beam injector theoretically, especially the spherical aberration caused by the negative ion beam expansion due to the space charge effect. The negative ion current density profiles with the spherical aberration are compared with those without the spherical aberration. It is found that the negative ion current density profiles in a log scale are tailed due to the spherical aberration.

  12. Effect of Coma Aberration on Orbital Angular Momentum Spectrum of Vortex Beams

    CHEN Zi-Yang; PU Ji-Xiong

    2009-01-01

    Spiral spectra of vortex beams with coma aberration are studied.It is shown that the orbital angular momentum (OAM) states of vortex beams with coma aberration are different from those aberration-free vortex beams.Spiral spectra of beams with coma aberration are spreading.It is found that in the presence of coma aberration,the vortex beams contain not only the original OAM component but also other components.A larger coma aberration coefficient and/or a larger beam waist will lead to a wider spreading of the spiral spectrum. The results may have potential applications in information encoding and transmittance.

  13. Relationship between wave aberrations and histological features in ex vivo porcine crystalline lenses

    Acosta, Eva; Bueno, Juan M.; Schwarz, Christina; Artal, Pablo

    2010-09-01

    Wave aberrations of isolated ex vivo porcine crystalline lenses were measured by using a point-diffraction interferometer. This method allowed us to gain greater insight into the detailed aberration structure of eye lenses showing systematic presence of some dominant aberrations. In order of significance, astigmatism together with spherical aberration, coma, and trefoil are the main aberrations present in all lenses. We found a high correlation between the axis of both astigmatism and trefoil with the Y-shaped suture planes of the lens, revealing a subtle relationship between the induced aberrations and the histological features.

  14. Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice.

    Bhattacharya, Aditi; Mamcarz, Maggie; Mullins, Caitlin; Choudhury, Ayesha; Boyle, Robert G; Smith, Daniel G; Walker, David W; Klann, Eric

    2016-07-01

    Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1. However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases, which are based on aberrant translation and protein expression. One such condition is fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorder (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macroorchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble-burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS, and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling. PMID:26708105

  15. Aberration Corrected Photoemission Electron Microscopy with Photonics Applications

    Fitzgerald, Joseph P. S.

    Photoemission electron microscopy (PEEM) uses photoelectrons excited from material surfaces by incident photons to probe the interaction of light with surfaces with nanometer-scale resolution. The point resolution of PEEM images is strongly limited by spherical and chromatic aberration. Image aberrations primarily originate from the acceleration of photoelectrons and imaging with the objective lens and vary strongly in magnitude with specimen emission characteristics. Spherical and chromatic aberration can be corrected with an electrostatic mirror, and here I develop a triode mirror with hyperbolic geometry that has two adjacent, field-adjustable regions. I present analytic and numerical models of the mirror and show that the optical properties agree to within a few percent. When this mirror is coupled with an electron lens, it can provide a large dynamic range of correction and the coefficients of spherical and chromatic aberration can be varied independently. I report on efforts to realize a triode mirror corrector, including design, characterization, and alignment in our microscope at Portland State University (PSU). PEEM may be used to investigate optically active nanostructures, and we show that photoelectron emission yields can be identified with diffraction, surface plasmons, and dielectric waveguiding. Furthermore, we find that photoelectron micrographs of nanostructured metal and dielectric structures correlate with electromagnetic field calculations. We conclude that photoemission is highly spatially sensitive to the electromagnetic field intensity, allowing the direct visualization of the interaction of light with material surfaces at nanometer scales and over a wide range of incident light frequencies.

  16. Chromosomal aberrations and SCEs as biomarkers of cancer risk

    Norppa, H.; Bonassi, S.; Hansteen, I. L.; Hagmar, L.; Strömberg, U.; Rössner st., Pavel; Boffetta, P.; Lindholm, C.; Gundy, S.; Lazutka, J.; Cebulska-Wasilewska, A.; Fabiánová, E.; Šrám, Radim; Knudsen, L. E.; Barale, R.; Fucic, A.

    2006-01-01

    Roč. 600, - (2006), s. 37-45. ISSN 0027-5107 Institutional research plan: CEZ:AV0Z50390512 Keywords : biomarkers * chromosomal aberration * sister chromatid exchange Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.111, year: 2006

  17. Geometric aberrations in final focussing for heavy ion fusion

    A general formulation is developed to estimate third-order distortions of ion beams without detailed calculations. Several candidate heavy ion fusion (HIF) beams are discussed in detail as examples. Some general ideas on constraints which third-order aberrations place on HIF parameters are developed

  18. Impact of primary aberrations on coherent lidar performance

    Hu, Qi; Rodrigo, Peter John; Iversen, Theis Faber Quist;

    2014-01-01

    demonstration of these tendencies. Furthermore, our numerical and experimental results show good agreement. We also demonstrate how the truncation of the transmit beam affects the system performance. It is both experimentally and numerically proven that aberration effects have profound impact on the antenna...

  19. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer

    Bonassi, Stefano; Norppa, Hannu; Ceppi, Marcello;

    2008-01-01

    Mechanistic evidence linking chromosomal aberration (CA) to early stages of cancer has been recently supported by the results of epidemiological studies that associated CA frequency in peripheral lymphocytes of healthy individuals to future cancer incidence. To overcome the limitations of single...

  20. Frequency and distribution studies of asymmetrical versus symmetrical chromosome aberrations

    Two aspects of the relationship between Asymmetrical (A) and Symmetrical (S) radiation-induced chromosomal aberrations are considered in this paper. (1) Are A and S truly alternative modes of lesion interaction. Relative frequencies for chromatid-type and chromosome-type are examined, and new lymphocyte data using banding is used to look at this, and also for parallelism in chromosome participation of the two forms for various aberration categories. All the tests applied suggest that A and S are alternative interaction modes. (2) The long-term survival characteristics of A and S are discussed, and the differences in expected frequencies of derived S per surviving cell from chromosome-type and chromatid-types are stressed. Since many in vivo tissues have varying mixtures of potential chromatid and chromosome aberration-bearing target cells, ultimate cell survival and derived S frequencies may differ between tissues for the same absorbed dose. An Appendix gives Relative Corrected Lengths (RCL) for chromosomes of the human karyotype which should be used when testing the various exchange aberration categories for random chromosome participation. (orig.)

  1. Telomere Length in Circulating Lymphocytes: Association with Chromosomal Aberrations

    Hemminki, K.; Rachakonda, S.; Musak, L.; Vymetálková, Veronika; Halasová, E.; Forsti,, A.; Vodičková, Ludmila; Buchancová, J.; Vodička, Pavel; Kumar, R.

    2015-01-01

    Roč. 54, č. 3 (2015), s. 194-196. ISSN 1045-2257 Institutional support: RVO:68378041 Keywords : structural chromosome aberrations * healthy subjects * relative telomere length * genotoxicity * telomere biology Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.041, year: 2014

  2. Chromosomal aberrations in tire plant workers and interaction with

    Musak, L.; Souček, P.; Vodičková, Ludmila; Naccarati, Alessio; Halasová, E.; Poláková, Veronika; Slyšková, Jana; Susová, S.; Buchancová, J.; Šmerhovský, Z.; Sediková, J.; Klimentová, G.; Osina, O.; Hemminki, K.; Vodička, Pavel

    2008-01-01

    Roč. 641, 1-2 (2008), s. 36-42. ISSN 0027-5107 R&D Projects: GA MZd NR8563 Institutional research plan: CEZ:AV0Z50390512 Keywords : Chromosomal aberrations * Genetic polymorphisms * DNA repair genes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.198, year: 2008

  3. Chromosome aberrations induced in human lymphocytes by neutron irradiation

    In vitro dose-response curves of unstable chromosome aberrations in human lymphocytes have been obtained for neutron spectra of mean energies 0.7, 0.9, 7.6 and 14.7 MeV. The aberration yields have been fitted to the quadratic function Y = αD + βD2, which is consistent with the single-track and two-track model of aberration formation. However with high-LET radiation, the linear component of yield, corresponding to damage caused by single tracks, predominates, and this term becomes more dominant with increasing LET, so that for fission spectrum neutrons the relationship is linear, Y = αD. At low doses, such as those received by radiation workers, limiting r.b.e. values between 13 and 47 were obtained relative to 60Co γ-radiation. At higher doses, as used in radiotherapy, the values were much lower; ranging from 2.7 to 8 at 200 rad of equivalent γ-radiation. Both sets of r.b.e. values correlated well with track-averaged LET but not with dose-averaged LET. When the numbers of cells without aberrations were plotted against radiation dose, curves were obtained which are similar in shape to those for conventional cell-survival experiments with comparable neutron spectra. The D0 values obtained in the present study are close to those from other cell systems. (author)

  4. Frequency of primary amenorrhea due to chromosomal aberration

    Objective: To find out the frequency of primary amenorrhea due to chromosomal aberration and the different options available for management. Subjects and Methods: All patients with primary amenorrhea due to chromosomal aberrations were included in study. Patient's detailed history, general physical examination, presence or absence of secondary sexual characteristics, abdominal and pelvic examination finding were noted. Targeted investigations, including ultrasound, hormonal assay, buccal smear and karyotyping results were recorded. The management options were individually tailored with focus n psychological management. Results: Eighteen patients out of 30,000 patients were diagnosed as having primary amenorrhea. Six had primary amenorrhea due to chromosomal aberrations with the frequency of 0.02%. The age at presentation was 20 years and above in 50%. The most common cause was Turner's syndrome seen in 4 out of 6. The presenting symptoms were delay in onset of menstruation in 05 patients and primary infertility in 01 patient. Conclusion: Primary amenorrhea due to chromosomal aberration is an uncommon condition requiring an early and accurate diagnosis. Turner's syndrome is a relatively common cause of this condition. Management should be multi-disciplinary and individualized according to the patient's age and symptom at presentation. Psychological management is very important and counselling throughout treatment is recommended. (author)

  5. Oxidative stress and chromosomal aberrations in an environmentally exposed population

    Rössner ml., Pavel; Rössnerová, Andrea; Šrám, Radim

    2011-01-01

    Roč. 707, 1-2 (2011), s. 34-41. ISSN 0027-5107 R&D Projects: GA MŽP(CZ) SP/1B3/8/08 Institutional research plan: CEZ:AV0Z50390512 Keywords : air pollution * oxidative stress * chromosomal aberrations Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.850, year: 2011

  6. Radiation induced chromosomal aberrations after cardiac catheterization and angiocardiography

    The relationship between the radiation doses and the chromosomal aberrations of peripheral lymphocytes was studied in patients under-going catheterization with or without angiocardiography. The radiation doses were estimated and chromosomal aberration analyses were carried out in 17 cases. They consisted of 10 males and 7 females at the age of 4 to 26 years with an average of 14 years. Doses in the chest and gonadal regions were measured with calibrated thermoluminescent dosimeters. Peripheral blood samples were taken immediately before and after the diagnostic procedure for chromosome analyses. Results showed that the average doses in the gonad region during cardiac catheterization with and without angiocardiography were 2.4 and 0.83 kC/kg respectively, while those in the chest region were as high as 0.93 and 0.54 kC/kg respectively. The chromosome aberration rate in both groups were significantly higher (2.75-3.33%) than the control value (0.22-0.75%) which was determined before X ray examination. No statistically significant difference of chromosome aberration yield was found between the two groups with and without angiocardiography

  7. Active Optical Control of Quasi-Static Aberrations for ATST

    Johnson, L. C.; Upton, R.; Rimmele, T. R.; Hubbard, R.; Barden, S. C.

    2012-12-01

    The Advanced Technology Solar Telescope (ATST) requires active control of quasi-static telescope aberrations in order to achieve the image quality set by its science requirements. Four active mirrors will be used to compensate for optical misalignments induced by changing gravitational forces and thermal gradients. These misalignments manifest themselves primarily as low-order wavefront aberrations that will be measured by a Shack-Hartmann wavefront sensor. When operating in closed-loop with the wavefront sensor, the active optics control algorithm uses a linear least-squares reconstructor incorporating force constraints to limit force applied to the primary mirror while also incorporating a neutral-point constraint on the secondary mirror to limit pointing errors. The resulting system compensates for astigmatism and defocus with rigid-body motion of the secondary mirror and higher-order aberrations with primary mirror bending modes. We demonstrate this reconstruction method and present simulation results that apply the active optics correction to aberrations generated by finite-element modeling of thermal and gravitational effects over a typical day of ATST operation. Quasi-static wavefront errors are corrected to within limits set by wavefront sensor noise in all cases with very little force applied to the primary mirror surface and minimal pointing correction needed.

  8. Frequency of chromosomal aberrations in Prague mothers and their newborns.

    Rössnerová, Andrea; Balascak, I.; Rössner ml., Pavel; Šrám, Radim

    2010-01-01

    Roč. 699, 1-2 (2010), s. 29-34. ISSN 1383-5718 R&D Projects: GA MŠk 2B06088 Institutional research plan: CEZ:AV0Z50390512 Keywords : Carcinogenic polycyclic aromatic hydrocarbons * Chromosomal aberrations * Fluorescence in situ hybridization Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.938, year: 2010

  9. Expression and aberrant promoter methylation of Wnt inhibitory factor-1 in human astrocytomas

    Wu Jun

    2010-03-01

    Full Text Available Abstract Background Wnt inhibitory factor-1(WIF-1 acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas. Methods The tissue samples consisted of 53 astrocytomas and 6 normal brain tissues. The expression levels of WIF-1 were determined by immunohistochemistry and semiquantitative RT-PCR. The results were analyzed in correlation with clinicopathological data. Methylation status of WIF-1 gene promoter was investigated using methylation specific PCR. The relationship between methylation and expression of the genes was analyzed. Results The average expression levels of WIF-1 protein and mRNA in astrocytomas were decreased significantly compared with normal control tissues. The protein and mRNA expression of WIF-1 gene in astrocytomas was decreased with the increase of pathological grade. Furthermore, WIF-1 promoter methylation was observed by MS-PCR in astrocytomas which showed significant reduction of WIF-1 expression. The WIF-1 promoter hypermethylation was associated with reduced expression of WIF-1 expression. Conclusion Our results demonstrate that the WIF-1 gene is frequently down-regulated or silenced in astrocytomas by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.

  10. Interfacial atomic structure analysis at sub-angstrom resolution using aberration-corrected STEM

    2014-01-01

    The atomic structure of a SiGe/Si epitaxial interface grown via molecular beam epitaxy on a single crystal silicon substrate was investigated using an aberration-corrected scanning transmittance electron microscope equipped with a high-angle annular dark-field detector and an energy-dispersive spectrometer. The accuracy required for compensation of the various residual aberration coefficients to achieve sub-angstrom resolution with the electron optics system was also evaluated. It was found that the interfacial layer was composed of a silicon single crystal, connected coherently to epitaxial SiGe nanolaminates. In addition, the distance between the dumbbell structures of the Si and Ge atoms was approximately 0.136 nm at the SiGe/Si interface in the [110] orientation. The corresponding fast Fourier transform exhibited a sub-angstrom scale point resolution of 0.78 Å. Furthermore, the relative positions of the atoms in the chemical composition line scan signals could be directly interpreted from the corresponding incoherent high-angle annular dark-field image. PMID:25426003

  11. Interpreting the CMB aberration and Doppler measurements: boost or intrinsic dipole?

    Roldan, Omar; Quartin, Miguel

    2016-01-01

    The aberration and Doppler coupling effects of the Cosmic Microwave Background (CMB) were recently measured by the Planck satellite. The most straightforward interpretation leads to a direct detection of our peculiar velocity $\\beta$, consistent with the measurement of the well-known dipole. In this paper we discuss the assumptions behind such interpretation. We show that the Doppler couplings are a sum of two effects: our peculiar velocity and a second order large-scale effect due to the dipolar part of the gravitational potential. We find that the two effects are exactly degenerate but {\\it only} if we assume second-order initial conditions from single-field Inflation. Thus, detecting a discrepancy in the value of $\\beta$ from the dipole and the Doppler couplings implies the presence of non-Gaussianity. We also analyze the aberration signal and we show that it is a sum of two independent effects: our peculiar velocity and lensing due to a first order large-scale dipolar gravitational potential, independentl...

  12. Long-term persistence of chromosome aberrations in uranium miners.

    Mészáros, Gabriella; Bognár, Gabriella; Köteles, G J

    2004-07-01

    Chromosome aberration analyses were performed on blood samples from 165 active underground uranium miners between 1981 and 1985. After decommissioning the mine in 1997 chromosome aberration analyses were also included in the medical laboratory investigations of health conditions of 141 subjects between 1998 and 2002 within the framework of a follow-up-study. The numerical data are presented as functions of the exposure categories expressed in working level month up to 600. In the active groups the dicentric level was 7 to 12 times higher than in the unexposed population, the acentrics also higher with more than an order of magnitude, the frequency of total aberrations--including dicentrics, acentrics, rings, deletions, minits and numerical aberrations, i.e. both chromatid and chromosome type of aberrations were also well above the control level. In the group of former uranium miners although there were slight decreases in the dicentrics after 8 to 25 yr, the values were not significantly different from the values of active miners. The frequency of deletions was also maintained in the post-mining period. The frequency of acentrics, however, decreased significantly, but even the lowest values remained 2-3 times higher than the values in the unexposed population.The possibility is suggested that for the long-term persistence of cytogenetic alterations the permanent production and presence of clastogenic factors might be responsible. The comparison of the two datasets suggest a long-term persistence of cytogenetic alterations above the population average values in a large fraction of persons investigated. PMID:15308832

  13. Chromatin structure and ionizing-radiation-induced chromosome aberrations

    The possible influence of chromatic structure or activity on chromosomal radiosensitivity was studied. A cell line was isolated which contained some 105 copies of an amplified plasmid in a single large mosquito artificial chromosome (MAC). This chromosome was hypersensitive to DNase I. Its radiosensitivity was some three fold greater than normal mosquito chromosomes in the same cell. In cultured human cells irradiated during G0, the initial breakage frequency in chromosome 4, 19 and the euchromatic and heterochromatic portions of the Y chromosome were measured over a wide range of doses by inducing Premature Chromosome Condensation (PCC) immediately after irradiation with Cs-137 gamma rays. No evidence was seen that Y heterochromatin or large fragments of it remained unbroken. The only significant deviation from the expected initial breakage frequency per Gy per unit length of chromosome was that observed for the euchromatic portion of the Y chromosome, with breakage nearly twice that expected. The development of aberrations involving X and Y chromosomes at the first mitosis after irradation was also studied. Normal female cells sustained about twice the frequency of aberrations involving X chromosomes for a dose of 7.3 Gy than the corresponding male cells. Fibroblasts from individuals with supernumerary X chromosomes did not show any further increase in X aberrations for this dos. The frequency of aberrations involving the heterochromatic portion of the long arm of the Y chromosome was about what would be expected for a similar length of autosome, but the euchromatic portion of the Y was about 3 times more radiosensitive per unit length. 5-Azacytidine treatment of cultured human female fibroblasts or fibroblasts from a 49,XXXXY individual, reduced the methylation of cytosine residues in DNA, and resulted in an increased chromosomal radiosensitivity in general, but it did not increase the frequency of aberrations involving the X chromosomes

  14. Subjective face recognition difficulties, aberrant sensibility, sleeping disturbances and aberrant eating habits in families with Asperger syndrome

    Källman Tiia

    2005-04-01

    Full Text Available Abstract Background The present study was undertaken in order to determine whether a set of clinical features, which are not included in the DSM-IV or ICD-10 for Asperger Syndrome (AS, are associated with AS in particular or whether they are merely a familial trait that is not related to the diagnosis. Methods Ten large families, a total of 138 persons, of whom 58 individuals fulfilled the diagnostic criteria for AS and another 56 did not to fulfill these criteria, were studied using a structured interview focusing on the possible presence of face recognition difficulties, aberrant sensibility and eating habits and sleeping disturbances. Results The prevalence for face recognition difficulties was 46.6% in individuals with AS compared with 10.7% in the control group. The corresponding figures for subjectively reported presence of aberrant sensibilities were 91.4% and 46.6%, for sleeping disturbances 48.3% and 23.2% and for aberrant eating habits 60.3% and 14.3%, respectively. Conclusion An aberrant processing of sensory information appears to be a common feature in AS. The impact of these and other clinical features that are not incorporated in the ICD-10 and DSM-IV on our understanding of AS may hitherto have been underestimated. These associated clinical traits may well be reflected by the behavioural characteristics of these individuals.

  15. Numerical and structural chromosome aberrations in cauliflower (Brassica oleracea var. botrytis) and Arabidopsis thaliana

    Ji, X.

    2014-01-01

    Numerical and structural chromosome aberrations in cauliflower (Brassica oleracea var. botrytis) and Arabidopsis thaliana. I studied numerical and structural chromosome aberrations in cauliflower (Brassica oleracea var. botrytis) and Arabidopsis thaliana. The large genomic changes are important for

  16. Image transfer with spatial coherence for aberration corrected transmission electron microscopes.

    Hosokawa, Fumio; Sawada, Hidetaka; Shinkawa, Takao; Sannomiya, Takumi

    2016-08-01

    The formula of spatial coherence involving an aberration up to six-fold astigmatism is derived for aberration-corrected transmission electron microscopy. Transfer functions for linear imaging are calculated using the newly derived formula with several residual aberrations. Depending on the symmetry and origin of an aberration, the calculated transfer function shows characteristic symmetries. The aberrations that originate from the field's components, having uniformity along the z direction, namely, the n-fold astigmatism, show rotational symmetric damping of the coherence. The aberrations that originate from the field's derivatives with respect to z, such as coma, star, and three lobe, show non-rotational symmetric damping. It is confirmed that the odd-symmetric wave aberrations have influences on the attenuation of an image via spatial coherence. Examples of image simulations of haemoglobin and Si [211] are shown by using the spatial coherence for an aberration-corrected electron microscope. PMID:27155359

  17. Influence of misalignment and aberrations on antenna received power in free-space laser communications

    Tan, Liying; Yang, Yuqiang; Ma, Jing; Zheng, Guoxian

    2009-04-01

    To evaluate the influence of wavefront aberrations on antenna received power in free-space laser communications, an aberration attenuation factor is proposed, based on which the power penalty at the receiver due to misalignment and primary aberrations is investigated. It is shown that antenna received power decreases gradually with increasing misalignment and aberrations. A comparison shows that tilt (misalignment) has greater influence than other primary aberrations. When the rms aberration value is 0.1λ, the received power penalties caused by tilt, astigmatism, coma, curvature, and spherical aberrations are about 40%, 36%, 35%, 24%, and 23%, respectively. In addition, the obscuration ratio of the transmitter antenna has a noticeable but relatively minor influence on the aberration attenuation factor.

  18. The Effect of the Asphericity of Myopic Laser Ablation Profiles on the Induction of Wavefront Aberrations

    Bühren, Jens; Nagy, Lana; Yoon, Geunyoung; MacRae, Scott; Kohnen, Thomas; Huxlin, Krystel R.

    2010-01-01

    A PMMA model study showed that spherical aberration induction in laser refractive surgery is due to loss of ablation efficiency in the corneal periphery. Aspheric ablation induced less spherical aberration and provided better theoretical image quality.

  19. Smart microscope: an adaptive optics learning system for aberration correction in multiphoton confocal microscopy.

    Albert, O; Sherman, L; Mourou, G; Norris, T B; Vdovin, G

    2000-01-01

    Off-axis aberrations in a beam-scanning multiphoton confocal microscope are corrected with a deformable mirror. The optimal mirror shape for each pixel is determined by a genetic learning algorithm, in which the second-harmonic or two-photon fluorescence signal from a reference sample is maximized. The speed of the convergence is improved by use of a Zernike polynomial basis for the deformable mirror shape. This adaptive optical correction scheme is implemented in an all-reflective system by use of extremely short (10-fs) optical pulses, and it is shown that the scanning area of an f:1 off-axis parabola can be increased by nine times with this technique. PMID:18059779

  20. Identification of radiation-induced chromosome aberrations by G-band staining

    A comparative study was made concerning chromosome aberration, especially symmetrical aberration in 23 serious A-bomb survivors (exposed with more than 100 rad) based upon the observations by using an ordinary staining method (O-method) and a G-band staining method (G-method). By both staining methods, 548 cells of 896 which could be analyzed were identified as normal. Aberration was detected in remaining 348 cells by either method. The number of cells in which aberration was observed by G-method but not by O-method was 55. Cells where aberration was observed by O-method but not by G-method were only 6 in number. Concerning overall aberrations, there were 197 cells in which the number detected kind of aberration by both methods was inconsistent. Also there were 31 cells, aberration of which could not be identified by G-method. The number of cells identified as abnormal by G-method was 342 and 293 by O-method, namely identification of aberration by O-method was 86% of that by G-method. The kinds of aberration are now studying. Results obtained from this study were summarized as follows; aberration which could not be detected by O-method are frequently identified by G-method and most of these aberration are symmetrical. (Kanao, N.)

  1. Retrospective chromosome aberration analysis of former uranium miners

    In this paper we present our data collected in the period of 1981-1985 on 165 persons exposed by different radon concentrations expressed in working level month (WLM) units from 100 up to 600. Following the decommissioning of the uranium mine in Hungary in 1997 cytogenetic status of 131 persons were within a follow-up-study of their health conditions initiated by the Hungarian Academy of Science. The persons have terminated their underground activities 5 to 20 years before testing. The comparison of the two datasets suggest a long-term persistence of cytogenetic alterations above the population average values in large percentages of persons investigated. The frequency of chromosome aberrations of uranium miners was found increased in function of their exposure to radon. The comparison of the miner's categories 20 years ago and in the recent years demonstrated the long-term existence of aberrations for many years after completion of underground mining activities. (authors)

  2. Relationships between DNA double-strand breaks and chromosomal aberrations

    Evidence suggests that double strand breaks are induced linearly with radiation dose at frequencies of 30-40 DSB/cell/Gy. It seems possible that there is a fast component not normally related to the induction of chromosomal aberrations, and a second slower component underlying the observed joining of chromosome and chromatid breaks. Radiation induces a mixture of blunt and cohesive-ended DSB probably with a preponderance of the latter which are much less effective at inducing aberrations. Visible chromatid breaks are also induced linearly with dose at much lower frequency than DSB and rejoin with a half-time reminiscent of slowly repairing DSB. It is possible that this slow rejoining reflects underlying repair of biologically important DSB. Rejoining of chromatid breaks and misjoining giving rise to exchanges are thought to be determined by different mechanisms. (UK)

  3. Studies on chromosome aberrations in workers occupationally exposed to radiation

    Cytogenetic assays for unstable chromosomes were performed on 54 medical radiation workers who are occupationally exposed to radiation and 42 controls. A total of 15,577 metaphase cells were scored. The frequencies of dicentrics and acentric chromosomes on controls were 0.52*10-3 and 0.82*10-2, respectively. On radiation workers those were 2.28*10-3 and 1.34*10-2, respectively. Though the frequencies of all types of chromosome aberrations in the workers were higher than those in the controls, the only significant difference was found in the case of dicentrics (P 0.05) except exposure dose of recent one year (P < 0.05). These results could indicate that low level exposure to ionizing radiation can induce unstable chromosome aberrations in blood lymphocytes

  4. Chromosome aberrations in A-bomb survivors, Hiroshima and Nagasaki

    Radiation-induced chromosome rearrangements are known to have persisted in the peripheral blood lymphocytes of atomic bomb survivors in Hiroshima and Nagasaki. A dose-response relationship for chromosome aberration frequencies has been observed in both cities. A preliminary analysis of cytogenetic data indicates that the inter-city difference observed with the T65D dose estimate becomes less pronounced with the new DS86 dosimetry system. The regression coefficient of the dose-response curves is nevertheless higher in Hiroshima than in Nagasaki. The majority of chromosome aberrations detectable to date are of the stable type, such as translocations and inversions, and they have formed the dose-response relationship. (author)

  5. Mathematical Modeling of Carcinogenesis Based on Chromosome Aberration Data

    Xiao-bo Li

    2009-01-01

    Objective: The progression of human cancer is characterized by the accumulation of genetic instability. An increasing number of experimental genetic molecular techniques have been used to detect chromosome aberrations. Previous studies on chromosome abnormalities often focused on identifying the frequent loci of chromosome alterations, but rarely addressed the issue of interrelationship of chromosomal abnormalities. In the last few years, several mathematical models have been employed to construct models of carcinogenesis, in an attempt to identify the time order and cause-and-effect relationship of chromosome aberrations. The principles and applications of these models are reviewed and compared in this paper. Mathematical modeling of carcinogenesis can contribute to our understanding of the molecular genetics of tumor development, and identification of cancer related genes, thus leading to improved clinical practice of cancer.

  6. Chromosome Aberrations in Human Lymphocytes Irradiated with Ionizing Radiation

    The purpose of the present experiment was to provide data on the dose-dependent production of chromosome aberrations such as dicentrics, centric rings, and excess acentrics. Radiation is one of the more dangerous clastogens in the environment. Ionizing radiation causes chromosome breakages and various cytogenetic aberrations in exposed cells. In an investigation into radiation emergencies, it is important to estimate the dose to exposed persons for several reasons. Physical dosimeters (e. g., film badges) may misrepresent the actual radiation dose and may not be available in a radiological accident or terrorism incident. Biological dosimetry is suitable for estimating the radiation dose during such accidents. The dicentric chromosome assay is very sensitive and a reliable bio-indicator in cases of accidental overexposure

  7. Aberrant Phenotype in Iranian Patients with Acute Myeloid Leukemia

    Mehdi Jahedi

    2014-03-01

    Full Text Available Purpose: The aim of this study was to evaluate the incidence of aberrant phenotypes and possible prognostic value in peripheral and bone marrow blood mononuclear cells of Iranian patients with AML. Methods: 56 cases of de novo AML (2010-2012 diagnosed by using an acute panel of monoclonal antibodies by multiparametric flowcytometry. Immunophenotyping was done on fresh bone marrow aspirate and/or peripheral blood samples using the acute panel of MoAbs is stained with Phycoerythrin (PE /fluorescein isothiocyanate (FITC, Allophycocyanin (APC and Peridinin-chlorophyll protein complex (perCP. We investigated Co-expression of lymphoid-associated markers CD2, CD3, CD7, CD 10, CD19, CD20 and CD22 in myeloblasts. Results: Out of the 56 cases, 32 (57.1% showed AP. CD7 was positive in 72.7% of cases in M1 and 28.5% in M2 but M3 and M4 cases lacked this marker. We detected CD2 in 58.35 of M1cases, 21.40% of M2 cases, 33.3 of M3 and 20% of M5; but M4 patients lacked this marker. The CBC analysis demonstrated a wide range of haemoglobin concentration, Platelet and WBC count which varied from normal to anaemia, thrombocytopenia to thrombocytosis and leukopenia to hyper leukocytosis. Conclusions: Our findings showed that CD7 and CD2 were the most common aberrant marker in Iranian patients with AML. However, we are not find any significant correlation between aberrant phenotype changing and MRD in our population. Taken together, this findings help to provide new insights in to the investigation of other aberrant phenotypes that may play roles in diagnosis and therapeutic of AML.

  8. Aberrant left pulmonary artery associated with right pulmonary hypoplasia

    Aberrant left pulmonary artery (ALPA), or pulmonary artery sling, is an uncommon vascular malformation that is frequently associated with obstructive disorders of the tracheobronquial tree. In newborns, it produces severe respiratory problems. In contrast, in adults, it is usually discovered by change. ALPA has been associated with right pulmonary hypoplasia (RPH) in a small number of cases. We present a new case of ALP associated with right pulmonary hypoplasia in an adult woman, diagnosed by CT and MR. 12 refs

  9. Aberrant functional brain connectome in people with antisocial personality disorder

    Yan Tang; Jun Long; Wei Wang(College of William and Mary); Jian Liao; Hua Xie; Guihu Zhao; Hao Zhang

    2016-01-01

    Antisocial personality disorder (ASPD) is characterised by a disregard for social obligations and callous unconcern for the feelings of others. Studies have demonstrated that ASPD is associated with abnormalities in brain regions and aberrant functional connectivity. In this paper, topological organisation was examined in resting-state fMRI data obtained from 32 ASPD patients and 32 non-ASPD controls. The frequency-dependent functional networks were constructed using wavelet-based correlation...

  10. Antimutagenic effects of garlic extract on chromosomal aberrations.

    Shukla, Yogeshwer; Taneja, Pankaj

    2002-02-01

    Garlic (Allium sativum) has been used since ancient times, as a spice and also for its medicinal properties. In present set of investigations antimutagenic effect of garlic extract (GE) has been evaluated using 'in vivo chromosomal aberration assay' in Swiss albino mice. Cyclophosphamide (CP), a well-known mutagen, was given at a single dose of 25 mg/kg b.w. intraperitoneally. Pretreatment with 1, 2.5 and 5% of freshly prepared GE was given through oral intubation for 5 days prior to CP administration. Animals from all the groups were sacrificed at sampling times of 24 and 48 h and their bone marrow tissue was analyzed for chromosomal damage. The animals of the positive control group (CP alone) shows a significant increase in chromosomal aberrations both at 24 and 48 h sampling time. GE, alone did not significantly induced aberrations at either sampling time, confirming its non-mutagenicity. However in the GE pre-treated and CP post-treated groups, a dose dependent decrease in cytogenetic damage was recorded. A significant suppression in the chromosomal aberrations was recorded following pretreatment with 2.5 and 5% GE administration. The anticytotoxic effects of GE were also evident, as observed by significant increase in mitotic index, when compared to positive control group. Reduction in CP induced clastogenicity by GE was evident at 24 h and to a much greater extent at 48 h of cell cycle. Thus results of the present investigations revealed that GE has chemopreventive potential against CP induced chromosomal mutations in Swiss albino mice. PMID:11790451

  11. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

    Sintupisut, Nardnisa; Liu, Pei-Ling; Yeang, Chen-Hsiang

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between ‘effector’ molecular aberrations and ‘target’ gene expressions in GBMs. A rich collection of prior st...

  12. Ocular aberrations after wavefront optimized LASIK for myopia

    Padmanabhan Prema; Basuthkar Subam; Joseph Roy

    2010-01-01

    Purpose: To study the change in ocular aberrations after wavefront optimized (WFO) laser in situ keratomileusis ( Lasik ) for correction of myopia and to analyze causative factors that may influence them. Materials and Methods: This was a prospective case series. WFO Lasik was performed for the correction of myopia, using the hansatome (Bausch and Lomb) microkeratome to create the flap and the Allegretto laser (Wavelight Technologie) to perform the ablation. The Allegretto wave analyser ...

  13. On the prediction of optical aberrations by personalized eye models

    Navarro, Rafael; González, Luis M; Hernández-Matamoros, José Luis

    2006-01-01

    Purpose. The purpose of this study is to develop and analyze a method to obtain optical schematic models of individual eyes. Each model should be able to reproduce the measured monochromatic wave aberration with high fidelity. Methods. First, we choose a generic eye model as the input guess and then apply a two-stage customization procedure. Stage 1 consists of replacing, in the initial generic model, those anatomic and optical parameters with experimental data measured on the eye under analy...

  14. Aberrant Gene Promoter Methylation Associated with Sporadic Multiple Colorectal Cancer

    Victoria Gonzalo; Juan José Lozano; Jenifer Muñoz; Francesc Balaguer; Maria Pellisé; Cristina Rodríguez de Miguel; Montserrat Andreu; Rodrigo Jover; Xavier Llor; M Dolores Giráldez; Teresa Ocaña; Anna Serradesanferm; Virginia Alonso-Espinaco; Mireya Jimeno; Miriam Cuatrecasas

    2010-01-01

    BACKGROUND: Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-...

  15. An aberrant right lateral branch from right internal thoracic artery

    Salve VM; Ratnaprabha C

    2010-01-01

    The internal thoracic artery is the largest artery of the thoracic wall. The internal thoracic artery is often mobilized for coronary artery bypass grafting. During routine dissection (MBBS Batch 2009-2010) of a middle aged male cadaver at Dr. Pinnamaneni Siddhartha Institute of Medical Sciences & Research Foundation, Gannavaram, (INDIA); an aberrant right lateral branch from right internal thoracic artery was found. It arose from right internal thoracic artery behind right first rib. It ran ...

  16. Perceptual aberrations impair mental own-body transformations

    Mohr, C.; Blanke, O.; Brugger, P

    2006-01-01

    Dysfunctional self and bodily processing have been reported from the schizophrenia spectrum. Here, the authors tested 72 students (40 women) to determine whether performance in a mental own-body transformation task relates to self-rated frequency of spontaneously experienced schizotypal body schema alterations (perceptual aberration). Participants provided speeded left-right decisions concerning the body of a visually depicted human figure (front view vs. back view). For men, reaction times t...

  17. Use of chromosome aberrations for predicting genetic hazards to man

    The question of the use of chromosome aberrations for predicting genetic hazards to man is discussed under the following headings: interspecific comparisons of dicentric and deletion production in peripheral leukocytes; comparison of dicentric yields in leukocytes to reciprocal translocation yield in spermatogonia; recovery of spermatogonia induced translocations in the sons of irradiated males; cytologically and genetically detected deletions; and current gaps in our knowledge and problems of future interest

  18. Evaluation of corneal higher order aberrations in normal topographic patterns

    Mirzajani, Ali; Aghataheri, Sattar; Ghoreishi, Mohammad; Jafarzadepour, Ebrahim; Mohammadinia, Mohadese

    2016-01-01

    Purpose This study reports the characteristics of corneal higher order aberrations (HOAs) in eyes with normal topographic pattern using the Pentacam scheimpflug system. Methods In this prospective, observational, comparative study, 165 eyes of 97 patients separated into five groups based on corneal topographic patterns were enrolled. All eyes received a comprehensive ophthalmologic examination including corneal tomographic analysis with the Pentacam system. Keratometry, corneal cylinder, and ...

  19. Electron Vortex Production and Control Using Aberration Induced Diffraction Catastrophes

    Petersen, T. C.; Weyland, M.; Paganin, D. M.; Simula, T. P.; Eastwood, S. A.; Morgan, M. J.

    2013-01-01

    An aberration corrected electron microscope is used to create electron diffraction catastrophes, containing arrays of intensity zeros threading vortex cores. Vortices are ascribed to these arrays using catastrophe theory, scalar diffraction integrals, and experimentally retrieved phase maps. From measured wave function phases, obtained using focal-series phase retrieval, the orbital angular momentum density is mapped for highly astigmatic electron probes. We observe vortex rings and topological reconnections of nodal lines by tracking the vortex cores using the retrieved phases.

  20. Aberration analysis and efficiency improvement of a bidirectional optical subassembly

    Wu, Hao; Huang, Zhangdi; Yu, Ziyan; Qian, Xiaoshi; Xu, Fei; Chen, Beckham; Lu, Yanqing

    2009-10-01

    An approach to improve the coupling efficiency of bidirectional optical subassembly (BOSA) modules is proposed and experimentally demonstrated. We analyzed the wavefront aberration coefficients of a typical BOSA. It was found that the 45-deg wavelength filter induces coma and astigmatism, and then it further deteriorates the laser diode to fiber coupling. We measured the BOSA efficiencies based on a series of different filters. For a typical 0.5-mm filter, 25% coupling efficiency improvement was achieved by optimizing the filter parameters.

  1. Chromosome aberrations and environmental exposures in acute leukemia

    Lindquist, Ragnhild Rosengren

    2009-01-01

    The aims of this thesis are to evaluate the role of environmental exposures, especially professional exposure to organic solvents and petroleum products in the etiology of acute leukemia and to investigate if there is a correlation between the exposure to a specific leukemogen factor and a clonal chromosome aberration of the leukemic cells. Papers I and II present results of a case-control study of environmental exposures, in all occupations during life-time, medical treatm...

  2. Low Order Aberrations in Band-Limited Lyot Coronagraphs

    Sivaramakrishnan, A; Sivaramakrishnan, A V; Lloyd, J P; Oppenheimer, B R; Makidon, R B; Sivaramakrishnan, Anand; Soummer, Remi; Sivaramakrishnan, Allic V.; Lloyd, James P.; Oppenheimer, Ben R.

    2005-01-01

    We study the way Lyot coronagraphs with unapodized entrance pupils respond to small, low order phase aberrations. This study is applicable to ground-based adaptive optics coronagraphs operating at 90% and higher Strehl ratios, as well as to some space-based coronagraphs with intrinsically higher Strehl ratio imaging. We utilize a second order expansion of the monochromatic point-spread function (written as a power spectrum of a power series in the phase aberration over clear aperture) to derive analytical expressions for the response of a `band-limited' Lyot coronagraph (BLC) to small, low order, phase aberrations. The BLC possesses a focal plane mask with an occulting spot whose opacity profile is a spatially band-limited function rather than a hard-edged, opaque disk. The BLC is, to first order, insensitive to tilt and astigmatism. Undersizing the stop in the re-imaged pupil plane (the Lyot plane) following the focal plane mask can alleviate second order effects of astigmatism, at the expense of system thro...

  3. Membrane based Deformable Mirror: Intrinsic aberrations and alignment issues

    Bayanna, A Raja; Chatterjee, S; Mathew, Shibu K; Venkatakrishnan, P

    2015-01-01

    A Deformable Mirror (DM) is an important component of an Adaptive Optics system. It is known that an on-axis spherical/parabolic optical component, placed at an angle to the incident beam introduces defocus as well as astigmatism in the image plane. Although the former can be compensated by changing the focal plane position, the latter cannot be removed by mere optical re-alignment. Since the DM is to be used to compensate a turbulence-induced curvature term in addition to other aberrations, it is necessary to determine the aberrations induced by such (curved DM surface) an optical element when placed at an angle (other than 0 degree) of incidence in the optical path. To this effect, we estimate to a first order, the aberrations introduced by a DM as a function of the incidence angle and deformation of the DM surface. We record images using a simple setup in which the incident beam is reflected by a 37 channel Micro-machined Membrane Deformable Mirror for various angles of incidence. It is observed that astig...

  4. A survey of chromosomal aberrations in lymphocytes of Chernobyl liquidators

    Sevan`kaev, A.V.; Moiseenko, V.V.; Zhloba, A.A. [Medical Radiological Research Centre, Obninsk (Russian Federation); Lloyd, D.C.; Edwards, A.A. [National Radiological Protection Board, Chilton (United Kingdom); Braselmann, H. [G.S.F. Institut fuer Strahlenbiologie (Germany)

    1995-04-01

    Chromosomal aberrations in lymphocytes of 875 Chernobyl liquidators have been scored and by comparison with control subjects the dicentric plus ring and excess acentric fragment frequencies are higher for persons who worked in the exclusion zone in 1986-1988 but not in 1989. Aberration yields are too low for individual biological dosimetry but, after taking account of the time interval between irradiation and blood sampling, the dicentric plus ring frequencies indicate average doses for 1986, 1987 and 1989 in good agreement with the annual averages in the Obninsk Registry. For 1988 the cytogenetic data indicate a significant higher average dose than the Registry. Liquidators who were not issued with a personal film badge tend to have higher aberration yields than those for whom badge data are recorded. This is particularly evident for those persons who worked in the first three months after the accident where physical dosimetry data are less complete or reliable. The persons probably experienced the highest exposures of all liquidators and the chromosomal data suggest an average value of about 300 mGy. (author).

  5. Aberrant behavior and cognitive ability in preschool children

    Bala Gustav

    2007-01-01

    Full Text Available The sample included 712 preschool boys and girls at the age of 4 to 7 years (mean 5.96 decimal years and standard deviation .96 from preschool institutions in Novi Sad, Sombor, Sremska Mitrovica and Bačka Palanka. Information concerning 36 indicators of aberrant behavior of the children were supplied by their parents, whereas their cognitive ability was tested by Raven’s progressive colored matrices. Based on factor analysis (promax method, four factors i.e. generators of aberrant behavior in children were singled out: aggression, anxiousness, dissociation, and hysteria, whose relations with cognitive functioning and age were also analyzed by factor analysis. Aberrant behavior and cognitive abilities show significant interrelatedness. Owing to orderly developed cognitive abilities, a child understands essence and reality of problems, realizes possibilities and manners of solving them, and succeeds in realizing successful psycho-social functioning. Developed cognitive abilities enable a child to recognize and understand her/his own reactions in different situations and develop manners of reacting, which leads to strengthening psycho-social safety and adapting behavior in accordance with her/his age and abilities.

  6. Chromosome aberrations in ataxia telangiectasia cells exposed to heavy ions

    Kawata, T.; Cucinotta, F.; George, K.; Wu, H.; Shigematsu, N.; Furusawa, Y.; Uno, T.; Isobe, K.; Ito, H.

    Understanding of biological effects of heavy ions is important to assess healt h risk in space. One of the most important issues may be to take into account individual susceptibility. Ataxia telangiectasia (A-T) cells are known to exhibit abnormal responses to radiations but the mechanism of hyper radiosensitivity of A-T still remains unknown. We report chromosome aberrations in normal human fibroblasts and AT fibroblasts exposed to low- and high-LET radiations. A chemical-induced premature chromosome condensation (PCC) technique combined with chromosome- painting technique was applied to score chromosome aberrations in G2/M-phase cells. Following gamma irradiation, GM02052 cells were approximately 5 times more sensitive to g-rays than AG1522 cells. GM02052 cells had a much higher frequency of deletions and misrejoining than AG1522 cells. When the frequency of complex type aberrations was compared, GM02052 cells showed more than 10 times higher frequency than AG1522 cells. The results will be compared with those obtained from high-LET irradiations.

  7. Molecular mechanisms in the induction of chromosome aberrations

    In more recent years there have been attempts to understand the mechanisms giving rise to aberrations on a more molecular basis. This was initially stimulated by the demonstrations of enzyme repair systems in bacteria which repair mutagen-damaged DNA and the obvious suggestion that similar kinds of repair processes in eukaryotes could be responsible for spontaneous and mutagen-induced exchanges in somatic cells, and for recombinational exchanges in meiotic cells. This impetus has been maintained largely by discovery and the acquisition of information on five fronts: (i) increasing knowledge of the and organisation of the eukaryotic chromosome; (ii) a better understanding of the types of lesions induced in DNA by a wide variety of mutagens; (iii) the demonstrations of a variety of repair systems that restore damaged DNA in eukaryotes including man; (iv) the identification and characterisation of mutants defective in DNA repair and which give unusual reponses to aberration induction by specific mutagens; (v) the development of new techniques to visulise sister chromatid exchange and other facets of chromosome substructure. In this presentation some developments are considered and a picture is sketched of our current notions on how recent chromosomal aberrations are formed, by posing a number of questions and attempting to answer them. (Auth.)

  8. Polarization Aberrations in Astronomical Telescopes: The Point Spread Function

    Breckinridge, James B.; Lam, Wai Sze T.; Chipman, Russell A.

    2015-05-01

    Detailed knowledge of the image of the point spread function (PSF) is necessary to optimize astronomical coronagraph masks and to understand potential sources of errors in astrometric measurements. The PSF for astronomical telescopes and instruments depends not only on geometric aberrations and scalar wave diffraction but also on those wavefront errors introduced by the physical optics and the polarization properties of reflecting and transmitting surfaces within the optical system. These vector wave aberrations, called polarization aberrations, result from two sources: (1) the mirror coatings necessary to make the highly reflecting mirror surfaces, and (2) the optical prescription with its inevitable non-normal incidence of rays on reflecting surfaces. The purpose of this article is to characterize the importance of polarization aberrations, to describe the analytical tools to calculate the PSF image, and to provide the background to understand how astronomical image data may be affected. To show the order of magnitude of the effects of polarization aberrations on astronomical images, a generic astronomical telescope configuration is analyzed here by modeling a fast Cassegrain telescope followed by a single 90° deviation fold mirror. All mirrors in this example use bare aluminum reflective coatings and the illumination wavelength is 800 nm. Our findings for this example telescope are: (1) The image plane irradiance distribution is the linear superposition of four PSF images: one for each of the two orthogonal polarizations and one for each of two cross-coupled polarization terms. (2) The PSF image is brighter by 9% for one polarization component compared to its orthogonal state. (3) The PSF images for two orthogonal linearly polarization components are shifted with respect to each other, causing the PSF image for unpolarized point sources to become slightly elongated (elliptical) with a centroid separation of about 0.6 mas. This is important for both astrometry

  9. Analysis of chromosome aberration data by hybrid-scale models

    This paper presents a new methodology for analyzing data of chromosome aberrations, which is useful to understand the characteristics of dose-response relationships and to construct the calibration curves for the biological dosimetry. The hybrid scale of linear and logarithmic scales brings a particular plotting paper, where the normal section paper, two types of semi-log papers and the log-log paper are continuously connected. The hybrid-hybrid plotting paper may contain nine kinds of linear relationships, and these are conveniently called hybrid scale models. One can systematically select the best-fit model among the nine models by among the conditions for a straight line of data points. A biological interpretation is possible with some hybrid-scale models. In this report, the hybrid scale models were applied to separately reported data on chromosome aberrations in human lymphocytes as well as on chromosome breaks in Tradescantia. The results proved that the proposed models fit the data better than the linear-quadratic model, despite the demerit of the increased number of model parameters. We showed that the hybrid-hybrid model (both variables of dose and response using the hybrid scale) provides the best-fit straight lines to be used as the reliable and readable calibration curves of chromosome aberrations. (author)

  10. Alignment induced aberration fields of next generation telescopes

    Schmid, Tobias; Thompson, Kevin; Rolland, Jannick

    2008-08-01

    There is a long list of new ground-based optical telescopes being considered around the world. While many are conventional Cassegrain and Ritchey-Chretien designs, some are from a family of three mirror anastigmatic (TMA) telescopes that are configured with an offset field (but still obscured) that trace back to designs developed in the 1970s for military applications. The nodal theory of aberrations, developed in the late 1970s, provides valuable insights into the response of TMA telescopes to alignment errors. Here it is shown for the first time that the alignment limiting aberration in any TMA telescope is a 3rd order astigmatism term with a new field dependence, termed field-asymmetric, field-linear 3rd order astigmatism. It is also shown that a TMA telescope under assembly that is only measured to have excellent/perfect performance onaxis is not aligned in any significant way. This is because the new astigmatic term is always zero on-axis, even though it is large over the field of view. Knowledge of this intrinsic misalignment aberration field for any TMA telescope aids greatly in ensuring it can be aligned successfully. The James Webb Space Telescope (JWST), is used an example of a relevant TMA system.

  11. Effect of therapeutic hypothermia on chromosomal aberration in perinatal asphyxia

    Bahubali D Gane

    2016-01-01

    Full Text Available Introduction: Perinatal asphyxia is a major cause for neonatal mortality and morbidity around the world. The reduction of O2results in the generation of reactive oxygen species which interact with nucleic acid and make alteration in the structure and functioning of the genome. We studied the effect of therapeutic hypothermia on chromosomes with karyotyping. Subjects and Methods: Babies in the hypothermia group were cooled for the first 72 h, using gel packs. Rectal temperature of 33–34°C was maintained. Blood sample was collected after completion of therapeutic hypothermia for Chromosomal analysis. It was done with IKAROS Karyotyping system, Metasystems, based on recommendations of International system of human cytogenetic nomenclature. Results: The median chromosomal aberration was lower in hypothermia [2(0-5] than control group [4(1-7] and chromatid breakage was commonest aberration seen. Chromosomal aberration was significantly higher in severe encephalopathy group than moderate encephalopathy group. Conclusion: We conclude that the TH significantly reduces DNA damage in perinatal asphyxia.

  12. mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse.

    Neasta, Jeremie; Barak, Segev; Hamida, Sami Ben; Ron, Dorit

    2014-07-01

    The mammalian (or mechanistic) target of rapamycin (mTOR) complex 1 (mTORC1) is a serine and threonine kinase that regulates cell growth, survival, and proliferation. mTORC1 is a master controller of the translation of a subset of mRNAs. In the central nervous system mTORC1 plays a crucial role in mechanisms underlying learning and memory by controlling synaptic protein synthesis. Here, we review recent evidence suggesting that the mTORC1 signaling pathway promotes neuroadaptations following exposure to a diverse group of drugs of abuse including stimulants, cannabinoids, opiates, and alcohol. We further describe potential molecular mechanisms by which drug-induced mTORC1 activation may alter brain functions. Finally, we propose that mTORC1 is a focal point shared by drugs of abuse to mediate drug-related behaviors such as reward seeking and excessive drug intake, and offer future directions to decipher the contribution of the kinase to mechanisms underlying addiction. Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders. PMID:24666346

  13. Genetic alterations of Wnt signal components in cancer cells

    Kikuchi, Akira; Kinshasa, S.

    2006-01-01

    The genetics of development and cancer have converged in the identification of intra- and extra-cellular signaling pathways that are aberrantly regulated in cancer and are also central to embryonic patterning. The Wnt signaling pathway has provided an outstanding example of this. The genes for β-catenin, APC, and Axin in the Wnt signaling pathway are often mutated in human cancers. In all such cases, the common denominator is the accumulation of cytosolic and nuclear β-catenin and the activat...

  14. Simultaneous fluorescence and high-resolution bright-field imaging with aberration correction over a wide field-of-view with Fourier ptychographic microscopy (FPM) (Conference Presentation)

    Chung, Jaebum; Kim, Jinho; Ou, Xiaoze; Horstmeyer, Roarke; Yang, Changhuei

    2016-03-01

    We present a method to acquire both fluorescence and high-resolution bright-field images with correction for the spatially varying aberrations over a microscope's wide field-of-view (FOV). First, the procedure applies Fourier ptychographic microscopy (FPM) to retrieve the amplitude and phase of a sample, at a resolution that significantly exceeds the cutoff frequency of the microscope objective lens. At the same time, FPM algorithm is able to leverage on the redundancy within the set of acquired FPM bright-field images to estimate the microscope aberrations, which usually deteriorate in regions further away from the FOV's center. Second, the procedure acquires a raw wide-FOV fluorescence image within the same setup. Lack of moving parts allows us to use the FPM-estimated aberration map to computationally correct for the aberrations in the fluorescence image through deconvolution. Overlaying the aberration-corrected fluorescence image on top of the high-resolution bright-field image can be done with accurate spatial correspondence. This can provide means to identifying fluorescent regions of interest within the context of the sample's bright-field information. An experimental demonstration successfully improves the bright-field resolution of fixed, stained and fluorescently tagged HeLa cells by a factor of 4.9, and reduces the error caused by aberrations in a fluorescence image by 31%, over a field of view of 6.2 mm by 9.3 mm. For optimal deconvolution, we show the fluorescence image needs to have a signal-to-noise ratio of ~18.

  15. On the spontaneous frequency of the structural chromosome aberrations (anomalies) in lymphocytes from human blood

    Chromosomal aberrations are observed both in irradiated cells and in cells which have not been irradiated but submitted to the action of the natural radioactive background. The reasons for these ''spontaneous chromosomal aberrations'' are both the natural radioactivity and a complex of physical, chemical and biological factors. A cytogenetic analysis of 6000 lymphocytes metaphases from the peripheral blood of 47 people indicates that the overall amount of the spontaneous aberrations is 2% with a ratio of chromosomal type aberrations to chromatide type aberrations of 1:5. Chromatide type aberrations are seen as the result of purely mechanical factors acting during slides preparation but yet another unknown moments cannot be excluded. They are more one hit type aberrations - chromatide and chromosomal fragments, wereas the two hit aberrations are very rare - one dicentric per 3000 cells. The chromosome type aberrations are proposed for comparison with radiation induced aberrations in human lymphocytes. They have a frequency of 0.0035 per cell or 0.0040 breakages per cell. Ionizing radiation does not induce qualitatively specific type of aberrations but increases many times the yield of anomalies, which are spontaneously observed. (A.B.)

  16. Wnt Signaling in Cancer Stem Cell Biology

    de Sousa e Melo, Felipe; Vermeulen, Louis

    2016-01-01

    Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer. PMID:27355964

  17. Cordycepin Down-Regulates Multiple Drug Resistant (MDR/HIF-1α through Regulating AMPK/mTORC1 Signaling in GBC-SD Gallbladder Cancer Cells

    Wei-Ding Wu

    2014-07-01

    Full Text Available Gallbladder cancer is the most common malignancy of the bile duct, with low 5-year survival rate and poor prognosis. Novel effective treatments are urgently needed for the therapy of this disease. Here, we showed that cordycepin, the bioactive compound in genus Cordyceps, induced growth inhibition and apoptosis in cultured gallbladder cancer cells (Mz-ChA-1, QBC939 and GBC-SD lines. We found that cordycepin inhibited mTOR complex 1 (mTORC1 activation and down-regulated multiple drug resistant (MDR/hypoxia-inducible factor 1α (HIF-1α expression through activating of AMP-activated protein kinase (AMPK signaling in gallbladder cancer GBC-SD cells. Contrarily, AMPKα1-shRNA depletion dramatically inhibited cordycepin-induced molecular changes as well as GBC-SD cell apoptosis. Further, our results showed that co-treatment with a low concentration cordycepin could remarkably enhance the chemosensitivity of GBC-SD cells to gemcitabine and 5-fluorouracil (5-FU, and the mechanism may be attributed to AMPK activation and MDR degradation. In summary, cordycepin induces growth inhibition and apoptosis in gallbladder cancer cells via activating AMPK signaling. Cordycepin could be a promising new drug or chemo-adjuvant for gallbladder cancer.

  18. One-shot and aberration-tolerable homodyne detection for holographic storage readout through double-frequency grating-based lateral shearing interferometry.

    Yu, Yeh-Wei; Xiao, Shuai; Cheng, Chih-Yuan; Sun, Ching-Cherng

    2016-05-16

    A simple method to decode the stored phase signal of volume holographic data storage with adequate wave aberration tolerance is highly demanded. We proposed and demonstrated a one-shot scheme to decode a binary-phase encoding signal through double-frequency-grating based shearing interferometry (DFGSI). The lateral shearing amount is dependent on the focal length of the collimated lens and the frequency difference between the gratings. Diffracted waves with phase encoding were successfully decoded through experimentation. An optical model for the DFGSI was built to analyze phase-error induction and phase-difference control by shifting the double-frequency grating longitudinally and laterally, respectively. The optical model was demonstrated experimentally. Finally, a high aberration tolerance of the DFGSI was demonstrated using the optical model. PMID:27409865

  19. Loss of centromeric histone H2AT120 phosphorylation accompanies somatic chromosomes inactivation in the aberrant spermatocytes of Acricotopus lucidus (Diptera, Chironomidae).

    Staiber, Wolfgang

    2016-01-01

    In the germ line of the chironomid Acricotopus lucidus, two cells with quite different chromosome constitutions result from the last unequal gonial mitosis. In the male, the future primary spermatocyte receives all the germ line-limited chromosomes (=Ks) together with somatic chromosomes (=Ss), and later on undergoes meiotic divisions, while the connected aberrant spermatocyte gets only Ss and remains undivided with chromosomes inactivated in a metaphase-like condensed state. This raises the question whether the centromeres of the permanently condensed Ss of the aberrant spermatocyte remain active during meiosis of the connected regular spermatocyte. Active centromeres exhibit an epigenetic phosphorylation mark at threonine 120 of histone H2A. To visualise the centromeric H2A phosphorylation of the Ss in the aberrant spermatocyte, meiotic stages were immunostained with different anti-phospho histone H2AT120 antibodies. Clear H2AT120ph signals appear at the centromeres of the Ss during prophase, persist on the metaphase-like condensed Ss during meiosis I of the connected primary spermatocyte and disappear during transition to meiosis II. The centromeres of the Ss and Ks of the regular spermatocytes display H2AT120ph signals from prophase I to anaphase II. The loss of the H2AT120 phosphorylation detected on the centromeres of the Ss of the aberrant spermatocyte indicating their deactivation supports the idea of a programmed inactivation of the Ss to block the entry of the germ line-derived aberrant spermatocyte, lacking Ks, into meiosis, and thus to prevent the generation of sperms possessing only Ss. This mechanism would ensure the presence of the Ks in the germ line. PMID:25820679

  20. Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction

    Persson, Tobias; Yde, Christina W.; Rasmussen, Jakob Ewald;

    2007-01-01

    Densely functionalised pyrazole carboxamides and carboxylic acids were synthesised in an expedient manner through saponification and transamidation, respectively, of ester-functionalised pyrazoles. This synthetic protocol allowed for three diversifying steps in which appendages on the pyrazole...

  1. Outsmarting androgen receptor: creative approaches for targeting aberrant androgen signaling in advanced prostate cancer

    Karen E Knudsen; Kelly, William Kevin

    2011-01-01

    Prostatic adenocarcinomas are reliant on androgen receptor (AR) activity for survival and progression. Therefore, first-line therapeutic intervention for disseminated disease entails the use of AR-directed therapeutics, achieved through androgen deprivation and direct AR antagonists. While initially effective, recurrent, ‘castrate-resistant’ prostate cancers arise, for which there is no durable means of treatment. An abundance of clinical study and preclinical modeling has led to the revelati...

  2. Dopamine signaling leads to loss of Polycomb repression and aberrant gene activation in experimental parkinsonism

    Södersten, Erik; Feyder, Michael; Lerdrup, Mads;

    2014-01-01

    Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark H3K27me3, catalyzed by the Polycomb repressive complex 2. ...

  3. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

    J. Chang (Jufang); M.M. Nicolau (Monica); T.R. Cox (Thomas); D. Wetterskog (Daniel); J.W.M. Martens (John); H. E Barker (Holly); J.T. Erler (Janine)

    2013-01-01

    textabstractIntroduction: Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expr

  4. Signal Words

    SIGNAL WORDS TOPIC FACT SHEET NPIC fact sheets are designed to answer questions that are commonly asked by the ... making decisions about pesticide use. What are Signal Words? Signal words are found on pesticide product labels, ...

  5. Aberration-Coreected Electron Microscopy at Brookhaven National Laboratory

    Zhu,Y.; Wall, J.

    2008-04-01

    The last decade witnessed the rapid development and implementation of aberration correction in electron optics, realizing a more-than-70-year-old dream of aberration-free electron microscopy with a spatial resolution below one angstrom [1-9]. With sophisticated aberration correctors, modern electron microscopes now can reveal local structural information unavailable with neutrons and x-rays, such as the local arrangement of atoms, order/disorder, electronic inhomogeneity, bonding states, spin configuration, quantum confinement, and symmetry breaking [10-17]. Aberration correction through multipole-based correctors, as well as the associated improved stability in accelerating voltage, lens supplies, and goniometers in electron microscopes now enables medium-voltage (200-300kV) microscopes to achieve image resolution at or below 0.1nm. Aberration correction not only improves the instrument's spatial resolution but, equally importantly, allows larger objective lens pole-piece gaps to be employed thus realizing the potential of the instrument as a nanoscale property-measurement tool. That is, while retaining high spatial resolution, we can use various sample stages to observe the materials response under various temperature, electric- and magnetic- fields, and atmospheric environments. Such capabilities afford tremendous opportunities to tackle challenging science and technology issues in physics, chemistry, materials science, and biology. The research goal of the electron microscopy group at the Dept. of Condensed Matter Physics and Materials Science and the Center for Functional Nanomaterials, as well as the Institute for Advanced Electron Microscopy, Brookhaven National Laboratory (BNL), is to elucidate the microscopic origin of the physical- and chemical-behavior of materials, and the role of individual, or groups of atoms, especially in their native functional environments. We plan to accomplish this by developing and implementing various quantitative

  6. 肿瘤相关的自噬信号转导通路%Neoplasms-associated autophagy signaling pathways

    林盛明; 相建峰; 张闽光

    2012-01-01

    Autophagy is a cellular catabolic pathway that is essential for survival,differentiation,development and homeostasis.The dual roles of autophagy as a tumor-promoting mechanism and a tumor suppressor mechanism have been elucidated in the recent cancer research.The double function is accomplished by some neoplasms-associated signaling pathways which include mTOR-dependent signaling pathway,Beclin1 network,LKB1-AMPK signaling pathway,p53 and p53-related regulators of autophagy.Thus it can be seen that these signaling pathways function dependently and correlatively as inducing and inhibiting autophagy and play different roles in the process that involves growth and development of neoplasms.%自噬是细胞内分解代谢的途径,它对于细胞的生存、分化、发展和内环境的稳定有着重要的作用.最近研究表明自噬具有促进和抑制肿瘤的双重作用.这种双重作用是通过一些肿瘤相关信号转导通路完成的,其中包括哺乳动物的雷帕霉素靶蛋白复合物1(mTORC1)依赖的信号转导通路、Beclin1网络系统、LKB1-AMPK信号转导通路和p53及相关自噬信号转导通路.各通路在诱导和抑制自噬方面彼此独立又相互关联,在肿瘤的发生和发展的过程中发挥着不同的作用.

  7. Optimal incision sites to reduce corneal aberration variations after small incision phacoemulsification cataract surgery

    Chu, Ling; Zhao, Jiang-Yue; Zhang, Jin-Song; Meng, Jie; Wang, Ming-Wu; Yang, Ya-Jing; Yu, Jia-Ming

    2016-01-01

    AIM To analyze the effect of steep meridian small incision phacoemulsification cataract surgery on anterior, posterior and total corneal wavefront aberration. METHODS Steep meridian small incision phacoemulsification cataract surgery was performed in age-related cataract patients which were divided into three groups according to the incision site: 12 o'clock, 9 o'clock and between 9 and 12 o'clock (BENT) incision groups. The preoperative and 3-month postoperative root mean square (RMS) values of anterior, posterior and total corneal wavefront aberration including coma, spherical aberration, and total higher-order aberrations (HOAs), were measured by Pentacam scheimpflug imaging. The mean preoperative and postoperative corneal wavefront aberrations were documented. RESULTS Total corneal aberration and total lower-order aberrations decreased significantly in three groups after operation. RMS value of total HOAs decreased significantly postoperatively in the 12 o'clock incision group (Pastigmatism changes in all three corneal incision location. CONCLUSION Corneal incision of phacoemulsification cataract surgery can affect corneal wavefront aberration. The 12 o'clock corneal incision eliminated more HOAs and the spherical aberrations decreased in BENT incision group obviously when we selected steep meridian small incision. Cataract lens replacement using wavefront-corrected intraocular lens combined with optimized corneal incision site would improve ocular aberration results. PMID:27162725

  8. The fluctuation of high-order aberration's sensitivity in ArF immersion lithography

    Zhang, Fei; Li, Yanqui

    2006-01-01

    To achieve smaller and smaller feature sizes in the semiconductor industry, extreme demands are placed on the lithographic optics, specifically the projection lens. Higher numerical aperture (NA) is adopted to obtain higher resolution. However, higher NA scales the impact of geometrical aberrations on lithography performance. Thus, a detailed understanding of the effect of geometrical aberrations on the lithographic process is indispensable. In this paper, we consider some of the surprising phenomena that occur at such high NA. We discuss the impact of flare, polarization state and MSD on higher-order aberration's sensitivity using ArF immersion lithography to print elbow pattern exposed features in photo resist on 65nm node. The higher-order aberration's sensitivity is analyzed when the annular illumination (NA=1.2, sigma out=0.76, sigma in=0.52) is employed. The 3rd, 5th, 7th, 9th geometrical aberrations according to the Fringe convention are discussed. The sensitivities to individual geometrical aberrations are calculated by introducing a fixed amount of aberration for each Zernike coefficient with all other aberrations being zero. On 65nm node, with annular illumination, the high-order aberration's sensitivity is calculated respectively according to the variation of flare, polarization state, and MSD. The results show that flare, polarization state, and MSD can contribute to the high-order aberration's sensitivity. The aberration sensitivities are increasing with the MSD and flare's value rising. The aberration sensitivities can be decreased when the horizontal linear polarized light is adopted. The merits of adjusting polarization state to choke back the aberration sensitivities are presented.

  9. Chromosomal aberrations in Sigmodon hispidus from a Superfund site

    Cotton rats (Sigmodon hispidus) were collected from an EPA Superfund site located on an abandoned oil refinery. Three trapping grids were located on the refinery and three similar grids were located at uncontaminated localities which served as reference sites. Bone marrow metaphase chromosome preparations were examined for chromosomal damage. For each individual, 50 cells were scored for six classes of chromosomal lesions. For the fall 1991 trapping period, mean number of aberrant cells per individual was 2.33, 0.85, and 1.50 for the three Superfund grids., Mean number of aberrant cells per individual was 2.55, 2.55, and 2.12 from the reference grids. Mean number of lesions per cell was 2.77, 0.86, and 1.9 from the Superfund grids, and 3.55, 2.77, and 2.50 from the reference grids. For the spring 1992 trapping period, more damage was observed in animals from both Superfund and reference sites; however, animals from Superfund grids had more damage than animals from reference grids. Mean number of aberrant cells per individual was 3.50, 3.25, and 3.70 from the Superfund grids, and 2.40, 2.11, and 1.40 from the reference grids. Mean number of lesions per cell was 4.80, 4.25, and 5.50 from the Superfund grids, and 2.60, 2.33, and 1.50 from the reference grids. These data suggest animals may be more susceptible to chromosomal damage during winter months, and animals from the Superfund grids appear to be more severely affected than animals from reference grids

  10. Breast tumor copy number aberration phenotypes and genomic instability

    Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability. We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability. Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome

  11. Genome-wide identification of significant aberrations in cancer genome

    Yuan Xiguo

    2012-07-01

    Full Text Available Abstract Background Somatic Copy Number Alterations (CNAs in human genomes are present in almost all human cancers. Systematic efforts to characterize such structural variants must effectively distinguish significant consensus events from random background aberrations. Here we introduce Significant Aberration in Cancer (SAIC, a new method for characterizing and assessing the statistical significance of recurrent CNA units. Three main features of SAIC include: (1 exploiting the intrinsic correlation among consecutive probes to assign a score to each CNA unit instead of single probes; (2 performing permutations on CNA units that preserve correlations inherent in the copy number data; and (3 iteratively detecting Significant Copy Number Aberrations (SCAs and estimating an unbiased null distribution by applying an SCA-exclusive permutation scheme. Results We test and compare the performance of SAIC against four peer methods (GISTIC, STAC, KC-SMART, CMDS on a large number of simulation datasets. Experimental results show that SAIC outperforms peer methods in terms of larger area under the Receiver Operating Characteristics curve and increased detection power. We then apply SAIC to analyze structural genomic aberrations acquired in four real cancer genome-wide copy number data sets (ovarian cancer, metastatic prostate cancer, lung adenocarcinoma, glioblastoma. When compared with previously reported results, SAIC successfully identifies most SCAs known to be of biological significance and associated with oncogenes (e.g., KRAS, CCNE1, and MYC or tumor suppressor genes (e.g., CDKN2A/B. Furthermore, SAIC identifies a number of novel SCAs in these copy number data that encompass tumor related genes and may warrant further studies. Conclusions Supported by a well-grounded theoretical framework, SAIC has been developed and used to identify SCAs in various cancer copy number data sets, providing useful information to study the landscape of cancer genomes

  12. Higher Order Aberration and Astigmatism in Children with Hyperopic Amblyopia

    Choi, Seung Kwon; Chang, Ji Woong

    2016-01-01

    Purpose To investigate the changes in corneal higher-order aberration (HOA) during amblyopia treatment and the correlation between HOA and astigmatism in hyperopic amblyopia children. Methods In this retrospective study, a total of 72 eyes from 72 patients ranging in age from 38 to 161 months were included. Patients were divided into two groups based on the degree of astigmatism. Corneal HOA was measured using a KR-1W aberrometer at the initial visit and at 3-, 6-, and 12-month follow-ups. Co...

  13. Exploiting lens aberrations to create electron vortex beams

    Clark, L; Guzzinati, G; Lubk, A; Mazilu, M; Van Boxem, R; Verbeeck, J

    2013-01-01

    A model for a new electron vortex beam production method is proposed and experimentally demonstrated. The technique calls on the controlled manipulation of the degrees of freedom of the lens aberrations to achieve a helical phase front. These degrees of freedom are accessible by using the corrector lenses of a transmission electron microscope. The vortex beam is produced through a particular alignment of these lenses into a specifically designed astigmatic state and applying an annular aperture in the condensor plane. Experimental results are found to be in good agreement with simulations.

  14. Modeling aberrations in the Advanced Camera for Surveys

    Houairi, K.; Casertano, S.; Lallo, M.; Makidon, R. B.

    2006-10-01

    We present an analysis of the optical model for HST and ACS that shows the possible impact of misalignments of various optical elements on apparent image aberrations. The analysis was aimed at identifying possible causes for apparent variations in coma and astigmatism seen on orbital time scales in HST images. Results indicate that any combinations of mirrors and motions that reproduce the observed coma and astigmatism changes, also predict either large shifts in the image, which is not observed, or require unrealistically large movements of the elements.

  15. Construction of minimum generalized aberration two-level orthogonal arrays

    Evangelaras, Haralambos

    2015-01-01

    In this paper we explore the problem of constructing two-level Minimum Generalized Aberration (MGA) orthogonal arrays with strength $t$, $n$ runs and $q>t$ columns, using a method that employs the $J$-characteristics of a two-level design. General results for the construction of MGA orthogonal arrays with $t+1$, $t+2$ and $t+3$ columns are given, while all MGA designs with strength $t\\ge 2$, $n \\equiv$ 0 mod 4 runs and $q\\le 6$ are constructed. Results are also given for two-level orthogonal ...

  16. Intrinsic Instability of Aberration-Corrected Electron Microscopes

    Schramm, S M; Tromp, R M

    2012-01-01

    Aberration-corrected microscopes with sub-atomic resolution will impact broad areas of science and technology. However, the experimentally observed lifetime of the corrected state is just a few minutes. Here we show that the corrected state is intrinsically unstable; the higher its quality, the more unstable it is. Analyzing the Contrast Transfer Function near optimum correction, we define an 'instability budget' which allows a rational trade-off between resolution and stability. Unless control systems are developed to overcome these challenges, intrinsic instability poses a fundamental limit to the resolution practically achievable in the electron microscope.

  17. Membrane based Deformable Mirror: Intrinsic aberrations and alignment issues

    Bayanna, A. Raja; Louis, Rohan E.; Chatterjee, S; Mathew, Shibu K.; Venkatakrishnan, P

    2015-01-01

    A Deformable Mirror (DM) is an important component of an Adaptive Optics system. It is known that an on-axis spherical/parabolic optical component, placed at an angle to the incident beam introduces defocus as well as astigmatism in the image plane. Although the former can be compensated by changing the focal plane position, the latter cannot be removed by mere optical re-alignment. Since the DM is to be used to compensate a turbulence-induced curvature term in addition to other aberrations, ...

  18. Explanation of test and assessment of chromosomal aberrations on occupational health examinations for radiation workers

    Test and Assessment of Chromosomal Aberrations on Occupational Health Examinations for Radiation Workers was formulated for standardizing analysis and outcome assessment of chromosomal aberrations on occupational health examinations for radiation workers. In order to provide experimental and theoretical basis for implementation and extension of this standard, this paper interpreted the standard comprehensively, including some existed problems that methods on detection and outcome assessment of chromosomal aberrations is not unified in different laboratories in China, and related criteria,laws and regulations at home and abroad are not fit for the detection of chromosomal aberrations for radiation workers very well; some introduction on methods of chromosomal slide preparation, discriminant analysis and outcome assessment of chromosomal aberration; and some influencing factors in the quality of chromosomal aberration detection. (authors)

  19. Effects of Turbulent Aberrations on Probability Distribution of Orbital Angular Momentum for Optical Communication

    ZHANG Yi-Xin; CANG Ji

    2009-01-01

    Effects of atmospheric turbulence tilt, defocus, astigmatism and coma aberrations on the orbital angular mo-mentum measurement probability of photons propagating in weak turbulent regime are modeled with Rytov approximation. By considering the resulting wave as a superposition of angular momentum eigenstates, the or-bital angular momentum measurement probabilities of the transmitted digit axe presented. Our results show that the effect of turbulent tilt aberration on the orbital angular momentum measurement probabilities of photons is the maximum among these four kinds of aberrations. As the aberration order increases, the effects of turbulence aberrations on the measurement probabilities of orbital angular momentum generally decrease, whereas the effect of turbulence defoens can be ignored. For tilt aberration, as the difference between the measured orbital angular momentum and the original orbital angular momentum increases, the orbital angular momentum measurement probabifity decreases.

  20. Effects of Turbulent Aberrations on Probability Distribution of Orbital Angular Momentum for Optical Communication

    Effects of atmospheric turbulence tilt, defocus, astigmatism and coma aberrations on the orbital angular momentum measurement probability of photons propagating in weak turbulent regime are modeled with Rytov approximation. By considering the resulting wave as a superposition of angular momentum eigenstates, the orbital angular momentum measurement probabilities of the transmitted digit are presented. Our results show that the effect of turbulent tilt aberration on the orbital angular momentum measurement probabilities of photons is the maximum among these four kinds of aberrations. As the aberration order increases, the effects of turbulence aberrations on the measurement probabilities of orbital angular momentum generally decrease, whereas the effect of turbulence defocus can be ignored. For tilt aberration, as the difference between the measured orbital angular momentum and the original orbital angular momentum increases, the orbital angular momentum measurement probability decreases. (fundamental areas of phenomenology (including applications))

  1. Fifth-order canonical geometric aberration analysis of electrostatic round lenses

    Liu Zhi Xiong

    2002-01-01

    In this paper the fifth-order canonical geometric aberration patterns are analyzed and a numerical example is given on the basis of the analytical expressions of fifth-order aberration coefficients derived in the present work. The fifth-order spherical aberration, astigmatism and field curvature, and distortion are similar to the third-order ones and the fifth-order coma is slightly different. Besides, there are two more aberrations which do not exist in the third-order aberration: they are peanut aberration and elliptical coma in accordance with their shapes. In the numerical example, by using a cross-check of the calculated coefficients with those computed through the differential algebraic method, it has been verified that all the expressions are correct and the computational results are reliable with high precision.

  2. The impact of aberrations on object reconstruction with interferometric synthetic aperture microscopy

    Adie, Steven G.; Graf, Benedikt W.; Ahmad, Adeel; Darbarsyah, Budiman; Boppart, Stephen A.; Carney, P. Scott

    2011-03-01

    Interferometric synthetic aperture microscopy (ISAM) reconstructs the scattering potential of a sample with spatially invariant resolution, based on the incident beam profile, the beam scan pattern, the physical model of light sample interaction, and subsequent light collection by the system. In practice, aberrations may influence the beam profile, particularly at higher NA, when ISAM is expected to provide maximum benefit over optical coherence microscopy. Thus it is of interest to determine the effects of aberrations on ISAM reconstructions. In this paper we present the forward model incorporating the effects of aberrations, which forms the basis for aberration correction in ISAM. Simulations and experimental results show that when operating far from focus, modest amounts of spherical aberration can introduce artifacts to the point-spread function, even at relatively low NA ~ 0.1-0.2. Further work will investigate computational methods to correct the effects of aberrations, i.e. to perform virtual adaptive optics.

  3. Correction of optical aberrations in elliptic neutron guides

    Bentley, Phillip M., E-mail: phillip.bentley@esss.se [Australian Nuclear Science and Technology Organisation (ANSTO), Locked Bag 2001, Kirrawee DC, NSW 2232 (Australia); European Spallation Source ESS AB, Box 176, 221 00 Lund (Sweden); Kennedy, Shane J. [Australian Nuclear Science and Technology Organisation (ANSTO), Locked Bag 2001, Kirrawee DC, NSW 2232 (Australia); Andersen, Ken H. [European Spallation Source ESS AB, Box 176, 221 00 Lund (Sweden); Martin Rodriguez, Damian [Juelich Centre for Neutron Science, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany); Mildner, David F.R. [National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States)

    2012-11-21

    Modern, nonlinear ballistic neutron guides are an attractive concept in neutron beam delivery and instrumentation because they offer increased performance over straight or linearly tapered guides. However, like other ballistic geometries they have the potential to create significantly non-trivial instrumental resolution functions. We address the source of the most prominent optical aberration, namely coma, and we show that for extended sources the off-axis rays have a different focal length from on-axis rays, leading to multiple reflections in the guide system. We illustrate how the interplay between coma, sources of finite size, and mirrors with non-perfect reflectivity can therefore conspire to produce uneven distributions in the neutron beam divergence, a source of complicated resolution functions. To solve these problems, we propose a hybrid elliptic-parabolic guide geometry. Using this new kind of neutron guide shape, it is possible to condition the neutron beam and remove almost all of the aberrations, whilst providing the same performance in beam current as a standard elliptic neutron guide. We highlight the positive implications for neutron scattering instruments that this new shape can bring.

  4. Robustness of BW Aberrance Indices Against Test Length

    Tsai-Wei Huang

    2011-09-01

    Full Text Available Many research had shown person fit indices might be influenced by the factor of test length on their detection rates of aberrant responses. The purpose of this study was to examine test length effects on the BW aberrance indices. Three conditions were designed in this study: test length (K, including 25, 50,100, and 200 items, ability ratio (T/K, defined as the total person score divided by test length K, and error ratio (E/K, defined as the number of errors within ability level divided by test length. Four 100-person times varying-item data matrices (100x25, 100x50, 100x100, and 100x200 were randomly generated and permuted 500 times for each data matrix through 20 repeats. Results showed that after partialling out the factors of E/K and T/K, the effect of test length on the association between the two indices was very slight. In nonlinear regression analyses, E/K and T/K can predict more than 76 and 73 percent of the variances of the B index and that of the W index, respectively, but test length with both very slight contributions on them. Furthermore, a very good model fit generated from SEM analyses also showed the effect of test length on the B and W indices were very tiny. All these pieces of evidence endorsed the B and W indices were robust with test length.

  5. New Views of Materials through Aberration-Corrected STEM

    Pennycook, Stephen J [ORNL; Chisholm, Matthew F [ORNL; Lupini, Andrew R [ORNL; Varela del Arco, Maria [ORNL; Borisevich, Albina Y [ORNL; Pantelides, Sokrates T. [Vanderbilt University; van Benthem, Klaus [ORNL; Shibata, Naoya [University of Tokyo, Tokyo, Japan; Molina Rubio, Sergio I [ORNL; Rashkeev, Sergey [ORNL

    2009-01-01

    The successful correction of lens aberrations in scanning transmission electron microscopy has allowed an improvement in resolution by a factor of two in just a few years. The benefits for materials research are far greater than a factor of two might imply, because enhanced resolution also brings enhanced image contrast, and therefore a vast increase in sensitivity to single atoms, both for imaging and electron energy loss spectroscopy. In addition, aberration correction enables simultaneous, aberrationcorrected, Z-contrast and phase contrast imaging, and brings a depth resolution at the nanometer level. It becomes possible to focus directly on features at different depths in the specimen thickness, and three-dimensional information can be extracted with single atom sensitivity. In conjunction with density functional and elasticity theory, these advances provide a new level of insight into the atomistic origins of materials properties. Several examples are discussed that illustrate the potential for applications, including the segregation of rare earth elements to grain boundaries in Si3N4 ceramics, the quantitative analysis of strain-induced growth phenomena in semiconductor quantum wells, the explanation of the enhanced thermal stability of La-doped -alumina as a catalyst support, and the origin of the remarkable catalytic activity of Au nanoparticles.

  6. Chromosome aberrations in workers of beach sand mineral industries

    Beach Sand Mining (BSM) is a profitable industry earning a sizable income for the country by way of foreign exchange. The Indian coast is rich in rare earths such as ilmenite, rutile, leucoxene, zircon, garnet and sillimanite, and is invariably associated with radioactive monazite. Due to the nature of the separation processes involved and the manual handling, workers in these factories are continuously being exposed to suspended particles containing naturally occurring radioactive materials. An attempt was made to estimate DNA damage using a chromosome aberration assay to monitor radiation effects in workers of BSM industries in India. The study group comprised 27 BSM workers and 20 controls. Percentage yields of dicentrics, acentric fragments and chromatid breaks observed in the control group were 0.058 ± 0.017, 0.073 ± 0.03 and 0.22 ± 0.112, respectively. Percentage yields of dicentrics + centric rings, acentric fragments and chromatid breaks observed in the BSM group were 0.029 ± 0.01 (P value 0.19), 0.24 ± 0.06 (P value 0.006) and 0.455 ± 0.06 (P value 0.0004), respectively. Elevated levels of fragments and chromatid aberrations are suggestive of low-dose radiation effects and also chemically-induced DNA damage. (authors)

  7. Aberrant activity in degenerated retinas revealed by electrical imaging

    Günther eZeck

    2016-02-01

    Full Text Available In this review I present and discuss the current understanding of aberrant electrical activity found in the ganglion cell layer (GCL of rod-degenerated (rd mouse retinas. The reported electrophysiological properties revealed by electrical imaging using high-density microelectrode arrays can be subdivided between spiking activity originating from retinal ganglion cells (RGCs and local field potentials reflecting strong trans-membrane currents within the GCL. RGCs in rod-degenerated retinas show increased and rhythmic spiking compared to age-matched wild-type retinas. Fundamental spiking frequencies range from 5 to 15 Hz in various mouse models. The rhythmic RGC spiking is driven by a presynaptic network comprising AII amacrine and bipolar cells. In the healthy retina this rhythm-generating circuit is inhibited by photoreceptor input. A unique physiological feature of rd retinas is rhythmic local field potentials (LFP manifested as spatially-restricted low-frequency (5–15 Hz voltage changes. Their spatiotemporal characterization revealed propagation and correlation with RGC spiking. LFPs rely on gap-junctional coupling and are shaped by glycinergic and by GABAergic transmission. The aberrant RGC spiking and LFPs provide a simple readout of the functionality of the remaining retinal circuitry which can be used in the development of improved vision restoration strategies.

  8. Generic Misalignment Aberration Patterns in Wide-Field Telescopes

    Schechter, Paul L

    2010-01-01

    Axially symmetric telescopes produce well known "Seidel" off-axis third-order aberration patterns: coma, astigmatism, curvature of field and distortion. When axial symmetry is broken by the small misalignments of optical elements, additional third-order aberration patterns arise: one each for coma, astigmatism and curvature of field and two for distortion. Each of these misalignment patterns is characterized by an associated two-dimensional vector, each of which in turn is a linear combination of the tilt and decenter vectors of the individual optical elements. For an N-mirror telescope, 2(N - 1) patterns must be measured to keep the telescope aligned. For N = 3, as in a three mirror anastigmat, there is a two-dimensional "subspace of benign misalignment" over which the misalignment patterns for third-order coma, astigmatism and curvature of field are identically zero. One would need to measure at least one of the two distortion patterns to keep the telescope aligned. Alternatively, one might measure one of t...

  9. Correction for polychromatic aberration in computed tomography images

    A method and apparatus for correcting a computed tomography image for polychromatic aberration caused by the non-linear interaction (i.e. the energy dependent attenuation characteristics) of different body constituents, such as bone and soft tissue, with a polychromatic X-ray beam are described in detail. An initial image is conventionally computed from path measurements made as source and detector assembly scan a body section. In the improvement, each image element of the initial computed image representing attenuation is recorded in a store and is compared with two thresholds, one representing bone and the other soft tissue. Depending on the element value relative to the thresholds, a proportion of the respective constituent is allocated to that element location and corresponding bone and soft tissue projections are determined and stored. An error projection generator calculates projections of polychromatic aberration errors in the raw image data from recalled bone and tissue projections using a multidimensional polynomial function which approximates the non-linear interaction involved. After filtering, these are supplied to an image reconstruction computer to compute image element correction values which are subtracted from raw image element values to provide a corrected reconstructed image for display. (author)

  10. Mechanistic modeling of aberrant energy metabolism in human disease

    Vineet eSangar

    2012-10-01

    Full Text Available Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell.

  11. Correction of optical aberrations in elliptic neutron guides

    Modern, nonlinear ballistic neutron guides are an attractive concept in neutron beam delivery and instrumentation because they offer increased performance over straight or linearly tapered guides. However, like other ballistic geometries they have the potential to create significantly non-trivial instrumental resolution functions. We address the source of the most prominent optical aberration, namely coma, and we show that for extended sources the off-axis rays have a different focal length from on-axis rays, leading to multiple reflections in the guide system. We illustrate how the interplay between coma, sources of finite size, and mirrors with non-perfect reflectivity can therefore conspire to produce uneven distributions in the neutron beam divergence, a source of complicated resolution functions. To solve these problems, we propose a hybrid elliptic–parabolic guide geometry. Using this new kind of neutron guide shape, it is possible to condition the neutron beam and remove almost all of the aberrations, whilst providing the same performance in beam current as a standard elliptic neutron guide. We highlight the positive implications for neutron scattering instruments that this new shape can bring.

  12. Chromosomal aberrations as etiological factors of intrauterine growth retardation

    Petrović Bojana

    2008-01-01

    Full Text Available Background/Aim. Intrauterine growth retardation (IUGR is a pathological condition of pregnancy characterised by birth weight below the 10th centile. A number of fetal, placental and maternal causes can lead to IUGR; although, in most cases no specific causes can be identified. The aim of this study was to determine the part of chromosomal abnormalities in IUGR etiology. Methods. Fetal blood karyotype taken by cordocentesis from 168 fetuses with diagnosed IUGR was analyzed. Results. Chromosomal rearrangements both numerical and structural were detected in 14 cases (12.2%. Two cases were triploid. Patau syndrome, Edwards syndrome and Down syndrome were found in two cases each. There was one case of trisomy 7 (47, XY, +7 and one case of trisomy 16 (47, XX, +16; one translocation, 46, XY, t (2; 14(q23; q32 and a deletion 46, XYdel (12 (p12 as well as two cases of sex chromosomes abnormalities, 45, X (Turner syndrome and 47, XYY. Conclusion. These findings suggest that a consistent number of symmetrical IUGR cases (about 12% can be associated with chromosomal rearrangements. Chromosomal aberrations that cause IUGR are heterogeneous, aberration of autosomes, mostly autosomal trisomies, being the most common.

  13. X-ray induction of mitotic and meiotic chromosome aberrations

    In 1964 six pairs of rat kangaroo (Potorous tridactylis) were obtained from Australia. The tissues of these animals were used to initiate cell lines. Since this species has a low chromosome number of six pairs, each pair with its own distinctive morphology, it is particularly favorable for cytogenetic research. In cell cultures derived from the corneal endothelial tissues of one animal there emerged a number of haploid cells. The number of haploid cells in the cultures reached as high as 20% of the total mitotic configurations. The in vitro diploid and haploid mixture cell cultures could be a resemblance or a coincidence to the mixture existence of the diploid primary spermatocytes and the haploid secondary spermatocytes (gametes) in the in vivo testicular tissues of the male animals. It would be interesting to compare reactions of the haploid and diploid cell mixture, either in the cultures or in the testes, to x-ray exposure. Two other studies involving x-ray effects on Chinese hamster oocyte maturation and meiotic chromosomes and the x-ray induction of Chinese hamster spermatocyte meiotic chromosome aberrations have been done in this laboratory. A review of these three studies involving diploid and haploid chromosomes may lead to further research in the x-ray induction of chromosome aberrations

  14. Aberrant functional brain connectome in people with antisocial personality disorder

    Tang, Yan; Long, Jun; Wang, Wei; Liao, Jian; Xie, Hua; Zhao, Guihu; Zhang, Hao

    2016-01-01

    Antisocial personality disorder (ASPD) is characterised by a disregard for social obligations and callous unconcern for the feelings of others. Studies have demonstrated that ASPD is associated with abnormalities in brain regions and aberrant functional connectivity. In this paper, topological organisation was examined in resting-state fMRI data obtained from 32 ASPD patients and 32 non-ASPD controls. The frequency-dependent functional networks were constructed using wavelet-based correlations over 90 brain regions. The topology of the functional networks of ASPD subjects was analysed via graph theoretical analysis. Furthermore, the abnormal functional connectivity was determined with a network-based statistic (NBS) approach. Our results revealed that, compared with the controls, the ASPD patients exhibited altered topological configuration of the functional connectome in the frequency interval of 0.016–0.031 Hz, as indicated by the increased clustering coefficient and decreased betweenness centrality in the medial superior frontal gyrus, precentral gyrus, Rolandic operculum, superior parietal gyrus, angular gyrus, and middle temporal pole. In addition, the ASPD patients showed increased functional connectivity mainly located in the default-mode network. The present study reveals an aberrant topological organisation of the functional brain network in individuals with ASPD. Our findings provide novel insight into the neuropathological mechanisms of ASPD. PMID:27257047

  15. Aberrant functional brain connectome in people with antisocial personality disorder.

    Tang, Yan; Long, Jun; Wang, Wei; Liao, Jian; Xie, Hua; Zhao, Guihu; Zhang, Hao

    2016-01-01

    Antisocial personality disorder (ASPD) is characterised by a disregard for social obligations and callous unconcern for the feelings of others. Studies have demonstrated that ASPD is associated with abnormalities in brain regions and aberrant functional connectivity. In this paper, topological organisation was examined in resting-state fMRI data obtained from 32 ASPD patients and 32 non-ASPD controls. The frequency-dependent functional networks were constructed using wavelet-based correlations over 90 brain regions. The topology of the functional networks of ASPD subjects was analysed via graph theoretical analysis. Furthermore, the abnormal functional connectivity was determined with a network-based statistic (NBS) approach. Our results revealed that, compared with the controls, the ASPD patients exhibited altered topological configuration of the functional connectome in the frequency interval of 0.016-0.031 Hz, as indicated by the increased clustering coefficient and decreased betweenness centrality in the medial superior frontal gyrus, precentral gyrus, Rolandic operculum, superior parietal gyrus, angular gyrus, and middle temporal pole. In addition, the ASPD patients showed increased functional connectivity mainly located in the default-mode network. The present study reveals an aberrant topological organisation of the functional brain network in individuals with ASPD. Our findings provide novel insight into the neuropathological mechanisms of ASPD. PMID:27257047

  16. Mirror-based broadband scanner with minimized aberration

    Yu, Jiun-Yann; Tzeng, Yu-Yi; Huang, Chen-Han; Chui, Hsiang-Chen; Chu, Shi-Wei

    2009-02-01

    To obtain specific biochemical information in optical scanning microscopy, labeling technique is routinely required. Instead of the complex and invasive sample preparation procedures, incorporating spectral acquisition, which commonly requires a broadband light source, provides another mechanism to enhance molecular contrast. But most current optical scanning system is lens-based and thus the spectral bandwidth is limited to several hundred nanometers due to anti-reflection coating and chromatic aberration. The spectral range of interest in biological research covers ultraviolet to infrared. For example, the absorption peak of water falls around 3 μm, while most proteins exhibit absorption in the UV-visible regime. For imaging purpose, the transmission window of skin and cerebral tissues fall around 1300 and 1800 nm, respectively. Therefore, to extend the spectral bandwidth of an optical scanning system from visible to mid-infrared, we propose a system composed of metallic coated mirrors. A common issue in such a mirror-based system is aberrations induced by oblique incidence. We propose to compensate astigmatism by exchanging the sagittal and tangential planes of the converging spherical mirrors in the scanning system. With the aid of an optical design software, we build a diffraction-limited broadband scanning system with wavefront flatness better than λ/4 at focal plane. Combined with a mirror-based objective this microscopic system will exhibit full spectral capability and will be useful in microscopic imaging and therapeutic applications.

  17. Altered Theta Oscillations and Aberrant Cortical Excitatory Activity in the 5XFAD Model of Alzheimer’s Disease

    Magdalena Elisabeth Siwek

    2015-01-01

    Full Text Available Alzheimer’s disease (AD is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling.

  18. Interdependent epidermal growth factor receptor signalling and trafficking.

    Jones, Sylwia; Rappoport, Joshua Z

    2014-06-01

    Epidermal growth factor (EGF) receptor (EGFR) signalling regulates diverse cellular functions, promoting cell proliferation, differentiation, migration, cell growth and survival. EGFR signalling is critical during embryogenesis, in particular in epithelial development, and disruption of the EGFR gene results in epithelial immaturity and perinatal death. EGFR signalling also functions during wound healing responses through accelerating wound re-epithelialisation, inducing cell migration, proliferation and angiogenesis. Upregulation of EGFR signalling is often observed in carcinomas and has been shown to promote uncontrolled cell proliferation and metastasis. Therefore aberrant EGFR signalling is a common target for anticancer therapies. Various reports indicate that EGFR signalling primarily occurs at the plasma membrane and EGFR degradation following endocytosis greatly attenuates signalling. Other studies argue that EGFR internalisation is essential for complete activation of downstream signalling cascades and that endosomes can serve as signalling platforms. The aim of this review is to discuss current understanding of intersection between EGFR signalling and trafficking. PMID:24681003

  19. Chromosome aberrations in workers of ignalina nuclear power plant

    Full text of publication follows: The Ignalina Nuclear Power Plant (I.N.P.P.) workers and outside workers including visitors constitute the largest occupational group exposed to low doses of ionizing radiation in Lithuania. In 2004, the annual collective dose to these workers (4392 persons) was 6,83 man Sv. The maximum annual individual dose of I.N.P.P. workers was 19,16 mSv, and of outside workers was 29,41 mSv. However, according to calculations performed by the Lithuanian Radiation Protection Centre, the decommissioning of I.N.P.P. (the I.N.P.P. is to be shut down by 2009) will result in collective dose of 35 man Sv. Therefore, a special attention should be given to implementation of radiation protection programme. The importance of cytogenetic studies in the medical surveillance of radiation-exposed persons is generally acknowledged. The aim of the present study was to analyse chromosome aberration frequencies in lymphocytes of I.N.P.P. workers. The blood sampling of 27 male workers was performed in October 2004, after planned outage of I.N.P.P.. It was estimated that outages of I.N.P.P. Units contributed 84% to all annual occupational collective dose. Average cumulative dose of 18 workers was 290,7 mSv (group A), and of 9 workers - 71,7 mSv (group B). The mean annual doses averaged over the three-year-period were 15,2 mSv and 0,76 mSv, respectively. None of the exposed workers had ever exceeded the permissible dose limit. The average age of group A workers was 45,2 years, and group B 48,2 years. A questionnaire form with details on age, occupational history, smoking habit and alcohol intake, medication, history of recent illness was completed for each person at the time of blood collection. 64 non-exposed male donors approximately matched by age were used as controls (group C). Heparinized venous blood samples were taken and cultures were initiated within 24 h according to the standard procedures. At least 500 first cycle metaphases were analysed from each

  20. MULTISCALE GUIDED DEBLURRING: CHROMATIC ABERRATION CORRECTION IN COLOR AND NEAR-INFRARED IMAGING

    Sadeghipoor Kermani, Zahra; Lu, Yue; Mendez, Erick; Süsstrunk, Sabine

    2015-01-01

    Chromatic aberration, caused by photographic lens imperfections, results in the image of only one spectral channel being sharp, while the other channels are blurred depending on their wavelengths difference with the sharp channel. We study chromatic aberration for a system that jointly records color and near-infrared (NIR) images on a single sensor. Chromatic aberration in such a system leads to a blurred NIR image when the color image is in-focus and sharp. We propose an algorithm that deblu...

  1. Method for measuring ocular aberrations induced by thermal lensing in vivo

    Vincelette, Rebecca; Oliver, Jeff; Noojin, Gary; Schuster, Kurt; Shingledecker, Aurora; Welch, Ashley J.

    2010-02-01

    An adaptive optics imaging system was used to qualitatively observe the types of aberrations induced by an infrared laser in a rhesus eye. Thermal lensing was induced with an infrared laser radiation wavelength of 1150-nm. The adaptive optics system tracked the temporal response of the aberrations at a frequency of 30 Hz for continuous-wave exposures. Results are compared against thermal lensing aberrations induced in an artificial eye.

  2. ABERRATIONS MINIMIZATION FOR IMPROVING CHARACTERISTICS OF COMPACT HIGH-APERTURE DISPERSIVE SPECTROMETERS

    E. S. Voropay

    2015-04-01

    Full Text Available Schemes of high-aperture and compact optical spectrometers and giperspectrometer with minimized aberrations are presented. In the first scheme usage of inclined plane-parallel plate allows decreasing of astigmatism. In the second scheme off-axis aberrations are practically removed due to axial propagation of light. For giperspectrometer narrowing of light propagation angle through the object lens and turning the light out of dispersion plane lead to minimizing of picture aberrations.

  3. Correction of cell-induced optical aberrations in a fluorescence fluctuation microscope.

    Leroux, Charles-Edouard; Grichine, Alexei; Wang, Irène; Delon, Antoine

    2013-01-01

    International audience We describe the effect of optical aberrations on fluorescence fluctuations microscopy (FFM), when focusing through a single living cell. FFM measurements are performed in an aqueous fluorescent solution and prove to be a highly sensitive tool to assess the optical aberrations introduced by the cell. We demonstrate an adaptive optics (AO) system to remove the aberration-related bias in the FFM measurements. Our data show that AO is not only useful when imaging deep in...

  4. Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia

    Sonnet, Miriam; Claus, Rainer; Becker, Natalia; Zucknick, Manuela; Petersen, Jana; Lipka, Daniel B.; Oakes, Christopher C.; Andrulis, Mindaugas; Lier, Amelie; Milsom, Michael D.; Witte, Tania; Gu, Lei; Kim-Wanner, Soo-Zin; Schirmacher, Peter; Wulfert, Michael

    2014-01-01

    Background Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. Methods We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylati...

  5. ANALYSES OF CHROMOSOME ABERRATIONS IN LYMPHOCYTES AND BONE MARROW CELLS INDUCED BY RADIATION OR BENZENE

    张鸿源; 王兰金; 等

    1995-01-01

    The chromosomoe and chromatid type aberration can be induced by benzene and the dicentric and ring ones were not observed in vitro experiment but observed in vivo one.In vitro experiment a good linear reression can be given between benzene concentrations and total aberration cells while power regression for radiation dose.The chromosome aberrations induced by benzene combined with radiation in rabbit blood lymphocytes are higher than in bone marryow cells.

  6. Relationship of DNA lesions and their repair to chromosomal aberration production

    Recent work on the roles of specific kinds of DNA lesions and their enzymatic repair systems in the production of chromosomal aberrations seems consistent with a simple molecular model of chromosomal aberrations formation. Evidence from experiments with the human repair-deficient genetic diseases xeroderma pigmentosom, ataxia telangiectasia, and Fanconi's anemia is reviewed in the light of the contributions to aberration production of single and double polynucleotide strand breaks, base damage, polynucleotide strand crosslinks, and pyrimidine cyclobutane dimers

  7. Optimization of holographic data storage system based on Seidel aberrations reduction

    Liu, Ren-Chung; Lin, Shiuan-Huei; Hsu, Ken-Yuh

    2015-08-01

    In this research, we investigate the influence of Seidel aberrations on the point spread function and the probability density function of holographic data storage systems, and thus the storage capacity and bit error rate of storage system can be obtained. The aberrations tolerances of storage systems with different numerical aperture are obtained. Optimization on BER and SC of holographic data storage systems by reducing Seidel aberrations will be demonstrated numerically.

  8. EVALUATION OF CORRECTION METHODS OF CHROMATIC ABERRATION IN DIGITAL CAMERA IMAGES

    Matsuoka, R; Asonuma, K.; Takahashi, G; Danjo, T.; Hirana, K.

    2012-01-01

    This paper reports an experiment conducted to evaluate correction methods of chromatic aberrations in images acquired by a nonmetric digital camera. The chromatic aberration correction methods evaluated in the experiment are classified into two kinds. One is the method to correct image coordinates by using camera calibration results of color-separated images. The other is the method based on the assumption that the magnitude of chromatic aberrations can be expressed by a function of ...

  9. A double pole-gap design for low spherical aberration in thin solenoids

    Chandran, Sona, E-mail: sona@rrcat.gov.in; Biswas, Bhaskar

    2015-10-21

    We here report a new design of a double air-slot or pole-gap type, axially thin, shielded solenoid with lower spherical aberration than conventional single pole-gap type solenoids. The net on-axis field from two optimally distanced pole gaps reduces the spherical aberration. The working principle of the model is also given by a pair of coaxial, in-air, identical current loops which can have lower spherical aberration than a single current loop. The new design is useful to achieve low spherical aberration in axially thin shielded solenoids.

  10. A double pole-gap design for low spherical aberration in thin solenoids

    We here report a new design of a double air-slot or pole-gap type, axially thin, shielded solenoid with lower spherical aberration than conventional single pole-gap type solenoids. The net on-axis field from two optimally distanced pole gaps reduces the spherical aberration. The working principle of the model is also given by a pair of coaxial, in-air, identical current loops which can have lower spherical aberration than a single current loop. The new design is useful to achieve low spherical aberration in axially thin shielded solenoids

  11. Spherical aberration from trajectories in real and hard-edge solenoid fields

    BISWAS B

    2016-06-01

    For analytical, real and hard-edge solenoidal axial magnetic fields, the low-energy electron trajectories are obtained using the third-order paraxial ray equation. Using the particle trajectories, it is shown that the spherical aberration in the hard-edge model is high and it increases monotonously with hard edginess, although the focal length converges, in agreement with a recentfield and spherical aberration model. The model paved the way for a hard-edge approximation that gives correct focal length and spherical aberration, which is verified here by the trajectory method. In essence, we show that exact hard-edge fields give infinite spherical aberrations.

  12. X-ray-induced chromosome aberrations in Down lymphocytes: an explanation of their increased sensitivity

    Unstimulated lymphocytes from individuals with Down Syndrome (trisomy 21) are more sensitive to the induction of dicentric and ring aberrations by X rays than normal lymphocytes. Several explanations involving the more rapid rejoining of X-ray-induced lesions in Down cells have been offered. It is shown here that the repair of the DNA damage converted into chromosome aberrations is more rapid in Down cells than normal cells. This more rapid repair results in a higher probability of producing chromosome aberrations, and hence higher aberration frequencies in Down than normal cells

  13. X-ray-induced chromosome aberrations in Down lymphocytes: an explanation of their increased sensitivity

    Unstimulated lymphocytes from individuals with Down Syndrome (trisomy 21) are more sensitive to the induction of dicentric and ring aberrations by X rays than normal lymphocytes. Several explanations involving the more rapid rejoining of X-ray--induced lesions in Down cells have been offered. It is shown here that the repair of the DNA damage converted into chromosome aberrations is more rapid in Down cells than normal cells. This more rapid repair results in a higher probability of producing chromosomes aberrations, and hence higher aberration frequencies in Down than normal cells

  14. MTOR signaling and ubiquitin-proteosome gene expression in the preservation of fat free mass following high protein, calorie restricted weight loss

    McIver Cassandra M

    2012-09-01

    Full Text Available Abstract Caloric restriction is one of the most efficient ways to promote weight loss and is known to activate protective metabolic pathways. Frequently reported with weight loss is the undesirable consequence of fat free (lean muscle mass loss. Weight loss diets with increased dietary protein intake are popular and may provide additional benefits through preservation of fat free mass compared to a standard protein, high carbohydrate diet. However, the precise mechanism by which a high protein diet may mitigate dietary weight loss induced reductions in fat free mass has not been fully elucidated. Maintenance of fat free mass is dependent upon nutrient stimulation of protein synthesis via the mTOR complex, although during caloric restriction a decrease (atrophy in skeletal muscle may be driven by a homeostatic shift favouring protein catabolism. This review evaluates the relationship between the macronutrient composition of calorie restricted diets and weight loss using metabolic indicators. Specifically we evaluate the effect of increased dietary protein intake and caloric restricted diets on gene expression in skeletal muscle, particularly focusing on biosynthesis, degradation and the expression of genes in the ubiquitin-proteosome (UPP and mTOR signaling pathways, including MuRF-1, MAFbx/atrogin-1, mTORC1, and S6K1.

  15. Hedgehog Signaling in Pancreatic Fibrosis and Cancer.

    Bai, Yongyu; Bai, Yongheng; Dong, Jiaojiao; Li, Qiang; Jin, Yuepeng; Chen, Bicheng; Zhou, Mengtao

    2016-03-01

    The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies. PMID:26962810

  16. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update

    Melnik BC

    2015-07-01

    Full Text Available Bodo C Melnik Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Germany Abstract: Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1 hyperglycemic carbohydrates, 2 milk and dairy products, 3 saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs. Diet-induced insulin/insulin-like growth factor (IGF-1-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs, glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1. Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1, the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ, liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c, crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA- and Δ6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea and composition (dysseborrhea promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a “danger signal,” stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte

  17. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.

    Melnik, Bodo C

    2015-01-01

    Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1) hyperglycemic carbohydrates, 2) milk and dairy products, 3) saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs). Diet-induced insulin/insulin-like growth factor (IGF-1)-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs), glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1). Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c), crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA- and Δ6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea) and composition (dysseborrhea) promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a "danger signal," stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte proliferation. Oleate stimulates P. acnes adhesion, keratinocyte proliferation, and comedogenesis via interleukin-1α release. Thus, diet

  18. Broadband Focal Plane Wavefront Control of Amplitude and Phase Aberrations

    Groff, Tyler D; Carlotti, Alexis; Riggs, A J Eldorado

    2012-01-01

    The Stroke Minimization algorithm developed at the Princeton High Contrast Imaging Laboratory has proven symmetric dark hole generation using minimal stroke on two deformable mirrors (DM) in series. The windowed approach to Stroke Minimization has proven symmetric dark holes over small bandwidths by using three wavelengths to define the bandwidth of correction in the optimization problem. We address the relationship of amplitude and phase aberrations with wavelength, how this changes with multiple DMs, and the implications for simultaneously correcting both to achieve symmetric dark holes. Operating Stroke Minimization in the windowed configuration requires multiple wavelength estimates. To save on exposures, a single estimate is extrapolated to bounding wavelengths using the established relationship in wavelength to produce multiple estimates of the image plane electric field. Here we demonstrate better performance by improving this extrapolation of the estimate to other wavelengths. The accuracy of the func...

  19. Propagation of Aberrations through Phase Induced Amplitude Apodization coronagraph

    Pueyo, Laurent; Shaklan, Stuart; 10.1364/JOSAA.28.000189

    2011-01-01

    The specification of polishing requirements for the optics in coronagraphs dedicated to exo-planet detection requires careful and accurate optical modelling. Numerical representations of the propagation of aberrations through the system as well as simulations of the broadband wavefront compensation system using multiple DMs are critical when one devises an error budget for such a class of instruments. In this communication we introduce an analytical tool that serves this purpose for Phase Induced Amplitude Apodisation (PIAA) coronagraphs. We first start by deriving the analytical form of the propagation of a harmonic ripple through a PIAA unit. Using this result we derive the chromaticity of the field at any plane in the optical train of a telescope equipped with such a coronagraph. Finally we study the chromatic response of a sequential DM wavefront actuator correcting such a corrugated field and thus quantify the requirements on the manufacturing of PIAA mirrors

  20. Biological dosimetry of ionizing radiation by chromosomal aberration analysis

    Biological dosimetry consists of estimating absorbed doses for people exposed to radiation by mean biological methods. Several indicators used are based in haematological, biochemical, and cytogenetic data, although nowadays without doubt, the cytogenetic method is considered to be the most reliable. In this case, the study ol chromosomal aberrations, normally dicentric chromosomes, in peripheral lymphocytes can be related to absorbed dose through an experimental calibration curve. An experimental dose-response curve, using dicentric chromosomes analysis, X-rays at 300 kVp, 114 rad/min and temperature 37 degree celsius has been produced. Experimental data is fitted to model Y =α + β1D + β2D 2 , where Y is the number of dicentrics per cell and D the dose. The curve is compared with those produced elsewhere. (Author) 14 refs

  1. Cytogenetic effects of radiotherapy. Breakpoint distribution in induced chromosome aberrations

    A total of 660 breakpoints were identified in the chromosome aberrations detected in lymphocytes from cancer patients after radiotherapy. The results show that chromosomes 1, 3, and 7 were significantly more affected than other chromosomes by ionizing radiation in vivo. Chromosome arms 1p, 1q, 7q, and 11p were also significantly more affected. Some bands also showed a special sensitivity to radiation, and band 1q32 was the most affected. This band is proposed as a hot point for the clastogenic effect of ionizing radiation. A significant clustering of breakpoints in G bands was also found, especially at the telomeres, as previously described by other authors. Clustering of breakpoints was also observed in bands where fragile sites, protooncogenes, breakpoints involved in chromosomal cancer rearrangements, and breakpoints involved in chromosomal evolution of the Hominoidea are located

  2. Chromosomal aberrations and SCEs as biomarkers of cancer risk

    Norppa, H; Bonassi, S; Hansteen, I-L; Hagmar, L; Strömberg, U; Rössner, P; Boffetta, P; Lindholm, C; Gundy, S; Lazutka, J; Cebulska-Wasilewska, A; Fabiánová, E; Srám, R J; Knudsen, Lisbeth E.; Barale, R; Fucic, A

    Previous studies have suggested that the frequency of chromosomal aberrations (CAs), but not of sister chromatid exchanges (SCEs), predicts cancer risk. We have further examined this relationship in European cohorts comprising altogether almost 22,000 subjects, in the framework of a European...... collaborative project (CancerRiskBiomarkers). The present paper gives an overview of some of the results of the project, especially as regards CAs and SCEs. The results confirm that a high level of CAs is associated with an increased risk of cancer and indicate that this association does not depend on the time...... between CA analysis and cancer detection, i.e., is obviously not explained by undetected cancer. The present evidence indicates that both chromatid-type and chromosome-type CAs predict cancer, even though some data suggest that chromosome-type CAs may have a more pronounced predictive value than chromatid...

  3. Sphere-cone-polynomial special window with good aberration characteristic

    Optical windows with external surfaces shaped to satisfy operational environment needs are known as special windows. A novel special window, a sphere-cone-polynomial (SCP) window, is proposed. The formulas of this window shape are given. An SCP MgF2 window with a fineness ratio of 1.33 is designed as an example. The field-of-regard (FOR) angle is ±75°. From the window system simulation results obtained with the calculated fluid dynamics (CFD) and optical design software, we find that compared to the conventional window forms, the SCP shape can not only introduce relatively less drag in the airflow, but also have the minimal effect on imaging. So the SCP window optical system can achieve a high image quality across a super wide FOR without adding extra aberration correctors. The tolerance analysis results show that the optical performance can be maintained with a reasonable fabricating tolerance to manufacturing errors

  4. Analysis of a low-aberration holographic scanner.

    Shiozawa, T; Iwaoka, H

    1988-05-15

    Low-aberration holographic scanners that eliminate the need tor lenses or mirrors promise to greatly reduce the cost of laser printers and image scanners. This paper describes how the spot profile of such a scanner can be predicted using the Fresnel-Kirchhoff diffraction integral, and the diffraction efficiency of the scanner can be predicted using Kogelnik's coupled-wave theory. Experimental results verity the accuracy of these design methods. For a prototype scanner used in a high-resolution He-Ne laser printer, the measured linearity error was under +/- 100 microm, and the spot size (half-intensity beamwidth) was under 60 microm for a span (scan width) of 280 mm. PMID:20531695

  5. Inhibition of Notch Signaling Blocks Growth of Glioblastoma Cell Lines and Tumor Neurospheres

    Chen, Jie; Kesari, Santosh; Rooney, Christine; Strack, Peter R.; Chen, Jihua; Shen, Huangxuan; Wu, Lizi; Griffin, James D.

    2010-01-01

    Glioblastoma (GBM) is the most common malignant brain tumor that is characterized by high proliferative rate and invasiveness. Since dysregulation of Notch signaling is implicated in the pathogenesis of many human cancers, here we investigated the role of Notch signaling in GBM. We found that there is aberrant activation of Notch signaling in GBM cell lines and human GBM-derived neurospheres. Inhibition of Notch signaling via the expression of a dominant negative form of the Notch coactivator...

  6. Aberrant meiotic behavior in Agave tequilana Weber var. azul

    Rodríguez-Garay Benjamin

    2002-10-01

    Full Text Available Abstract Background Agave tequilana Weber var. azul, is the only one variety permitted by federal law in México to be used for tequila production which is the most popular contemporary alcoholic beverage made from agave and recognized worldwide. Despite the economic, genetic, and ornamental value of the plant, it has not been subjected to detailed cytogenetic research, which could lead to a better understanding of its reproduction for future genetic improvement. The objective of this work was to study the meiotic behavior in pollen mother cells and its implications on the pollen viability in Agave tequilana Weber var. azul. Results The analysis of Pollen Mother Cells in anaphase I (A-I showed 82.56% of cells with a normal anaphase and, 17.44% with an irregular anaphase. In which 5.28% corresponded to cells with side arm bridges (SAB; 3.68% cells with one bridge and one fragment; 2.58% of irregular anaphase showed cells with one or two lagging chromosomes and 2.95% showed one acentric fragment; cells with two bridges and cells with two bridges and one acentric fragment were observed in frequencies of 1.60% and 1.35% respectively. In anaphase II some cells showed bridges and fragments too. Aberrant A-I cells had many shrunken or empty pollen grains (42.00% and 58.00 % viable pollen. Conclusion The observed meiotic irregularities suggest that structural chromosome aberrations have occurred, such as heterozygous inversions, sister chromatid exchanges, deletions and duplications which in turn are reflected in a low pollen viability.

  7. Aberrant laryngeal location of Onchocerca lupi in a dog.

    Alho, Ana Margarida; Cruz, Luís; Coelho, Ana; Martinho, Filipe; Mansinho, Mário; Annoscia, Giada; Lia, Riccardo P; Giannelli, Alessio; Otranto, Domenico; de Carvalho, Luís Madeira

    2016-06-01

    Onchocerca lupi (Spirurida, Onchocercidae) is an emerging vector-borne helminth that causes nodular lesions associated with acute or chronic ocular disease in dogs and cats. Since its first description in dogs in 1991, this zoonotic filarioid has been increasingly reported in Europe and the United States. An 8-year-old outdoor mixed-breed female dog from the Algarve (southern Portugal) was presented with a history of severe dyspnoea. Cervical and thoracic radiographs revealed a slight reduction in the diameter of the cervical trachea and a moderate increase in radiopacity of the laryngeal soft tissue. An exploratory laryngoscopy was performed, revealing filiform worms associated with stenosis of the thyroid cartilage and a purulent necrotic tissue in the larynx lumen. A single sessile nodule, protruding from the dorsal wall of the laryngeal lumen caused a severe reduction of the glottis and tracheal diameter. Fragments of the worms were morphologically and molecularly identified as O. lupi. Histological examination of the nodule showed a granulomatous reaction with sections of coiled gravid female nematodes. Following laryngoscopy, a tracheostomy tube was inserted to relieve dyspnoea and ivermectin (300μg/kg, once a week, for 8weeks) combined with prednisolone was prescribed. The dog showed a complete recovery. Although O. lupi has been isolated in human patients from the spinal cord, this is the first report of an aberrant migration of O. lupi in a dog. The veterinary medical community should pay attention to aberrant location of O. lupi and consider onchocercosis as a differential diagnosis for airway obstruction in dogs. PMID:26732654

  8. Anti-topoisomerase drugs as potent inducers of chromosomal aberrations

    Loredana Bassi

    2000-12-01

    Full Text Available DNA topoisomerases catalyze topological changes in DNA that are essential for normal cell cycle progression and therefore they are a preferential target for the development of anticancer drugs. Anti-topoisomerase drugs can be divided into two main classes: "cleavable complex" poisons and catalytic inhibitors. The "cleavable complex" poisons are very effective as anticancer drugs but are also potent inducers of chromosome aberrations so they can cause secondary malignancies. Catalytic inhibitors are cytotoxic but they do not induce chromosome aberrations. Knowledge about the mechanism of action of topoisomerase inhibitors is important to determine the best anti-topoisomerase combinations, with a reduced risk of induction of secondary malignancies.As topoisomerases de DNA catalisam alterações topológicas no DNA que são essenciais para a progressão do ciclo celular normal e, portanto, são um alvo preferencial para o desenvolvimento de drogas anticâncer. Drogas anti-topoisomerases podem ser divididas em duas classes principais: drogas anti-"complexos cliváveis" e inibidores catalíticos. As drogas anti-"complexos cliváveis" são muito eficazes como drogas anticancerígenas, mas são também potentes indutores de aberrações cromossômicas, podendo causar neoplasias malignas secundárias. Inibidores catalíticos são citotóxicos mas não induzem aberrações cromossômicas. Conhecimento a respeito do mecanismo de ação de inibidores de topoisomerases é importante para determinar as melhores combinações anti-topoisomerases, com um reduzido risco de indução de neoplasias malignas secundárias.

  9. Genomic aberrations frequently alter chromatin regulatory genes in chordoma.

    Wang, Lu; Zehir, Ahmet; Nafa, Khedoudja; Zhou, Nengyi; Berger, Michael F; Casanova, Jacklyn; Sadowska, Justyna; Lu, Chao; Allis, C David; Gounder, Mrinal; Chandhanayingyong, Chandhanarat; Ladanyi, Marc; Boland, Patrick J; Hameed, Meera

    2016-07-01

    Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a ∼8 Mb segment at 3p21.1-p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (∼23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (∼40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes. © 2016 Wiley Periodicals, Inc. PMID:27072194

  10. Altered BCR signalling quality predisposes to autoimmune disease and a pre-diabetic state

    Königsberger, Sebastian; Prodöhl, Jan; Stegner, David; Weis, Vanessa; Andreas, Martin; Stehling, Martin; Schumacher, Theresa; Böhmer, Ruben; Thielmann, Ina; van Eeuwijk, Judith M M; Nieswandt, Bernhard; Kiefer, Friedemann

    2012-01-01

    The related tyrosine kinases Syk and Zap-70 are key signalling proteins downstream of antigen receptors. A knock-in strategy reveals that the two kinases differentially affect BCR signalling, leading to aberrant B cell section and increased risk of autoimmune disease.

  11. Global effects of kinase inhibitors on signaling networks revealed by quantitative phosphoproteomics

    Pan, Cuiping; Olsen, Jesper V; Daub, Henrik;

    2009-01-01

    Aberrant signaling causes many diseases, and manipulating signaling pathways with kinase inhibitors has emerged as a promising area of drug research. Most kinase inhibitors target the conserved ATP-binding pocket; therefore specificity is a major concern. Proteomics has previously been used to id...

  12. A Statistical Framework for Utilization of Simultaneous Pupil Plane and Focal Plane Telemetry for Exoplanet Imaging, Part I: Accounting for Polarization Aberration in Multiple Planes

    Frazin, Richard A

    2016-01-01

    A new generation of telescopes with mirror diameters of 20 m or more, called extremely large telescopes (ELTs) has the potential to provide unprecedented imaging and spectroscopy of exo-planetary systems, if the difficulties in achieving the extremely high dynamic range required to differentiate the planetary signal from the star can be overcome to a sufficient degree. Fully utilizing the potential of ELTs for exoplanet imaging will likely require simultaneous and self-consistent determination both the planetary image and the unknown aberrations in multiple planes of the optical system, using statistical inference based on the wavefront sensor and science camera data streams. This paper is the first in a series on this subject, in which a formalism is established for the exoplanet imaging problem in a polarizing optical system that has optical aberrations in multiple planes. Every effort has been made to be rigorous and complete, so that that validity of approximations to be made later can be assessed. It is ...

  13. Molecular Confirmation that Fasciola gigantica Can Undertake Aberrant Migrations in Human Hosts▿

    Le, Thanh Hoa; Van, Nguyen; Agatsuma, Takeshi; Blair, David; Vercruysse, Jozef; Dorny, Pierre; Nguyen, Thanh Giang Thi; McManus, Donald P.

    2006-01-01

    Two cases of aberrant migration by the liver fluke Fasciola gigantica in humans are reported. In both cases, subadult worms emerged through the skin. The identity of the worms was confirmed from their DNA sequences. This uncommon human pathogen might be more likely than F. hepatica to undertake aberrant migrations in humans.

  14. Antipain-mediated suppression of X-ray-induced chromosomal aberrations in human lymphocytes

    The protease inhibitor antipain is known to modulate the number of chromosomal aberrations induced by the S-phase-dependent alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. Experiments have now been carried out to see if antipain might also affect the yield of aberrations induced by X-rays, which are S-independent and thus produce chromosomal aberrations by a different mechanism. The results show that human lymphocytes exposed to 0.4 or 1.5 Gy of X-rays at 48 h of culture and fixed at 3, 6, 8, 10 or 12 h thereafter contain 27-52% fewer chromatid breaks if the cells are also treated with antipain before irradiation. Because previous studies postulated that antipain could affect the induction of of chromosomal aberrations by suppressing free radical reactions within cells, we also tested whether antipain affects X-ray-induced aberrations when present only during the time of irradiation, as is the case for free radical scavengers, such as L-cysteine. The results indicate that, in contrast to L-cysteine, antipain can suppress the induction of X-ray-induced aberrations even when administered as late as 2 h after irradiation, suggesting that the effects of antipain on aberrations are not attributable to its interference with short-lived radicals within the cells. These data indicate that the formation of chromosome aberrations by S-independent agents can involve an antipain-sensitive process. (author)

  15. Chromosomal Aberrations Associated with Clonal Evolution and Leukemic Transformation in Fanconi Anemia: Clinical and Biological Implications

    Stefan Meyer; Heidemarie Neitzel; Holger Tönnies

    2012-01-01

    Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities, bone marrow failure, and extreme risk of leukemic transformation. Bone marrow surveillance is an important part of the clinical management of FA and often reveals cytogenetic aberrations. Here, we review bone marrow findings in FA and discuss the clinical and biological implications of chromosomal aberrations associated with leukemic transformation.

  16. Criteria for admissible values of smooth aberrations for nondiffractive laser beams

    Malashko, Ya I; Khabibulin, V M [JSC ' Concern PVO ' Almaz-Antey' , Moscow (Russian Federation)

    2014-04-28

    We have derived analytical expressions, verified by the methods of numerical simulation, to evaluate the angular divergence of nondiffractive laser beams containing smooth aberrations, i.e., spherical defocusing, astigmatism and toroid. Using these expressions we have formulated the criteria for admissible values of smooth aberrations. (laser applications and other topics in quantum electronics)

  17. Numerical and structural chromosome aberrations in cauliflower (Brassica oleracea var. botrytis) and Arabidopsis thaliana

    Ji, X.

    2014-01-01

    Numerical and structural chromosome aberrations in cauliflower (Brassica oleracea var. botrytis) and Arabidopsis thaliana. I studied numerical and structural chromosome aberrations in cauliflower (Brassica oleracea var. botrytis) and Arabidopsis thaliana. The large genomic changes are important for gene balance control, gene expression and regulation, and may affect the plant’s phenotype. Moreover, chromosome changes, in particular polyploidy, inversions and translocations play a signif...

  18. Aberrant ovarian artery arising from the common Iliac artery: Case report

    Kim, Won Kyung [Dept. of Radiology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon (Korea, Republic of); Yang, Seung Boo; Lee, Jae Myeong [Dept. of Radiology, Soonchunhyang University Gumi Hospital, Soonchunhyang University College of Medicine, Gumi (Korea, Republic of); Goo, Dong Erk; Kim, Yong Jae; Chang, Yun Woo [Dept. of Radiology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul (Korea, Republic of)

    2013-01-15

    A 46-year-old Vietnamese woman received embolization therapy in order to control postpartum hemorrhage. Angiography revealed an aberrant ovarian artery arising from the right common iliac artery. Superselective catheterization and subsequent embolization of the aberrant ovarian artery and bilateral uterine arteries were performed. Precise knowledge of the anatomic variations of the ovarian artery is important for successful embolization.

  19. Epigenetic disruption of cell signaling in nasopharyngeal carcinoma

    Li-Li Li; Xing-Sheng Shu; Zhao-Hui Wang; Ya Cao; Qian Tao

    2011-01-01

    Nasopharyngeal carcinoma (NPC) is a malignancy with remarkable ethnic and geographic distribution in southern China and Southeast Asia. Alternative to genetic changes, aberrant epigenetic events disrupt multiple genes involved in cell signaling pathways through DNA methylation of promoter CpG islands and/ or histone modifications. These epigenetic alterations grant cell growth advantage and contribute to the initiation and progression of NPC. In this review, we summariye the epigenetic deregulation of cell signaling in NPC tumorigenesis and highlight the importance of identifying epigenetic cell signaling regulators in NPC research. Developing pharmacologic strategies to reverse the epigenetic-silencing of cell signaling regulators might thus be useful to NPC prevention and therapy.

  20. Effects of residual aberrations explored on single-walled carbon nanotubes

    The effects of geometric residual aberrations such as coma B2 and two-fold astigmatism A1 on the contrast in aberration corrected high resolution transmission electron microscopy (HRTEM) images are investigated on single-walled carbon nanotubes (SWNT). The individual aberrations are adjusted and set up manually using an imaging CS-corrector. We demonstrate how coma B2 can be recognized by an experienced user directly in the image and how it blurs the contrast. Even with uncorrected (resolution limiting) spherical aberration CS the coma B2 has to be considered and must be minimized. Limits for a tolerable coma are given. The experiments are confirmed by image simulations. -- Highlights: ► Individual effects of residual aberrations such as B2, A1, and CS are demonstrated. ► Experimental HRTEM and simulated images of carbon nanotubes are compared. ► A detection limit of 50 nm B2 in a single HRTEM image is determined.

  1. Non-linear character of dose dependences of chromosome aberration frequency in radiation-damaged root

    The dose dependences of the aberrant anaphases in the root meristem in 48 hours after the irradiation have non-linear character and a plateau in the region about 6-8 Gy. The plateau indicates the activation of recovery processes. In the plateau range, the level of damages for this genotype is 33% for aberrant anaphases (FAA), 2.3 aberrations per aberrant anaphase (A/AC), and 0.74 aberrations for the total number of anaphases. At 10 Gy, the dose curve forms the exponential region caused by the involvement of the large number of new cells with unrepaired damages in the mutation process. The increase of A/AC to 1.1 indicate the ''criticality'' of the meristem radiation damage.

  2. Correlation between Post-LASIK Starburst Symptom and Ocular Wavefront Aberrations

    LIU Yong-Ji; MU Guo-Guang; WANG Zhao-Qi; WANG Yan

    2006-01-01

    Monochromatic aberrations in post laser in-situ keratomileusis (LASIK) eyes are measured. The data are categorized into reference group and starburst group according to the visual symptoms. Statistic analysis has been made to find the correJation between the ocular wavefront aberrations and the starburst symptom. The rms aberrations of the 3rd and 4th orders for the starburst group are significantly larger than those for the reference group. The starburst symptom shows a strong correlation with vertical coma, total coma, spherical aberrations. For 3-mm pupil size and 5.8-mm pupil size, the modulation transfer function (MTF) of the starburst group are lower than those of the reference group, but their visual acuities are close. MTF and PSF analyses are made for two groups, and the results are consistent with the statistical analysis, which means the difference between the two groups is mainly due to the third- and fourth-order Zernike aberrations.

  3. Influence of wave-front aberrations on bit error rate in inter-satellite laser communications

    Yang, Yuqiang; Han, Qiqi; Tan, Liying; Ma, Jing; Yu, Siyuan; Yan, Zhibin; Yu, Jianjie; Zhao, Sheng

    2011-06-01

    We derive the bit error rate (BER) of inter-satellite laser communication (lasercom) links with on-off-keying systems in the presence of both wave-front aberrations and pointing error, but without considering the noise of the detector. Wave-front aberrations induced by receiver terminal have no influence on the BER, while wave-front aberrations induced by transmitter terminal will increase the BER. The BER depends on the area S which is truncated out by the threshold intensity of the detector (such as APD) on the intensity function in the receiver plane, and changes with root mean square (RMS) of wave-front aberrations. Numerical results show that the BER rises with the increasing of RMS value. The influences of Astigmatism, Coma, Curvature and Spherical aberration on the BER are compared. This work can benefit the design of lasercom system.

  4. Chromosomal aberration analysis of persons occupationally exposed to radiation in Iran (2)

    The results of chromosome aberration analysis on lymphocytes from 333 persons suspected of being overexposed to X and gamma rays in recent years at Iran is presented. 91 persons were associated with industrial radiography, 124 with radiology and 118 with medical research and therapy centers. The total yields of chromosome aberration per 100 cells were respectively 3.76, 2.92 and 2.96. The frequencies of dicentrics which are important in biological dosimetry were respectively 0.18, 0.17 and 0.21. In this investigation, 50 subjects were also examined as control with a mean aberration of 1.14 per 100 cells. With regard to incidence of chromosome aberrations as mentioned, the rate of chromosome aberrations in industrial radiographers was the most significant

  5. Transitionality in addiction: A "temporal continuum" hypotheses involving the aberrant motivation, the hedonic dysregulation, and the aberrant learning.

    Patrono, Enrico; Gasbarri, Antonella; Tomaz, Carlos; Nishijo, Hisao

    2016-08-01

    Addiction is a chronic compulsion and relapsing disorder. It involves several brain areas and circuits, which encode vary functions such as reward, motivation, and memory. Drug addiction is defined as a "pathological pattern of use of a substance", characterized by the loss of control on drug-taking-related behaviors, the pursuance of those behaviors even in the presence of negative consequences, and a strong motivated activity to assume substances. Three different theories guide experimental research on drug addiction. Each of these theories consider singles features, such as an aberrant motivation, a hedonic dysregulation, and an aberrant habit learning as the main actor to explain the entire process of the addictive behaviors. The major goal of this study is to present a new hypotheses of transitionality from a controlled use to abuse of addictive substances trough the overview of the three different theories, considering all the single features of each single theory together on the same "temporal continuum" from use to abuse of addictive substances. Recently, it has been suggested that common neural systems may be activated by natural and pharmacological stimuli, raising the hypotheses that binge-eating disorders could be considered as addictive behaviors. The second goal of this study is to present evidences in order to highlight a possible psycho-bio-physiological superimposition between drug and "food addiction". Finally, interesting questions are brought up starting from last findings about a theoretical/psycho-bio-physiological superimposition between drug and "food addiction" and their possibly same transitionality along the same "temporal continuum" from use to abuse of addictive substances in order to investigate new therapeutic strategies based on new therapeutic strategies based on the individual moments characterizing the transition from the voluntary intake of substances to the maladaptive addictive behavior. PMID:27372858

  6. IGF-II transgenic mice display increased aberrant colon crypt multiplicity and tumor volume after 1,2-dimethylhydrazine treatment

    Oesterle Doris

    2006-01-01

    Full Text Available Abstract In colorectal cancer insulin-like growth factor II (IGF-II is frequently overexpressed. To evaluate, whether IGF-II affects different stages of tumorigenesis, we induced neoplastic alterations in the colon of wild-type and IGF-II transgenic mice using 1,2-dimethylhydrazine (DMH. Aberrant crypt foci (ACF served as markers of early lesions in the colonic mucosa, whereas adenomas and carcinomas characterized the endpoints of tumor development. DMH-treatment led initially to significantly more ACF in IGF-II transgenic than in wild-type mice. This increase in ACF was especially prominent for those consisting of ≥three aberrant crypts (AC. Nevertheless, adenomas and adenocarcinomas of the colon, present after 34 weeks in both genetic groups, were not found at different frequency. Tumor volumes, however, were significantly higher in IGF-II transgenic mice and correlated with serum IGF-II levels. Immunohistochemical staining for markers of proliferation and apoptosis revealed increased cell proliferation rates in tumors of IGF-II transgenic mice without significant affection of apoptosis. Increased proliferation was accompanied by elevated localization of β-catenin in the cytosol and cell nuclei and reduced appearance at the inner plasma membrane. In conclusion, we provide evidence that IGF-II, via activation of the β-catenin signaling cascade, promotes growth of ACF and tumors without affecting tumor numbers.

  7. Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint

    Rodriguez, Pilar [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Barquinero, Joan Francesc [Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Duran, Assumpta [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Caballin, Maria Rosa [Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain); Ribas, Montserrat [Servei de Radiofisica i Radioproteccio de l' Hospital de la Santa Creu i Sant Pau, 08025 Barcelona (Spain); Barrios, Leonardo, E-mail: Lleonard.Barrios@uab.cat [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Bellaterra (Spain)

    2009-11-02

    Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of {gamma}-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.

  8. Epigenetic repression of ribosomal RNA transcription by ROCK-dependent aberrant cytoskeletal organization

    Wu, Tse-Hsiang; Kuo, Yuan-Yeh; Lee, Hsiao-Hui; Kuo, Jean-Cheng; Ou, Meng-Hsin; Chang, Zee-Fen

    2016-01-01

    It is known that ribosomal RNA (rRNA) synthesis is regulated by cellular energy and proliferation status. In this study, we investigated rRNA gene transcription in response to cytoskeletal stress. Our data revealed that the cell shape constrained by isotropic but not elongated micropatterns in HeLa cells led to a significant reduction in rRNA transcription dependent on ROCK. Expression of a dominant-active form of ROCK also repressed rRNA transcription. Isotropic constraint and ROCK over-activation led to different types of aberrant F-actin organization, but their suppression effects on rRNA transcription were similarly reversed by inhibition of histone deacetylase (HDAC) or overexpression of a dominant negative form of Nesprin, which shields the signal transmitted from actin filament to the nuclear interior. We further showed that the binding of HDAC1 to the active fraction of rDNA genes is increased by ROCK over-activation, thus reducing H3K9/14 acetylation and suppressing transcription. Our results demonstrate an epigenetic control of active rDNA genes that represses rRNA transcription in response to the cytoskeletal stress. PMID:27350000

  9. Opening of the TAR hairpin in the HIV-1 genome causes aberrant RNA dimerization and packaging

    Das Atze T

    2012-07-01

    Full Text Available Abstract Background The TAR hairpin is present at both the 5′ and 3′ end of the HIV-1 RNA genome. The 5′ element binds the viral Tat protein and is essential for Tat-mediated activation of transcription. We recently observed that complete TAR deletion is allowed in the context of an HIV-1 variant that does not depend on this Tat-TAR axis for transcription. Mutations that open the 5′ stem-loop structure did however affect the leader RNA conformation and resulted in a severe replication defect. In this study, we set out to analyze which step of the HIV-1 replication cycle is affected by this conformational change of the leader RNA. Results We demonstrate that opening the 5′ TAR structure through a deletion in either side of the stem region caused aberrant dimerization and reduced packaging of the unspliced viral RNA genome. In contrast, truncation of the TAR hairpin through deletions in both sides of the stem did not affect RNA dimer formation and packaging. Conclusions These results demonstrate that, although the TAR hairpin is not essential for RNA dimerization and packaging, mutations in TAR can significantly affect these processes through misfolding of the relevant RNA signals.

  10. [HPV-associated head and neck cancer : mutational signature and genomic aberrations].

    Wagner, S; Würdemann, N; Hübbers, C; Reuschenbach, M; Prigge, E-S; Wichmann, G; Hess, J; Dietz, A; Dürst, M; Tinhofer, I; von Knebel-Döberitz, M; Wittekindt, C; Klussmann, J P

    2015-11-01

    A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies. PMID:26507715

  11. Cells bearing chromosome aberrations lacking one telomere are selectively blocked at the G2/M checkpoint

    Cell cycle checkpoints are part of the cellular mechanisms to maintain genomic integrity. After ionizing radiation exposure, the cells can show delay or arrest in their progression through the cell cycle, as well as an activation of the DNA repair machinery in order to reduce the damage. The G2/M checkpoint prevents G2 cells entering mitosis until the DNA damage has been reduced. The present study evaluates which G0 radiation-induced chromosome aberrations are negatively selected in the G2/M checkpoint. For this purpose, peripheral blood samples were irradiated at 1 and 3 Gy of γ-rays, and lymphocytes were cultured for 48 h. Calyculin-A and Colcemid were used to analyze, in the same slide, cells in G2 and M. Chromosome spreads were consecutively analyzed by solid stain, pancentromeric and pantelomeric FISH and mFISH. The results show that the frequency of incomplete chromosome elements, those lacking a telomeric signal at one end, decreases abruptly from G2 to M. This indicates that cells with incomplete chromosome elements can progress from G0 to G2, but at the G2/M checkpoint suffer a strong negative selection.

  12. Expression of aberrant forms of AUXIN RESPONSE FACTOR8 stimulates parthenocarpy in Arabidopsis and tomato.

    Goetz, Marc; Hooper, Lauren C; Johnson, Susan D; Rodrigues, Julio Carlyle Macedo; Vivian-Smith, Adam; Koltunow, Anna M

    2007-10-01

    Fruit initiation in Arabidopsis (Arabidopsis thaliana) is generally repressed until fertilization occurs. However, mutations in AUXIN RESPONSE FACTOR8 (ARF8) uncouple fruit initiation from fertilization, resulting in the formation of seedless, parthenocarpic fruit. Here we induced parthenocarpy in wild-type Arabidopsis by introducing either the mutant genomic (g) Atarf8-4 sequence or gAtARF8:beta-glucuronidase translational fusion constructs by plant transformation. Silencing of endogenous AtARF8 transcription was not observed, indicating that the introduced, aberrant ARF8 transcripts were compromising the function of endogenous ARF8 and/or associated factors involved in suppressing fruit initiation. To analyze the role of ARF8 in tomato (Solanum lycopersicum) we initially emasculated 23 tomato cultivars to test for background parthenocarpy. Surprisingly, all had a predisposition to initiate fertilization-independent fruit growth. Expression of gAtarf8-4 in transgenic tomato ('Monalbo') resulted in a significant increase in the number and size of parthenocarpic fruit. Isolation of tomato ARF8 cDNA indicated significant sequence conservation with AtARF8. SlARF8 may therefore control tomato fruit initiation in a similar manner as AtARF8 does in Arabidopsis. Two SlARF8 cDNAs differing in size by 5 bp were found, both arising from the same gene. The smaller cDNA is a splice variant and is also present in Arabidopsis. We propose that low endogenous levels of the splice variant products might interfere with efficient formation/function of a complex repressing fruit initiation, thereby providing an explanation for the observed ovary expansion in tomato and also Arabidopsis after emasculation. Increasing the levels of aberrant Atarf8-4 transcripts may further destabilize formation/function of the complex in a dosage-dependent manner enhancing tomato parthenocarpic fruit initiation frequency and size and mimicking the parthenocarpic dehiscent silique phenotype found in

  13. In-line-focus monitoring technique using lens aberration effect

    Yamamoto, Tomohiko; Sawano, Toshio; Yao, Teruyoshi; Kobayashi, Katsuyoshi; Asai, Satoru

    2005-05-01

    Process windows have become narrower as nano-processing technology has advanced. The semiconductor industry, faced with this situation, has had to impose extremely severe tool controls. Above all, with the advent of 90-nm device production, demand has arisen for strict levels of control that exceed the machine specifications of ArF exposure systems. Consequently, high-accuracy focus control and focus monitoring techniques for production wafers will be necessary in order for this to be achieved for practical use. Focus monitoring techniques that measure pattern placement errors and resist features using special reticle and mark have recently been proposed. Unfortunately, these techniques have several disadvantages. They are unable to identify the direction of a focus error, and there are limits on the illumination conditions. Furthermore, they require the use of a reticle that is more expensive than normal and they suffer from a low level of measurement accuracy. To solve these problems, the authors examined methods of focus control and focus error measurement for production wafers that utilize the lens aberration of the exposure tool system. The authors call this method FMLA (focus monitoring using lens aberration). In general, astigmatism causes a difference in the optimum focal point between the horizontal and vertical patterns in the same image plane. If a focus error occurs, regardless of the reason, a critical dimension (CD) difference arises between the sparse horizontal and vertical lines. In addition, this CD difference decreases or increases monotonously with the defocus value. That is to say, it is possible to estimate the focus errors to measure the vertical and horizontal line CD formed by exposure tool with astigmatism. In this paper, the authors examined the FMLA technique using astigmatism. First, focus monitoring accuracy was investigated. Using normal scholar type simulation, FMLA was able to detect a 32.3-nm focus error when 10-mλ astigmatism was

  14. Micronuclei versus Chromosomal Aberrations Induced by X-Ray in Radiosensitive Mammalian Cells.

    Cristina Plamadeala

    2015-03-01

    Full Text Available An experimental study was accomplished to compare estimation methods of ionizing radiations genotoxicity in mammalian cell cultures by means of two cytogenetic parameters with focus on aberrant cells characterized by multiple chromosomal damages.In vitro study was carried out on the genotoxicity of low-medium doses of 190 kV X-rays absorbed in Chinese hamster ovary cell cultures. Micronuclei and ten types of chromosomal aberrations were identified with Giemsa dying and optical microscope screening.The first parameter consisting in micronuclei relative frequency has led to higher linear correlation coefficient than the second one consistent with chromosomal aberrations relative frequency. However, the latter parameter estimated as the sum of all chromosomal aberrations appeared to be more sensitive to radiation dose increasing in the studied dose range, from 0 to 3 Gy. The number of micronuclei occurring simultaneously in a single cell was not higher than 3, while the number of chromosomal aberrations observed in the same cell reached the value of 5 for doses over 1 Gy.Polynomial dose-response curves were evidenced for cells with Ni micronuclei (i=1,3 while non-monotonic curves were evidenced through detailed analysis of aberrant cells with Ni chromosomal changes [Formula: see text] - in concordance with in vitro studies from literature. The investigation could be important for public health issues where micronucleus screening is routinely applied but also for research purposes where various chromosomal aberrations could be of particular interest.

  15. Intra- and interindividual variability in lymphocyte chromosomal aberrations: implications for cancer risk assessment.

    Peters, Susan; Portengen, Lützen; Bonassi, Stefano; Sram, Radim; Vermeulen, Roel

    2011-08-15

    Chromosomal aberration frequency in peripheral lymphocytes of healthy individuals has been found to be predictive of future cancer risk. The variability of chromosomal aberrations over time, which is largely unknown, should be clarified to interpret the strength of this association and to determine its use in cancer prediction. Intra- and interindividual variability in chromosomal aberration frequency was therefore determined. From a pooled database comprising 11 national cohorts (1965-2002), the authors included 9,433 blood samples from 3,550 subjects with at least one repeated chromosomal aberration measurement. The generalized concordance correlation coefficient of 0.19 was low, indicating high intraindividual variability compared with interindividual variability, resulting in a high likelihood of misclassification. The relation between chromosomal aberration frequency and future cancer risk has probably been underestimated in previous studies. A single chromosomal aberration measurement seems not to be representative of the whole lifespan level of chromosome instability and greatly limits the use of chromosomal aberration frequency-as measured with Giemsa staining-for individual risk assessment. PMID:21652601

  16. Related research on corneal higher-order aberrations after different ways refractive surgery

    Shu-Xi He

    2015-08-01

    Full Text Available AIM:To evaluate the changes of corneal high-order aberration(including Coma, Spab, RMShafter laser in situ keratomileusis(LASIKwith femtosecond laser, sub-Bowman keratomileusis(SBKand laser epithelial keratomileusis(LASEK.METHODS: Of 82 myopic patients(164 eyes, 31 patients(62 eyeswere treated by FS-LASIK, 31 patients(62 eyeswere treated by SBK, 20 patients(40 eyeswere treated by LASEK. Sirius system was used for measuring the coma aberration, spherical aberration, and high order aberration at 1, 15d,1, 3mo after surgery.RESULTS: 1Vision: The uncorrected visual acuity of the three groups had no differences(P>0.05. 2Corneal aberrations: Three kinds of surgical procedure for patients with corneal aberration had significant impact. The C7, C8, C12 and RMSh of three groups were increased significantly(P0.05. The C7, C8, C12 and RMSh were not recovered to preoperative levels after 3mo. But the increase of patients after FS-LASIK was smaller than the other two groups, with statistical significance(P0.05.CONCLUSION: Compared with SBK and LASEK,FS-LASIK has better visual acuity in the early postoperative and corneal higher-order aberrations increase is relatively small.

  17. Chromosome aberrations in relation to radiation dose following partial-body exposures in three populations

    Structural chromosome aberrations were evaluated in peripheral blood samples obtained from three populations exposed to partial-body irradiation. These included 143 persons who received radiotherapy for enlarged thymus glands during infancy and 50 sibling controls; 79 persons irradiated for enlarged tonsils and 81 persons surgically treated for the same condition during childhood; and 77 women frequently exposed as young adults to fluoroscopic chest X rays during lung collapse treatment for tuberculosis (TB) and 66 women of similar ages treated for TB with other therapies. Radiation exposures occurred 30 and more years before blood was drawn. Doses to active bone marrow averaged over the entire body were 21, 6, and 14 cGy for the exposed thymic, tonsil, and TB subjects, respectively. Two hundred metaphases were scored for each subject, and the frequencies of symmetrical (stable) and asymmetrical (unstable) chromosome aberrations were quantified in 97,200 metaphases. Cells with stable aberrations were detected with greater frequency in the irradiated subjects compared with nonirradiated subjects in all three populations, and an overall test for an association between stable aberrations and partial-body ionizing radiation was highly significant (P less than 0.001). We found no evidence that radiation-induced aberrations varied by age at exposure. These data show that exposure of children or young adults to partial-body fractionated radiation can result in detectable increased frequencies of stable chromosome aberrations in circulating lymphocytes 30 years later, and that these aberrations appear to be informative as biological markers of population exposure

  18. The nonlinear relationship of radiation dose to chromosome aberrations among atomic bomb survivors, Hiroshima and Nagasaki

    The quantitative relationship of the frequency of cells with radiation-induced chromosome aberrations in peripheral leukocytes in atomic bomb survivors has been evaluated as a function of gamma and neutron doses. Three different models have been examined; each assumes a nonlinear-response to gamma rays and a linear-response to neutrons. From the standpoint of the goodness of fit of these models, the model which ''best'' fits the data of radiation-induced chromosome aberrations is the exponit model, where the frequency of aberrant cells increases exponentially with dose. It is of radiobiological interest that the goodness of fit for this model shows the frequencies of cells with any chromosome aberration or an exchange aberration to be dependent cubically on the gamma ray dose and linearly on the neutron dose. The relative biological effectiveness (RBE) of neutrons is calculated to be 129Dn sup(-2/3) (95% confidence intervals: (121 -- 137)Dn sup(-2/3)) for frequency of cells with any chromosome aberration, and 125Dn sup(-2/3) (95% confidence intervals: (117 -- 132)Dn sup(-2/3)) for the frequency of cells with an exchange aberration where Dn is the neutron dose. (author)

  19. Influence of wavefront aberration on the imaging performance of the solar grating spectrometer.

    Zheng, L H; Rao, C H; Gu, N T; Huang, L H; Qiu, Q

    2016-01-11

    The solar grating spectrometer is an important tool to study the thermodynamic properties of the solar atmosphere with different height distribution, but its imaging performance will be degraded by the wavefront aberration. On the other hand, narrow slit of the grating spectrometer will filter the wavefront aberration to a certain extent. In this paper, the mathematical relation between the wavefront aberration and the imaging performance of the grating spectrometer is derived. The numerical simulation is performed and is validated by the experiment. The results demonstrate that: The influence of the wavefront aberration with the different types and magnitudes on the spectral resolution and the energy utilization is different. The influence of the different slits on the wavefront aberrations is different. Generally, the smaller the slit is, the better the spectral resolution is. However, this is not true for the low-frequency dominated aberration, e.g. the defocus, since its low frequency will also be blocked by the narrow slit. If the influence of the filter slit on the wavefront aberration cannot be taken into account, it will lead to adaptive optics over-compensation. PMID:26832247

  20. Impact of astigmatism and high-order aberrations on subjective best focus.

    Marcos, Susana; Velasco-Ocana, Miriam; Dorronsoro, Carlos; Sawides, Lucie; Hernandez, Martha; Marin, Gildas

    2015-08-01

    We studied the role of native astigmatism and ocular aberrations on best-focus setting and its shift upon induction of astigmatism in 42 subjects (emmetropes, myopes, hyperopes, with-the-rule [WTR] and against-the-rule [ATR] myopic astigmats). Stimuli were presented in a custom-developed adaptive optics simulator, allowing correction for native aberrations and astigmatism induction (+1 D; 6-mm pupil). Best-focus search consisted on randomized-step interleaved staircase method. Each subject searched best focus for four different images, and four different conditions (with/without aberration correction, with/without astigmatism induction). The presence of aberrations induced a significant shift in subjective best focus (0.4 D; p astigmatism produced a statistically significant shift of the best-focus setting in all groups under natural aberrations (p = 0.001), and in emmetropes and in WTR astigmats under corrected aberrations (p induced astigmatism was significantly different across groups, both for natural aberrations and AO-correction (p astigmats upon induction of astigmatism, symmetrically with respect to the best-focus shift in nonastigmatic myopes. The shifts are consistent with a bias towards vertical and horizontal retinal blur in WTR and ATR astigmats, respectively, indicating adaptation to native astigmatism. PMID:26237300