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  1. Isothiazolidinone (IZD) as a phosphoryl mimetic in inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH

    International Nuclear Information System (INIS)

    Kim, Sung-Eun; Bahta, Medhanit; Lountos, George T.; Ulrich, Robert G.; Burke, Terrence R. Jr; Waugh, David S.

    2011-01-01

    The first X-ray crystal structure of the Y. pestis protein tyrosine phosphatase YopH in complex with an isothiazolidinone-based lead-fragment compound is reported. Isothiazolidinone (IZD) heterocycles can act as effective components of protein tyrosine phosphatase (PTP) inhibitors by simultaneously replicating the binding interactions of both a phosphoryl group and a highly conserved water molecule, as exemplified by the structures of several PTP1B–inhibitor complexes. In the first unambiguous demonstration of IZD interactions with a PTP other than PTP1B, it is shown by X-ray crystallography that the IZD motif binds within the catalytic site of the Yersinia pestis PTP YopH by similarly displacing a highly conserved water molecule. It is also shown that IZD-based bidentate ligands can inhibit YopH in a nonpromiscuous fashion at low micromolar concentrations. Hence, the IZD moiety may represent a useful starting point for the development of YopH inhibitors

  2. Developmental Changes in Visual and Auditory Inhibition in Early Childhood

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    Guy, Jacalyn; Rogers, Maria; Cornish, Kim

    2012-01-01

    The development of executive functions in the preschool years is not fully understood. Although there exists a large body of research investigating the maturation of executive functioning in school-aged children, little is known about the emergence of such skills, in particular inhibition, among preschool-aged children. Understanding developmental…

  3. Microsomal protein synthesis inhibition: an early manifestation of gentamicin nephrotoxicity

    International Nuclear Information System (INIS)

    Bennett, W.M.; Mela-Riker, L.M.; Houghton, D.C.; Gilbert, D.N.; Buss, W.C.

    1988-01-01

    Aminoglycoside antibiotics achieve bacterial killing by binding to bacterial ribosomes and inhibiting protein synthesis. To examine whether similar mechanisms could be present in renal tubular cells prior to the onset of overt proximal tubular necrosis due to these drugs, we isolated microsomes from Fischer rats given 20 mg/kg gentamicin every 12 h subcutaneously for 2 days and from vehicle-injected controls. Concomitant studies of renal structure, function, and mitochondrial respiration were carried out. [3H]leucine incorporation into renal microsomes of treated animals was reduced by 21.9% (P less than 0.01), whereas brain and liver microsomes from the same animals were unaffected. Gentamicin concentration in the renal microsomal preparation was 56 micrograms/ml, a value 7- to 10-fold above concentrations necessary to inhibit bacterial growth. Conventional renal function studies were normal (blood urea, serum creatinine, creatinine clearance). Treated animals showed only a mild reduction of inulin clearance, 0.71 compared with 0.93 ml.min-1.100 g-1 in controls (P less than 0.05), and an increase in urinary excretion of N-acetylglucosaminidase of 20 compared with 14.8 units/l (P less than 0.05). Renal slice transport of p-aminohippuric acid, tetraethylammonium, and the fractional excretion of sodium were well preserved. There was no evidence, as seen by light microscopy, of proximal tubular necrosis. Mitochondrial cytochrome concentrations were normal and respiratory activities only slightly reduced. Processes similar to those responsible for bacterial killing could be involved in experimental gentamicin nephrotoxicity before overt cellular necrosis

  4. Early Exercise Protects against Cerebral Ischemic Injury through Inhibiting Neuron Apoptosis in Cortex in Rats

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    Junfa Wu

    2013-03-01

    Full Text Available Early exercise is an effective strategy for stroke treatment, but the underlying mechanism remains poorly understood. Apoptosis plays a critical role after stroke. However, it is unclear whether early exercise inhibits apoptosis after stroke. The present study investigated the effect of early exercise on apoptosis induced by ischemia. Adult SD rats were subjected to transient focal cerebral ischemia by middle cerebral artery occlusion model (MCAO and were randomly divided into early exercise group, non-exercise group and sham group. Early exercise group received forced treadmill training initiated at 24 h after operation. Fourteen days later, the cell apoptosis were detected by TdT-mediated dUTP-biotin nick-end labeling (TUNEL and Fluoro-Jade-B staining (F-J-B. Caspase-3, cleaved caspase-3 and Bcl-2 were determined by western blotting. Cerebral infarct volume and motor function were evaluated by cresyl violet staining and foot fault test respectively. The results showed that early exercise decreased the number of apoptotic cells (118.74 ± 6.15 vs. 169.65 ± 8.47, p < 0.05, n = 5, inhibited the expression of caspase-3 and cleaved caspase-3 (p < 0.05, n = 5, and increased the expression of Bcl-2 (p < 0.05, n = 5. These data were consistent with reduced infarct volume and improved motor function. These results suggested that early exercise could provide neuroprotection through inhibiting neuron apoptosis.

  5. Early Inherited Risk for Anxiety Moderates the Association between Fathers’ Child-Centered Parenting and Early Social Inhibition

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    Brooker, Rebecca J.; Alto, Kathleen M.; Marceau, Kristine; Najjar, Reema; Leve, Leslie D.; Ganiban, Jody M.; Shaw, Daniel S.; Reiss, David; Neiderhiser, Jenae M.

    2016-01-01

    Studies of the role of the early environment in shaping children’s risk for anxiety problems have produced mixed results. It is possible that inconsistencies in previous findings result from a lack of consideration of a putative role for inherited influences moderators on the impact of early experiences. Early inherited influences not only contribute to vulnerabilities for anxiety problems throughout the lifespan, but can also modulate the ways that the early environment impacts child outcomes. In the current study, we tested the effects of child-centered parenting behaviors on putative anxiety risk in young children who differed in levels of inherited vulnerability. We tested this using a parent-offspring adoption design and a sample in which risk for anxiety problems and parenting behaviors were assessed in both mothers and fathers. Inherited influences on anxiety problems were assessed as anxiety symptoms in biological parents. Child-centered parenting was observed in adoptive mothers and fathers when children were 9 months old. Social inhibition, an early temperament marker of anxiety risk, was observed at child ages 9 and 18 months. Inherited influences on anxiety problems moderated the link between paternal child-centered parenting during infancy and social inhibition in toddlerhood. For children whose birth parents reported high levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to greater social inhibition 9 months later. For children whose birth parents reported low levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to less social inhibition across the same period. PMID:27572913

  6. Early inherited risk for anxiety moderates the association between fathers' child-centered parenting and early social inhibition.

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    Brooker, R J; Alto, K M; Marceau, K; Najjar, R; Leve, L D; Ganiban, J M; Shaw, D S; Reiss, D; Neiderhiser, J M

    2016-12-01

    Studies of the role of the early environment in shaping children's risk for anxiety problems have produced mixed results. It is possible that inconsistencies in previous findings result from a lack of consideration of a putative role for inherited influences moderators on the impact of early experiences. Early inherited influences not only contribute to vulnerabilities for anxiety problems throughout the lifespan, but can also modulate the ways that the early environment impacts child outcomes. In the current study, we tested the effects of child-centered parenting behaviors on putative anxiety risk in young children who differed in levels of inherited vulnerability. We tested this using a parent-offspring adoption design and a sample in which risk for anxiety problems and parenting behaviors were assessed in both mothers and fathers. Inherited influences on anxiety problems were assessed as anxiety symptoms in biological parents. Child-centered parenting was observed in adoptive mothers and fathers when children were 9 months old. Social inhibition, an early temperament marker of anxiety risk, was observed at child ages 9 and 18 months. Inherited influences on anxiety problems moderated the link between paternal child-centered parenting during infancy and social inhibition in toddlerhood. For children whose birth parents reported high levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to greater social inhibition 9 months later. For children whose birth parents reported low levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to less social inhibition across the same period.

  7. Stable Early Maternal Report of Behavioral Inhibition Predicts Lifetime Social Anxiety Disorder in Adolescence

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    Chronis-Tuscano, Andrea; Degnan, Kathryn Amey; Pine, Daniel S.; Perez-Edgar, Koraly; Henderson, Heather A.; Diaz, Yamalis; Raggi, Veronica L.; Fox, Nathan A.

    2009-01-01

    The odds of a lifetime diagnosis of social anxiety disorder increased by 3.79 times for children who had a stable report of behavioral inhibition from their mothers. This finding has important implications for the early identification and prevention of social anxiety disorder.

  8. Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy.

    Science.gov (United States)

    Blom, Jan J; Giove, Thomas J; Favazza, Tara L; Akula, James D; Eldred, William D

    2011-06-01

    The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.

  9. Abrogation of Early Apoptosis Does Not Alter Late Inhibition of Hippocampal Neurogenesis After Irradiation

    International Nuclear Information System (INIS)

    Li Yuqing; Aubert, Isabelle; Wong, C. Shun

    2010-01-01

    Purpose: Irradiation of the adult brain results in acute apoptosis of neural progenitors and vascular endothelial cells, as well as late dysfunction of neural progenitors and inhibition of neurogenesis. We sought to determine whether the early apoptotic response has a causative role in late inhibition of neurogenesis after cranial irradiation. Methods and Materials: Using a genetic approach with p53 and smpd1 transgenic mice and a pharmacologic approach with basic fibroblast growth factor (bFGF) to abrogate the early apoptotic response, we evaluated the late inhibition of neurogenesis in the hippocampal dentate gyrus after cranial irradiation. Results: In dentate gyrus, subgranular neural progenitors underwent p53-dependent apoptosis within 24 h after irradiation. Despite a near abrogation of neural progenitor apoptosis in p53-/- mice, the reduction in newborn neurons in dentate gyrus at 9 weeks after irradiation in p53-/- mice was not different from that observed in wildtype controls. Endothelial cell apoptosis after radiation is mediated by membrane damage initiated by activation of acid sphingomyelinase (ASMase). Deletion of the smpd1 gene (which encodes ASMase) attenuated the apoptotic response of endothelial cells. At 9 weeks after irradiation, the inhibition of hippocampal neurogenesis was not rescued by ASMase deficiency. Intravenous administration of bFGF protected both endothelial cells and neural progenitors against radiation-induced apoptosis. There was no protection against inhibition of neurogenesis at 9 weeks after irradiation in bFGF-treated mice. Conclusion: Early apoptotic death of neural progenitors, endothelial cells, or both does not have a causative association with late inhibition of neurogenesis after irradiation.

  10. Externalizing behavior from early childhood to adolescence: Prediction from inhibition, language, parenting, and attachment.

    Science.gov (United States)

    Roskam, Isabelle

    2018-03-22

    The aim of the current research was to disentangle four theoretically sound models of externalizing behavior etiology (i.e., attachment, language, inhibition, and parenting) by testing their relation with behavioral trajectories from early childhood to adolescence. The aim was achieved through a 10-year prospective longitudinal study conducted over five waves with 111 referred children aged 3 to 5 years at the onset of the study. Clinical referral was primarily based on externalizing behavior. A multimethod (questionnaires, testing, and observations) approach was used to estimate the four predictors in early childhood. In line with previous studies, the results show a significant decrease of externalizing behavior from early childhood to adolescence. The decline was negatively related to mothers' coercive parenting and positively related to attachment security in early childhood, but not related to inhibition and language. The study has implications for research into externalizing behavior etiology recommending to gather hypotheses from various theoretically sound models to put them into competition with one another. The study also has implications for clinical practice by providing clear indications for prevention and early intervention.

  11. Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2.

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    Kelly R VanDenBerg

    Full Text Available Nuclear factor erythroid 2-related factor 2 (Nrf2 is a stress-activated transcription factor that induces a variety of cytoprotective genes. Nrf2 also mediates immunosuppressive effects in multiple inflammatory models. Upon activation, Nrf2 dissociates from its repressor protein, Keap1, and translocates to the nucleus where it induces Nrf2 target genes. The Nrf2-Keap1 interaction is disrupted by the environmental toxicant and chemotherapeutic agent arsenic trioxide (ATO. The purpose of the present study was to determine the effects of ATO on early events of T cell activation and the role of Nrf2 in those effects. The Nrf2 target genes Hmox-1, Nqo-1, and Gclc were all upregulated by ATO (1-2 μM in splenocytes derived from wild-type, but not Nrf2-null, mice, suggesting that Nrf2 is activated by ATO in splenocytes. ATO also inhibited IFNγ, IL-2, and GM-CSF mRNA and protein production in wild-type splenocytes activated with the T cell activator, anti-CD3/anti-CD28. However, ATO also decreased production of these cytokines in activated splenocytes from Nrf2-null mice, suggesting the inhibition is independent of Nrf2. Interestingly, ATO inhibited TNFα protein secretion, but not mRNA expression, in activated splenocytes suggesting the inhibition is due to post-transcriptional modification. In addition, c-Fos DNA binding was significantly diminished by ATO in wild-type and Nrf2-null splenocytes activated with anti-CD3/anti-CD28, consistent with the observed inhibition of cytokine production by ATO. Collectively, this study suggests that although ATO activates Nrf2 in splenocytes, inhibition of early T cell cytokine production by ATO occurs independently of Nrf2 and may instead be due to impaired AP-1 DNA binding.

  12. Impaired Early-Response Inhibition in Overweight Females with and without Binge Eating Disorder.

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    Jennifer Svaldi

    Full Text Available Several studies report increased reward sensitivity towards food in overweight individuals. By contrast, data is inconclusive with respect to response inhibition in overweight individuals without binge eating disorder (BED. Hence, the latter was addressed in the present study in a group of overweight/obese females with and without BED and a normal-weight control group without eating disorders.A group of women with BED (n = 29, a group of overweight women without BED (n = 33 and normal-weight females (n = 30 participated in a pictorial priming paradigm, with food items (relevant primes and office utensils (neutral primes and color blobs (neutral primes as stimuli. Increased response priming effects (i.e. priming with switches between stimulus categories were taken as indicators of deficient behavioral inhibition.Priming effects for neutral primes were moderate and comparable across all groups. However, primes associated with the food task set lead to increased priming effects in both overweight groups. But, effects were comparable for overweight/obese participants with and without BED.Results suggest that early response inhibition in the context of food is impaired in overweight individuals compared to normal-weight individuals.

  13. Early behavioral inhibition and increased error monitoring predict later social phobia symptoms in childhood.

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    Lahat, Ayelet; Lamm, Connie; Chronis-Tuscano, Andrea; Pine, Daniel S; Henderson, Heather A; Fox, Nathan A

    2014-04-01

    Behavioral inhibition (BI) is an early childhood temperament characterized by fearful responses to novelty and avoidance of social interactions. During adolescence, a subset of children with stable childhood BI develop social anxiety disorder and concurrently exhibit increased error monitoring. The current study examines whether increased error monitoring in 7-year-old, behaviorally inhibited children prospectively predicts risk for symptoms of social phobia at age 9 years. A total of 291 children were characterized on BI at 24 and 36 months of age. Children were seen again at 7 years of age, when they performed a Flanker task, and event-related potential (ERP) indices of response monitoring were generated. At age 9, self- and maternal-report of social phobia symptoms were obtained. Children high in BI, compared to those low in BI, displayed increased error monitoring at age 7, as indexed by larger (i.e., more negative) error-related negativity (ERN) amplitudes. In addition, early BI was related to later childhood social phobia symptoms at age 9 among children with a large difference in amplitude between ERN and correct-response negativity (CRN) at age 7. Heightened error monitoring predicts risk for later social phobia symptoms in children with high BI. Research assessing response monitoring in children with BI may refine our understanding of the mechanisms underlying risk for later anxiety disorders and inform prevention efforts. Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.

  14. Lithium chloride inhibits early stages of foot-and-mouth disease virus (FMDV) replication in vitro.

    Science.gov (United States)

    Zhao, Fu-Rong; Xie, Yin-Li; Liu, Ze-Zhong; Shao, Jun-Jun; Li, Shi-Fang; Zhang, Yong-Guang; Chang, Hui-Yun

    2017-11-01

    Foot-and-mouth disease virus (FMDV) causes an economically important and highly contagious disease of cloven-hoofed animals such as cattle, swine, and sheep. FMD vaccine is the traditional way to protect against the disease, which can greatly reduce its occurrence. However, the use of FMD vaccines to protect early infection is limited. Therefore, the alternative strategy of applying antiviral agents is required to control the spread of FMDV in outbreak situations. As previously reported, LiCl has obviously inhibition effects on a variety of viruses such as transmissible gastroenteritis virus (TGEV), infectious bronchitis coronavirus (IBV), and pseudorabies herpesvirus and EV-A71 virus. In this study, our findings were the first to demonstrate that LiCl inhibition of the FMDV replication. In this study, BHK-21 cell was dose-dependent with LiCl at various stages of FMDV. Virus titration assay was calculated by the 50% tissue culture infected dose (TCID 50 ) with the Reed and Muench method. The cytotoxicity assay of LiCl was performed by the CCK8 kit. The expression level of viral mRNA was measured by RT-qPCR. The results revealed LiCl can inhibit FMDV replication, but it cannot affect FMDV attachment stage and entry stage in the course of FMDV life cycle. Further studies confirmed that the LiCl affect the replication stage of FMDV, especially the early stages of FMDV replication. So LiCl has potential as an effective anti-FMDV drug. Therefore, LiCl may be an effective drug for the control of FMDV. Based on that, the mechanism of the antiviral effect of LiCl on FMDV infection is need to in-depth research in vivo. © 2017 Wiley Periodicals, Inc.

  15. The Stochastic Early Reaction, Inhibition, and late Action (SERIA model for antisaccades.

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    Eduardo A Aponte

    2017-08-01

    Full Text Available The antisaccade task is a classic paradigm used to study the voluntary control of eye movements. It requires participants to suppress a reactive eye movement to a visual target and to concurrently initiate a saccade in the opposite direction. Although several models have been proposed to explain error rates and reaction times in this task, no formal model comparison has yet been performed. Here, we describe a Bayesian modeling approach to the antisaccade task that allows us to formally compare different models on the basis of their evidence. First, we provide a formal likelihood function of actions (pro- and antisaccades and reaction times based on previously published models. Second, we introduce the Stochastic Early Reaction, Inhibition, and late Action model (SERIA, a novel model postulating two different mechanisms that interact in the antisaccade task: an early GO/NO-GO race decision process and a late GO/GO decision process. Third, we apply these models to a data set from an experiment with three mixed blocks of pro- and antisaccade trials. Bayesian model comparison demonstrates that the SERIA model explains the data better than competing models that do not incorporate a late decision process. Moreover, we show that the early decision process postulated by the SERIA model is, to a large extent, insensitive to the cue presented in a single trial. Finally, we use parameter estimates to demonstrate that changes in reaction time and error rate due to the probability of a trial type (pro- or antisaccade are best explained by faster or slower inhibition and the probability of generating late voluntary prosaccades.

  16. Fisetin induces Sirt1 expression while inhibiting early adipogenesis in 3T3-L1 cells.

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    Kim, Sang Chon; Kim, Yoo Hoon; Son, Sung Wook; Moon, Eun-Yi; Pyo, Suhkneung; Um, Sung Hee

    2015-11-27

    Fisetin (3,7,3',4'-tetrahydroxyflavone) is a naturally found flavonol in many fruits and vegetables and is known to have anti-aging, anti-cancer and anti-viral effects. However, the effects of fisetin on early adipocyte differentiation and the epigenetic regulator controlling adipogenic transcription factors remain unclear. Here, we show that fisetin inhibits lipid accumulation and suppresses the expression of PPARγ in 3T3-L1 cells. Fisetin suppressed early stages of preadipocyte differentiation, and induced expression of Sirt1. Depletion of Sirt1 abolished the inhibitory effects of fisetin on intracellular lipid accumulation and on PPARγ expression. Mechanistically, fisetin facilitated Sirt1-mediated deacetylation of PPARγ and FoxO1, and enhanced the association of Sirt1 with the PPARγ promoter, leading to suppression of PPARγ transcriptional activity, thereby repressing adipogenesis. Lowering Sirt1 levels reversed the effects of fisetin on deacetylation of PPARγ and increased PPARγ transactivation. Collectively, our results suggest the effects of fisetin in increasing Sirt1 expression and in epigenetic control of early adipogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood

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    Kely ede Picoli Souza

    2015-04-01

    Full Text Available We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system is expressed and functional in the white adipose tissue (WAT and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass or saline, starting at the first day of life until the age of 16 days. Between days 90th and 180th, a group of these animals received high fat diet (HFD. Molecular, biochemical, histological and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY and cocaine- and amphetamine-regulated transcript (CART gene expression in hypothalamus, fatty acid synthase (FAS and hormone-sensitive lipase (HSL gene expression in retroperitoneal WAT and decreases peroxixome proliferators-activated receptor (PPAR γ, PPARα, uncoupling protein (UCP 2 and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood.

  18. Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination

    International Nuclear Information System (INIS)

    Sakata, Koh-ichi; Someya, Masanori; Matsumoto, Yoshihisa; Takagi, Masaru; Hareyama, Masato; Tauchi, Hiroshi; Kai, Masahiro; Toyota, Minoru; Fukushima, Masakazu

    2011-01-01

    Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. Small interfering RNA (siRNA) for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair. (author)

  19. Combining child social skills training with a parent early intervention program for inhibited preschool children.

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    Lau, Elizabeth X; Rapee, Ronald M; Coplan, Robert J

    2017-10-01

    Previous studies have demonstrated the efficacy of early intervention for anxiety in preschoolers through parent-education. The current study evaluated a six-session early intervention program for preschoolers at high risk of anxiety disorders in which a standard educational program for parents was supplemented by direct training of social skills to the children. Seventy-two children aged 3-5 years were selected based on high behavioural inhibition levels and concurrently having a parent with high emotional distress. Families were randomly assigned to either the intervention group, which consisted of six parent-education group sessions and six child social skills training sessions, or waitlist. After six months, families on waitlist were offered treatment consisting of parent-education only. Relative to waitlist, children in the combined condition showed significantly fewer clinician-rated anxiety disorders and diagnostic severity and maternal (but not paternal) reported anxiety symptoms and life interference at six months. Mothers also reported less overprotection. These gains were maintained at 12-month follow-up. Parent only education following waitlist produced similar improvements among children. Quasi-experimental comparison between combined and parent-only interventions indicated greater reductions from combined intervention according to clinician reports, but no significant differences on maternal reports. Results suggest that this brief early intervention program for preschoolers with both parent and child components significantly reduces risk and disorder in vulnerable children. The inclusion of a child component might have the potential to increase effects over parent-only intervention. However, future support for this conclusion through long-term, randomised controlled trials is needed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Lithium prevents early cytosolic calcium increase and secondary injurious calcium overload in glycolytically inhibited endothelial cells

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    Bosche, Bert, E-mail: bert.bosche@uk-essen.de [Department of Neurology, University of Duisburg-Essen (Germany); Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne (Germany); Schäfer, Matthias, E-mail: matthias.schaefer@sanofi.com [Institute of Physiology, Justus-Liebig-University Giessen (Germany); Graf, Rudolf, E-mail: rudolf.graf@nf.mpg.de [Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne (Germany); Härtel, Frauke V., E-mail: frauke.haertel@tu-dresden.de [Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden (Germany); Schäfer, Ute, E-mail: ute.schaefer@medunigraz.at [Research Unit for Experimental Neurotraumatology, Medical University of Graz (Austria); Noll, Thomas, E-mail: thomas.noll@tu-dresden.de [Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden (Germany)

    2013-05-03

    Highlights: •We investigate free calcium as a central signalling element in endothelial cells. •Inhibition of glycolysis with 2-deoxy-D-glucose reduces cellular ATP. •This manoeuvre leads to a biphasic increase and overload of free calcium. •Pre-treatment with lithium for 24 h abolishes both phases of the calcium increase. •This provides a new strategy to protect endothelial calcium homeostasis and barrier function. -- Abstract: Cytosolic free calcium concentration ([Ca{sup 2+}]{sub i}) is a central signalling element for the maintenance of endothelial barrier function. Under physiological conditions, it is controlled within narrow limits. Metabolic inhibition during ischemia/reperfusion, however, induces [Ca{sup 2+}]{sub i} overload, which results in barrier failure. In a model of cultured porcine aortic endothelial monolayers (EC), we addressed the question of whether [Ca{sup 2+}]{sub i} overload can be prevented by lithium treatment. [Ca{sup 2+}]{sub i} and ATP were analysed using Fura-2 and HPLC, respectively. The combined inhibition of glycolytic and mitochondrial ATP synthesis by 2-desoxy-D-glucose (5 mM; 2-DG) plus sodium cyanide (5 mM; NaCN) caused a significant decrease in cellular ATP content (14 ± 1 nmol/mg protein vs. 18 ± 1 nmol/mg protein in the control, n = 6 culture dishes, P < 0.05), an increase in [Ca{sup 2+}]{sub i} (278 ± 24 nM vs. 71 ± 2 nM in the control, n = 60 cells, P < 0.05), and the formation of gaps between adjacent EC. These observations indicate that there is impaired barrier function at an early state of metabolic inhibition. Glycolytic inhibition alone by 10 mM 2-DG led to a similar decrease in ATP content (14 ± 2 nmol/mg vs. 18 ± 1 nmol/mg in the control, P < 0.05) with a delay of 5 min. The [Ca{sup 2+}]{sub i} response of EC was biphasic with a peak after 1 min (183 ± 6 nM vs. 71 ± 1 nM, n = 60 cells, P < 0.05) followed by a sustained increase in [Ca{sup 2+}]{sub i}. A 24-h pre-treatment with 10 mM of lithium

  1. Inhibition of Rho kinase regulates specification of early differentiation events in P19 embryonal carcinoma stem cells.

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    Roman J Krawetz

    Full Text Available The Rho kinase pathway plays a key role in many early cell/tissue determination events that take place in embryogenesis. Rho and its downstream effector Rho kinase (ROCK play pivotal roles in cell migration, apoptosis (membrane blebbing, cell proliferation/cell cycle, cell-cell adhesion and gene regulation. We and others have previously demonstrated that inhibition of ROCK blocks endoderm differentiation in embryonal carcinoma stem cells, however, the effect of ROCK inhibition on mesoderm and ectoderm specification has not been fully examined. In this study, the role of ROCK within the specification and differentiation of all three germ layers was examined.P19 cells were treated with the specific ROCK inhibitor Y-27623, and increase in differentiation efficiency into neuro-ectodermal and mesodermal lineages was observed. However, as expected a dramatic decrease in early endodermal markers was observed when ROCK was inhibited. Interestingly, within these ROCK-inhibited RA treated cultures, increased levels of mesodermal or ectodermal markers were not observed, instead it was found that the pluripotent markers SSEA-1 and Oct-4 remained up-regulated similar to that seen in undifferentiated cultures. Using standard and widely accepted methods for reproducible P19 differentiation into all three germ layers, an enhancement of mesoderm and ectoderm differentiation with a concurrent loss of endoderm lineage specification was observed with Y-27632 treatment. Evidence would suggest that this effect is in part mediated through TGF-β and SMAD signaling as ROCK-inhibited cells displayed aberrant SMAD activation and did not return to a 'ground' state after the inhibition had been removed.Given this data and the fact that only a partial rescue of normal differentiation capacity occurred when ROCK inhibition was alleviated, the effect of ROCK inhibition on the differentiation capacity of pluripotent cell populations should be further examined to elucidate the

  2. Local arginase inhibition during early reperfusion mediates cardioprotection via increased nitric oxide production.

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    Adrian T Gonon

    Full Text Available Consumption of L-arginine contributes to reduced bioavailability of nitric oxide (NO that is critical for the development of ischemia-reperfusion injury. The aim of the study was to determine myocardial arginase expression and activity in ischemic-reperfusion myocardium and whether local inhibition of arginase within the ischemic myocardium results in increased NO production and protection against myocardial ischemia-reperfusion. Anesthetized pigs were subjected to coronary artery occlusion for 40 min followed by 4 h reperfusion. The pigs were randomized to intracoronary infusion of vehicle (n = 7, the arginase inhibitor N-hydroxy-nor-L-arginine (nor-NOHA, 2 mg/min, n = 7, the combination of nor-NOHA and the NO synthase inhibitor N(G-monomethyl-L-arginine (L-NMMA, 0.35 mg/min, n = 6 into the jeopardized myocardial area or systemic intravenous infusion of nor-NOHA (2 mg/min, n = 5 at the end of ischemia and start of reperfusion. The infarct size of the vehicle group was 80 ± 4% of the area at risk. Intracoronary nor-NOHA reduced infarct size to 46 ± 5% (P<0.01. Co-administration of L-NMMA abrogated the cardioprotective effect mediated by nor-NOHA (infarct size 72 ± 6%. Intravenous nor-NOHA did not reduce infarct size. Arginase I and II were expressed in cardiomyocytes, endothelial, smooth muscle and poylmorphonuclear cells. There was no difference in cytosolic arginase I or mitochondrial arginase II expression between ischemic-reperfused and non-ischemic myocardium. Arginase activity increased 2-fold in the ischemic-reperfused myocardium in comparison with non-ischemic myocardium. In conclusion, ischemia-reperfusion increases arginase activity without affecting cytosolic arginase I or mitochondrial arginase II expression. Local arginase inhibition during early reperfusion reduces infarct size via a mechanism that is dependent on increased bioavailability of NO.

  3. Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia

    DEFF Research Database (Denmark)

    Nitescu, Nicoletta; Grimberg, Elisabeth; Ricksten, Sven-Erik

    2007-01-01

    Sepsis is associated with an activation of the coagulation system and multiorgan failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced...

  4. Interleukin-6 inhibits early differentiation of ATDC5 chondrogenic progenitor cells.

    Science.gov (United States)

    Nakajima, Shoko; Naruto, Takuya; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Nishimaki, Shigeru; Yokota, Shumpei

    2009-08-01

    Interleukin (IL)-6 is a causative agent of systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease complicated with severe growth impairment. Recent trials of anti-IL-6 receptor monoclonal antibody, tocilizumab, indicated that tocilizumab blocks IL-6/IL-6 receptor-mediated inflammation, and induces catch-up growth in children with sJIA. This study evaluates the effects of IL-6 on chondrogenesis by ATDC5 cells, a clonal murine chondrogenic cell line that provides an excellent model for studying endochondral ossification at growth plate. ATDC5 cells were examined for the expression of IL-6 receptor and gp130 by fluorescence-activated cell sorting analysis. Recombinant murine IL-6 was added to ATDC5 cultures to observe cell differentiation, using a quantitative RT-PCR for the chondrogenic differentiation markers type II collagen, aggrecan, and type X collagen. To block IL-6, the anti-mouse IL-6 receptor monoclonal antibody MR16-1 was added. As a result, the cells expressed IL-6 receptor and gp130. The expression of chondrogenic differentiation marker gene was reduced by IL-6, but this was abrogated by MR16-1. We conclude that IL-6 inhibits early chondrogenesis of ATDC5 cells suggesting that IL-6 may affect committed stem cells at a cellular level during chondrogenic differentiation of growth plate chondrocytes, and that IL-6 may be a cellular-level factor in growth impairment in sJIA.

  5. A CI-Independent Form of Replicative Inhibition: Turn Off of Early Replication of Bacteriophage Lambda

    Science.gov (United States)

    Hayes, Sidney; Horbay, Monique A.; Hayes, Connie

    2012-01-01

    Several earlier studies have described an unusual exclusion phenotype exhibited by cells with plasmids carrying a portion of the replication region of phage lambda. Cells exhibiting this inhibition phenotype (IP) prevent the plating of homo-immune and hybrid hetero-immune lambdoid phages. We have attempted to define aspects of IP, and show that it is directed to repλ phages. IP was observed in cells with plasmids containing a λ DNA fragment including oop, encoding a short OOP micro RNA, and part of the lambda origin of replication, oriλ, defined by iteron sequences ITN1-4 and an adjacent high AT-rich sequence. Transcription of the intact oop sequence from its promoter, pO is required for IP, as are iterons ITN3–4, but not the high AT-rich portion of oriλ. The results suggest that IP silencing is directed to theta mode replication initiation from an infecting repλ genome, or an induced repλ prophage. Phage mutations suppressing IP, i.e., Sip, map within, or adjacent to cro or in O, or both. Our results for plasmid based IP suggest the hypothesis that there is a natural mechanism for silencing early theta-mode replication initiation, i.e. the buildup of λ genomes with oop + oriλ+ sequence. PMID:22590552

  6. Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells.

    Science.gov (United States)

    Duan, Yuntao; Wang, Shih-Hsiu; Song, Juan; Mironova, Yevgeniya; Ming, Guo-li; Kolodkin, Alex L; Giger, Roman J

    2014-10-14

    Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A-/- GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A-/- mutants, PlexinA2-/- mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A-/- mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders.

  7. Early childhood behavioral inhibition, adult psychopathology and the buffering effects of adolescent social networks: a twenty-year prospective study.

    Science.gov (United States)

    Frenkel, Tahl I; Fox, Nathan A; Pine, Daniel S; Walker, Olga L; Degnan, Kathryn A; Chronis-Tuscano, Andrea

    2015-10-01

    We examined whether the temperament of behavioral inhibition is a significant marker for psychopathology in early adulthood and whether such risk is buffered by peer social networks. Participants (N = 165) were from a prospective study spanning the first two decades of life. Temperament was characterized during infancy and early childhood. Extent of involvement in peer social networks was measured during adolescence, and psychopathology was assessed in early adulthood. Latent Class Analyses generated comprehensive variables at each of three study time-points. Regressions assessed (a) the direct effect of early behavioral inhibition on adult psychopathology (b) the moderating effect of adolescent involvement in social peer networks on the link between temperamental risk and adult psychopathology. Stable behavioral inhibition in early childhood was negatively associated with adult mental health (R(2 ) = .07, p = .005, β = -.26), specifically increasing risk for adult anxiety disorders (R(2) = .04, p = .037, β = .19). These temperament-pathology relations were significantly moderated by adolescent peer group social involvement and network size (Total R(2) = .13, p = .027, β = -.22). Temperament predicted heightened risk for adult anxiety when adolescent social involvement was low (p = .002, β = .43), but not when adolescent social involvement was high. Stable behavioral inhibition throughout early childhood is a risk factor for adult anxiety disorders and interacts with adolescent social involvement to moderate risk. This is the first study to demonstrate the critical role of adolescent involvement in socially active networks in moderating long-lasting temperamental risk over the course of two decades, thus informing prevention/intervention approaches. © 2015 Association for Child and Adolescent Mental Health.

  8. Gradual remapping results in early retinotopic and late spatiotopic inhibition of return.

    NARCIS (Netherlands)

    Mathôt, S.; Theeuwes, J.

    2010-01-01

    Here we report that immediately following the execution of an eye movement, oculomotor inhibition of return resides in retinotopic (eye-centered) coordinates. At longer postsaccadic intervals, inhibition resides in spatiotopic (world-centered) coordinates. These results are explained in terms of

  9. MiR-193b regulates early chondrogenesis by inhibiting the TGF-beta2 signaling pathway.

    Science.gov (United States)

    Hou, Changhe; Yang, Zibo; Kang, Yan; Zhang, Ziji; Fu, Ming; He, Aishan; Zhang, Zhiqi; Liao, Weiming

    2015-04-13

    Cartilage generation and degradation are regulated by miRNAs. Our previous study has shown altered expression of miR-193b in chondrogenic human adipose-derived mesenchymal stem cells (hADSCs). In the current study, we investigated the role of miR-193b in chondrogenesis and cartilage degradation. Luciferase reporter assays showed that miR-193b targeted seed sequences of the TGFB2 and TGFBR3 3'-UTRs. MiR-193b suppressed the expression of early chondrogenic markers in chondrogenic ATDC5 cells, and TNF-alpha expression in IL-1b-induced PMCs. In conclusion, MiR-193b may inhibit early chondrogenesis by targeting TGFB2 and TGFBR3, and may regulate inflammation by repressing TNF-alpha expression in inflamed chondrocytes. Copyright © 2015. Published by Elsevier B.V.

  10. A fluorescent probe distinguishes between inhibition of early and late steps of lipopolysaccharide biogenesis in whole cells

    Science.gov (United States)

    Moison, Eileen; Xie, Ran; Zhang, Ge; Lebar, Matthew D.; Meredith, Timothy C.; Kahne, Daniel

    2017-01-01

    Lipopolysaccharide (LPS) biogenesis in Gram-negative organisms involves its biosynthesis in the cytoplasm and subsequent transport across three cellular compartments to the cell surface. We developed a fluorescent probe that allows us to determine the spatial distribution of LPS in whole cells. We show that polymyxin B nonapeptide (PMBN) containing a dansyl fluorophore specifically binds to LPS in membranes. We show that this probe detects decreases in LPS levels on the cell surface when LPS biosynthesis is inhibited at an early step. We also can detect accumulation of LPS in particular subcellular locations when LPS assembly is blocked during transport, allowing us to differentiate inhibitors targeting early and late stages of LPS biogenesis. PMID:28248483

  11. Attention biases to threat and behavioral inhibition in early childhood shape adolescent social withdrawal.

    Science.gov (United States)

    Pérez-Edgar, Koraly; Bar-Haim, Yair; McDermott, Jennifer Martin; Chronis-Tuscano, Andrea; Pine, Daniel S; Fox, Nathan A

    2010-06-01

    Behavioral inhibition (BI) is a temperament characterized in young children by a heightened sensitivity to novelty, social withdrawal, and anxious behaviors. For many children, these social difficulties dissipate over time. For others, patterns of social withdrawal continue into adolescence. Over time, attention biases to threat may influence the stability of BI and its association with social withdrawal, ultimately modulating the risk for anxiety disorders in BI children. However, we know relatively little about the cognitive processes that accompany BI and shape later socio-emotional functioning. We examined the relations among BI in childhood, attention biases to threat in adolescence, and adolescent social withdrawal in a longitudinal study (N = 126, Mean age = 15 years). As has been reported in anxious adults, adolescents who were behaviorally inhibited as toddlers and young children showed heightened attention bias to threat. In addition, attention bias to threat moderated the relation between childhood BI and adolescent social withdrawal.

  12. IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage.

    Science.gov (United States)

    Barik, Subhasis; Miller, Mindy M; Cattin-Roy, Alexis N; Ukah, Tobechukwu K; Chen, Weirong; Zaghouani, Habib

    2017-10-15

    Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Rα and IL-13Rα1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR + ETPs, but not HR - ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPα, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR + ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR - ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development. Copyright © 2017 by The American Association of Immunologists, Inc.

  13. Inhibition of MHC-I by Brucella abortus is an early event during infection and involves EGFR pathway.

    Science.gov (United States)

    Velásquez, Lis N; Milillo, M Ayelén; Delpino, M Victoria; Trotta, Aldana; Mercogliano, M Florencia; Pozner, Roberto G; Schillaci, Roxana; Elizalde, Patricia V; Giambartolomei, Guillermo H; Barrionuevo, Paula

    2017-04-01

    Brucella abortus is able to persist inside the host despite the development of potent CD8 + T-cell responses. We have recently reported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surface expression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacity and the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 - are able to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist inside human monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could be observed at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growth factor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymes which generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGF and transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-I downmodulation. Finally, when infection was performed in the presence of an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8 + T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.

  14. Evaluation of hypothesized adverse outcome pathway linking thyroid peroxidase inhibition to fish early life stage toxicity

    Science.gov (United States)

    There is an interest in developing alternatives to the fish early-life stage (FELS) test (OECD test guideline 210), for predicting adverse outcomes (e.g., impacts on growth and survival) using less resource-intensive methods. Development and characterization of adverse outcome pa...

  15. Investigating Practices in Teacher Education That Promote and Inhibit Technology Integration Transfer in Early Career Teachers

    Science.gov (United States)

    Brenner, Aimee M.; Brill, Jennifer M.

    2016-01-01

    The purpose of this study was to identify instructional technology integration strategies and practices in preservice teacher education that contribute to the transfer of technology integration knowledge and skills to the instructional practices of early career teachers. This study used a two-phase, sequential explanatory strategy. Data were…

  16. Infant attachment security and early childhood behavioral inhibition interact to predict adolescent social anxiety symptoms.

    Science.gov (United States)

    Lewis-Morrarty, Erin; Degnan, Kathryn A; Chronis-Tuscano, Andrea; Pine, Daniel S; Henderson, Heather A; Fox, Nathan A

    2015-01-01

    Insecure attachment and behavioral inhibition (BI) increase risk for internalizing problems, but few longitudinal studies have examined their interaction in predicting adolescent anxiety. This study included 165 adolescents (ages 14-17 years) selected based on their reactivity to novelty at 4 months. Infant attachment was assessed with the Strange Situation. Multimethod BI assessments were conducted across childhood. Adolescents and their parents independently reported on anxiety. The interaction of attachment and BI significantly predicted adolescent anxiety symptoms, such that BI and anxiety were only associated among adolescents with histories of insecure attachment. Exploratory analyses revealed that this effect was driven by insecure-resistant attachment and that the association between BI and social anxiety was significant only for insecure males. Clinical implications are discussed. © 2014 The Authors. Child Development © 2014 Society for Research in Child Development, Inc.

  17. NOX2 Inhibition Impairs Early Muscle Gene Expression Induced by a Single Exercise Bout.

    Science.gov (United States)

    Henríquez-Olguín, Carlos; Díaz-Vegas, Alexis; Utreras-Mendoza, Yildy; Campos, Cristian; Arias-Calderón, Manuel; Llanos, Paola; Contreras-Ferrat, Ariel; Espinosa, Alejandra; Altamirano, Francisco; Jaimovich, Enrique; Valladares, Denisse M

    2016-01-01

    Reactive oxygen species (ROS) participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2) in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg) or vehicle for 3 days, were swim-exercised for 60 min. Phospho-p47(phox) levels were significantly upregulated by exercise in flexor digitorum brevis (FDB). Moreover, exercise significantly increased NOX2 complex assembly (p47(phox)-gp91(phox) interaction) demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx), citrate synthase (CS), mitochondrial transcription factor A (tfam) and interleukin-6 (IL-I6) in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-κB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p < 0.001). These results were corroborated using gp91-dstat in an in vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise.

  18. NOX2 inhibition impairs early muscle gene expression induced by a single exercise bout

    Directory of Open Access Journals (Sweden)

    Carlos Henríquez-Olguín

    2016-07-01

    Full Text Available Reactive oxygen species (ROS participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2 in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg or vehicle for 3 days, were swim-exercised for 60 min. Phospho-p47phox levels were significantly upregulated by exercise in flexor digitorum brevis (FDB. Moreover, exercise significantly increased NOX2 complex assembly (p47phox-gp91phox interaction demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD, glutathione peroxidase (GPx, citrate synthase (CS, mitochondrial transcription factor A (tfam and interleukin-6 (IL-6 in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-κB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p<0.001. These results were corroborated using gp91-dstat in an in-vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise.

  19. Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity.

    Science.gov (United States)

    Groselj, Blaz; Ruan, Jia-Ling; Scott, Helen; Gorrill, Jessica; Nicholson, Judith; Kelly, Jacqueline; Anbalagan, Selvakumar; Thompson, James; Stratford, Michael R L; Jevons, Sarah J; Hammond, Ester M; Scudamore, Cheryl L; Kerr, Martin; Kiltie, Anne E

    2018-02-01

    As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo , using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects. Mol Cancer Ther; 17(2); 381-92. ©2017 AACR See all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." ©2017 American Association for Cancer Research.

  20. Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats.

    Science.gov (United States)

    Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe; Dalby, Nils Ole

    2014-09-01

    A compromised γ-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-D-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmission in adulthood. The present study examines prefrontal GABAergic transmission in adult rats administered with the NMDA receptor channel blocker, phencyclidine (PCP), for 3 days during the second postnatal week. Whole-cell patch-clamp recordings from pyramidal cells in PCP-treated rats showed a 22% reduction in the frequency of miniature inhibitory postsynaptic currents in layer II/III, but not in layer V pyramidal neurons of the prefrontal cortex. Furthermore, early postnatal PCP treatment caused insensitivity toward effects of the GABA transporter 1 (GAT-1) inhibitor, 1,2,5,6-tetrahydro-1-[2-[[(diphenyl-methylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid, and also diminished currents passed by δ-subunit-containing GABAA receptors in layer II/III pyramidal neurons. The observed impairments in GABAergic function are compatible with the alteration of GABAergic markers as well as cognitive dysfunction observed in early postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish.

    Science.gov (United States)

    Lee, Yeon-Joo; Choi, Hyeon-Son; Seo, Min-Jung; Jeon, Hui-Jeon; Kim, Kui-Jin; Lee, Boo-Yong

    2015-08-01

    Kaempferol is a flavonoid present in Kaempferia galanga and Opuntia ficus indica var. saboten. Recent studies have suggested that it has anti-oxidant, anti-inflammatory, anti-cancer, and anti-obesity effects. In this study, we focused on the anti-adipogenic effects of kaempferol during adipocyte differentiation. The results showed that kaempferol inhibits lipid accumulation in adipocytes and zebrafish. Oil Red O and Nile Red staining showed that the number of intracellular lipid droplets decreased in adipocytes and zebrafish treated with kaempferol. LPAATθ (lysophosphatidic acid acyltransferase), lipin1, and DGAT1 (triglyceride synthetic enzymes) and FASN and SREBP-1C (fatty acid synthetic proteins) showed decreased expression levels in the presence of kaempferol. In addition, treatment of kaempferol showed an inhibitory activity on cell cycle progression. Kaempferol delayed cell cycle progression from the S to G2/M phase through the regulation of cyclins in a dose-dependent manner. Kaempferol blocked the phosphorylation of AKT (protein kinase B) and mammalian target of rapamycin (mTOR) signaling pathway during the early stages of adipogenesis. In addition, kaempferol down-regulated pro-early adipogenic factors such as CCAAT-enhancer binding proteins β (C/EBPβ), and Krüppel-like factors (KLFs) 4 and 5, while anti-early adipogenic factors, such as KLF2 and pref-1(preadipocyte factor-1), were upregulated. These kaempferol-mediated regulations of early adipogenic factors resulted in the attenuation of late adipogenic factors such as C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ). These results were supported in zebrafish based on the decrease in lipid accumulation and expression of adipogenic factors. Our results indicated that kaempferol might have an anti-obesity effect by regulating lipid metabolism.

  2. Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.

    Science.gov (United States)

    Zhang, Hai-Tao; Zhang, Ping; Gao, Yi; Li, Chen-Long; Wang, Hong-Jun; Chen, Ling-Chao; Feng, Yan; Li, Rui-Yan; Li, Yong-Li; Jiang, Chuan-Lu

    2017-01-01

    Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90‑min period, either an anti‑VEGF neutralizing antibody (RB‑222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB‑222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB‑222 was more effective than a 5 µg dose of the antibody. In addition, RB‑222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB‑222 significantly repressed VEGF expression as well as decreased MMP‑2 and MMP‑9 expression. However, it enhanced occludin and collagen‑IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.

  3. [Curcumin alleviates early brain injury following subarachnoid hemorrhage in rats by inhibiting JNK/c-Jun signal pathway].

    Science.gov (United States)

    Li, Xia; Zhu, Ji

    2018-03-01

    Objective To investigate the inhibitory effect of curcumin on early brain injury following subarachnoid hemorrhage (SAH) by inhibiting JNK/ c-Jun signal pathway. Methods Sixty adult male SD rats were randomly divided into four groups: sham operation group (sham group), SAH group, SAH group treated with 100 mg/(kg.d) curcumin and SAH group treated with 200 mg/(kg.d) curcumin, with 15 rats in each group. Endovascular puncture was used to induce SAH model. Nissl staining was used to test whether neurons were broken. TUNEL staining was used to detect apoptosis. Immunohistochemistry was used to investigate the expression of caspase-3. Western blot analysis was used to detect the expressions of p-JNK, JNK, p-c-Jun, c-Jun, and caspase-3. Results Nissl staining indicated the decrease of Nissl bodies in SAH group, but increase of Nissl bodies in SAH group treated with curcumin. TUNEL staining showed that there were more apoptotic neurons in SAH group compared with sham group, while apoptotic neurons decreased after the treatment with curcumin, more obviously in the group treated with 200 mg/(kg.d) curcumin. The expressions of p-JNK, JNK, p-c-Jun, c-Jun, and caspase-3 were up-regulated in SAH group compared with sham group. However, the expressions of those proteins were down-regulated after the treatment with curcumin, especially by higher-dose curcumin treatment. Conclusion Curcumin might suppress early brain injury after SAH by inhibiting JNK/c-Jun signal pathway and neuron apoptosis.

  4. Dual roles of palladin protein in in vitro myogenesis: inhibition of early induction but promotion of myotube maturation.

    Directory of Open Access Journals (Sweden)

    Ngoc-Uyen-Nhi Nguyen

    Full Text Available Palladin is a microfilament-associated phosphoprotein whose function in skeletal muscle has rarely been studied. Therefore, we investigate whether myogenesis is influenced by the depletion of palladin expression known to interfere with the actin cytoskeleton dynamic required for skeletal muscle differentiation. The inhibition of palladin in C2C12 myoblasts leads to precocious myogenic differentiation with a concomitant reduction in cell apoptosis. This premature myogenesis is caused, in part, by an accelerated induction of p21, myogenin, and myosin heavy chain, suggesting that palladin acts as a negative regulator in early differentiation phases. Paradoxically, palladin-knockdown myoblasts are unable to differentiate terminally, despite their ability to perform some initial steps of differentiation. Cells with attenuated palladin expression form thinner myotubes with fewer myonuclei compared to those of the control. It is noteworthy that a negative regulator of myogenesis, myostatin, is activated in palladin-deficient myotubes, suggesting the palladin-mediated impairment of late-stage myogenesis. Additionally, overexpression of 140-kDa palladin inhibits myoblast differentiation while 200-kDa and 90-kDa palladin-overexpressed cells display an enhanced differentiation rate. Together, our data suggest that palladin might have both positive and negative roles in maintaining the proper skeletal myogenic differentiation in vitro.

  5. Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats

    Directory of Open Access Journals (Sweden)

    Pablo Muñoz

    2016-01-01

    Full Text Available Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2 to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS, the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA impaired hippocampal long-term potentiation (LTP. Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP.

  6. Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats.

    Science.gov (United States)

    Muñoz, Pablo; Estay, Carolina; Díaz, Paula; Elgueta, Claudio; Ardiles, Álvaro O; Lizana, Pablo A

    2016-01-01

    Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS), the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA) impaired hippocampal long-term potentiation (LTP). Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP.

  7. Barriers Inhibiting Inquiry-Based Science Teaching and Potential Solutions: Perceptions of Positively Inclined Early Adopters

    Science.gov (United States)

    Fitzgerald, Michael; Danaia, Lena; McKinnon, David H.

    2017-07-01

    In recent years, calls for the adoption of inquiry-based pedagogies in the science classroom have formed a part of the recommendations for large-scale high school science reforms. However, these pedagogies have been problematic to implement at scale. This research explores the perceptions of 34 positively inclined early-adopter teachers in relation to their implementation of inquiry-based pedagogies. The teachers were part of a large-scale Australian high school intervention project based around astronomy. In a series of semi-structured interviews, the teachers identified a number of common barriers that prevented them from implementing inquiry-based approaches. The most important barriers identified include the extreme time restrictions on all scales, the poverty of their common professional development experiences, their lack of good models and definitions for what inquiry-based teaching actually is, and the lack of good resources enabling the capacity for change. Implications for expectations of teachers and their professional learning during educational reform and curriculum change are discussed.

  8. Caffeine induces high expression of cyp-35A family genes and inhibits the early larval development in Caenorhabditis elegans.

    Science.gov (United States)

    Min, Hyemin; Kawasaki, Ichiro; Gong, Joomi; Shim, Yhong-Hee

    2015-03-01

    Intake of caffeine during pregnancy can cause retardation of fetal development. Although the significant influence of caffeine on animal development is widely recognized, much remains unknown about its mode of action because of its pleiotropic effects on living organisms. In the present study, by using Caenorhabditis elegans as a model organism, the effects of caffeine on development were examined. Brood size, embryonic lethality, and percent larval development were investigated, and caffeine was found to inhibit the development of C. elegans at most of the stages in a dosage-dependent fashion. Upon treatment with 30 mM caffeine, the majority (86.1 ± 3.4%) of the L1 larvae were irreversibly arrested without further development. In contrast, many of the late-stage larvae survived and grew to adults when exposed to the same 30 mM caffeine. These results suggest that early-stage larvae are more susceptible to caffeine than later-stage larvae. To understand the metabolic responses to caffeine treatment, the levels of expression of cytochrome P450 (cyp) genes were examined with or without caffeine treatment using comparative micro-array, and it was found that the expression of 24 cyp genes was increased by more than 2-fold (p family was the most prominent. Interestingly, depletion of the cyp-35A family genes one-by-one or in combination through RNA interference resulted in partial rescue from early larval developmental arrest caused by caffeine treatment, suggesting that the high-level induction of cyp-35A family genes can be fatal to the development of early-stage larvae.

  9. Genetic pharmacotherapy as an early CNS drug development strategy: testing glutaminase inhibition for schizophrenia treatment in adult mice

    Directory of Open Access Journals (Sweden)

    Susana eMingote

    2016-01-01

    Full Text Available Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to test the therapeutic potential of glutaminase inhibition. We specifically asked whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG ERT2 cre/+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction — mimicking pharmacological inhibition — strongly

  10. Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways.

    Science.gov (United States)

    Jang, Yeon Jeong; Koo, Hyun Jung; Sohn, Eun-Hwa; Kang, Se Chan; Rhee, Dong-Kwon; Pyo, Suhkneung

    2015-07-01

    Obesity is characterized by hypertrophy and/or by the differentiation or adipogenesis of pre-existing adipocytes. In this study, we investigated the inhibitory effects of theobromine, a type of alkaloid in cocoa, on adipocyte differentiation of 3T3-L1 preadipocytes and its mechanisms of action. Theobromine inhibited the accumulation of lipid droplets, the expression of PPARγ and C/EBPα, and the mRNA expression of aP2 and leptin. The inhibition of adipogenic differentiation by theobromine occurred primarily in the early stages of differentiation. In addition, theobromine arrested the cell cycle at the G0/G1 phase and regulated the expressions of CDK2, p27, and p21. Theobromine treatment increased AMPK phosphorylation and knockdown of AMPKα1/α2 prevented the ability of theobromine to inhibit PPARγ expression in the differentiating 3T3-L1 cells. Theobromine reduced the phosphorylation of ERK and JNK. Moreover, the secretion and the mRNA level of TNF-α and IL-6 were inhibited by theobromine treatment. These data suggest that theobromine inhibits adipocyte differentiation during the early stages of adipogenesis by regulating the expression of PPARγ and C/EBPα through the AMPK and ERK/JNK signaling pathways in 3T3-L1 preadipocytes.

  11. The response of early neural genes to FGF signaling or inhibition of BMP indicate the absence of a conserved neural induction module

    Directory of Open Access Journals (Sweden)

    Rogers Crystal D

    2011-12-01

    Full Text Available Abstract Background The molecular mechanism that initiates the formation of the vertebrate central nervous system has long been debated. Studies in Xenopus and mouse demonstrate that inhibition of BMP signaling is sufficient to induce neural tissue in explants or ES cells respectively, whereas studies in chick argue that instructive FGF signaling is also required for the expression of neural genes. Although additional signals may be involved in neural induction and patterning, here we focus on the roles of BMP inhibition and FGF8a. Results To address the question of necessity and sufficiency of BMP inhibition and FGF signaling, we compared the temporal expression of the five earliest genes expressed in the neuroectoderm and determined their requirements for induction at the onset of neural plate formation in Xenopus. Our results demonstrate that the onset and peak of expression of the genes vary and that they have different regulatory requirements and are therefore unlikely to share a conserved neural induction regulatory module. Even though all require inhibition of BMP for expression, some also require FGF signaling; expression of the early-onset pan-neural genes sox2 and foxd5α requires FGF signaling while other early genes, sox3, geminin and zicr1 are induced by BMP inhibition alone. Conclusions We demonstrate that BMP inhibition and FGF signaling induce neural genes independently of each other. Together our data indicate that although the spatiotemporal expression patterns of early neural genes are similar, the mechanisms involved in their expression are distinct and there are different signaling requirements for the expression of each gene.

  12. Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4

    Science.gov (United States)

    Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L.; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C.; Staudt, Louis M.; Niesvizky, Ruben; Moore, Malcolm A. S.

    2012-01-01

    Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. PMID:22718837

  13. Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.

    Science.gov (United States)

    Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C; Staudt, Louis M; Niesvizky, Ruben; Moore, Malcolm A S; Chen-Kiang, Selina

    2012-08-02

    Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

  14. Brain-derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy.

    Science.gov (United States)

    Lim, Whasun; Bae, Hyocheol; Bazer, Fuller W; Song, Gwonhwa

    2017-12-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family binds to two transmembrane receptors; neurotrophic receptor tyrosine kinase 2 (NTRK2) with high affinity and p75 with low affinity. Although BDNF-NTRK2 signaling in the central nervous system is known, signaling in the female reproductive system is unknown. Therefore, we determined effects of BDNF on porcine endometrial luminal epithelial (pLE) cells isolated from Day 12 of pregnancy, as well as expression of BDNF and NTRK2 in endometria of cyclic and pregnant pigs. BDNF-NTRK2 genes were expressed in uterine glandular (GE) and luminal (LE) epithelia during early pregnancy. In addition, their expression in uterine GE and LE decreased with increasing parity of sows. Recombinant BDNF increased proliferation in pLE cells in a dose-dependent, as well as expression of PCNA and Cyclin D1 in nuclei of pLE cells. BDNF also activated phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38 proteins in pLE cells. In addition, cell death resulting from tunicamycin-induced ER stress was prevented when pLE cells were treated with the combination of tunicamycin and BDNF which also decreased cells in the Sub-G 1 phase of the cell cycle. Furthermore, tunicamycin-induced unfolded protein response genes were mostly down-regulated to the basal levels as compared to non-treated pLE cells. Our finding suggests that BDNF acts via NTRK2 to induce development of pLE cells for maintenance of implantation and pregnancy by activating cell signaling via the PI3K and MAPK pathways and by inhibiting ER stress. © 2017 Wiley Periodicals, Inc.

  15. Expression and inhibition of matrix metalloproteinase (MMP)-8, MMP-9 and MMP-12 in early colonic anastomotic repair

    DEFF Research Database (Denmark)

    Krarup, Peter-Martin; Eld, Mikkel; Heinemeier, Katja

    2013-01-01

    of specific MMPs responsible for the weakening of anastomoses can be used to optimise MMP inhibition therapy. We aimed to quantify transcript and protein levels of multiple MMPs in colonic anastomoses and evaluate the effect of inhibiting the MMPs that displayed the highest expression levels on anastomotic...

  16. Myosin-1 inhibition by PClP affects membrane shape, cortical actin distribution and lipid droplet dynamics in early Zebrafish embryos.

    Directory of Open Access Journals (Sweden)

    Prabuddha Gupta

    Full Text Available Myosin-1 (Myo1 represents a mechanical link between the membrane and actin-cytoskeleton in animal cells. We have studied the effect of Myo1 inhibitor PClP in 1-8 cell Zebrafish embryos. Our results indicate a unique involvement of Myo1 in early development of Zebrafish embryos. Inhibition of Myo1 (by PClP and Myo2 (by Blebbistatin lead to arrest in cell division. While Myo1 isoforms appears to be important for both the formation and the maintenance of cleavage furrows, Myo2 is required only for the formation of furrows. We found that the blastodisc of the embryo, which contains a thick actin cortex (~13 μm, is loaded with cortical Myo1. Myo1 appears to be crucial for maintaining the blastodisc morphology and the actin cortex thickness. In addition to cell division and furrow formation, inhibition of Myo1 has a drastic effect on the dynamics and distribution of lipid droplets (LDs in the blastodisc near the cleavage furrow. All these results above are effects of Myo1 inhibition exclusively; Myo2 inhibition by blebbistatin does not show such phenotypes. Therefore, our results demonstrate a potential role for Myo1 in the maintenance and formation of furrow, blastodisc morphology, cell-division and LD organization within the blastodisc during early embryogenesis.

  17. The effect of ultraviolet radiation on early stages of activation of human lymphocytes: inhibition is independent of effects on DNA

    DEFF Research Database (Denmark)

    Castellanos, G; Owens, T; Rudd, C

    1982-01-01

    whether activation was measured by the incorporation of labelled leucine, uridine, or thymidine. If UV was applied at 44 h after culture in presence of Con A, the incorporation of [3H]thymidine measured 4 h later was seen to be inhibited but transcription and translation were scarcely affected. UV...... lymphocytes, when this was measured by means of 86Rb uptake after 2-4 h culture. The mitogen-stimulated activation of cation pump function has previously been shown to be unaffected by concentrations of cycloheximide and actinomycin D which produce virtually complete inhibition of protein and RNA synthesis...

  18. Impact of Behavioral Inhibition and Parenting Style on Internalizing and Externalizing Problems from Early Childhood through Adolescence

    Science.gov (United States)

    Williams, Lela Rankin; Degnan, Kathryn A.; Perez-Edgar, Koraly E.; Henderson, Heather A.; Rubin, Kenneth H.; Pine, Daniel S.; Steinberg, Laurence; Fox, Nathan A.

    2009-01-01

    Behavioral inhibition (BI) is characterized by a pattern of extreme social reticence, risk for internalizing behavior problems, and possible protection against externalizing behavior problems. Parenting style may also contribute to these associations between BI and behavior problems (BP). A sample of 113 children was assessed for BI in the…

  19. Inhibition of Early Stages of HIV-1 Assembly by INI1/hSNF5 Transdominant Negative Mutant S6 ▿

    Science.gov (United States)

    Cano, Jennifer; Kalpana, Ganjam V.

    2011-01-01

    INI1/hSNF5 is an HIV-1 integrase (IN) binding protein specifically incorporated into virions. A truncated mutant of INI1 (S6, amino acids 183 to 294) harboring the minimal IN binding Rpt1 domain potently inhibits HIV-1 particle production in a transdominant manner. The inhibition requires interaction of S6 with IN within Gag-Pol. While INI1 is a nuclear protein and harbors a masked nuclear export signal (NES), the transdominant negative mutant S6 is cytoplasmic, due to the unmasking of NES. Here, we examined the effects of subcellular localization of S6 on HIV-1 inhibition and further investigated the stages of assembly that are affected. We found that targeting a nuclear localization signal-containing S6 variant [NLS-S6(Rpt1)] to the nucleoplasm (but not to the nucleolus) resulted in complete reversal of inhibition of particle production. Electron microscopy indicated that although no electron-dense particles at any stage of assembly were seen in cells expressing S6, virions were produced in cells expressing the rescue mutant NLS-S6(Rpt1) to wild-type levels. Immunofluorescence analysis revealed that p24 exhibited a diffuse pattern of localization within the cytoplasm in cells expressing S6 in contrast to accumulation along the membrane in controls. Pulse-chase analysis indicated that in S6-expressing cells, although Gag(Pr55gag) protein translation was unaffected, processing and release of p24 were defective. Together, these results indicate that expression of S6 in the cytoplasm interferes with trafficking of Gag-Pol/Gag to the membrane and causes a defective processing leading to inhibition of assembly at an early stage prior to particle formation and budding. PMID:21159874

  20. Executive functions in early childhood: interrelations and structural development of inhibition, set-shifting and working memory

    Directory of Open Access Journals (Sweden)

    Paolo Stievano

    2013-04-01

    Full Text Available The aim of the present study is to examine the interrelations of executive function (EF tasks with general cognitive ability and linguistic level in preschool children. The analyses of the correlation between EF sub-domains, particularly inhibition and set-shifting, have been studied to comprehend the ontogenesis of EFs. Task analysis has allowed us to identify which EF sub-domains are prevalent in each task, with particular attention to inhibition and set-shifting definitions. The sample was composed of 40 typically developing children from 48 to 69 months old (M=58 months, SD=5.02; 28 boys and 12 girls. The results give some insight into the development of executive functions, their utility in clinical assessment and indication.

  1. Impact of behavioral inhibition and parenting style on internalizing and externalizing problems from early childhood through adolescence.

    Science.gov (United States)

    Williams, Lela Rankin; Degnan, Kathryn A; Perez-Edgar, Koraly E; Henderson, Heather A; Rubin, Kenneth H; Pine, Daniel S; Steinberg, Laurence; Fox, Nathan A

    2009-11-01

    Behavioral inhibition (BI) is characterized by a pattern of extreme social reticence, risk for internalizing behavior problems, and possible protection against externalizing behavior problems. Parenting style may also contribute to these associations between BI and behavior problems (BP). A sample of 113 children was assessed for BI in the laboratory at 14 and 24 months of age, self-report of maternal parenting style at 7 years of age, and maternal report of child internalizing and externalizing BP at 4, 7, and 15 years. Internalizing problems at age 4 were greatest among behaviorally inhibited children who also were exposed to permissive parenting. Furthermore, greater authoritative parenting was associated with less of an increase in internalizing behavior problems over time and greater authoritarian parenting was associated with a steeper decline in externalizing problems. Results highlight the importance of considering child and environmental factors in longitudinal patterns of BP across childhood and adolescence.

  2. Impact of Behavioral Inhibition and Parenting Style on Internalizing and Externalizing Problems from Early Childhood through Adolescence

    Science.gov (United States)

    Williams, Lela Rankin; Perez-Edgar, Koraly E.; Henderson, Heather A.; Rubin, Kenneth H.; Pine, Daniel S.; Steinberg, Laurence; Fox, Nathan A.

    2009-01-01

    Behavioral inhibition (BI) is characterized by a pattern of extreme social reticence, risk for internalizing behavior problems, and possible protection against externalizing behavior problems. Parenting style may also contribute to these associations between BI and behavior problems (BP). A sample of 113 children was assessed for BI in the laboratory at 14 and 24 months of age, self-report of maternal parenting style at 7 years of age, and maternal report of child internalizing and externalizing BP at 4, 7, and 15 years. Internalizing problems at age 4 were greatest among behaviorally inhibited children who also were exposed to permissive parenting. Furthermore, greater authoritative parenting was associated with less of an increase in internalizing behavior problems over time and greater authoritarian parenting was associated with a steeper decline in externalizing problems. Results highlight the importance of considering child and environmental factors in longitudinal patterns of BP across childhood and adolescence. PMID:19521761

  3. Impact of Behavioral Inhibition and Parenting Style on Internalizing and Externalizing Problems from Early Childhood through Adolescence

    OpenAIRE

    Williams, Lela Rankin; Degnan, Kathryn A.; Perez-Edgar, Koraly E.; Henderson, Heather A.; Rubin, Kenneth H.; Pine, Daniel S.; Steinberg, Laurence; Fox, Nathan A.

    2009-01-01

    Behavioral inhibition (BI) is characterized by a pattern of extreme social reticence, risk for internalizing behavior problems, and possible protection against externalizing behavior problems. Parenting style may also contribute to these associations between BI and behavior problems (BP). A sample of 113 children was assessed for BI in the laboratory at 14 and 24 months of age, self-report of maternal parenting style at 7 years of age, and maternal report of child internalizing and externaliz...

  4. Circuit motifs for contrast-adaptive differentiation in early sensory systems: the role of presynaptic inhibition and short-term plasticity.

    Science.gov (United States)

    Zhang, Danke; Wu, Si; Rasch, Malte J

    2015-01-01

    In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems.

  5. Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage

    Directory of Open Access Journals (Sweden)

    Ferda Hoşgörler

    2016-10-01

    Full Text Available Background: Matrix metalloproteinase (MMP inhibitors decrease inflammation in normal tissues and suppress cancer progress in normal tissues. Valproic acid (VA and doxycycline (DX are MMP inhibitors that have radio-protective effects. Their ability to inhibit MMPs in irradiated tissue is unknown and the role of MMPs in radio-protective effects has not been tested to date. Aims: The purpose of this study was to examine whether administration of VA and DX to rats before irradiation affects tissue inflammation and apoptosis in the early phase of radiation, and whether the effect of these drugs is mediated by MMP inhibition. Study Design: Animal experimentation. Methods: Twenty-six Wistar rats were randomized into four groups: control (CTRL, radiation (RT, VA plus radiation (VA+RT, and DX plus radiation (DX+RT.Three study groups were exposed to a single dose of abdominal 10 Gy gamma radiation; the CTRL group received no radiation. Single doses of VA 300 mg/kg and DX 100 mg/kg were administered to each rat before radiation and all rats were sacrificed 8 hours after irradiation, at which point small intestine tissue samples were taken for analyses. Levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6 and matrix metalloproteinases (MMP-2 and MMP 9 were measured by ELISA, MMP activities were measured by gelatin and casein zymography and apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: VA decreased the levels of TNF-α and IL-1β proteins insignificantly and decreased apoptosis significantly in the irradiated tissue, but did not inhibit MMPs. In contrast, VA protected the basal MMP activities, which decreased in response to irradiation. No effect of DX was observed on the levels of inflammatory cytokines or activities of MMPs in the early phases of radiation apoptosis. Conclusion: Our findings indicated that VA protects against inflammation and apoptosis, and DX exhibits anti-apoptotic effects in

  6. Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery

    NARCIS (Netherlands)

    Rouleau, Jean L.; Warnica, Wayne J.; Baillot, Richard; Block, Pierre J.; Chocron, Sidney; Johnstone, David; Myers, Martin G.; Calciu, Cristina-Dana; Dalle-Ave, Sonia; Martineau, Pierre; Mormont, Christine; van Gilst, Wiek H.

    2008-01-01

    Background-Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors. Methods and Results-The Ischemia Management with Accupril post -bypass Graft via

  7. Too little, too late or too much, too early? Differential hemodynamics of response inhibition in high and low sensation seekers.

    Science.gov (United States)

    Collins, Heather R; Corbly, Christine R; Liu, Xun; Kelly, Thomas H; Lynam, Donald; Joseph, Jane E

    2012-10-24

    High sensation seeking is associated with strong approach behaviors and weak avoidance responses. The present study used functional magnetic resonance imaging (fMRI) to further characterize the neurobiological underpinnings of this behavioral profile using a Go/No-go task. Analysis of brain activation associated with response inhibition (No-go) versus response initiation and execution (Go) revealed the commonly reported right lateral prefrontal, insula, cingulate, and supplementary motor area network. However, right lateral activation was associated with greater No-go than Go responses only in low sensation seekers. High sensation seekers showed no differential activation in these regions but a more pronounced Go compared to No-go response in several other regions that are involved in salience detection (insula), motor initiation (anterior cingulate) and attention (inferior parietal cortex). Temporal analysis of the hemodynamic response for Go and No-go conditions revealed that the stronger response to Go than No-go trials in high sensation seekers occurred in in the earliest time window in the right middle frontal gyrus, right mid-cingulate and right precuneus. In contrast, the greater No-go than Go response in low sensation seekers occurred in the later time window in these same regions. These findings indicate that high sensation seekers more strongly attend to or process Go trials and show delayed or minimal inhibitory responses on No-go trials in regions that low sensation seekers use for response inhibition. Failure to engage such regions for response inhibition may underlie some of the risky and impulsive behaviors observed in high sensation seekers. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Inhibition or Stimulation of Autophagy Affects Early Formation of Lipofuscin-Like Autofluorescence in the Retinal Pigment Epithelium Cell

    Directory of Open Access Journals (Sweden)

    Lei Lei

    2017-03-01

    Full Text Available The accumulation of lipofuscin in the retinal pigment epithelium (RPE is dependent on the effectiveness of photoreceptor outer segment material degradation. This study explored the role of autophagy in the fate of RPE lipofuscin degradation. After seven days of feeding with either native or modified rod outer segments, ARPE-19 cells were treated with enhancers or inhibitors of autophagy and the autofluorescence was detected by fluorescence-activated cell sorting. Supplementation with different types of rod outer segments increased lipofuscin-like autofluorescence (LLAF after the inhibition of autophagy, while the induction of autophagy (e.g., application of rapamycin decreased LLAF. The effects of autophagy induction were further confirmed by Western blotting, which showed the conversion of LC3-I to LC3-II, and by immunofluorescence microscopy, which detected the lysosomal activity of the autophagy inducers. We also monitored LLAF after the application of several autophagy inhibitors by RNA-interference and confocal microscopy. The results showed that, in general, the inhibition of the autophagy-related proteins resulted in an increase in LLAF when cells were fed with rod outer segments, which further confirms the effect of autophagy in the fate of RPE lipofuscin degradation. These results emphasize the complex role of autophagy in modulating RPE autofluorescence and confirm the possibility of the pharmacological clearance of RPE lipofuscin by small molecules.

  9. Inhibition of early AAA formation by aortic intraluminal pentagalloyl glucose (PGG) infusion in a novel porcine AAA model

    DEFF Research Database (Denmark)

    Kloster, Brian O; Lund, Lars; Lindholt, Jes S

    2016-01-01

    to prevent or delay their expansion. In this study, we investigated whether intraluminal delivered pentagalloyl glucose (PGG) can impair the early AAA development in a porcine model. METHODS: The infrarenal aorta was exposed in thirty pigs. Twenty underwent an elastase based AAA inducing procedure and ten...... of these received an additional intraluminal PGG infusion. The final 10 were sham operated and served as controls. RESULTS: All pigs who only had an elastase infusion developed macroscopically expanding AAAs. In pigs treated with an additional PGG infusion the growth rate of the AP-diameter rapidly returned...... and histology. CONCLUSION: In our model, intraluminal delivered PGG is able to penetrate the aortic wall from the inside and impair the early AAA development by stabilizing the elastic lamellae and preserving their integrity. The principle holds a high clinical potential if it can be translated to human...

  10. Inhibition of early AAA formation by aortic intraluminal pentagalloyl glucose (PGG) infusion in a novel porcine AAA model.

    Science.gov (United States)

    Kloster, Brian O; Lund, Lars; Lindholt, Jes S

    2016-05-01

    The vast majority of abdominal aortic aneurysms found in screening programs are small, and as no effective treatment exits, many will expand until surgery is indicated. Therefore, it remains intriguing to develop a safe and low cost treatment of these small aneurysms, that is able to prevent or delay their expansion. In this study, we investigated whether intraluminal delivered pentagalloyl glucose (PGG) can impair the early AAA development in a porcine model. The infrarenal aorta was exposed in thirty pigs. Twenty underwent an elastase based AAA inducing procedure and ten of these received an additional intraluminal PGG infusion. The final 10 were sham operated and served as controls. All pigs who only had an elastase infusion developed macroscopically expanding AAAs. In pigs treated with an additional PGG infusion the growth rate of the AP-diameter rapidly returned to physiological values as seen in the control group. In the elastase group, histology revealed more or less complete resolution of the elastic lamellae in the media while they were more abundant, coherent and structurally organized in the PGG group. The control group displayed normal physiological growth and histology. In our model, intraluminal delivered PGG is able to penetrate the aortic wall from the inside and impair the early AAA development by stabilizing the elastic lamellae and preserving their integrity. The principle holds a high clinical potential if it can be translated to human conditions, since it, if so, potentially could represent a new drug for stabilizing small abdominal aneurysms.

  11. Pharmacologic inhibition of phospholipase C in the brain attenuates early memory formation in the honeybee (Apis mellifera L.

    Directory of Open Access Journals (Sweden)

    Shota Suenami

    2018-01-01

    Full Text Available Although the molecular mechanisms involved in learning and memory in insects have been studied intensively, the intracellular signaling mechanisms involved in early memory formation are not fully understood. We previously demonstrated that phospholipase C epsilon (PLCe, whose product is involved in calcium signaling, is almost selectively expressed in the mushroom bodies, a brain structure important for learning and memory in the honeybee. Here, we pharmacologically examined the role of phospholipase C (PLC in learning and memory in the honeybee. First, we identified four genes for PLC subtypes in the honeybee genome database. Quantitative reverse transcription-polymerase chain reaction revealed that, among these four genes, three, including PLCe, were expressed higher in the brain than in sensory organs in worker honeybees, suggesting their main roles in the brain. Edelfosine and neomycin, pan-PLC inhibitors, significantly decreased PLC activities in homogenates of the brain tissues. These drugs injected into the head of foragers significantly attenuated memory acquisition in comparison with the control groups, whereas memory retention was not affected. These findings suggest that PLC in the brain is involved in early memory formation in the honeybee. To our knowledge, this is the first report of a role for PLC in learning and memory in an insect.

  12. Inhibition of Nipah virus infection in vivo: targeting an early stage of paramyxovirus fusion activation during viral entry.

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    Matteo Porotto

    2010-10-01

    Full Text Available In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses.

  13. In Vitro Biotransformation of Two Human CYP3A Probe Substrates and Their Inhibition during Early Zebrafish Development.

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    Verbueken, Evy; Alsop, Derek; Saad, Moayad A; Pype, Casper; Van Peer, Els M; Casteleyn, Christophe R; Van Ginneken, Chris J; Wilson, Joanna; Van Cruchten, Steven J

    2017-01-22

    At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP)-a group of drug-metabolizing enzymes-in microsomes from whole zebrafish embryos (ZEM) of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf) by means of a mammalian CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR). The same CYP activity assays were performed in adult zebrafish liver microsomes (ZLM) to serve as a reference for the embryos. In addition, activity assays with the human CYP3A4-specific Luciferin isopropyl acetal (Luciferin-IPA) as well as inhibition studies with ketoconazole and CYP3cide were carried out to identify CYP activity in ZLM. In the present study, biotransformation of BOMR was detected at 72 and 96 hpf; however, metabolite formation was low compared with ZLM. Furthermore, Luciferin-IPA was not metabolized by the zebrafish. In conclusion, the capacity of intrinsic biotransformation in zebrafish embryos appears to be lacking during a major part of organogenesis.

  14. In Vitro Biotransformation of Two Human CYP3A Probe Substrates and Their Inhibition during Early Zebrafish Development

    Directory of Open Access Journals (Sweden)

    Evy Verbueken

    2017-01-01

    Full Text Available At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP—a group of drug-metabolizing enzymes—in microsomes from whole zebrafish embryos (ZEM of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf by means of a mammalian CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR. The same CYP activity assays were performed in adult zebrafish liver microsomes (ZLM to serve as a reference for the embryos. In addition, activity assays with the human CYP3A4-specific Luciferin isopropyl acetal (Luciferin-IPA as well as inhibition studies with ketoconazole and CYP3cide were carried out to identify CYP activity in ZLM. In the present study, biotransformation of BOMR was detected at 72 and 96 hpf; however, metabolite formation was low compared with ZLM. Furthermore, Luciferin-IPA was not metabolized by the zebrafish. In conclusion, the capacity of intrinsic biotransformation in zebrafish embryos appears to be lacking during a major part of organogenesis.

  15. Reduced Social Network Drinking is Associated with Improved Response Inhibition in Women During Early Recovery from Alcohol Use Disorders: A Pilot Study.

    Science.gov (United States)

    McCutcheon, Vivia V; Luke, Douglas A; Lessov-Schlaggar, Christina N

    2016-01-01

    Social support for recovery from alcohol use disorders (AUDs) is associated with improvements in self-reported impulsive behavior in individuals treated for AUDs. We build on these findings using a behavioral task-based measure of response inhibition, a well-defined component of impulsivity, to examine the association of disinhibition with alcohol-specific social network characteristics during early recovery. Women (n = 28) were recruited from treatment for AUD within 3 to 4 weeks of their last drink and were assessed at baseline and again 3 months later. Outcome measures were level of disinhibition at baseline and change in disinhibition from baseline to follow-up, measured using a computer-based continuous performance test. The primary independent variables were level of drinking in the social network at baseline and change in network drinking from baseline to follow-up. The sample [50% black, age M (SD) = 42.3 (9.5)] reported high rates of physical and sexual abuse before age 13 (43%), psychiatric disorder (71%), drug use disorder (78%), and previous treatment (71%). More drinking in participants' social networks was associated with greater disinhibition at baseline (β = 12.5, 95% CI = 6.3, 18.7). A reduction in network drinking from baseline to follow-up was associated with reduced disinhibition (β = -6.0, 95% CI = -11.3, -0.78) independent of IQ, recent alcohol consumption, and self-reported negative urgency. This study extends previous findings of an association between social networks and self-reported impulsivity to a neurobehavioral phenotype, response inhibition, suggesting that abstinence-supporting social networks may play a role in cognitive change during early recovery from AUDs. Copyright © 2015 by the Research Society on Alcoholism.

  16. Paradoxical Effects of Sodium-Calcium Exchanger Inhibition on Torsade de Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model.

    Science.gov (United States)

    Chang, Po-Cheng; Lu, Yu-Ying; Lee, Hui-Ling; Lin, Shien-Fong; Chu, Yen; Wen, Ming-Shien; Chou, Chung-Chuan

    2018-05-03

    Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis secondary Ca rise and EADs-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats (PVBs) but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM10103 had a neutral effect on the amplitude of secondary Cai rise in control and HF groups. In this model, most EADs generated from the long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced PVB burden but was unable to suppress secondary Ca rise, EADs development nor inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

  17. Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice.

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    Qu, Wenhui; Johnson, Andrea; Kim, Joo Hyun; Lukowicz, Abigail; Svedberg, Daniel; Cvetanovic, Marija

    2017-05-25

    Polyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Currently, there are no treatments available to delay or ameliorate SCA1. We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1. Transgenic mouse model of SCA1, ATXN1[82Q] mice, and wild-type littermate controls were treated with PLX from 3 weeks of age. The effects of PLX on microglial density, astrogliosis, motor behavior, atrophy, and gene expression of Purkinje neurons were examined at 3 months of age. PLX treatment resulted in the elimination of 70-80% of microglia from the cerebellum of both wild-type and ATXN1[82Q] mice. Importantly, PLX ameliorated motor deficits in SCA1 mice. While we have not observed significant improvement in the atrophy or disease-associated gene expression changes in Purkinje neurons upon PLX treatment, we have detected reduced expression of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and increase in the protein levels of wild-type ataxin-1 and post-synaptic density protein 95 (PSD95) that may help improve PN function. A decrease in the number of microglia during an early stage of disease resulted in the amelioration of motor deficits in SCA1 mice.

  18. Combined small-molecule inhibition accelerates the derivation of functional, early-born, cortical neurons from human pluripotent stem cells

    Science.gov (United States)

    Qi, Yuchen; Zhang, Xin-Jun; Renier, Nicolas; Wu, Zhuhao; Atkin, Talia; Sun, Ziyi; Ozair, M. Zeeshan; Tchieu, Jason; Zimmer, Bastian; Fattahi, Faranak; Ganat, Yosif; Azevedo, Ricardo; Zeltner, Nadja; Brivanlou, Ali H.; Karayiorgou, Maria; Gogos, Joseph; Tomishima, Mark; Tessier-Lavigne, Marc; Shi, Song-Hai; Studer, Lorenz

    2017-01-01

    Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into functional neurons. However, the protracted timing of human neuron specification and functional maturation remains a key challenge that hampers the routine application of hPSC-derived lineages in disease modeling and regenerative medicine. Using a combinatorial small-molecule screen, we previously identified conditions for the rapid differentiation of hPSCs into peripheral sensory neurons. Here we generalize the approach to central nervous system (CNS) fates by developing a small-molecule approach for accelerated induction of early-born cortical neurons. Combinatorial application of 6 pathway inhibitors induces post-mitotic cortical neurons with functional electrophysiological properties by day 16 of differentiation, in the absence of glial cell co-culture. The resulting neurons, transplanted at 8 days of differentiation into the postnatal mouse cortex, are functional and establish long-distance projections, as shown using iDISCO whole brain imaging. Accelerated differentiation into cortical neuron fates should facilitate hPSC-based strategies for disease modeling and cell therapy in CNS disorders. PMID:28112759

  19. BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology.

    Science.gov (United States)

    Wilson, E N; Do Carmo, S; Iulita, M F; Hall, H; Ducatenzeiler, A; Marks, A R; Allard, S; Jia, D T; Windheim, J; Cuello, A C

    2017-08-01

    Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

  20. Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS

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    Yongjian Wu

    2018-02-01

    Full Text Available Beta-defensins 2 and 3 (BD2 and BD3 are inducible peptides present at the sites of infection, and they are well characterized for their antimicrobial activities and immune-regulatory functions. However, no study has thoroughly investigated their immunomodulatory effects on macrophage-mediated immune responses against Pseudomonas aeruginosa (PA. Here, we use THP-1 and RAW264.7 cell lines and demonstrate that BD2 and BD3 suppressed macrophage autophagy but enhanced the engulfment of PA and Zymosan bioparticles as well as the formation of phagolysosomes, using immunofluorescence staining and confocal microscopy. Plate count assay showed that macrophage-mediated phagocytosis and intracellular killing of PA were promoted by BD2 and BD3. Furthermore, microarray and real-time PCR showed that the expression of two genes, early growth response gene-1 (EGR1 and c-FOS, was attenuated by BD2 and BD3. Western blot revealed that BD2 and BD3 inhibited the expression and nuclear translocation of EGR1 and c-FOS. Knockdown of EGR1 and c-FOS by siRNA transfection suppressed macrophage autophagy before and after PA infection; while overexpression of these two transcription factors enhanced autophagy but reversed the role of BD2 and BD3 on macrophage-mediated PA eradication. Together, these results demonstrate a novel immune defense activity of BD2 and BD3, which promotes clearance of PA by inhibiting macrophage autophagy through downregulation of EGR1 and c-FOS.

  1. Inhibition of hypoxia inducible factor-1α downregulates the expression of epithelial to mesenchymal transition early marker proteins without undermining cell survival in hypoxic lens epithelial cells.

    Science.gov (United States)

    Cammarata, Patrick R; Neelam, Sudha; Brooks, Morgan M

    2015-01-01

    The purpose of this study was to identify potential therapeutic strategies to slow down or prevent the expression of early-onset epithelial to mesenchymal transition (EMT) marker proteins (fibronectin and alpha smooth muscle actin, α-SMA) without sacrificing the synthesis and accumulation of the prosurvival protein vascular endothelial growth factor (VEGF) in cultured virally transformed human lens epithelial (HLE) cells. HLE-B3 cells, maintained in a continuous hypoxic environment (1% oxygen), were treated with SB216763, a specific inhibitor of glycogen synthase kinase-3β (GSK-3β) catalytic activity. Western blot analysis was employed to detect the cytoplasmic and nuclear levels of β-catenin, as well as the total lysate content of fibronectin and α-SMA. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of VEGF in cell culture medium. A hypoxia-inducible factor-1α (HIF-1α) translation inhibitor and an HIF-2α translation inhibitor were independently employed to evaluate the effect of hypoxia inducible factor inhibition on EMT marker protein and VEGF expression. XAV932 was used to assess the suppression of nuclear β-catenin and its downstream effect on EMT marker proteins and VEGF expression. SB216763-treated HLE-B3 cells caused marked inhibition of GSK-3β activity prompting a significant increase in the translocation of cytoplasmic β-catenin to the nucleus. The enhancement of nuclear β-catenin looked as if it positively correlated with a significant increase in the basal expression of VEGF as well as increased expression of fibronectin and α-SMA. In conjunction with SB216763, coadministration of an HIF-1α translation inhibitor, but not an HIF-2α translation inhibitor, markedly suppressed the expression of fibronectin and α-SMA without affecting VEGF levels. Treatment with XAV932 significantly reduced the level of nuclear β-catenin, but the levels of neither the EMT marker proteins nor VEGF were changed. Recently, we reported

  2. Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes.

    Science.gov (United States)

    Severino, Anna; Zara, Chiara; Campioni, Mara; Flego, Davide; Angelini, Giulia; Pedicino, Daniela; Giglio, Ada Francesca; Trotta, Francesco; Giubilato, Simona; Pazzano, Vincenzo; Lucci, Claudia; Iaconelli, Antonio; Ruggio, Aureliano; Biasucci, Luigi Marzio; Crea, Filippo; Liuzzo, Giovanna

    2017-03-14

    Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms.Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 μg/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-γ-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P 3-fold changes).The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03).Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.

  3. Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat.

    Science.gov (United States)

    Borgohain, Manash P; Lahkar, Mangala; Ahmed, Sahabuddin; Chowdhury, Liakat; Kumar, Saurabh; Pant, Rajat; Choubey, Abhinav

    2017-05-01

    Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  4. δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages.

    Science.gov (United States)

    Chen, Jayson X; Liu, Anna; Lee, Mao-Jung; Wang, Hong; Yu, Siyuan; Chi, Eric; Reuhl, Kenneth; Suh, Nanjoo; Yang, Chung S

    2017-01-01

    Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (α-T), beta (β-T), gamma (γ-T), and delta (δ-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with α-T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of α-T is weak compared to other tocopherol forms. In the present study, we investigated the effects of δ-T, γ-T, and α-T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10 wk. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-κB p65 and p-STAT3) in tumors and adjacent tissues. By administering δ-T at different time periods, we obtained results suggesting that the inhibitory effect of δ-T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of δ-T and γ-T in a physiologically relevant model of human colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B

    Science.gov (United States)

    Mendes-Sousa, Antonio F.; do Vale, Vladimir Fazito; Silva, Naylene C. S.; Guimaraes-Costa, Anderson B.; Pereira, Marcos H.; Sant’Anna, Mauricio R. V.; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, José M. C.; Andersen, John F.; Valenzuela, Jesus G.; Araujo, Ricardo N.

    2017-01-01

    Saliva of the blood feeding sand fly Lutzomyia longipalpis was previously shown to inhibit the alternative pathway (AP) of the complement system. Here, we have identified Lufaxin, a protein component in saliva, as the inhibitor of the AP. Lufaxin inhibited the deposition of C3b, Bb, Properdin, C5b, and C9b on agarose-coated plates in a dose-dependent manner. It also inhibited the activation of factor B in normal serum, but had no effect on the components of the membrane attack complex. Surface plasmon resonance (SPR) experiments demonstrated that Lufaxin stabilizes the C3b-B proconvertase complex when passed over a C3b surface in combination with factor B. Lufaxin was also shown to inhibit the activation of factor B by factor D in a reconstituted C3b-B, but did not inhibit the activation of C3 by reconstituted C3b-Bb. Proconvertase stabilization does not require the presence of divalent cations, but addition of Ni2+ increases the stability of complexes formed on SPR surfaces. Stabilization of the C3b-B complex to prevent C3 convertase formation (C3b-Bb formation) is a novel mechanism that differs from previously described strategies used by other organisms to inhibit the AP of the host complement system. PMID:28912782

  6. The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B

    Directory of Open Access Journals (Sweden)

    Antonio F. Mendes-Sousa

    2017-08-01

    Full Text Available Saliva of the blood feeding sand fly Lutzomyia longipalpis was previously shown to inhibit the alternative pathway (AP of the complement system. Here, we have identified Lufaxin, a protein component in saliva, as the inhibitor of the AP. Lufaxin inhibited the deposition of C3b, Bb, Properdin, C5b, and C9b on agarose-coated plates in a dose-dependent manner. It also inhibited the activation of factor B in normal serum, but had no effect on the components of the membrane attack complex. Surface plasmon resonance (SPR experiments demonstrated that Lufaxin stabilizes the C3b-B proconvertase complex when passed over a C3b surface in combination with factor B. Lufaxin was also shown to inhibit the activation of factor B by factor D in a reconstituted C3b-B, but did not inhibit the activation of C3 by reconstituted C3b-Bb. Proconvertase stabilization does not require the presence of divalent cations, but addition of Ni2+ increases the stability of complexes formed on SPR surfaces. Stabilization of the C3b-B complex to prevent C3 convertase formation (C3b-Bb formation is a novel mechanism that differs from previously described strategies used by other organisms to inhibit the AP of the host complement system.

  7. The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B.

    Science.gov (United States)

    Mendes-Sousa, Antonio F; do Vale, Vladimir Fazito; Silva, Naylene C S; Guimaraes-Costa, Anderson B; Pereira, Marcos H; Sant'Anna, Mauricio R V; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, José M C; Andersen, John F; Valenzuela, Jesus G; Araujo, Ricardo N

    2017-01-01

    Saliva of the blood feeding sand fly Lutzomyia longipalpis was previously shown to inhibit the alternative pathway (AP) of the complement system. Here, we have identified Lufaxin, a protein component in saliva, as the inhibitor of the AP. Lufaxin inhibited the deposition of C3b, Bb, Properdin, C5b, and C9b on agarose-coated plates in a dose-dependent manner. It also inhibited the activation of factor B in normal serum, but had no effect on the components of the membrane attack complex. Surface plasmon resonance (SPR) experiments demonstrated that Lufaxin stabilizes the C3b-B proconvertase complex when passed over a C3b surface in combination with factor B. Lufaxin was also shown to inhibit the activation of factor B by factor D in a reconstituted C3b-B, but did not inhibit the activation of C3 by reconstituted C3b-Bb. Proconvertase stabilization does not require the presence of divalent cations, but addition of Ni 2+ increases the stability of complexes formed on SPR surfaces. Stabilization of the C3b-B complex to prevent C3 convertase formation (C3b-Bb formation) is a novel mechanism that differs from previously described strategies used by other organisms to inhibit the AP of the host complement system.

  8. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model

    Directory of Open Access Journals (Sweden)

    Claudia Tulotta

    2016-02-01

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

  9. Inhibition of the early stage of Salmonella enterica serovar Enteritidis biofilm development on stainless steel by cell-free supernatant of a Hafnia alvei culture.

    Science.gov (United States)

    Chorianopoulos, Nikos G; Giaouris, Efstathios D; Kourkoutas, Yiannis; Nychas, George-John E

    2010-03-01

    Compounds present in Hafnia alvei cell-free culture supernatant cumulatively negatively influence the early stage of biofilm development by Salmonella enterica serovar Enteritidis on stainless steel while they also reduce the overall metabolic activity of S. Enteritidis planktonic cells. Although acylhomoserine lactones (AHLs) were detected among these compounds, the use of several synthetic AHLs was not able to affect the initial stage of biofilm formation by this pathogen.

  10. Short-term inhibition of prostaglandin synthesis has no effect on the elevated glomerular filtration rate of early insulin-dependent diabetes

    DEFF Research Database (Denmark)

    Christiansen, J S; Feldt-Rasmussen, B; Parving, H H

    1985-01-01

    Glomerular filtration rate and renal plasma flow (constant infusion technique using 125I-iothalamate and 131I-hippuran) were measured twice within a 1-week interval in nine young males with insulin-dependent diabetes of short duration (2-5 years). The study was performed in a randomized double...... +/- 43 versus 560 +/- 52 ml/min X 1.73 m2), when measured during placebo or indomethacin treatment, respectively. It is concluded that the steady-state enhancement of glomerular filtration rate and renal plasma flow found in early insulin-dependent diabetes is not due to an excessive activity...

  11. An indole alkaloid from a tribal folklore inhibits immediate early event in HSV-2 infected cells with therapeutic efficacy in vaginally infected mice.

    Directory of Open Access Journals (Sweden)

    Paromita Bag

    Full Text Available Herpes genitalis, caused by HSV-2, is an incurable genital ulcerative disease transmitted by sexual intercourse. The virus establishes life-long latency in sacral root ganglia and reported to have synergistic relationship with HIV-1 transmission. Till date no effective vaccine is available, while the existing therapy frequently yielded drug resistance, toxicity and treatment failure. Thus, there is a pressing need for non-nucleotide antiviral agent from traditional source. Based on ethnomedicinal use we have isolated a compound 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM from the traditional herb Ophiorrhiza nicobarica Balkr, and evaluated its efficacy on isolates of HSV-2 in vitro and in vivo. The cytotoxicity (CC50, effective concentrations (EC50 and the mode of action of HM was determined by MTT, plaque reduction, time-of-addition, immunofluorescence (IFA, Western blot, qRT-PCR, EMSA, supershift and co-immunoprecipitation assays; while the in vivo toxicity and efficacy was evaluated in BALB/c mice. The results revealed that HM possesses significant anti-HSV-2 activity with EC50 of 1.1-2.8 µg/ml, and selectivity index of >20. The time kinetics and IFA demonstrated that HM dose dependently inhibited 50-99% of HSV-2 infection at 1.5-5.0 µg/ml at 2-4 h post-infection. Further, HM was unable to inhibit viral attachment or penetration and had no synergistic interaction with acyclovir. Moreover, Western blot and qRT-PCR assays demonstrated that HM suppressed viral IE gene expression, while the EMSA and co-immunoprecipitation studies showed that HM interfered with the recruitment of LSD-1 by HCF-1. The in vivo studies revealed that HM at its virucidal concentration was nontoxic and reduced virus yield in the brain of HSV-2 infected mice in a concentration dependent manner, compared to vaginal tissues. Thus, our results suggest that HM can serve as a prototype to develop non-nucleotide antiviral lead targeting the viral IE

  12. An indole alkaloid from a tribal folklore inhibits immediate early event in HSV-2 infected cells with therapeutic efficacy in vaginally infected mice.

    Science.gov (United States)

    Bag, Paromita; Ojha, Durbadal; Mukherjee, Hemanta; Halder, Umesh Chandra; Mondal, Supriya; Chandra, Nidhi S; Nandi, Suman; Sharon, Ashoke; Sarkar, Mamta Chawla; Chakrabarti, Sekhar; Chattopadhyay, Debprasad

    2013-01-01

    Herpes genitalis, caused by HSV-2, is an incurable genital ulcerative disease transmitted by sexual intercourse. The virus establishes life-long latency in sacral root ganglia and reported to have synergistic relationship with HIV-1 transmission. Till date no effective vaccine is available, while the existing therapy frequently yielded drug resistance, toxicity and treatment failure. Thus, there is a pressing need for non-nucleotide antiviral agent from traditional source. Based on ethnomedicinal use we have isolated a compound 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM) from the traditional herb Ophiorrhiza nicobarica Balkr, and evaluated its efficacy on isolates of HSV-2 in vitro and in vivo. The cytotoxicity (CC50), effective concentrations (EC50) and the mode of action of HM was determined by MTT, plaque reduction, time-of-addition, immunofluorescence (IFA), Western blot, qRT-PCR, EMSA, supershift and co-immunoprecipitation assays; while the in vivo toxicity and efficacy was evaluated in BALB/c mice. The results revealed that HM possesses significant anti-HSV-2 activity with EC50 of 1.1-2.8 µg/ml, and selectivity index of >20. The time kinetics and IFA demonstrated that HM dose dependently inhibited 50-99% of HSV-2 infection at 1.5-5.0 µg/ml at 2-4 h post-infection. Further, HM was unable to inhibit viral attachment or penetration and had no synergistic interaction with acyclovir. Moreover, Western blot and qRT-PCR assays demonstrated that HM suppressed viral IE gene expression, while the EMSA and co-immunoprecipitation studies showed that HM interfered with the recruitment of LSD-1 by HCF-1. The in vivo studies revealed that HM at its virucidal concentration was nontoxic and reduced virus yield in the brain of HSV-2 infected mice in a concentration dependent manner, compared to vaginal tissues. Thus, our results suggest that HM can serve as a prototype to develop non-nucleotide antiviral lead targeting the viral IE transcription for the

  13. Oocyte exposure to ZnO nanoparticles inhibits early embryonic development through the γ-H2AX and NF-κB signaling pathways.

    Science.gov (United States)

    Liu, Jing; Zhao, Yong; Ge, Wei; Zhang, Pengfei; Liu, Xinqi; Zhang, Weidong; Hao, Yanan; Yu, Shuai; Li, Lan; Chu, Meiqiang; Min, Lingjiang; Zhang, Hongfu; Shen, Wei

    2017-06-27

    The impacts of zinc oxide nanoparticles on embryonic development following oocyte stage exposure are unknown and the underlying mechanisms are sparsely understood. In the current investigation, intact nanoparticles were detected in ovarian tissue in vivo and cultured cells in vitro under zinc oxide nanoparticles treatment. Zinc oxide nanoparticles exposure during the oocyte stage inhibited embryonic development. Notably, in vitro culture data closely matched in vivo embryonic data, in that the impairments caused by Zinc oxide nanoparticles treatment passed through cell generations; and both gamma-H2AX and NF-kappaB pathways were involved in zinc oxide nanoparticles caused embryo-toxicity. Copper oxide and silicon dioxide nanoparticles have been used to confirm that particles are important for the toxicity of zinc oxide nanoparticles. The toxic effects of zinc oxide nanoparticles emanate from both intact nanoparticles and Zn2+. Our investigation along with others suggests that zinc oxide nanoparticles are toxic to the female reproductive system [ovaries (oocytes)] and subsequently embryo-toxic and that precaution should be taken regarding human exposure to their everyday use.

  14. Early and late inhibitions elicited by a peripheral visual cue on manual response to a visual target: Are they based on Cartesian coordinates?

    Directory of Open Access Journals (Sweden)

    Fábio V. Magalhães

    2005-01-01

    Full Text Available A non-informative cue (C elicits an inhibition of manual reaction time (MRT to a visual target (T. We report an experiment to examine if the spatial distribution of this inhibitory effect follows Polar or Cartesian coordinate systems. C appeared at one out of 8 isoeccentric (7o positions, the C-T angular distances (in polar coordinates were 0º or multiples of 45º and ISI were 100 or 800ms. Our main findings were: (a MRT was maximal when C- T distance was 0o and minimal when C-T distance was 180o and (b besides an angular distance effect, there is a meridian effect. When C and T occurred in the same quadrant, MRT was longer than when T and C occurred at the same distance (45o but on different sides of vertical or horizontal meridians. The latter finding indicates that the spatial distribution of the cue inhibitory effects is based on a Cartesian coordinate system.

  15. Inhibition of iridovirus protein synthesis and virus replication by antisense morpholino oligonucleotides targeted to the major capsid protein, the 18 kDa immediate-early protein, and a viral homolog of RNA polymerase II

    International Nuclear Information System (INIS)

    Sample, Robert; Bryan, Locke; Long, Scott; Majji, Sai; Hoskins, Glenn; Sinning, Allan; Olivier, Jake; Chinchar, V. Gregory

    2007-01-01

    Frog virus 3 (FV3) is a large DNA virus that encodes ∼ 100 proteins. Although the general features of FV3 replication are known, the specific roles that most viral proteins play in the virus life cycle have not yet been elucidated. To address the question of viral gene function, antisense morpholino oligonucleotides (asMOs) were used to transiently knock-down expression of specific viral genes and thus infer their role in virus replication. We designed asMOs directed against the major capsid protein (MCP), an 18 kDa immediate-early protein (18K) that was thought to be a viral regulatory protein, and the viral homologue of the largest subunit of RNA polymerase II (vPol-IIα). All three asMOs successfully inhibited translation of the targeted protein, and two of the three asMOs resulted in marked phenotypic changes. Knock-down of the MCP resulted in a marked reduction in viral titer without a corresponding drop in the synthesis of other late viral proteins. Transmission electron microscopy (TEM) showed that in cells treated with the anti-MCP MO assembly sites were devoid of viral particles and contained numerous aberrant structures. In contrast, inhibition of 18K synthesis did not block virion formation, suggesting that the 18K protein was not essential for replication of FV3 in fathead minnow (FHM) cells. Finally, consistent with the view that late viral gene expression is catalyzed by a virus-encoded or virus-modified Pol-II-like protein, knock-down of vPol-IIα triggered a global decline in late gene expression and virus yields without affecting the synthesis of early viral genes. Collectively, these results demonstrate the utility of using asMOs to elucidate the function of FV3 proteins

  16. Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma

    International Nuclear Information System (INIS)

    Del Vecchio, Silvana; Zannetti, Antonella; Aloj, Luigi; Caraco, Corradina; Ciarmiello, Andrea; Salvatore, Marco

    2003-01-01

    Lack of technetium-99m methoxyisobutylisonitrile ( 99m Tc-MIBI) uptake is consistently reported to predict poor response to subsequent chemotherapy in a variety of human malignant tumours. Since 99m Tc-MIBI accumulates within mitochondria, which also play a central role in apoptosis through the integration of death signals by Bcl-2 family members, we tested whether early 99m Tc-MIBI uptake is affected by alterations of the apoptotic pathway. Forty-two breast cancer patients were intravenously injected with 740 MBq of 99m Tc-MIBI and planar images were obtained 10 min post injection with the patients in the prone lateral position. Ten carcinomas failed to accumulate 99m Tc-MIBI and could not be visualised on scintigraphic images despite being larger than 1.8 cm (MIBI negative). Thirty-two of the 42 breast carcinomas showed focal uptake of 99m Tc-MIBI (MIBI positive), and 10 min tumour-to-background ratios (T/B) varied between 1.14 and 6.93. The apoptotic index, the rate of proliferation, and the expression of the anti-apoptotic Bcl-2 protein and pro-apoptotic Bax protein were assessed in surgically excised tumours. All MIBI-negative carcinomas showed a dramatic and statistically significant reduction in the apoptotic index as compared with MIBI-positive lesions (mean±SD, 0.14±0.15 vs 1.28±0.83, P 99m Tc-MIBI in breast carcinomas is affected by alterations of apoptotic pathway. High levels of Bcl-2, despite the stabilisation of mitochondrial membrane potentials, prevent accumulation of 99m Tc-MIBI in tumour cells. In conclusion, absent or reduced early 99m Tc-MIBI uptake in large tumours may indicate a Bcl-2-mediated resistance to chemo- and radiotherapy. (orig.)

  17. EMF radiations (1800 MHz)-inhibited early seedling growth of maize (Zea mays) involves alterations in starch and sucrose metabolism.

    Science.gov (United States)

    Kumar, Arvind; Singh, Harminder Pal; Batish, Daizy R; Kaur, Shalinder; Kohli, Ravinder Kumar

    2016-07-01

    The present study investigated the impact of 1800-MHz electromagnetic field radiations (EMF-r), widely used in mobile communication, on the growth and activity of starch-, sucrose-, and phosphate-hydrolyzing enzymes in Zea mays seedlings. We exposed Z. mays to modulated continuous wave homogenous EMF-r at specific absorption rate (SAR) of 1.69±0.0 × 10(-1) W kg(-1) for ½, 1, 2, and 4 h. The analysis of seedlings after 7 days revealed that short-term exposure did not induce any significant change, while longer exposure of 4 h caused significant growth and biochemical alterations. There was a reduction in the root and coleoptile length with more pronounced effect on coleoptile growth (23 % reduction on 4-h exposure). The contents of photosynthetic pigments and total carbohydrates declined by 13 and 18 %, respectively, in 4-h exposure treatments compared to unexposed control. The activity of starch-hydrolyzing enzymes-α- and β-amylases-increased by ∼92 and 94 %, respectively, at an exposure duration of 4 h, over that in the control. In response to 4-h exposure treatment, the activity of sucrolytic enzymes-acid invertases and alkaline invertases-was increased by 88 and 266 %, whereas the specific activities of phosphohydrolytic enzymes (acid phosphatases and alkaline phosphatases) showed initial increase up to ≤2 h duration and then declined at >2 h exposure duration. The study concludes that EMF-r-inhibited seedling growth of Z. mays involves interference with starch and sucrose metabolism.

  18. Inhibition of nitric oxide synthase in hyperdynamic circulation of rats with early or late cirrhosis secondary to common bile duct ligation

    International Nuclear Information System (INIS)

    Kato, Yoshihito; Katsuta, Yasumi; Zhang, Xue-Jun; Ohsuga, Masaru; Miyamoto, Akiko; Komeichi, Hirokazu; Shimizu, Shuji; Mizuno, Kyoichi; Akimoto, Toshio

    2011-01-01

    Preventing internal hemorrhage extends the lifespan of rats with chronic bile duct ligation (CBDL), a common animal model of portal hypertension. We investigated hemodynamics during the early and late stages of cirrhosis caused by CBDL. We also evaluated the hemodynamic influence of nitric oxide (NO), which is the chief vasodilator in hyperdynamic syndrome, by administration of an NO synthase inhibitor (N G -nitro-L-arginine methyl ester: L-NAME; 10 mg/kg). In 24 Sprague-Dawley rats (9 sham rats and 15 CBDL rats), hemodynamics were assessed under conscious and unrestrained conditions 4 and 8 weeks after surgery. Before and 30 minutes after L-NAME administration, the cardiac index (CI) and regional blood flow were measured with the reference sample method using 141 Ce- and 113 Sn-microspheres (15 μm in diameter). A hyperdynamic systemic circulation and splanchnic hyperemia were observed after CBDL, and these changes increased with the progression of cirrhosis. L-NAME significantly diminished the hyperdynamic circulation and also reduced splanchnic hyperemia. In 4-week CBDL rats, a low hemoglobin concentration made an important contribution to the hyperdynamic circulation, and the portal collateral system collapsed when inflow to the portal territory was reduced by L-NAME treatment. In 8-week CBDL rats, systemic hemodynamics were closely linked to both the splanchnic circulation and the renal circulation before and after L-NAME administration, apart from hepatic artery blood flow. The distinctive hemodynamic changes of portal hypertension were found in 8-week CBDL rats. Thus, 8-week CBDL rats may be a better animal model of human portal hypertension than 4-week CBDL rats. (author)

  19. Lycopene mitigates β-amyloid induced inflammatory response and inhibits NF-κB signaling at the choroid plexus in early stages of Alzheimer's disease rats.

    Science.gov (United States)

    Liu, Chong-Bin; Wang, Rui; Yi, Yan-Feng; Gao, Zhen; Chen, Yi-Zhu

    2018-03-01

    The choroid plexus is able to modulate the cognitive function, through changes in the neuroinflammatory response and in brain immune surveillance. However, whether lycopene is involved in inflammatory responses at the choroid plexus in the early stages of Alzheimer's disease, and its molecular underpinnings are elusive. In this rat study, lycopene was used to investigate its protective effects on inflammation caused by β-amyloid. We characterized the learning and memory abilities, cytokine profiles of circulating TNF-α, IL-1β and IL-6β in the serum and the expressions of Toll like receptor 4 and nuclear factor-κB p65 mRNA and protein at the choroid plexus. The results showed that functional deficits of learning and memory in lycopene treatment groups were significantly improved compared to the control group without lycopene treatment in water maze test. The levels of serum TNF-α, IL-1β and IL-6β were significantly increased, and the expressions of TLR4 and NF-κB p65 mRNA and protein at the choroid plexus were up-regulated, indicating inflammation response was initiated following administration of Aβ 1-42 . After intragastric pretreatment with lycopene, inflammatory cytokines were significantly reduced and lycopene also reversed the Aβ 1-42 induced up-regulation of TLR4 and NF-κB p65 mRNA and protein expressions at the choroid plexus. These results provided a novel evidence that lycopene significantly improved cognitive deficits and were accompanied by the attenuation of inflammatory injury via blocking the activation of NF-κB p65 and TLR4 expressions and production of cytokines, thereby endorsing its usefulness for diminishing β-amyloid deposition in the hippocampus tissues. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol treatment in the TRAMP model of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Adebusola Alagbala Ajibade

    Full Text Available The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW, were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg, or QW (50 µg/kg were administered to 4 week-old TRAMP mice intraperitoneal (i.p. 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW. However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086, and reduced tumor proliferation (p = 0.0467. By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823. Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age(p = 0.0003. Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.

  1. Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis

    Directory of Open Access Journals (Sweden)

    Napat Armartmuntree

    2018-04-01

    Full Text Available Early B cell factor 1 (EBF1 is a transcription factor involved in the differentiation of several stem cell lineages and it is a negative regulator of estrogen receptors. EBF1 is down-regulated in many tumors, and is believed to play suppressive roles in cancer promotion and progression. However, the functional roles of EBF1 in carcinogenesis are unclear. Liver fluke-infection-associated cholangiocarcinoma (CCA is an oxidative stress-driven cancer of bile duct epithelium. In this study, we investigated EBF1 expression in tissues from CCA patients, CCA cell lines (KKU-213, KKU-214 and KKU-156, cholangiocyte (MMNK1 and its oxidative stress-resistant (ox-MMNK1-L cell lines. The formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG was used as an oxidative stress marker. Our results revealed that EBF1 expression was suppressed in cancer cells compared with the individual normal bile duct cells at tumor adjacent areas of CCA tissues. CCA patients with low EBF1 expression and high formation of 8-oxodG were shown to correlate with poor survival. Moreover, EBF1 was suppressed in the oxidative stress-resistant cell line and all of CCA cell lines compared to the cholangiocyte cell line. This suggests that prolonged oxidative stress suppressed EBF1 expression and the reduced EBF1 level may facilitate CCA genesis. To elucidate the significance of EBF1 suppression in CCA genesis, EBF1 expression of the MMNK1 cell line was down-regulated by siRNA technique, and its effects on stem cell properties (CD133 and Oct3/4 expressions, tumorigenic properties (cell proliferation, wound healing and cell migration, estrogen responsive gene (TFF1, estrogen-stimulated wound healing, and cell migration were examined. The results showed that CD133, Oct3/4 and TFF1 expression levels, wound healing, and cell migration of EBF1 knockdown-MMNK1 cells were significantly increased. Also, cell migration of EBF1-knockdown cells was significantly enhanced after 17

  2. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  3. Early LC3 lipidation induced by d-limonene does not rely on mTOR inhibition, ERK activation and ROS production and it is associated with reduced clonogenic capacity of SH-SY5Y neuroblastoma cells.

    Science.gov (United States)

    Berliocchi, Laura; Chiappini, Carlotta; Adornetto, Annagrazia; Gentile, Debora; Cerri, Silvia; Russo, Rossella; Bagetta, Giacinto; Corasaniti, Maria Tiziana

    2018-02-01

    stimulates ROS generation, yet none of these events is implicated in lipidation of LC3, which was only partly reduced by chelation of intracellular calcium. The early LC3 lipidation induced by d-limonene is associated with inhibition of clonogenic capacity which is reverted by the autophagy inhibitor chloroquine. d-Limonene rapidly stimulates the autophagic flux in cultured cancer cells, which could be usefully exploited for therapeutic purposes. Copyright © 2018 Elsevier GmbH. All rights reserved.

  4. Early events elicited by Bombesin and structurally related peptides in quiescent Swiss 3T3 cells. I. Activation of protein kinase C and inhibition of epidermal growth factor binding

    International Nuclear Information System (INIS)

    Zachary, I.; Sinnett-Smith, J.W.; Rozengurt, E.

    1986-01-01

    Addition of bombesin to quiescent cultures of Swiss 3T3 cells caused a rapid increase in the phosphorylation of an M/sub r/ 80,000 cellular protein (designated 80k). The effect was both concentration and time dependent. The 80k phosphoproteins generated in response to bombesin and to phorbol 12,13-dibutyrate were identical as judged by one- and two-dimensional PAGE and by peptide mapping after partial proteolysis with Staphylococcus aureus V8 protease. In addition, prolonged pretreatment of 3T3 cells with phorbol 12,13-dibutyrate, which leads to the disappearance of protein kinase C activity, blocked the ability of bombesin to stimulate 80k. Bombesin also caused a rapid (1 min) inhibition of 125 I-labeled epidermal growth factor ( 125 I-EGF) binding to Swiss 3T3 cells. The inhibition was both concentration and temperature dependent and resulted from a marked decrease in the affinity of the EGF receptor for its ligand. These results strongly suggest that these responses are mediated by specific high-affinity receptors that recognize the peptides of the bombesin family in Swiss 3T3 cells. While an increase in cytosolic Ca 2+ concentration does not mediate the bombesin inhibition of 125 I-EGF binding, the activation of protein kinase C in intact Swiss 3T3 cells by peptides of the bombesin family may lead to rapid inhibition of the binding of 125 I-EGF to its cellular receptor

  5. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  6. Beyond the "First Hit": Marked Inhibition by N-Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol-Induced Saccharin Motivation.

    Science.gov (United States)

    Quintanilla, María Elena; Rivera-Meza, Mario; Berríos-Cárcamo, Pablo; Salinas-Luypaert, Catalina; Herrera-Marschitz, Mario; Israel, Yedy

    2016-05-01

    A number of studies have shown that acetaldehyde synthesized in the brain is necessary to induce ethanol (EtOH) reinforcement in naïve animals (acquisition phase). However, after chronic intake is achieved (maintenance phase), EtOH intake becomes independent of acetaldehyde generation or its levels. Glutamate has been reported to be associated with the maintenance of chronic EtOH intake. The levels of brain extracellular glutamate are modulated by 2 glial processes: glutamate reabsorption via an Na(+) -glutamate transporter (GLT1) and a cystine-glutamate exchanger. Chronic EtOH intake lowers GLT1 levels and increases extracellular glutamate. The administration of N-acetyl cysteine (NAC), a precursor of cystine, has been shown to reduce the relapse of several drugs of abuse, while NAC has not been tested on chronic EtOH intake or on EtOH's influence on the motivation for another drug. These were investigated in the present study. (i) Rats bred for their high EtOH intake were allowed access to 10% EtOH and water up to 87 days. NAC was administered (30 and 60 mg/kg daily, intraperitoneally) for 14 consecutive days, either during the acquisition phase or the maintenance phase of EtOH drinking. (ii) In additional experiments, rats were allowed EtOH (10%) and water access for 61 days, after which EtOH was replaced by saccharin (0.3%) to determine both if chronic EtOH consumption influences saccharin intake and whether NAC modifies the post chronic EtOH saccharin intake. NAC did not influence the acquisition ("first hit") of chronic EtOH intake, but greatly inhibited (60 to 70%; p intake when NAC was administered to animals that were consuming EtOH chronically. NAC did not influence saccharin intake in naïve animals. In animals that had consumed EtOH chronically and were thereafter offered a saccharin solution (0.3%), saccharin intake increased over 100% versus that of EtOH-untreated animals, an effect that was fully suppressed by NAC. N-acetyl cysteine, a drug

  7. Inhibition of autophagy initiation potentiates chemosensitivity in mesothelioma.

    Science.gov (United States)

    Follo, Carlo; Cheng, Yao; Richards, William G; Bueno, Raphael; Broaddus, Virginia Courtney

    2018-03-01

    The benefits of inhibiting autophagy in cancer are still controversial, with differences in outcome based on the type of tumor, the context and the particular stage of inhibition. Here, we investigated the impact of inhibiting autophagy at different stages on chemosensitivity using 3-dimensional (3D) models of mesothelioma, including ex vivo human tumor fragment spheroids. As shown by LC3B accumulation, we successfully inhibited autophagy using either an early stage ULK1/2 inhibitor (MRT 68921) or a late stage inhibitor (hydroxychloroquine). We found that inhibition of autophagy at the early stage, but not at late stage, potentiated chemosensitivity. This effect was seen only in those spheroids with high autophagy and active initiation at steady state. Inhibition of autophagy alone, at either early or late stage, did not cause cell death, showing that the inhibitors were non-toxic and that mesothelioma did not depend on autophagy at baseline, at least over 24 h. Using ATG13 puncta analysis, we found that autophagy initiation identified tumors that are more chemosensitive at baseline and after autophagy inhibition. Our results highlight a potential role of autophagy initiation in supporting mesothelioma cells during chemotherapy. Our work also highlights the importance of testing the inhibition of different stages in order to uncover the role of autophagy and the potential of its modulation in the treatment of cancer. © 2017 Wiley Periodicals, Inc.

  8. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

  9. Early discontinuation

    DEFF Research Database (Denmark)

    Hansen, Dorte Gilså; Felde, Lina; Gichangi, Anthony

    2007-01-01

    prevalence and rate of early discontinuation of different drugs consisting of, in this study, lipid-lowering drugs, antihypertensive drugs, antidepressants, antidiabetics and drugs against osteoporosis. Material and methods This was a register study based on prescription data covering a 4-year period...... and consisting of 470,000 citizens. For each practice and group of drug, a 1-year prevalence for 2002 and the rate of early discontinuation among new users in 2002-2003 were estimated. Early discontinuation was defined as no prescriptions during the second half-year following the first prescription....... There was a positive association between the prevalence of prescribing for the specific drugs studied (antidepressants, antidiabetics, drugs against osteoporosis and lipid-lowering drugs) and early discontinuation (r = 0.29 -0.44), but not for anti-hypertensive drugs. The analysis of the association between prevalence...

  10. Early literacy

    DEFF Research Database (Denmark)

    Jensen, Anders Skriver

    2012-01-01

    This paper discusses findings from the Danish contribution to the EASE project, a European research project running from 2008 to 2010 on early literacy in relation to the transition from childcare to school. It explores a holistic, inclusive approach to early literacy that resists a narrow...... and schools. The paper also draws on Gee’s (2001, 2003, 2004, 2008) sociocultural approach to literacy, and Honneth’s (2003, 2006) concept of recognition. Emphasizing participation and recognition as key elements, it claims that stakeholders in early liter- acy must pay attention to how diverse early literacy...... opportunities empower children, especially when these opportunities are employed in a project-based learning environ- ment in which each child is able to contribute to the shared literacy events....

  11. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  12. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  13. Cooperation for Better Inhibiting.

    Science.gov (United States)

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Early Math.

    Science.gov (United States)

    Van Nuys, Ute Elisabeth

    1986-01-01

    Presents reviews of the following mathematics software designed to teach young children counting, number recognition, visual discrimination, matching, addition, and subtraction skills; Stickybear Numbers, Learning with Leeper, Getting Ready to Read and Add, Counting Parade, Early Games for Young Children, Charlie Brown's 1,2,3's, Let's Go Fishing,…

  15. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  16. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  17. Monitoring therapy with MEK inhibitor U0126 in a novel Wilms tumor model in Wt1 knockout Igf2 transgenic mice using 18F-FDG PET with dual-contrast enhanced CT and MRI: early metabolic response without inhibition of tumor growth.

    Science.gov (United States)

    Flores, Leo G; Yeh, Hsin-Hsien; Soghomonyan, Suren; Young, Daniel; Bankson, James; Hu, Qianghua; Alauddin, Mian; Huff, Vicki; Gelovani, Juri G

    2013-04-01

    during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50-100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased (18)F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in (18)F-FDG SUV was observed, as compared to pre-treatment levels (p endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.

  18. Myrtenal inhibits acetylcholinesterase, a known Alzheimer target.

    Science.gov (United States)

    Kaufmann, Dorothea; Dogra, Anudeep Kaur; Wink, Michael

    2011-10-01

    Inhibition of acetylcholinesterase (AChE) is a common treatment for early stages of the most general form of dementia, Alzheimer's disease. In this study selected components of essential oils, which carry a variety of important functional groups, were tested for their in-vitro anti-acetylcholinesterase activity. In-vitro anti-acetylcholinesterase activity was measured by an adapted version of Ellman's colorimetric assay. 1,8-cineole, carvacrol, myrtenal and verbenone apparently inhibited AChE; the highest inhibitory activity was observed for myrtenal (IC50 = 0.17 mm). This is the first study showing the AChE inhibitory activity of myrtenal. Our investigations provided evidence for the efficacy of monoterpenes as inhibitors of AChE. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  19. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need....... In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated...... early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic...

  20. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat.

    Science.gov (United States)

    Seluanov, Andrei; Hine, Christopher; Azpurua, Jorge; Feigenson, Marina; Bozzella, Michael; Mao, Zhiyong; Catania, Kenneth C; Gorbunova, Vera

    2009-11-17

    The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed "early contact inhibition." Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27(Kip1). In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16(Ink4a). Furthermore, we show that the roles of p16(Ink4a) and p27(Kip1) in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16(Ink4a), and regular contact inhibition is controlled by p27(Kip1). We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.

  1. Anxiety and retrieval inhibition: support for an enhanced inhibition account.

    Science.gov (United States)

    Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E

    2017-02-01

    Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.

  2. Community Screening for Preschool Child Inhibition to Offer the "Cool Little Kids" Anxiety Prevention Programme

    Science.gov (United States)

    Beatson, Ruth M.; Bayer, Jordana K.; Perry, Alexandra; Mathers, Megan; Hiscock, Harriet; Wake, Melissa; Beesley, Kate; Rapee, Ronald M.

    2014-01-01

    Temperamental inhibition has been identified as a key risk factor for childhood anxiety and internalizing problems. An efficacious early prevention programme for shy/inhibited children has been developed; however, accurate, efficient and acceptable screening is needed to support wider implementation. We explore community screening options in the…

  3. Attention Biases to Threat Link Behavioral Inhibition to Social Withdrawal over Time in Very Young Children

    Science.gov (United States)

    Perez-Edgar, Koraly; Reeb-Sutherland, Bethany C.; McDermott, Jennifer Martin; White, Lauren K.; Henderson, Heather A.; Degnan, Kathryn A.; Hane, Amie A.; Pine, Daniel S.; Fox, Nathan A.

    2011-01-01

    Behaviorally inhibited children display a temperamental profile characterized by social withdrawal and anxious behaviors. Previous research, focused largely on adolescents, suggests that attention biases to threat may sustain high levels of behavioral inhibition (BI) over time, helping link early temperament to social outcomes. However, no prior…

  4. Inhibition of polyphenoloxidase by sulfite

    International Nuclear Information System (INIS)

    Sayavedra-Soto, L.A.; Montgomery, M.W.

    1986-01-01

    When polyphenoloxidase (PPO) was exposed to sulfite prior to substrate addition, inhibition was irreversible. Trials to regenerate PPO activity, using extensive dialysis, column chromatography, and addition of copper salts were not successful. Increased concentrations of sulfite and pH levels less than 5 enhanced the inhibition of PPO by sulfite. At pH 4, concentrations greater than 0.04 mg/mL completely inhibited 1000 units of PPO activity almost instantaneously. This suggested that the HSO 3 - molecule was the main component in the sulfite system inhibiting PPO. Column chromatography, extensive dialysis, and gel electrophoresis did not demonstrate 35 SO 2 bound to purified pear PPO protein. Formation of extra protein bands of sulfite inhibited purified pear PPO fractions on gel electrophoresis was demonstrated. This and other evidence suggested that the major mode of direct irreversible inhibition of PPO was modification of the protein structure, with retention of its molecular unity

  5. Interferon-γ Inhibits Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  6. Interferon-γ Inhibits Ebola Virus Infection.

    Science.gov (United States)

    Rhein, Bethany A; Powers, Linda S; Rogers, Kai; Anantpadma, Manu; Singh, Brajesh K; Sakurai, Yasuteru; Bair, Thomas; Miller-Hunt, Catherine; Sinn, Patrick; Davey, Robert A; Monick, Martha M; Maury, Wendy

    2015-01-01

    Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  7. Modeling intentional inhibition of actions

    NARCIS (Netherlands)

    Thilakarathne, D.J.; Treur, J.

    2015-01-01

    Inspired by cognitive and neurological literature on action ownership and action awareness, in this paper a computational cognitive model for intentional inhibition (i.e.; the capacity to voluntarily suspend or inhibit an action) is introduced. The interplay between (positive) potential selection of

  8. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  9. Wild Honey Inhibits Growth od Some Phytopathogenic Fungi in vitro

    Directory of Open Access Journals (Sweden)

    K.I. Al-Mughrabi

    2003-12-01

    Full Text Available Wild honey was diluted to 1000 ppm with sterile distilled water and tested in vitro for inhibition of the plant pathogenic fungi Fusarium oxysporum, Rhizoctonia solani, Alternaria solani, Stemphylium solani, Colletotrichum sp., and Phytophthora infestans. Wild honey was effective against all these fungi, particularly A. solani and P. infestans, the causal agents of early and late blight diseases respectively; also against R. solani and F. oxysporum, and to a less extent against S. solani and Colletotrichum sp. This is the first report on the inhibiting effect of wild honey against plant pathogenic fungi.

  10. Intraglomerular inhibition shapes the strength and temporal structure of glomerular output.

    Science.gov (United States)

    Shao, Zuoyi; Puche, Adam C; Liu, Shaolin; Shipley, Michael T

    2012-08-01

    Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABA(A) receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs.

  11. SGLT2 inhibition in the diabetic kidney – an update

    Science.gov (United States)

    Novikov, Aleksandra; Vallon, Volker

    2016-01-01

    Purpose of review The sodium glucose cotransporter SGLT2 reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption thereby lowering blood glucose levels and have been approved as new anti-hyperglycemic drugs. While the therapeutic strategy is very promising, many questions remain. Recent findings Using validated antibodies SGLT2 expression was localized to the brush border of the early proximal tubule in human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional glucose reabsorption of 40–50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alpha cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers GFR in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy. Summary The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors. PMID:26575393

  12. Evidence for a genetic etiology of early-onset delinquency.

    Science.gov (United States)

    Taylor, J; Iacono, W G; McGue, M

    2000-11-01

    Age at onset of antisocial behavior discriminates persistent and transitory offenders. The authors proposed that early-onset delinquency has an underlying genetic influence that manifests in problems related to inhibition, whereas late-onset delinquency is more environmentally mediated. To test these notions, they selected 36 early starters, 86 late starters, and 25 nondelinquent controls from a large sample of 11-year-old twins and compared them on several measures related to inhibition and a peer group measure. As expected, early starters had more psychological, behavioral, and emotional problems related to inhibition than late starters and controls. A longitudinal analysis indicated an increase an antisocial behavior among peers of late starters shortly before their delinquency onset. Family history data and a twin analysis provided evidence of greater genetic influence on early-onset than late-onset delinquency.

  13. Kindergarteners' self-reported social inhibition and observed social reticence: moderation by adult-reported social inhibition and social anxiety disorder symptoms.

    Science.gov (United States)

    Kiel, Elizabeth J; Buss, Kristin A; Molitor, Joseph G

    2015-04-01

    Prevention of later anxiety problems would best be accomplished by identifying at-risk children early in development. For example, children who develop Social Anxiety Disorder (SAD) may show social withdrawal in the form of social inhibition (i.e., shyness with unfamiliar adults and peers) at school entry. Although the use of children's perceptions of their own social inhibition would provide insight into early risk, the utility of young children's self-reports remains unclear. The current study examined whether children deemed more extreme on social inhibition or social anxiety by adult report provided self-report of social inhibition that related to observed social reticence in the laboratory. Participants included 85 kindergarten children (36 female, 49 male), their parents, and their teachers. Moderation analyses revealed that children's self-reported social inhibition related significantly to observed social reticence under the conditions of high parent-reported social inhibition, high teacher-reported social inhibition, and high SAD symptoms. These results suggest that the most inhibited children are aware of their behavior and can report it in a meaningfully way as young as kindergarten age.

  14. Kindergarteners’ Self-Reported Social Inhibition and Observed Social Reticence: Moderation by Adult-Reported Social Inhibition and Social Anxiety Disorder Symptoms

    Science.gov (United States)

    Kiel, Elizabeth J.; Buss, Kristin A.; Molitor, Joseph G.

    2014-01-01

    Prevention of later anxiety problems would best be accomplished by identifying at-risk children early in development. For example, children who develop Social Anxiety Disorder (SAD) may show social withdrawal in the form of social inhibition (i.e., shyness with unfamiliar adults and peers) at school entry. Although the use of children’s perceptions of their own social inhibition would provide insight into early risk, the utility of young children’s self-reports remains unclear. The current study examined whether children deemed more extreme on social inhibition or social anxiety by adult report provided self-report of social inhibition that related to observed social reticence in the laboratory. Participants included 85 kindergarten children (36 female, 49 male), their parents, and their teachers. Moderation analyses revealed that children’s self-reported social inhibition related significantly to observed social reticence under the conditions of high parent-reported social inhibition, high teacher-reported social inhibition, and high SAD symptoms. These results suggest that the most inhibited children are aware of their behavior and can report it in a meaningfully way as young as kindergarten age. PMID:25113397

  15. Bioassays for the determination of nitrification inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Grunditz, Camilla

    1999-07-01

    Requirements for nitrogen reduction in wastewater treatment plants were introduced in Sweden in the early 1990's. This was a governmental move to reduce the nitrogen discharges to the Baltic and Kattegat in order to prevent eutrophication. The nitrification process in wastewater treatment plants is performed by nitrifying bacteria. These are susceptible to inhibition and it is of great importance that the influent water does not contain toxic compounds. Therefore, there is a need for assays for the determination of nitrification inhibition. This thesis describes the development and applications of such bioassays. Pure cultures of Nitrosomonas sp. and Nitrobacter sp. were isolated from activated sludge of a wastewater treatment plant. These cultures were used as test organisms in the development of bioassays for nitrification inhibition measurements. The assays are based on two different principles; cell suspensions of the bacteria, performed in test tubes, and mediated amperometric biosensors with the bacteria immobilised. Ammonia oxidation and nitrite oxidation are studied separately without interference from other organisms, which makes it easier to interpret the results. The cell suspension assays were applied to samples of industrial and municipal wastewater. The Nitrosomonas and Nitrobacter assays showed to have different inhibition patterns. A large percentage of the Swedish municipal wastewater treatment plants were found to receive inhibitory influent water, but the inhibition level was generally low. Compared to an assay based on activated sludge, the screening method, the pure culture assays found more samples of influent water strongly inhibitory or stimulating. The highest correlation was found between the screening method and the Nitrosomonas assay. The Nitrobacter assay was found to be the most sensitive method. Assessment of toxicity of a number of chemical substances was studied using the biosensors, together with the cell suspension assays

  16. The contribution of forward masking to saccadic inhibition of return.

    Science.gov (United States)

    Souto, David; Born, Sabine; Kerzel, Dirk

    2018-03-08

    Inhibition of return is the name typically given to the prolonged latency of motor responses directed to a previously cued target location. There is intense debate about the origins of this effect and its function, but most take for granted (despite lack of evidence) that it depends little on forward masking. Therefore, we re-examined the role of forward masking in inhibition of return. Forward masking was indexed by slower saccadic reaction times (SRTs) when the target orientation repeated the cue orientation at the same location. We confirmed effects of orientation repetition in the absence of an attentional bias when cues were presented on both sides of fixation (bilateral presentation). The effect of orientation repetition was reduced with high target contrast, consistent with a low-level origin such as contrast gain control in early visual areas. When presenting cues on only one side of fixation (unilateral presentation), we obtained inhibition of return with longer cue-target intervals and facilitation with targets presented shortly after the cue. The effect of orientation repetition was reduced when facilitation was observed, but was as strong as with bilateral cues when inhibition of return was observed. Therefore, forward masking may contribute to the inhibition of return effect by delaying reaction times to repeated features at the same location, but is not a principal cause of inhibition of return; in agreement with previous views. The saccadic inhibition of return effect is a reaction-time cost when responding to a pre-cued location. Additional object updating costs are typically invoked to explain reaction-time costs observed when cue and target have the same shape. Yet, lower-level, forward masking of the target by the cue can not be ruled out. Importantly, we show an effect of orientation repetition that is consistent with low-level forward masking rather than object updating costs and that does not interact with inhibition of return.

  17. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  18. [Concepts of inhibition in psychiatry].

    Science.gov (United States)

    Auroux, Y; Bourrat, M M; Brun, J P

    1978-01-01

    Following a historical approach, the authors first describe the original development of the concept of inhibition in neurophysiology and then analyze the subsequent adaptations made in psychiatry around such concept including those of: -- Pavlov, Hull, Watson and the behaviorists, -- Freud and the Freudian School, -- clinicians and psychopharmacologists. The concept of inhibition has thus various meanings in psychiatry. Although some unity is achieved on the semiological level, this aspect cannot explain the extent of the process.

  19. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  20. Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection.

    Science.gov (United States)

    Mentzer, Robert M; Lasley, Robert D; Jessel, Andreas; Karmazyn, Morris

    2003-02-01

    Although the mechanisms underlying ischemia/reperfusion injury remain elusive, evidence supports the etiologic role of intracellular calcium overload and oxidative stress induced by reactive oxygen species. Activation of the sodium hydrogen exchanger (NHE) is associated with intracellular calcium accumulation. Inhibition of the NHE-1 isoform may attenuate the consequences of this injury. Although there is strong preclinical and early clinical evidence that NHE inhibitors may be cardioprotective, definitive proof of this concept in humans awaits the results of ongoing clinical trials.

  1. Early or Premature Menopause

    Science.gov (United States)

    ... email updates Enter email Submit Early or premature menopause Menopause that happens before age 40 is called ... What is the difference between early and premature menopause? Early or premature menopause happens when ovaries stop ...

  2. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway.

  3. Early hospital discharge and early puerperal complications.

    Science.gov (United States)

    Ramírez-Villalobos, Dolores; Hernández-Garduño, Adolfo; Salinas, Aarón; González, Dolores; Walker, Dilys; Rojo-Herrera, Guadalupe; Hernández-Prado, Bernardo

    2009-01-01

    To evaluate the association between time of postpartum discharge and symptoms indicative of complications during the first postpartum week. Women with vaginal delivery at a Mexico City public hospital, without complications before the hospital discharge, were interviewed seven days after delivery. Time of postpartum discharge was classified as early (25 hours). The dependent variable was defined as the occurrence and severity of puerperal complication symptoms. Out of 303 women, 208 (68%) were discharged early. However, women with early discharge and satisfactory prenatal care had lower odds of presenting symptoms in early puerperium than women without early discharge and inadequate prenatal care (OR 0.36; 95% confidence intervals = 0.17-0.76). There was no association between early discharge and symptoms of complications during the first postpartum week; the odds of complications were lower for mothers with early discharge and satisfactory prenatal care.

  4. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  5. Homo Economicus Belief Inhibits Trust

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

  6. Inhibition of Retinoblastoma Protein Inactivation

    Science.gov (United States)

    2017-11-01

    CONTRACT NUMBER Inhibition of Retinoblastoma Protein Inactivation 5b. GRANT NUMBER W81XWH-14-1-0329 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Seth M...confirmed 108 compounds as giving a dose-response curve with at least 30% inhibition at 10 µM. The flowchart of hit progression is shown on the...Cancer Research Program under Award No. W81XWH-14-1-0329 to S.M.R. Opinions, interpretations, conclusions, and recommendations are those of the author

  7. Is forgetting caused by inhibition?

    NARCIS (Netherlands)

    Raaijmakers, J.G.W.; Jakab, E.

    2013-01-01

    A well-known finding in memory research is the forgetting effect that occurs because of practicing some Item A on the recall of a related Item B. The traditional explanation for such interference effects is based on the notion of competition. According to the inhibition theory of forgetting,

  8. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  9. Early Childhood Systems: Transforming Early Learning

    Science.gov (United States)

    Kagan, Sharon Lynn, Ed.; Kauertz, Kristie, Ed.

    2012-01-01

    In this seminal volume, leading authorities strategize about how to create early childhood systems that transcend politics and economics to serve the needs of all young children. The authors offer different interpretations of the nature of early childhood systems, discuss the elements necessary to support their development, and examine how…

  10. Inhibiting cancer cell hallmark features through nuclear export inhibition.

    Science.gov (United States)

    Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

    2016-01-01

    Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

  11. Relationship between self-reported childhood behavioral inhibition and lifetime anxiety disorders in a clinical sample.

    Science.gov (United States)

    Gladstone, Gemma L; Parker, Gordon B; Mitchell, Phillip B; Wilhelm, Kay A; Malhi, Gin S

    2005-01-01

    To examine the association between an early inhibited temperament and lifetime anxiety disorders, we studied a sample of patients with major depression who were not selected on the basis of comorbid axis I anxiety disorders. One-hundred eighty-nine adults (range = 17-68 years) referred to a tertiary depression unit underwent structured diagnostic interviews for depression and anxiety and completed two self-report measures of behavioral inhibition, the retrospective measure of behavioural inhibition (RMBI) [Gladstone and Parker, 2005] and the adult measure of behavioural inhibition (AMBI) [Gladstone and Parker, 2005]. Patients' scores were classified into "low," "moderate," or "high" inhibition. While groups did not differ in terms of depression severity, there were differences across groups in clinically diagnosed nonmelancholic status and age of onset of first episode. Those reporting a high degree of childhood inhibition were significantly more likely to qualify for a diagnosis of social phobia, and this association was independent of their scores on the AMBI. Findings are discussed in light of the existing risk-factor literature and support the hypothesis that an early inhibited temperament may be a significant precursor to later anxiety, especially social anxiety disorder. Copyright 2005 Wiley-Liss, Inc.

  12. Pilot study for early prognosis of Azoospermia in relation to Y-STR ...

    African Journals Online (AJOL)

    Ahmed M. Refaat

    2015-07-06

    Jul 6, 2015 ... Azoospermia condition, which supports the idea of using Y-STR Profiling in early prognosis of ... feedback loop is interrupted (lack of feedback inhibition on. FSH). ..... From the statistical results represented in Tables 1–12, we.

  13. Memory consolidation in human sleep depends on inhibition of glucocorticoid release.

    Science.gov (United States)

    Plihal, W; Born, J

    1999-09-09

    Early sleep dominated by slow-wave sleep has been found to be particularly relevant for declarative memory formation via hippocampo-neocortical networks. Concurrently, early nocturnal sleep is characterized by an inhibition of glucocorticoid release from the adrenals. Here, we show in healthy humans that this inhibition serves to support declarative memory consolidation during sleep. Elevating plasma glucocorticoid concentration during early sleep by administration of cortisol impaired consolidation of paired associate words, but not of non-declarative memory of visuomotor skills. Since glucocorticoid concentration was enhanced only during retention sleep, but not during acquisition or retrieval, a specific effect on the consolidation process is indicated. Blocking mineralocorticoid receptors by canrenoate did not affect memory, suggesting inactivation of glucocorticoid receptors to be the essential prerequisite for memory consolidation during early sleep.

  14. On inhibition of dental erosion.

    Science.gov (United States)

    Rölla, Gunnar; Jonski, Grazyna; Saxegaard, Erik

    2013-11-01

    To examine the erosion-inhibiting effect of different concentrations of hydrofluoric acid. Thirty-six human molars were individually treated with 10 ml of 0.1 M citric acid for 30 min (Etch 1), acid was collected and stored until analysis. The teeth were randomly divided into six groups and then individually treated with 10 ml of one of six dilutions (from 0.1-1%) of hydrofluoric acid. The teeth were then again treated with citric acid (Etch 2). The individual acid samples from Etch 1 and 2 were analyzed for calcium by flame atomic absorption spectroscopy and difference in calcium loss was calculated. The highest erosion inhibiting effect was obtained in groups with the highest concentrations of hydrofluoric acid, where the pH was lowest, below pKa of 3.17, thus the hydrofluoric acids being mainly in an undissociated state. Diluted hydrofluoric acid is present in aqueous solution of SnF2 and TiF4 (which are known to inhibit dental erosion): SnF2 + 3H2O = Sn(OH)2 + 2HF + H2O and TiF4 + 5H2O = Ti(OH)4 + 4HF + H2O. It is also known that pure, diluted hydrofluoric acid can inhibit dental erosion. Teeth treated with hydrofluoric acid are covered by a layer of CaF2-like mineral. This mineral is acid resistant at pH acid resistant mineral, initiated by tooth enamel treatment with hydrofluoric acid. Hydrofluoric acid is different in having fluoride as a conjugated base, which provides this acid with unique properties.

  15. Entanglement and inhibited quantum evolution

    International Nuclear Information System (INIS)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W

    2003-01-01

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal

  16. Early discharge following birth

    DEFF Research Database (Denmark)

    Nilsson, Ingrid M. S.; Kronborg, Hanne; Knight, Christopher H.

    2017-01-01

    .26–0.48) and primiparous compared to multiparous had an OR of 0.22 (CI 0.17–0.29) for early discharge. Other predictors for early discharge were: no induction of labour, no epidural painkiller, bleeding less than 500 ml during delivery, higher gestational age, early expected discharge and positive breastfeeding experience...

  17. Inhibition of placenta growth factor with TB-403

    DEFF Research Database (Denmark)

    Nielsen, Dorte Lisbet; Sengeløv, Lisa

    2012-01-01

    INTRODUCTION: There is clinical evidence that therapies targeting the vascular endothelial growth factor pathway are effective in delaying cancer progression. However, tumors may be either intrinsically resistant or evolve resistance to such therapies. Hence, there is a need for new therapies...... targeting angiogenesis. AREAS COVERED: The data are obtained by searching in the PubMed database. The search terms used included antiangiogenic therapy, TB-403 (RO5323441), placenta growth factor (PlGF) and VEGFR-1 (Flt-1). We review preclinical data concerning the function and inhibition of Pl......GF and summarize data on expression of PlGF in cancer patients. Data from early-phase clinical trials of TB-403 (RO5323441), a monoclonal antibody inhibiting PlGF, are discussed. Future development strategies, therapeutic potentials and limitations of TB-403 are further evaluated. EXPERT OPINION: There are some...

  18. Inhibition Performance in Children with Math Disabilities

    OpenAIRE

    Winegar, Kathryn Lileth

    2013-01-01

    This study examined the inhibition deficit hypothesis in children with math disabilities (MD). Children with and without MD were compared on two inhibition tasks that included the random generation of numbers and letters. The results addressed three hypotheses. Weak support was found for the first hypothesis which stated difficulties related to inhibition are significantly related to math performance. I found partial support for this hypothesis in that inhibition was related to math problem s...

  19. Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

    International Nuclear Information System (INIS)

    Odri, Guillaume; Kim, Pui-Pui; Lamoureux, François; Charrier, Céline; Battaglia, Séverine; Amiaud, Jérôme; Heymann, Dominique; Gouin, François; Redini, Françoise

    2014-01-01

    Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 10 6 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs

  20. Homologous series of induced early mutants in indican rice. Pt.1. The production of homologous series of early mutants

    International Nuclear Information System (INIS)

    Chen Xiulan; Yang Hefeng; He Zhentian; Han Yuepeng; Liu Xueyu

    1999-01-01

    The percentage of homologous series of early mutants induced from the same Indican rice variety were almost the same (1.37%∼1.64%) in 1983∼1993, but the ones from the different eco-typical varieties were different. The early variety was 0.73%, the mid variety was 1.51%, and the late variety was 1.97%. The percentage of homologous series of early mutants from the varieties with the same pedigree and relationship were similar, but the one from the cog nation were lower than those from distant varieties. There are basic laws and characters in the homologous series of early mutants: 1. The inhibited phenotype is the basic of the homologous series of early mutants; 2. The production of the homologous series of early mutants is closely related with the growing period of the parent; 3. The parallel mutation of the stem and leaves are simultaneously happened with the variation of early or late maturing; 4. The occurrence of the homologous series of early mutants is in a state of imbalance. According to the law of parallel variability, the production of homologous series of early mutants can be predicted as long as the parents' classification of plant, pedigree and ecological type are identified. Therefore, the early breeding can be guided by the law of homologous series of early mutants

  1. Entanglement and inhibited quantum evolution

    Energy Technology Data Exchange (ETDEWEB)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W [Universitaet Hamburg, Institut fuer Laser-Physik, Jungiusstrasse 9, D-20355 Hamburg (Germany)

    2003-03-14

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal.

  2. Effects of postnatal anoxia on striatal dopamine metabolism and prepulse inhibition in rats

    DEFF Research Database (Denmark)

    Sandager-Nielsen, Karin; Andersen, Maibritt B; Sager, Thomas N

    2004-01-01

    in schizophrenic patients. There was no effect of postnatal anoxia on either baseline or d-amphetamine-induced deficit in the prepulse inhibition (PPI) paradigm in adulthood. Accordingly, although oxygen deficiency early in life has been discussed as vulnerability factor in developing schizophrenia, exposure...

  3. Computer training of attention and inhibition for youngsters with obesity : A pilot study

    NARCIS (Netherlands)

    Verbeken, S.; Braet, C.; Naets, T.; Houben, K.; Boendermaker, W. J.

    2018-01-01

    Obesity is a widespread problem that starts from an early age. Previous studies suggest that obese youngsters have an attentional bias and an automatic approach tendency towards high-calorie food and display difficulties inhibiting impulses, which may result in a higher intake of (high-calorie)

  4. Behavioral inhibition and obsessive-compulsive disorder.

    Science.gov (United States)

    Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

    2006-01-01

    Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.

  5. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  7. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  8. Early Transcendental Analysis

    OpenAIRE

    Cowell, Simon; Poulin, Philippe

    2015-01-01

    In Early Transcendentals (The American Mathematical Monthly, Vol. 104, No 7) Steven Weintraub presents a rigorous justifcation of the "early transcendental" calculus textbook approach to the exponential and logarithmic functions. However, he uses tools such as term-by-term differentiation of infinite series. We present a rigorous treatment of the early transcendental approach suitable for a first course in analysis, using mainly the supremum property of the real numbers.

  9. LcrQ and SycH function together at the Ysc type III secretion system in Yersinia pestis to impose a hierarchy of secretion.

    Science.gov (United States)

    Wulff-Strobel, Christine R; Williams, Andrew W; Straley, Susan C

    2002-01-01

    LcrQ is a regulatory protein unique to Yersinia. Previous study in Yersinia pseudotuberculosis and Yersinia enterocolitica prompted the model in which LcrQ negatively regulates the expression of a set of virulence proteins called Yops, and its secretion upon activation of the Yop secretion (Ysc) type III secretion system permits full induction of Yops expression. In this study, we tested the hypothesis that LcrQ's effects on Yops expression might be indirect. Excess LcrQ was found to exert an inhibitory effect specifically at the level of Yops secretion, independent of production, and a normal inner Ysc gate protein LcrG was required for this activity. However, overexpression of LcrQ did not prevent YopH secretion, suggesting that LcrQ's effects at the Ysc discriminate among the Yops. We tested this idea by determining the effects of deletion or overexpression of LcrQ, YopH and their common chaperone SycH on early Yop secretion through the Ysc. Together, our findings indicated that LcrQ is not a negative regulator directly, but it acts in partnership with SycH at the Ysc gate to control the entry of a set of Ysc secretion substrates. A hierarchy of YopH secretion before YopE appears to be imposed by SycH in conjunction with both LcrQ and YopH. LcrQ and SycH in addition influenced the deployment of LcrV, a component of the Yops delivery mechanism. Accordingly, LcrQ appears to be a central player in determining the substrate specificity of the Ysc.

  10. Yersinia enterocolitica YopH-Deficient Strain Activates Neutrophil Recruitment to Peyer's Patches and Promotes Clearance of the Virulent Strain.

    Science.gov (United States)

    Dave, Mabel N; Silva, Juan E; Eliçabe, Ricardo J; Jeréz, María B; Filippa, Verónica P; Gorlino, Carolina V; Autenrieth, Stella; Autenrieth, Ingo B; Di Genaro, María S

    2016-11-01

    Yersinia enterocolitica evades the immune response by injecting Yersinia outer proteins (Yops) into the cytosol of host cells. YopH is a tyrosine phosphatase critical for Yersinia virulence. However, the mucosal immune mechanisms subverted by YopH during in vivo orogastric infection with Y. enterocolitica remain elusive. The results of this study revealed neutrophil recruitment to Peyer's patches (PP) after infection with a YopH-deficient mutant strain (Y. enterocolitica ΔyopH). While the Y. enterocolitica wild-type (WT) strain in PP induced the major neutrophil chemoattractant CXCL1 mRNA and protein levels, infection with the Y. enterocolitica ΔyopH mutant strain exhibited a higher expression of the CXCL1 receptor, CXCR2, in blood neutrophils, leading to efficient neutrophil recruitment to the PP. In contrast, migration of neutrophils into PP was impaired upon infection with Y. enterocolitica WT strain. In vitro infection of blood neutrophils revealed the involvement of YopH in CXCR2 expression. Depletion of neutrophils during Y. enterocolitica ΔyopH infection raised the bacterial load in PP. Moreover, the clearance of WT Y. enterocolitica was improved when an equal mixture of Y. enterocolitica WT and Y. enterocolitica ΔyopH strains was used in infecting the mice. This study indicates that Y. enterocolitica prevents early neutrophil recruitment in the intestine and that the effector protein YopH plays an important role in the immune evasion mechanism. The findings highlight the potential use of the Y. enterocolitica YopH-deficient strain as an oral vaccine carrier. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  11. Aqueous Extracts of the Marine Brown Alga Lobophora variegata Inhibit HIV-1 Infection at the Level of Virus Entry into Cells

    KAUST Repository

    Kremb, Stephan; Helfer, Markus; Kraus, Birgit; Wolff, Horst; Wild, Christian; Schneider, Martha; Voolstra, Christian R.; Brack-Werner, Ruth

    2014-01-01

    -infection. Anti-viral potency was related to ecological factors and showed clear differences depending on light exposition or epiphyte growth. Assays addressing early events of the HIV-1 replication cycle indicated that L. variegata extracts inhibited entry

  12. Modulation of recurrent inhibition from knee extensors to ankle motoneurones during human walking

    DEFF Research Database (Denmark)

    Lamy, Jean-Charles; Iglesias, Caroline; Lackmy, Alexandra

    2008-01-01

    The neural control for muscle coordination during human locomotion involves spinal and supraspinal networks, but little is known about the exact mechanisms implicated. The present study focused on modulation of heteronymous recurrent inhibition from knee extensors to ankle motoneurones at different...... times in the gait cycle, when quadriceps (Quad) muscle activity overlaps that in tibialis anterior (TA) and soleus (Sol). The effects of femoral nerve stimulation on ankle motoneurones were investigated during treadmill walking and during tonic co-contraction of Quad and TA/Sol while standing. Recurrent...... inhibition of TA motoneurones depended on the level of background EMG, and was similar during walking and standing for matched background EMG levels. On the other hand, recurrent inhibition in Sol was reduced in early stance, with respect to standing, and enhanced in late stance. Reduced inhibition in Sol...

  13. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

    International Nuclear Information System (INIS)

    Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

    2008-01-01

    Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1

  14. Hyperoxia Inhibits T Cell Activation in Mice

    Science.gov (United States)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  15. Remote distractor effects and saccadic inhibition: spatial and temporal modulation.

    Science.gov (United States)

    Walker, Robin; Benson, Valerie

    2013-09-12

    The onset of a visual distractor remote from a saccade target is known to increase saccade latency (the remote distractor effect [RDE]). In addition, distractors may also selectively inhibit saccades that would be initiated about 90 ms after distractor onset (termed saccadic inhibition [SI]). Recently, it has been proposed that the transitory inhibition of saccades (SI) may underlie the increase in mean latency (RDE). In a first experiment, the distractor eccentricity was manipulated, and a robust RDE that was strongly modulated by distractor eccentricity was observed. However, the underlying latency distributions did not reveal clear evidence of SI. A second experiment manipulated distractor spatial location and the timing of the distractor onset in relation to the target. An RDE was again observed with remote distractors away from the target axis and under conditions with early-onset distractors that would be unlikely to produce SI, whereas later distractor onsets produced an RDE along with some evidence of an SI effect. A third experiment using a mixed block of target-distractor stimulus-onset asynchronies (SOAs) revealed an RDE that varied with both distractor eccentricity and SOA and changes to latency distributions consistent with the timing of SI. We argue that the notion that SI underpins the RDE is similar to the earlier argument that express saccades underlie the fixation offset (gap) effect and that changes in mean latency and to the shape of the underlying latency distributions following a visual onset may involve more than one inhibitory process.

  16. Early Retirement Payoff

    Science.gov (United States)

    Fitzpatrick, Maria D.; Lovenheim, Michael F.

    2014-01-01

    As public budgets have grown tighter over the past decade, states and school districts have sought ways to control the growth of spending. One increasingly common strategy employed to rein in costs is to offer experienced teachers with high salaries financial incentives to retire early. Although early retirement incentive (ERI) programs have been…

  17. Early Modern Philosophical Systems

    NARCIS (Netherlands)

    L. van Bunge (Wiep)

    2014-01-01

    textabstractThe occurrence of an entry on early modern philosophical systems in an encyclopaedia of Neo-Latin studies is fraught with complications, if only on account of the gradual disappearance during the early modern period of Latin as the main vehicle of philosophical communication. What

  18. Early Intervention in Budapest.

    Science.gov (United States)

    Gallai, Maria; Katona, Ferenc; Balogh, Erzsebet; Schultheisz, Judit; Deveny, Anna; Borbely, Sjoukje

    2000-01-01

    This article presents five models of early intervention used in Budapest. Diagnostic and treatment methods used by the Pediatric Institute and the Conductive Education System are described, along with the Deveny Special Manual Technique and Gymnastic Method, the Gezenguz method and techniques used in the Early Developmental Center. (CR)

  19. The early universe

    International Nuclear Information System (INIS)

    Steigman, G.

    1989-01-01

    The author discusses the physics of the early universe: the production and survival of relics from the big bang. The author comments on relic WIMPs as the dark matter in the universe. The remainder of this discussion is devoted to a review of the status of the only predictions from the early evolution of the universe that are accessible to astronomical observation: primordial nucleosynthesis

  20. Early College High Schools

    Science.gov (United States)

    Dessoff, Alan

    2011-01-01

    For at-risk students who stand little chance of going to college, or even finishing high school, a growing number of districts have found a solution: Give them an early start in college while they still are in high school. The early college high school (ECHS) movement that began with funding from the Bill and Melinda Gates Foundation 10 years ago…

  1. Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition.

    Science.gov (United States)

    Harrison, Ian F; Smith, Andrew D; Dexter, David T

    2018-02-14

    Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of

  2. STIR: Assessing and Training Response Inhibition Abilities

    Science.gov (United States)

    2014-07-30

    Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction ...requires an abstract application of the core learning principle1,2, and viable examples are often hard to find and/or assess. If exposure to non...inhibition training that expands upon previous successful “near transfer” response inhibition training efforts—such as treating alcohol addictions by

  3. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

    Science.gov (United States)

    Warner, W; Harris, L S; Carchman, R A

    1977-12-01

    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

  4. Inhibition of apparent photosynthesis by nitrogen oxides

    Energy Technology Data Exchange (ETDEWEB)

    Hill, A C; Bennett, J H

    1970-01-01

    The nitrogen oxides (NO/sub 2/ and NO) inhibited apparent photosynthesis of oats and alfalfa at concentrations below those required to cause visible injury. There appeared to be a threshold concentration of about 0.6 ppm for each pollutant. An additive effect in depressing apparent photosynthesis occurred when the plants were exposed to a mixture of NO and NO/sub 2/. Although NO produced a more rapid effect on the plants, lower concentrations of NO/sub 2/ were required to cause a given inhibition after 2 hour of exposure. Inhibition by nitric oxide was more closely related to its partial pressure than was inhibition by NO/sub 2/.

  5. Early Option Exercise

    DEFF Research Database (Denmark)

    Heje Pedersen, Lasse; Jensen, Mads Vestergaard

    A classic result by Merton (1973) is that, except just before expiration or dividend payments, one should never exercise a call option and never convert a convertible bond. We show theoretically that this result is overturned when investors face frictions. Early option exercise can be optimal when...... it reduces short-sale costs, transaction costs, or funding costs. We provide consistent empirical evidence, documenting billions of dollars of early exercise for options and convertible bonds using unique data on actual exercise decisions and frictions. Our model can explain as much as 98% of early exercises...

  6. Early Option Exercise

    DEFF Research Database (Denmark)

    Jensen, Mads Vestergaard; Heje Pedersen, Lasse

    2016-01-01

    A classic result by Merton (1973) is that, except just before expiration or dividend payments, one should never exercise a call option and never convert a convertible bond. We show theoretically that this result is overturned when investors face frictions. Early option exercise can be optimal when...... it reduces short-sale costs, transaction costs, or funding costs. We provide consistent empirical evidence, documenting billions of dollars of early exercise for options and convertible bonds using unique data on actual exercise decisions and frictions. Our model can explain as much as 98% of early exercises...

  7. Streptococcus mutans competence-stimulating peptide inhibits Candida albicans hypha formation.

    Science.gov (United States)

    Jarosz, Lucja M; Deng, Dong Mei; van der Mei, Henny C; Crielaard, Wim; Krom, Bastiaan P

    2009-11-01

    The oral cavity is colonized by microorganisms growing in biofilms in which interspecies interactions take place. Streptococcus mutans grows in biofilms on enamel surfaces and is considered one of the main etiological agents of human dental caries. Candida albicans is also commonly found in the human oral cavity, where it interacts with S. mutans. C. albicans is a polymorphic fungus, and the yeast-to-hypha transition is involved in virulence and biofilm formation. The aim of this study was to investigate interkingdom communication between C. albicans and S. mutans based on the production of secreted molecules. S. mutans UA159 inhibited C. albicans germ tube (GT) formation in cocultures even when physically separated from C. albicans. Only S. mutans spent medium collected in the early exponential phase (4-h-old cultures) inhibited the GT formation of C. albicans. During this phase, S. mutans UA159 produces a quorum-sensing molecule, competence-stimulating peptide (CSP). The role of CSP in inhibiting GT formation was confirmed by using synthetic CSP and a comC deletion strain of S. mutans UA159, which lacks the ability to produce CSP. Other S. mutans strains and other Streptococcus spp. also inhibited GT formation but to different extents, possibly reflecting differences in CSP amino acid sequences among Streptococcus spp. or differences in CSP accumulation in the media. In conclusion, CSP, an S. mutans quorum-sensing molecule secreted during the early stages of growth, inhibits the C. albicans morphological switch.

  8. Delta-9 tetrahydrocannabinol (THC inhibits lytic replication of gamma oncogenic herpesviruses in vitro

    Directory of Open Access Journals (Sweden)

    Friedman Herman

    2004-09-01

    Full Text Available Abstract Background The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC, has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication. Methods Tissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV and Epstein-Barr virus (EBV replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS of monkeys, murine gamma herpesvirus 68 (MHV 68, and herpes simplex type 1 (HSV-1 was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method. Results Micromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68. Conclusions THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC

  9. Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro.

    Science.gov (United States)

    Medveczky, Maria M; Sherwood, Tracy A; Klein, Thomas W; Friedman, Herman; Medveczky, Peter G

    2004-09-15

    The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication. Tissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV) and Epstein-Barr virus (EBV) replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS) of monkeys, murine gamma herpesvirus 68 (MHV 68), and herpes simplex type 1 (HSV-1) was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method. Micromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68. THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC. These studies may also provide the foundation for the development

  10. Early detection of psychosis

    DEFF Research Database (Denmark)

    Larsen, Tor Ketil; Melle, Ingrid; Auestad, B.

    2011-01-01

    Background During the last decades we have seen a new focus on early treatment of psychosis. Several reviews have shown that duration of untreated psychosis (DUP) is correlated to better outcome. However, it is still unknown whether early treatment will lead to a better long-term outcome....... This study reports the effects of reducing DUP on 5-year course and outcome. Method During 1997–2000 a total of 281 consecutive patients aged >17 years with first episode non-affective psychosis were recruited, of which 192 participated in the 5-year follow-up. A comprehensive early detection (ED) programme...... and cognitive factors and for global assessment of functioning for social functioning at 5-year follow-up. The ED group also had more contacts with friends. Regression analysis did not find that these differences could be explained by confounders. Conclusions Early treatment had positive effects on clinical...

  11. Early Head Start Evaluation

    Data.gov (United States)

    U.S. Department of Health & Human Services — Longitudinal information from an evaluation where children were randomly assigned to Early Head Start or community services as usual;direct assessments and...

  12. Guideline for Early Interventions

    National Research Council Canada - National Science Library

    Vries, de, Maaike

    2006-01-01

    .... During the last years, the demand for early interventions has been increasing. International literature has shown that the psychosocial effects of disaster and military deployment may last for years...

  13. Early Life Stages

    Science.gov (United States)

    Childhood should be viewed as a sequence of lifestages, from birth through infancy and adolescence. When assessing early life risks, consideration is given to risks resulting from fetal exposure via the pregnant mother, as well as postnatal exposures.

  14. Cancer treatment - early menopause

    Science.gov (United States)

    Premature menopause; Ovarian insufficiency - cancer ... Cancer treatments that can cause early menopause include: Surgery. Having both ovaries removed causes menopause to happen right away. If you are age 50 or younger, your provider may ...

  15. Early intervention in psychosis

    DEFF Research Database (Denmark)

    Csillag, Claudio; Nordentoft, Merete; Mizuno, Masafumi

    2017-01-01

    AIM: Early intervention in psychosis (EIP) is a well-established approach with the intention of early detection and treatment of psychotic disorders. Its clinical and economic benefits are well documented. This paper presents basic aspects of EIP services, discusses challenges to their implementa......AIM: Early intervention in psychosis (EIP) is a well-established approach with the intention of early detection and treatment of psychotic disorders. Its clinical and economic benefits are well documented. This paper presents basic aspects of EIP services, discusses challenges...... benefits alone is not enough to promote implementation, as economic arguments and political and social pressure have shown to be important elements in efforts to achieve implementation. CONCLUSIONS: Users' narratives, close collaboration with community organizations and support from policy-makers and known...

  16. Earth's early biosphere

    Science.gov (United States)

    Des Marais, D. J.

    1998-01-01

    Understanding our own early biosphere is essential to our search for life elsewhere, because life arose on Earth very early and rocky planets shared similar early histories. The biosphere arose before 3.8 Ga ago, was exclusively unicellular and was dominated by hyperthermophiles that utilized chemical sources of energy and employed a range of metabolic pathways for CO2 assimilation. Photosynthesis also arose very early. Oxygenic photosynthesis arose later but still prior to 2.7 Ga. The transition toward the modern global environment was paced by a decline in volcanic and hydrothermal activity. These developments allowed atmospheric O2 levels to increase. The O2 increase created new niches for aerobic life, most notably the more advanced Eukarya that eventually spawned the megascopic fauna and flora of our modern biosphere.

  17. Mercury's Early Geologic History

    Science.gov (United States)

    Denevi, B. W.; Ernst, C. M.; Klima, R. L.; Robinson, M. S.

    2018-05-01

    A combination of geologic mapping, compositional information, and geochemical models are providing a better understanding of Mercury's early geologic history, and allow us to place it in the context of the Moon and the terrestrial planets.

  18. Inhibition of photosynthesis by carbon monoxide and suspension of the carbon monoxide inhibition by light

    Energy Technology Data Exchange (ETDEWEB)

    Gewitz, H S; Voelker, W

    1963-08-01

    The experimental subject was the autotroph Chlorella pyrenoidosa. It was found that growth conditions determine whether the alga is inhibited by carbon monoxide or not. Respiration and photosynthesis are inhibited by carbon monoxide if the cells have grown rapidly under high light intensities. The inhibition of respiration and photosynthesis found in such cells is completely reversible. The inhibition depends not only on carbon monoxide pressure, but also on the oxygen pressure prevailing at the same time. 5 references, 1 figure, 3 tables.

  19. Embracing early literacy indicators

    DEFF Research Database (Denmark)

    Broström, Stig; Hansen, Ole Henrik; Jensen, Anders Skriver

    2010-01-01

    Abstract til paper om early literacy indikatorer. Det paper abstractet er knyttet til var en del af et inviteret, selvorganiseret symposium som afrapporterede EASE-projektet (www.ease-eu.com) på OMEP's 26. verdenskongres.......Abstract til paper om early literacy indikatorer. Det paper abstractet er knyttet til var en del af et inviteret, selvorganiseret symposium som afrapporterede EASE-projektet (www.ease-eu.com) på OMEP's 26. verdenskongres....

  20. Who Gets Early Tracheostomy?

    Science.gov (United States)

    Shaw, Joshua J.

    2015-01-01

    BACKGROUND: Although the benefits of early tracheostomy in patients dependent on ventilators are well established, the reasons for variation in time from intubation to tracheostomy remain unclear. We identified clinical and demographic disparities in time to tracheostomy. METHODS: We performed a level 3 retrospective prognostic study by querying the University HealthSystem Consortium (2007-2010) for adult patients receiving a tracheostomy after initial intubation. Time to tracheostomy was designated early ( 10 days). Cohorts were stratified by time to tracheostomy and compared using univariate tests of association and multivariable adjusted models. RESULTS: A total of 49,191 patients underwent tracheostomy after initial intubation: 42% early (n = 21,029) and 58% late (n = 28,162). On both univariate and multivariable analyses, women, blacks, Hispanics, and patients receiving Medicaid were less likely to receive an early tracheostomy. Patients in the early group also experienced lower rates of mortality (OR, 0.84; 95% CI, 0.79-0.88). CONCLUSIONS: Early tracheostomy was associated with increased survival. Yet, there were still significant disparities in time to tracheostomy according to sex, race, and type of insurance. Application of evidence-based algorithms for tracheostomy may reduce unequal treatment and improve overall mortality rates. Additional research into this apparent bias in referral/rendering of tracheostomy is needed. PMID:26313324

  1. 7-Piperazinethylchrysin inhibits melanoma cell proliferation by ...

    African Journals Online (AJOL)

    In B16F10 and A375 cells, treatment with PEC caused the inhibition ... Conclusion: PEC inhibited melanoma cell proliferation, apparently by blocking the cell cycle at G0/G1 .... all statistical analyses. .... Financial support from the Department of.

  2. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

    Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

  3. Inhibition: Mental Control Process or Mental Resource?

    Science.gov (United States)

    Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

    2015-01-01

    The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

  4. The pharmacology of visuospatial attention and inhibition

    NARCIS (Netherlands)

    Logemann, H.N.A.

    2013-01-01

    Attention and inhibition are of vital importance in everyday functioning. Problems of attention and inhibition are central to disorders such as Attention Deficit/Hyperactivity Disorder (ADHD). Both bias and disengagement key components of visuospatial attention. Bias refers to neuronal signals that

  5. Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L.

    Directory of Open Access Journals (Sweden)

    McCoy Joe-Ann

    2011-04-01

    Full Text Available Abstract Background The mint family (Lamiaceae produces a wide variety of constituents with medicinal properties. Several family members have been reported to have antiviral activity, including lemon balm (Melissa officinalis L., sage (Salvia spp., peppermint (Mentha × piperita L., hyssop (Hyssopus officinalis L., basil (Ocimum spp. and self-heal (Prunella vulgaris L.. To further characterize the anti-lentiviral activities of Prunella vulgaris, water and ethanol extracts were tested for their ability to inhibit HIV-1 infection. Results Aqueous extracts contained more anti-viral activity than did ethanol extracts, displaying potent antiviral activity against HIV-1 at sub μg/mL concentrations with little to no cellular cytotoxicity at concentrations more than 100-fold higher. Time-of-addition studies demonstrated that aqueous extracts were effective when added during the first five hours following initiation of infection, suggesting that the botanical constituents were targeting entry events. Further analysis revealed that extracts inhibited both virus/cell interactions and post-binding events. While only 40% inhibition was maximally achieved in our virus/cell interaction studies, extract effectively blocked post-binding events at concentrations similar to those that blocked infection, suggesting that it was targeting of these latter steps that was most important for mediating inhibition of virus infectivity. Conclusions We demonstrate that aqueous P. vulgaris extracts inhibited HIV-1 infectivity. Our studies suggest that inhibition occurs primarily by interference of early, post-virion binding events. The ability of aqueous extracts to inhibit early events within the HIV life cycle suggests that these extracts, or purified constituents responsible for the antiviral activity, are promising microbicides and/or antivirals against HIV-1.

  6. Inhibition of ethylene production by cobaltous ion

    International Nuclear Information System (INIS)

    Lau, O.L; Yang, S.F.

    1976-01-01

    The effect of Co 2+ on ethylene production by mung bean (Phaseolus aureus Roxb.) and by apple tissues was studied. Co 2+ , depending on concentrations applied, effectively inhibited ethylene production by both tissues. It also strongly inhibited the ethylene production induced by IAA, kinetin, IAA plus kinetin, Ca 2+ , kinetin plus Ca 2+ , or Cu 2+ treatments in mung bean hypocotyl segments. While Co 2+ greatly inhibited ethylene production, it had little effect on the respiration of apple tissue, indicating that Co 2+ does not exert its inhibitory effect as a general metabolic inhibitor. Ni 2+ , which belongs to the same group as Co 2+ in the periodic table, also markedly curtailed both the basal and the induced ethylene production by apple and mung bean hypocotyl tissues. In a system in which kinetin and Ca 2+ were applied together, kinetin greatly enhanced Ca 2+ uptake, thus enhancing ethylene production. Co 2+ , however, slightly inhibited the uptake of Ca 2+ but appreciably inhibited ethylene production, either in the presence or in the absence of kinetin. Tracer experiments using apple tissue indicated that Co 2+ strongly inhibited the in vivo conversion of L-[U-- 14 C]methionine to 14 C-ethylene. These data suggested that Co 2+ inhibited ethylene production by inhibiting the conversion of methionine to ethylene, a common step which is required for ethylene formation by higher plants. Co 2+ is known to promote elongation, leaf expansion, and hook opening in excised plant parts in response to applied auxins or cytokinins.Since ethylene is known to inhibit those growth phenomena, it is suggested that Co 2+ exerts its promotive effect, at least in part, by inhibiting ethylene formation

  7. Lysophospholipase inhibition by organophosphorus toxicants

    International Nuclear Information System (INIS)

    Quistad, Gary B.; Casida, John E.

    2004-01-01

    Lysophospholipases (LysoPLAs) are a large family of enzymes for removing lysophospholipids from cell membranes. Potent inhibitors are needed to define the importance of LysoPLAs as targets for toxicants and potential therapeutics. This study considers organophosphorus (OP) inhibitors with emphasis on mouse brain total LysoPLA activity relative to the mipafox-sensitive neuropathy target esterase (NTE)-LysoPLA recently established as 17% of the total activity and important in the action of OP delayed toxicants. The most potent inhibitors of total LysoPLA in mouse brain are isopropyl dodecylphosphonofluoridate (also for LysoPLA of Vibrio bacteria), ethyl octylphosphonofluoridate (EOPF), and two alkyl-benzodioxaphosphorin 2-oxides (BDPOs)[(S)-octyl and dodecyl] (IC50 2-8 nM). OP inhibitors acting in vitro and in vivo differentiate a more sensitive portion but not a distinct NTE-LysoPLA compared with total LysoPLA activity. For 10 active inhibitors, NTE-LysoPLA is 17-fold more sensitive than total LysoPLA, but structure-activity comparisons give a good correlation (r 2 = 0.94) of IC50 values, suggesting active site structural similarity or identity. In mice 4 h after intraperitoneal treatment with discriminating doses, EOPF, tribufos (a plant defoliant), and dodecanesulfonyl fluoride inhibit 41-57% of the total brain LysoPLA and 85-99% of the NTE-LysoPLA activity. Total LysoPLA as well as NTE-LysoPLA is decreased in activity in Nte +/- -haploinsufficient mice compared to their Nte +/+ littermates. The lysolecithin level of spinal cord but not brain is elevated significantly following EOPF treatment (3 mg/kg), thereby focusing attention on localized rather than general alterations in lysophospholipid metabolism in OP-induced hyperactivity and toxicity

  8. ECR-MAPK regulation in liver early development.

    Science.gov (United States)

    Zhao, Xiu-Ju; Zhuo, Hexian

    2014-01-01

    Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region)-socs2 (-SH2-containing signals/receptor tyrosine kinases)-ppp2r2a/pik3c3 (MAPK signaling)-hsd3b5/cav2 (metabolism/organization) plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

  9. ECR-MAPK Regulation in Liver Early Development

    Directory of Open Access Journals (Sweden)

    Xiu-Ju Zhao

    2014-01-01

    Full Text Available Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region-socs2 (-SH2-containing signals/receptor tyrosine kinases-ppp2r2a/pik3c3 (MAPK signaling-hsd3b5/cav2 (metabolism/organization plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

  10. Redefining early gastric cancer.

    Science.gov (United States)

    Barreto, Savio G; Windsor, John A

    2016-01-01

    The problem is that current definitions of early gastric cancer allow the inclusion of regional lymph node metastases. The increasing use of endoscopic submucosal dissection to treat early gastric cancer is a concern because regional lymph nodes are not addressed. The aim of the study was thus to critically evaluate current evidence with regard to tumour-specific factors associated with lymph node metastases in "early gastric cancer" to develop a more precise definition and improve clinical management. A systematic and comprehensive search of major reference databases (MEDLINE, EMBASE, PubMed and the Cochrane Library) was undertaken using a combination of text words "early gastric cancer", "lymph node metastasis", "factors", "endoscopy", "surgery", "lymphadenectomy" "mucosa", "submucosa", "lymphovascular invasion", "differentiated", "undifferentiated" and "ulcer". All available publications that described tumour-related factors associated with lymph node metastases in early gastric cancer were included. The initial search yielded 1494 studies, of which 42 studies were included in the final analysis. Over time, the definition of early gastric cancer has broadened and the indications for endoscopic treatment have widened. The mean frequency of lymph node metastases increased on the basis of depth of infiltration (mucosa 6% vs. submucosa 28%), presence of lymphovascular invasion (absence 9% vs. presence 53%), tumour differentiation (differentiated 13% vs. undifferentiated 34%) and macroscopic type (elevated 13% vs. flat 26%) and tumour diameter (≤2 cm 8% vs. >2 cm 25%). There is a need to re-examine the diagnosis and staging of early gastric cancer to ensure that patients with one or more identifiable risk factor for lymph node metastases are not denied appropriate chemotherapy and surgical resection.

  11. Effect of arachidonic acid supplementation and cyclooxygenase/lipoxygenase inhibition on the development of early bovine embryos Influência do ácido araquidónico e da inibição da ciclo-oxigenase ou lipo-oxigenase no desenvolvimento inicial de embriões bovinos

    Directory of Open Access Journals (Sweden)

    Rosa Maria Pereira

    2006-04-01

    Full Text Available The effect of arachidonic acid (AA cascade on bovine embryo development in a granulosa cell co-culture system was studied. Arachidonic acid (100 µM was supplemented from 1-cell to 8-16 cell block stage (first three days of co-culture and from 1-cell to hatching. Specific cyclooxygenase (indomethacin, 28 µM and lipoxygenase (nordihydroguaiaretic acid - NDGA, 28 µM inhibitors were used from 1-cell to 8-16 cell block stage with AA. Embryo development was assessed by cleavage, day 7-day 8 and hatched embryo rates and by measuring growth rates through development stages found in days 7-10 of culture (day 0 = insemination day. Embryo quality was scored at day 8. A 6.5-10.4% increase on cleavage rate after AA supplementation was found. This AA supplementation from 1-cell to hatching delayed embryo growth rate beyond day 7 and a reduction on hatching rate was detected. When AA supplementation was restricted to the first three days of co-culture those negative effects were overcome. Also, indomethacin and NDGA prevented the positive effect of AA and induced a significant reduction on cleavage, respectively. NDGA further decreased day 7 embryo rate and quality. Results suggest that AA has a two-phase action on bovine embryos, promoting early development and impairing embryo growth from day 7 onwards and hatching rates. Both cyclooxygenase and lipoxygenase were found to be important pathways to promote cleavage.Estudou-se a influência da cascata do ácido araquidónico (AA no desenvolvimento de embriões bovinos produzidos in vitro em co-cultura com células da granulosa. Os embriões foram suplementados com AA (100 µM desde o estádio de 1 célula até 8-16 células (primeiros três dias de co-cultura ou até a eclosão. Introduziram-se inibidores específicos da ciclo-oxigenase (indometacina, 28 µM e da lipo-oxigenase (ácido nordihidroguaiarético - NDGA, 28 µM, juntamente com o ácido araquidónico, desde o estádio de 1 célula até 8-16 c

  12. Selective mutism and temperament: the silence and behavioral inhibition to the unfamiliar.

    Science.gov (United States)

    Gensthaler, Angelika; Khalaf, Sally; Ligges, Marc; Kaess, Michael; Freitag, Christine M; Schwenck, Christina

    2016-10-01

    Behavioral inhibition (BI) is a suspected precursor of selective mutism. However, investigations on early behavioral inhibition of children with selective mutism are lacking. Children aged 3-18 with lifetime selective mutism (n = 109), social phobia (n = 61), internalizing behavior (n = 46) and healthy controls (n = 118) were assessed using the parent-rated Retrospective Infant Behavioral Inhibition (RIBI) questionnaire. Analyses showed that children with lifetime selective mutism and social phobia were more inhibited as infants and toddlers than children of the internalizing and healthy control groups, who displayed similar low levels of behavioral inhibition. Moreover, behavioral inhibition was higher in infants with lifetime selective mutism than in participants with social phobia according to the Total BI score (p = 0.012) and the Shyness subscale (p selective mutism. Results yield first evidence of the recently hypothesized temperamental origin of selective mutism. Children at risk should be screened for this debilitating child psychiatric condition.

  13. Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway

    International Nuclear Information System (INIS)

    Song, Wuqi; Kao, Wenping; Zhai, Aixia; Qian, Jun; Li, Yujun; Zhang, Qingmeng; Zhao, Hong; Hu, Yunlong; Li, Hui; Zhang, Fengmin

    2013-01-01

    Highlights: •IRF7 nuclear localisation was inhibited by BDV persistently infected. •BDV N protein resistant to IFN induction both in BDV infected OL cell and N protein plasmid transfected OL cell. •BDV N protein is related to the inhibition of IRF7 nuclear localisation. -- Abstract: The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1–IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway

  14. Developing the quality of early childhood mentoring institutions

    Directory of Open Access Journals (Sweden)

    Sri Hartini

    2017-09-01

    Full Text Available The study was to uncover the concept of quality improvement, the supporting and the inhibiting factors within the quality improve and the quality improvement in the early childhood mentoring institutions/kindergarten. The study was a qualitative research. The subjects in the study were kindergarten principals, kindergarten teachers and parents. The data were gathered by means of observation, interview and documentation. For the data analysis, the researcher selected the qualitative descriptive data analysis method. The results of the study were as follows. First, the concept of educational quality improvement in the early childhood mentoring institutions/ kindergarten has been improveed from the vision, the mission and the objectives and the concept includes the aspects of planning, process and output which has synergy from one to another. The planning has been formulated in the curriculum, the syllabus and the daily activity plan. Second, the approach, the strategy and the technique of quality improvement has maximized the well-qualified schools’ resources, have been supported by the sufficient facilities and have been funded by the sufficient budget. Third, the supporting factors within the quality improvement of early childhood mentoring institutions/kindergarten have been the increasing awareness within the society toward the significance of early childhood mentoring institutions, the massive socialization conducted by the Office of Education through the provision of training programs in relation to the early childhood mentoring institution/kindergarten management and the human resources empowerment toward developing the quality of early childhood mentoring institutions. Fourth, the inhibiting factors within the quality improvement of early childhood mentoring institutions have been the lack of society care and participation, the less quality human resources that early childhood mentoring institutions have, the fund limitation, the

  15. Early Dementia Screening

    Directory of Open Access Journals (Sweden)

    Peter K. Panegyres

    2016-01-01

    Full Text Available As the population of the world increases, there will be larger numbers of people with dementia and an emerging need for prompt diagnosis and treatment. Early dementia screening is the process by which a patient who might be in the prodromal phases of a dementing illness is determined as having, or not having, the hallmarks of a neurodegenerative condition. The concepts of mild cognitive impairment, or mild neurocognitive disorder, are useful in analyzing the patient in the prodromal phase of a dementing disease; however, the transformation to dementia may be as low as 10% per annum. The search for early dementia requires a comprehensive clinical evaluation, cognitive assessment, determination of functional status, corroborative history and imaging (including MRI, FDG-PET and maybe amyloid PET, cerebrospinal fluid (CSF examination assaying Aβ1–42, T-τ and P-τ might also be helpful. Primary care physicians are fundamental in the screening process and are vital in initiating specialist investigation and treatment. Early dementia screening is especially important in an age where there is a search for disease modifying therapies, where there is mounting evidence that treatment, if given early, might influence the natural history—hence the need for cost-effective screening measures for early dementia.

  16. Early cosmology constrained

    Energy Technology Data Exchange (ETDEWEB)

    Verde, Licia; Jimenez, Raul [Institute of Cosmos Sciences, University of Barcelona, IEEC-UB, Martí Franquès, 1, E08028 Barcelona (Spain); Bellini, Emilio [University of Oxford, Denys Wilkinson Building, Keble Road, Oxford, OX1 3RH (United Kingdom); Pigozzo, Cassio [Instituto de Física, Universidade Federal da Bahia, Salvador, BA (Brazil); Heavens, Alan F., E-mail: liciaverde@icc.ub.edu, E-mail: emilio.bellini@physics.ox.ac.uk, E-mail: cpigozzo@ufba.br, E-mail: a.heavens@imperial.ac.uk, E-mail: raul.jimenez@icc.ub.edu [Imperial Centre for Inference and Cosmology (ICIC), Imperial College, Blackett Laboratory, Prince Consort Road, London SW7 2AZ (United Kingdom)

    2017-04-01

    We investigate our knowledge of early universe cosmology by exploring how much additional energy density can be placed in different components beyond those in the ΛCDM model. To do this we use a method to separate early- and late-universe information enclosed in observational data, thus markedly reducing the model-dependency of the conclusions. We find that the 95% credibility regions for extra energy components of the early universe at recombination are: non-accelerating additional fluid density parameter Ω{sub MR} < 0.006 and extra radiation parameterised as extra effective neutrino species 2.3 < N {sub eff} < 3.2 when imposing flatness. Our constraints thus show that even when analyzing the data in this largely model-independent way, the possibility of hiding extra energy components beyond ΛCDM in the early universe is seriously constrained by current observations. We also find that the standard ruler, the sound horizon at radiation drag, can be well determined in a way that does not depend on late-time Universe assumptions, but depends strongly on early-time physics and in particular on additional components that behave like radiation. We find that the standard ruler length determined in this way is r {sub s} = 147.4 ± 0.7 Mpc if the radiation and neutrino components are standard, but the uncertainty increases by an order of magnitude when non-standard dark radiation components are allowed, to r {sub s} = 150 ± 5 Mpc.

  17. Regulation of spatial selectivity by crossover inhibition.

    Science.gov (United States)

    Cafaro, Jon; Rieke, Fred

    2013-04-10

    Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

  18. Fear inhibition in high trait anxiety.

    Directory of Open Access Journals (Sweden)

    Merel Kindt

    Full Text Available Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

  19. Early Islamic Syria

    DEFF Research Database (Denmark)

    Walmsley, Alan

    After more than a century of neglect, a profound revolution is occurring in the way archaeology addresses and interprets developments in the social history of early Islamic Syria-Palestine. This concise book offers an innovative assessment of social and economic developments in Syria-Palestine sh......After more than a century of neglect, a profound revolution is occurring in the way archaeology addresses and interprets developments in the social history of early Islamic Syria-Palestine. This concise book offers an innovative assessment of social and economic developments in Syria......-Palestine shortly before, and in the two centuries after, the Islamic expansion (the later sixth to the early ninth century AD), drawing on a wide range of new evidence from recent archaeological work. Alan Walmsley challenges conventional explanations for social change with the arrival of Islam, arguing...

  20. Early breastfeeding problems

    DEFF Research Database (Denmark)

    Feenstra, Maria Monberg; Kirkeby, Mette Jørgine; Thygesen, Marianne

    2018-01-01

    Objectives Breastfeeding problems are common and associated with early cessation. Stilllength of postpartum hospital stay has been reduced. This leaves new mothers to establish breastfeeding at home with less support from health care professionals. The objective was to explore mothers’ perspectives...... on when breastfeeding problems were the most challenging and prominent early postnatal. The aim was also toidentify possible factors associated with the breastfeeding problems. Methods In a cross-sectional study, a mixed method approach was used to analyse postal survey data from 1437 mothers with full...... term singleton infants. Content analysis was used to analyse mothers’ open text descriptions of their most challenging breastfeeding problem. Multiple logistic regression was used to calculate odds ratios for early breastfeeding problems according to sociodemographic- and psychosocial factors. Results...

  1. Early Intervention in Psychosis

    Science.gov (United States)

    McGorry, Patrick D.

    2015-01-01

    Abstract Early intervention for potentially serious disorder is a fundamental feature of healthcare across the spectrum of physical illness. It has been a major factor in the reductions in morbidity and mortality that have been achieved in some of the non-communicable diseases, notably cancer and cardiovascular disease. Over the past two decades, an international collaborative effort has been mounted to build the evidence and the capacity for early intervention in the psychotic disorders, notably schizophrenia, where for so long deep pessimism had reigned. The origins and rapid development of early intervention in psychosis are described from a personal and Australian perspective. This uniquely evidence-informed, evidence-building and cost-effective reform provides a blueprint and launch pad to radically change the wider landscape of mental health care and dissolve many of the barriers that have constrained progress for so long. PMID:25919380

  2. Early life vaccination

    DEFF Research Database (Denmark)

    Nazerai, Loulieta; Bassi, Maria Rosaria; Uddbäck, Ida Elin Maria

    2016-01-01

    Intracellular pathogens represent a serious threat during early life. Importantly, even though the immune system of newborns may be characterized as developmentally immature, with a propensity to develop Th2 immunity, significant CD8+ T-cell responses may still be elicited in the context of optimal...... the first period of life and provide a pertinent alternative in infant vaccinology. To address this, infant mice were vaccinated with three different adenoviral vectors and the CD8+ T-cell response after early life vaccination was explored. We assessed the frequency, polyfunctionality and in vivo...... cytotoxicity of the elicited memory CD8+ T cells, as well as the potential of these cells to respond to secondary infections and confer protection. We further tested the impact of maternal immunity against our replication-deficient adenoviral vector during early life vaccination. Overall, our results indicate...

  3. Early anaerobic metabolisms

    DEFF Research Database (Denmark)

    Canfield, Donald Eugene; Rosing, Minik T; Bjerrum, Christian

    2006-01-01

    probably driven by the cycling of H2 and Fe2+ through primary production conducted by anoxygenic phototrophs. Interesting and dynamic ecosystems would have also been driven by the microbial cycling of sulphur and nitrogen species, but their activity levels were probably not so great. Despite the diversity......Before the advent of oxygenic photosynthesis, the biosphere was driven by anaerobic metabolisms. We catalogue and quantify the source strengths of the most probable electron donors and electron acceptors that would have been available to fuel early-Earth ecosystems. The most active ecosystems were...... of potential early ecosystems, rates of primary production in the early-Earth anaerobic biosphere were probably well below those rates observed in the marine environment. We shift our attention to the Earth environment at 3.8Gyr ago, where the earliest marine sediments are preserved. We calculate, consistent...

  4. Informing early intervention: preschool predictors of anxiety disorders in middle childhood.

    Directory of Open Access Journals (Sweden)

    Jennifer L Hudson

    Full Text Available BACKGROUND: To inform early intervention practice, the present research examines how child anxiety, behavioural inhibition, maternal overinvolvement, maternal negativity, mother-child attachment and maternal anxiety, as assessed at age four, predict anxiety at age nine. METHOD: 202 children (102 behaviourally inhibited and 100 behaviourally uninhibited aged 3-4 years were initially recruited and the predictors outlined above were assessed. Diagnostic assessments, using the Anxiety Disorders Interview Schedule, were then conducted five years later. RESULTS: Behavioural inhibition, maternal anxiety, and maternal overinvolvement were significant predictors of clinical anxiety, even after controlling for baseline anxiety (p.1. CONCLUSIONS: Preschool children who show anxiety, are inhibited, have overinvolved mothers and mothers with anxiety disorders are at increased risk for anxiety in middle childhood. These factors can be used to identify suitable participants for early intervention and can be targeted within intervention programs.

  5. The Obstacle to Happiness: Early Maladaptive Schemas

    Directory of Open Access Journals (Sweden)

    S. Barbaros YALCIN

    2018-04-01

    Full Text Available Objective: The aim of this study is to determine whether individuals’ early maladaptive schemas predict their happiness levels or not and to find out what early maladaptive schemas prevent individuals’ happiness. Method: Relational screening model was used in the study. The study group consisted of the 253 university students; 198 (%78.3 females and 55 (%21.7 males. “The Qxford Happiness Questionnaire Short Form”, developed by Hills and Argyle (2002 and adapted into Turkish by Dogan and Cotok (2011, and “Young Schema Scale-Short Form 3”, developed by Young et al. (2003 and adapted into Turkish by Soygut, Karaosmanoglu, and Cakir (2009 were used to gather the data for the study. Results: According to the results obtained from the study, it was found out that there is a significantly negative relation between happiness and Vulnerability to Harm & Illness, Pessimism/Negativity, Failure, Social Isolation, Emotional Inhibition, Approval-Seeking and Insufficient Self-Control. Moreover, university students’ Pessimism/Negativity and Failure schemas were found to be the predictors of their happiness levels. Conclusion: Families, teachers and mental health workers should work together to resolve the Pessimism/Negativity and Failure early maladaptive schemas of university students’. It is considered as a preventive measure that the education system must be reviewed. [JCBPR 2018; 7(1.000: 7-13

  6. Neuroscience of inhibition for addiction medicine: from prediction of initiation to prediction of relapse.

    Science.gov (United States)

    Moeller, Scott J; Bederson, Lucia; Alia-Klein, Nelly; Goldstein, Rita Z

    2016-01-01

    A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior. Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differences from healthy nonaddicted controls during tasks of response inhibition accompanied by brain activation abnormalities as revealed by functional neuroimaging. However, it is less clear whether inhibition-related deficits predate the transition to problematic use, and, in turn, whether these deficits predict the transition out of problematic substance use. Here, we review longitudinal studies of response inhibition in children/adolescents with little substance experience and longitudinal studies of already addicted individuals attempting to sustain abstinence. Results show that response inhibition and its underlying neural correlates predict both substance use outcomes (onset and abstinence). Neurally, key roles were observed for multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex). In general, less activation of these regions during response inhibition predicted not only the onset of substance use, but interestingly also better abstinence-related outcomes among individuals already addicted. The role of subcortical areas, although potentially important, is less clear because of inconsistent results and because these regions are less classically reported in studies of healthy response inhibition. Overall, this review indicates that response inhibition is not simply a manifestation of current drug addiction, but rather a core neurocognitive dimension that predicts key substance use outcomes. Early intervention in inhibitory deficits could have high clinical and public health relevance. © 2016 Elsevier B.V. All rights reserved.

  7. PD-1 signaling and inhibition in AML and MDS.

    Science.gov (United States)

    Haroun, Faysal; Solola, Sade A; Nassereddine, Samah; Tabbara, Imad

    2017-09-01

    Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

  8. Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis

    Directory of Open Access Journals (Sweden)

    Thomas J. Hannan

    2014-11-01

    Full Text Available The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs. Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.

  9. Multiplicity in Early Stellar Evolution

    Science.gov (United States)

    Reipurth, B.; Clarke, C. J.; Boss, A. P.; Goodwin, S. P.; Rodríguez, L. F.; Stassun, K. G.; Tokovinin, A.; Zinnecker, H.

    Observations from optical to centimeter wavelengths have demonstrated that multiple systems of two or more bodies is the norm at all stellar evolutionary stages. Multiple systems are widely agreed to result from the collapse and fragmentation of cloud cores, despite the inhibiting influence of magnetic fields. Surveys of class 0 protostars with millimeter interferometers have revealed a very high multiplicity frequency of about 2/3, even though there are observational difficulties in resolving close protobinaries, thus supporting the possibility that all stars could be born in multiple systems. Near-infrared adaptive optics observations of class I protostars show a lower binary frequency relative to the class 0 phase, a declining trend that continues through the class II/III stages to the field population. This loss of companions is a natural consequence of dynamical interplay in small multiple systems, leading to ejection of members. We discuss observational consequences of this dynamical evolution, and its influence on circumstellar disks, and we review the evolution of circumbinary disks and their role in defining binary mass ratios. Special attention is paid to eclipsing PMS binaries, which allow for observational tests of evolutionary models of early stellar evolution. Many stars are born in clusters and small groups, and we discuss how interactions in dense stellar environments can significantly alter the distribution of binary separations through dissolution of wider binaries. The binaries and multiples we find in the field are the survivors of these internal and external destructive processes, and we provide a detailed overview of the multiplicity statistics of the field, which form a boundary condition for all models of binary evolution. Finally, we discuss various formation mechanisms for massive binaries, and the properties of massive trapezia.

  10. Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.

    Science.gov (United States)

    Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

    2018-04-01

    Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  11. Measurement of EPF for detection of cow pregnancy using rosette inhibition test.

    Science.gov (United States)

    Ghaffari Laleh, V; Ghaffari Laleh, R; Pirany, N; Moghadaszadeh Ahrabi, M

    2008-07-01

    Early embryonic death of calves due to sub-fertility in cows is of great economic concern to dairy industry. Early pregnancy factor (EPF) is a secretory protein with pregnancy associated immunosuppressive properties. Rosette inhibition test (RIT) was used to detect EPF in inseminated dairy cows. Blood samples were collected at two intervals, 1-3 and 5-7 days after insemination from 23 inseminated and 18 non-inseminated control cows for RIT and pregnancy diagnosis performed between 42 and 45 days on palpation. The study indicates that RIT (P<0.05) has the potential to distinguish pregnant from non-pregnant dairy cows in the first week of pregnancy.

  12. Informing early intervention: preschool predictors of anxiety disorders in middle childhood

    OpenAIRE

    Hudson, J. L.; Dodd, Helen F.

    2012-01-01

    Background: To inform early intervention practice, the present research examines how child anxiety, behavioural inhibition, maternal overinvolvement, maternal negativity, mother-child attachment and maternal anxiety, as assessed at age four, predict anxiety at age nine.\\ud \\ud Method: 202 children (102 behaviourally inhibited and 100 behaviourally uninhibited) aged 3–4 years were initially recruited and the predictors outlined above were assessed. Diagnostic assessments, using the Anxiety Dis...

  13. Biofilm formation and ethanol inhibition by bacterial contaminants of biofuel fermentation.

    Science.gov (United States)

    Rich, Joseph O; Leathers, Timothy D; Bischoff, Kenneth M; Anderson, Amber M; Nunnally, Melinda S

    2015-11-01

    Bacterial contaminants can inhibit ethanol production in biofuel fermentations, and even result in stuck fermentations. Contaminants may persist in production facilities by forming recalcitrant biofilms. A two-year longitudinal study was conducted of bacterial contaminants from a Midwestern dry grind corn fuel ethanol facility. Among eight sites sampled in the facility, the combined liquefaction stream and yeast propagation tank were consistently contaminated, leading to contamination of early fermentation tanks. Among 768 contaminants isolated, 92% were identified as Lactobacillus sp., with the most abundant species being Lactobacillus plantarum, Lactobacillus casei, Lactobacillus mucosae, and Lactobacillus fermentum. Seven percent of total isolates showed the ability to form biofilms in pure cultures, and 22% showed the capacity to significantly inhibit ethanol production. However, these traits were not correlated. Ethanol inhibition appeared to be related to acetic acid production by contaminants, particularly by obligately heterofermentative species such as L. fermentum and L. mucosae. Published by Elsevier Ltd.

  14. Inhibition of calcium phosphate precipitation under environmentally-relevant conditions

    International Nuclear Information System (INIS)

    Cao Xinde; Harris, Willie G.; Josan, Manohardeep S.; Nair, Vimala D.

    2007-01-01

    Precipitation of Ca phosphates plays an important role in controlling P activity and availability in environmental systems. The purpose of this study was to determine inhibitory effects on Ca phosphate precipitation by Mg 2+ , SO 4 2- , CO 3 2- , humic acid, oxalic acid, biogenic Si, and Si-rich soil clay commonly found in soils, sediments, and waste streams. Precipitation rates were determined by measuring decrease of P concentration in solutions during the first 60 min; and precipitated solid phases identified using X-ray diffraction and electron microscopy. Poorly-crystalline hydroxyapatite (HAP: Ca 5 (PO 4 ) 3 OH) formed in control solutions over the experiment period of 24 h, following a second-order dependence on P concentration. Humic acid and Mg 2+ significantly inhibited formation of HAP, allowing formation of a more soluble amorphous Ca phosphate phase (ACP), and thus reducing the precipitation rate constants by 94-96%. Inhibition caused by Mg 2+ results from its incorporation into Ca phosphate precipitates, preventing formation of a well-crystalline phase. Humic acid likely suppressed Ca phosphate precipitation by adsorbing onto the newly-formed nuclei. Presence of oxalic acid resulted in almost complete inhibition of HAP precipitation due to preemptive Ca-oxalate formation. Carbonate substituted for phosphate, decreasing the crystallinity of HAP and thus reducing precipitation rate constant by 44%. Sulfate and Si-rich solids had less impact on formation of HAP; while they reduced precipitation in the early stage, they did not differ from the control after 24 h. Results indicate that components (e.g., Mg 2+ , humic acid) producing relatively soluble ACP are more likely to reduce P stability and precipitation rate of Ca phosphate in soils and sediments than are components (e.g., SO 4 2- , Si) that have less effect on the crystallinity

  15. 75 FR 20830 - Early Learning

    Science.gov (United States)

    2010-04-21

    ... DEPARTMENT OF EDUCATION Early Learning AGENCY: Office of the Secretary, Department of Education... meetings and written submissions, is seeking input from State agencies responsible for early learning and... assistance providers, researchers of early learning, stakeholders who work with early learning and...

  16. Cognitive Development in Early Readers.

    Science.gov (United States)

    Briggs, Chari; Elkind, David

    Some studies of early readers are discussed. It is pointed out that study of early readers has relevance for practical and theoretical issues in psychology and education. Of interest in this document are the following questions: (1) Are there any special talents or traits distinguishing early from non-early readers? (2) Do children who read early…

  17. Inhibition of urinary calculi -- a spectroscopic study

    Science.gov (United States)

    Manciu, Felicia; Govani, Jayesh; Durrer, William; Reza, Layra; Pinales, Luis

    2008-10-01

    Although a considerable number of investigations have already been undertaken and many causes such as life habits, metabolic disorders, and genetic factors have been noted as sources that accelerate calculi depositions and aggregations, there are still plenty of unanswered questions regarding efficient inhibition and treatment mechanisms. Thus, in an attempt to acquire more insights, we propose here a detailed scientific study of kidney stone formation and growth inhibition based on a traditional medicine approach with Rotula Aquatica Lour (RAL) herbal extracts. A simplified single diffusion gel growth technique was used for synthesizing the samples for the present study. The unexpected Zn presence in the sample with RAL inhibitor, as revealed by XPS measurements, explains the inhibition process and the dramatic reflectance of the incident light observed in the infrared transmission studies. Raman data demonstrate potential binding of the inhibitor with the oxygen of the kidney stone. Photoluminescence results corroborate to provide additional evidence of Zn-related inhibition.

  18. Exogenously triggered response inhibition in developmental stuttering.

    Science.gov (United States)

    Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

    2018-06-01

    The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Hypnotic suggestibility, cognitive inhibition, and dissociation.

    Science.gov (United States)

    Dienes, Zoltán; Brown, Elizabeth; Hutton, Sam; Kirsch, Irving; Mazzoni, Giuliana; Wright, Daniel B

    2009-12-01

    We examined two potential correlates of hypnotic suggestibility: dissociation and cognitive inhibition. Dissociation is the foundation of two of the major theories of hypnosis and other theories commonly postulate that hypnotic responding is a result of attentional abilities (including inhibition). Participants were administered the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C. Under the guise of an unrelated study, 180 of these participants also completed: a version of the Dissociative Experiences Scale that is normally distributed in non-clinical populations; a latent inhibition task, a spatial negative priming task, and a memory task designed to measure negative priming. The data ruled out even moderate correlations between hypnotic suggestibility and all the measures of dissociation and cognitive inhibition overall, though they also indicated gender differences. The results are a challenge for existing theories of hypnosis.

  20. Corrosion inhibition by lithium zinc phosphate pigment

    International Nuclear Information System (INIS)

    Alibakhshi, E.; Ghasemi, E.; Mahdavian, M.

    2013-01-01

    Highlights: •Synthesis of lithium zinc phosphate (LZP) by chemical co-precipitation method. •Corrosion inhibition activity of pigments compare with zinc phosphate (ZP). •LZP showed superior corrosion inhibition effect in EIS measurements. •Evaluation of adhesion strength and dispersion stability. -- Abstract: Lithium zinc phosphate (LZP) has been synthesized through a co-precipitation process and characterized by XRD and IR spectroscopy. The inhibitive performances of this pigment for corrosion of mild steel have been discussed in comparison with the zinc phosphate (ZP) in the pigment extract solution by means of EIS and in the epoxy coating by means of salt spray. The EIS and salt spray results revealed the superior corrosion inhibitive effect of LZP compared to ZP. Moreover, adhesion strength and dispersion stability of the pigmented epoxy coating showed the advantage of LZP compared to ZP

  1. NMDAR inhibition-independent antidepressant actions of ketamine metabolites

    Science.gov (United States)

    Zanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S.S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate, Carlos A.; Gould, Todd D.

    2016-01-01

    Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants. PMID:27144355

  2. Mycobacterial growth inhibition is associated with trained innate immunity.

    Science.gov (United States)

    Joosten, Simone A; van Meijgaarden, Krista E; Arend, Sandra M; Prins, Corine; Oftung, Fredrik; Korsvold, Gro Ellen; Kik, Sandra V; Arts, Rob Jw; van Crevel, Reinout; Netea, Mihai G; Ottenhoff, Tom Hm

    2018-05-01

    The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset.

  3. Introduction to "Early psychosis

    DEFF Research Database (Denmark)

    McGorry, Patrick; Nordentoft, Merete; Simonsen, Erik

    2005-01-01

    warrants careful analysis. The Third International Early Psychosis Conference proved to be a watershed and was the largest and most vibrant meeting to that point. This preface aims to set the scene for a selection of contributions, derived from the array of new evidence reported in Copenhagen, and recently...

  4. Early Functional Abilities

    DEFF Research Database (Denmark)

    Lorentzen, Jakob; Poulsen, Ingrid

    2005-01-01

    Early Functional Abilities (EFA), - en skala til evaluering af behandlingsforløb af svært hjerneskadede patienter i forbindelse med tidlig rehabilitering. Formål At monitorere og dokumentere rehabiliteringsforløbet for svært hjerneskadede patienter, hvor funktionsniveauet endnu ikke kan registreres...

  5. Early Islamic Syria

    DEFF Research Database (Denmark)

    Walmsley, Alan George

    This book presents a new interpretation of social and economic developments in Syria-Palestine in the decades before and during the two centuries after the Islamic expansion into the region (roughly the later 6th to the early 9th century AD). Drawing on a wide range of evidence from recent...

  6. Teaching polymorphism early

    DEFF Research Database (Denmark)

    2005-01-01

    Is it possible to teach dynamic polymorphism early? What techniques could facilitate teaching it in Java. This panel will bring together people who have considered this question and attempted to implement it in various ways, some more completely than others. It will also give participants...

  7. Early childhood aggression

    NARCIS (Netherlands)

    Alink, Lenneke Rosalie Agnes

    2006-01-01

    In this thesis the development, stability, and correlates of early childhood aggression were investigated. The normative development was examined in a general population sample using questionnaires completed by the parents of 12-, 24-, and 36-month-old children and again one year later. Results

  8. Characteristics of early psychosis

    NARCIS (Netherlands)

    Schothorst, P.F.; Emck, C.; van Engeland, H.

    2006-01-01

    There is little research on characteristics related to course and prognosis of early-onset psychosis. The present article aims to advance our knowledge of this disorder for the purpose of proper diagnosis and treatment. It focuses on premorbid and prodromal characteristics, treatment history,

  9. Early practice: neurotology.

    Science.gov (United States)

    Breen, Joseph T; Vrabec, Jeffrey T

    2015-04-01

    Besides technical and surgical proficiency, some of the most important skills for a young Neurotologist to refine include communication and critical thinking abilities. This Early Practice article provides perspectives on common challenges and career development from a current Neurotology fellow and his mentor. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Early Building Design

    DEFF Research Database (Denmark)

    Østergård, Torben; Jensen, Rasmus Lund; Maagaard, Steffen

    2017-01-01

    Highlights •Development of a design methodology that can handle the vast design space in early building design. •A global design space is modelled from extensive Monte Carlo simulations. •Sensitivity analysis methods applied to guide decision-makers. •Interactive visualizations help the multi-act...

  11. Early Childhood Trauma

    Science.gov (United States)

    National Child Traumatic Stress Network, 2010

    2010-01-01

    Early childhood trauma generally refers to the traumatic experiences that occur to children aged 0-6. Because infants' and young children's reactions may be different from older children's, and because they may not be able to verbalize their reactions to threatening or dangerous events, many people assume that young age protects children from the…

  12. Early death, late death and repair factor in three human tumour cell lines

    International Nuclear Information System (INIS)

    Courdi, A.; Gioanni, J.; Mari, D.; Chauvel, P.

    1997-01-01

    The in vivo colony method used to generate survival curves following exposure to ionizing irradiation allows to score large clones, representing surviving cells, and small colonies, representing late reproductive death. By subtraction, early-dying cells can be estimated. In the three human tumour cell lines examined, we have observed that early cell death is a major mode of action of irradiation. The contribution of early cell death to total mortality increases as the dose increases. Moreover, repair due to dose-splitting and delayed plating in densely-inhibited cells is not observed in early-dying cells. (authors)

  13. Human milk glycoconjugates that inhibit pathogens.

    Science.gov (United States)

    Newburg, D S

    1999-02-01

    Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.

  14. [The early pregnancy factor (EPF) as an early marker of disorders in pregnancy].

    Science.gov (United States)

    Straube, W; Römer, T; Zeenni, L; Loh, M

    1995-01-01

    The early pregnancy factor (EPF) seems to be very helpful in clinical applications such as early detection of pregnancy, differential diagnosis of failure of fertilization or implementation and prognosis of a fertilized ovum. Our purpose was to investigate the diagnostic value of single and serial measurement of EPF, especially in the differential diagnosis of abortion and extrauterine pregnancy. Women with a history of 6-16 weeks amenorrhoea with/without vaginal bleeding were included in the prospective study. The EPF-test system was carried out by means of the rosette inhibition method. EPF proved to be always positive in normal pregnant women and always negative in nonpregnant controls. In case of threatened abortion the prognosis was good, when the EPF values were positive, and poor when they became negative. Patients suffering from spontaneous and missed abortion mostly showed negative EPF-values. This was also true in ectopic pregnancies. The sensitivity and specificity of EPF-test system were 83%. The positive predictive value was observed to be 54% and the negative predictive value 95%. The EPF as an early embryonic signal may be a suitable parameter for the clinical use detecting pregnancy disturbances very early.

  15. Wild Honey Inhibits Growth od Some Phytopathogenic Fungi in vitro

    OpenAIRE

    K.I. Al-Mughrabi

    2003-01-01

    Wild honey was diluted to 1000 ppm with sterile distilled water and tested in vitro for inhibition of the plant pathogenic fungi Fusarium oxysporum, Rhizoctonia solani, Alternaria solani, Stemphylium solani, Colletotrichum sp., and Phytophthora infestans. Wild honey was effective against all these fungi, particularly A. solani and P. infestans, the causal agents of early and late blight diseases respectively; also against R. solani and F. oxysporum, and to a less extent against S....

  16. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  17. Complex living conditions impair behavioral inhibition but improve attention in rats

    Directory of Open Access Journals (Sweden)

    Rixt evan der Veen

    2015-12-01

    Full Text Available Rapid adaptation to changes, while maintaining a certain level of behavioral inhibition is an important feature in every day functioning. How environmental context and challenges in life can impact on the development of this quality is still unknown. In the present study, we examined the effect of a complex rearing environment during adolescence on attention and behavioral inhibition in adult male rats. We also tested whether these effects were affected by an adverse early life challenge, maternal deprivation. We found that animals that were raised in large, two floor MarlauTM cages, together with 10 conspecifics, showed improved attention, but impaired behavioral inhibition in the 5-choice serial reaction time task. The early life challenge of 24h maternal deprivation on postnatal day 3 led to a decline in bodyweight during adolescence, but did not by itself influence responses in the 5-choice task in adulthood, nor did it moderate the effects of complex housing. Our data suggest that a complex rearing environment leads to a faster adaptation to changes in the environment, but at the cost of lower behavioral inhibition.

  18. The Ustilago maydis effector Pep1 suppresses plant immunity by inhibition of host peroxidase activity.

    Directory of Open Access Journals (Sweden)

    Christoph Hemetsberger

    Full Text Available The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1 as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of Δpep1 mutant penetrations, H₂O₂ strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the Δpep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

  19. Sulindac metabolites inhibit epidermal growth factor receptor activation and expression

    Directory of Open Access Journals (Sweden)

    Ahnen Dennis

    2005-01-01

    Full Text Available Abstract Background Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs is associated with a decreased mortality from colorectal cancer (CRC. NSAIDs induce apoptotic cell death in colon cancer cells in vitro and inhibit growth of neoplastic colonic mucosa in vivo however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2 signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF receptor (EGFR. Methods HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068, total EGFR, phosphorylated ERK1/2 (pERK1/2, total ERK1/2, activated caspase-3, and α-tubulin. Results EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation. Conclusion These results suggest that

  20. Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells

    Energy Technology Data Exchange (ETDEWEB)

    Conde, Patricia; Acosta-Saavedra, Leonor C.; Calderon-Aranda, Emma S. [Centro de Investigacion y de Estudios Avanzados, CINVESTAV, Seccion Toxicologia, P.O. Box 14-740, Mexico, D.F. (Mexico); Goytia-Acevedo, Raquel C. [Universidad Juarez del Estado de Durango, Facultad de Medicina, Gomez Palacio, Durango (Mexico)

    2007-04-15

    A proposed mechanism for the As-induced inhibition of cell proliferation is the inhibition of IL-2 secretion. However, the effects of arsenite on IL-2 mRNA expression or on the ERK pathway in activated-T cells have not yet been described. We examined the effect of arsenite on IL-2 mRNA expression, cell activation and proliferation in PHA-stimulated murine lymphocytes. Arsenite (1 and 10 {mu}M) decreased IL-2 mRNA expression, IL-2 secretion and cell proliferation. Arsenite (10 {mu}M) strongly inhibited ERK-phosphorylation. However, the partial inhibition (50%) of IL-2 mRNA produced by 1 {mu}M, consistent with the effects on IL-2 secretion and cell proliferation, could not be explained by the inhibition of ERK-phosphorylation, which was not affected at this concentration. The inhibition of IL-2 mRNA expression caused by 1 {mu}M could be associated to effects on pathways located downstream or parallel to ERK. Arsenite also decreased early activation (surface CD69{sup +} expression) in both CD4{sup +} and CD8{sup +}, and decreased total CD8{sup +} count without significantly affecting CD4{sup +}, supporting that the cellular immune response mediated by cytotoxic T cells is an arsenic target. Thus, our results suggest that arsenite decreases IL-2 mRNA levels and T-cell activation and proliferation. However, further studies on the effects of arsenite on IL-2 gene transcription and IL-2 mRNA stability are needed. (orig.)

  1. Impaired GABAergic Inhibition in the Prefrontal Cortex of Early Postnatal Phencyclidine (PCP)-Treated Rats

    DEFF Research Database (Denmark)

    Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe

    2014-01-01

    A compromised ¿-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-d-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmissio...... postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life....

  2. Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells

    OpenAIRE

    Duan, Yuntao; Wang, Shih-Hsiu; Song, Juan; Mironova, Yevgeniya; Ming, Guo-li; Kolodkin, Alex L; Giger, Roman J

    2014-01-01

    eLife digest Neurons communicate with one another at specialized junctions called synapses. There are two types of synapses, called excitatory synapses and inhibitory synapses, and the density and strength of both are tightly regulated because small deviations from the normal density and/or strength may lead to illness. For example, an excess of excitatory synapses has been observed in patients who have autism spectrum disorders and exhibit difficulties in social interaction. The gene that co...

  3. Early Detection and Screening for Breast Cancer.

    Science.gov (United States)

    Coleman, Cathy

    2017-05-01

    To review the history, current status, and future trends related to breast cancer screening. Peer-reviewed articles, web sites, and textbooks. Breast cancer remains a complex, heterogeneous disease. Serial screening with mammography is the most effective method to detect early stage disease and decrease mortality. Although politics and economics may inhibit organized mammography screening programs in many countries, the judicious use of proficient clinical and self-breast examination can also identify small tumors leading to reduced morbidity. Oncology nurses have exciting opportunities to lead, facilitate, and advocate for delivery of high-quality screening services targeting individuals and communities. A practical approach is needed to translate the complexities and controversies surrounding breast cancer screening into improved care outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  5. Early prenatal syphilis

    Directory of Open Access Journals (Sweden)

    Santosh Rathod

    2010-01-01

    Full Text Available Syphilis in pregnancy still remains a challenge despite the availability of adequate diagnostic tests for serological screening and penicillin therapy. We report a case of 2 month old female infant who presented with runny nose, papulosquamous lesions over both palms and soles and perianal erosions since 1 month after birth. Cutaneous examination revealed moist eroded areas in the perianal region and fine scaly lesions over palms and soles. Radiograph of both upper limbs and limbs revealed early periosteal changes in lower end of humerus and lower end of tibia. Diagnosis of early pre-natal syphilis was confirmed by Child′s Serum Rapid Plasma Reagin Antibody test [S.RPR] being positive with 1:64 dilution while that of mother was 1:8.

  6. Early Childhood Caries

    Directory of Open Access Journals (Sweden)

    Yumiko Kawashita

    2011-01-01

    Full Text Available Dental caries is one of the most common childhood diseases, and people continue to be susceptible to it throughout their lives. Although dental caries can be arrested and potentially even reversed in its early stages, it is often not self-limiting and progresses without proper care until the tooth is destroyed. Early childhood caries (ECC is often complicated by inappropriate feeding practices and heavy infection with mutans streptococci. Such children should be targeted with a professional preventive program that includes oral hygiene instructions for mothers or caregivers, along with fluoride and diet counseling. However, these strategies alone are not sufficient to prevent dental caries in high-risk children; prevention of ECC also requires addressing the socioeconomic factors that face many families in which ECC is endemic. The aim of this paper is to systematically review information about ECC and to describe why many children are suffering from dental caries.

  7. Inhibition of pancreatic tumoral cells by snake venom disintegrins.

    Science.gov (United States)

    Lucena, Sara; Castro, Roberto; Lundin, Courtney; Hofstetter, Amanda; Alaniz, Amber; Suntravat, Montamas; Sánchez, Elda Eliza

    2015-01-01

    Pancreatic cancer often has a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads rapidly and is rarely detected in its early stages, which is a major reason it is a leading cause of cancer death. Signs and symptoms may not appear until pancreatic cancer is quite advanced, and complete surgical removal is not possible. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. The importance of integrins in several cell types that affect tumor progression has made them an appealing target for cancer therapy. Some of the proteins found in the snake venom present a great potential as anti-tumor agents. In this study, we summarize the activity of two integrins antagonist, recombinant disintegrins mojastin 1 and viridistatin 2, on human pancreatic carcinoma cell line (BXPC-3). Both recombinant disintegrins inhibited some essential aspects of the metastasis process such as proliferation, adhesion, migration, and survival through apoptosis, making these proteins prominent candidates for the development of drugs for the treatment of pancreatic cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Perceptual load-dependent neural correlates of distractor interference inhibition.

    Directory of Open Access Journals (Sweden)

    Jiansong Xu

    2011-01-01

    Full Text Available The load theory of selective attention hypothesizes that distractor interference is suppressed after perceptual processing (i.e., in the later stage of central processing at low perceptual load of the central task, but in the early stage of perceptual processing at high perceptual load. Consistently, studies on the neural correlates of attention have found a smaller distractor-related activation in the sensory cortex at high relative to low perceptual load. However, it is not clear whether the distractor-related activation in brain regions linked to later stages of central processing (e.g., in the frontostriatal circuits is also smaller at high rather than low perceptual load, as might be predicted based on the load theory.We studied 24 healthy participants using functional magnetic resonance imaging (fMRI during a visual target identification task with two perceptual loads (low vs. high. Participants showed distractor-related increases in activation in the midbrain, striatum, occipital and medial and lateral prefrontal cortices at low load, but distractor-related decreases in activation in the midbrain ventral tegmental area and substantia nigra (VTA/SN, striatum, thalamus, and extensive sensory cortices at high load.Multiple levels of central processing involving midbrain and frontostriatal circuits participate in suppressing distractor interference at either low or high perceptual load. For suppressing distractor interference, the processing of sensory inputs in both early and late stages of central processing are enhanced at low load but inhibited at high load.

  9. Perceptual load-dependent neural correlates of distractor interference inhibition.

    Science.gov (United States)

    Xu, Jiansong; Monterosso, John; Kober, Hedy; Balodis, Iris M; Potenza, Marc N

    2011-01-18

    The load theory of selective attention hypothesizes that distractor interference is suppressed after perceptual processing (i.e., in the later stage of central processing) at low perceptual load of the central task, but in the early stage of perceptual processing at high perceptual load. Consistently, studies on the neural correlates of attention have found a smaller distractor-related activation in the sensory cortex at high relative to low perceptual load. However, it is not clear whether the distractor-related activation in brain regions linked to later stages of central processing (e.g., in the frontostriatal circuits) is also smaller at high rather than low perceptual load, as might be predicted based on the load theory. We studied 24 healthy participants using functional magnetic resonance imaging (fMRI) during a visual target identification task with two perceptual loads (low vs. high). Participants showed distractor-related increases in activation in the midbrain, striatum, occipital and medial and lateral prefrontal cortices at low load, but distractor-related decreases in activation in the midbrain ventral tegmental area and substantia nigra (VTA/SN), striatum, thalamus, and extensive sensory cortices at high load. Multiple levels of central processing involving midbrain and frontostriatal circuits participate in suppressing distractor interference at either low or high perceptual load. For suppressing distractor interference, the processing of sensory inputs in both early and late stages of central processing are enhanced at low load but inhibited at high load.

  10. Attention and inhibition in Mild Cognitive Impairment and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Clara Zancada-Menéndez

    2013-12-01

    Full Text Available Mild cognitive impairment is understood as a cognitive deficit of insufficient severity to fulfil the criteria for Alzheimer’s disease. Many studies have attempted to identify which cognitive functions are most affected by this type of impairment and which is the most sensitive neuropsychological test for early detection. This study investigated sustained and selective attention, processing speed, and the inhibition process using a sample of people divided into three groups mild cognitive impairment, Alzheimer disease and cognitively healthy controls selected and grouped based on their scores in the Mini Mental State Examination and Cambridge Cognitive Examination-revised. Three tests from the Cambridge Neuropsychological Test Automated Battery (Motor Screening Task, Stop Signal Task and Reaction time were used as well as the d2 attention test. The results show that that participants with mild cognitive impairment and Alzheimer disease showed lower levels of concentration compared with the cognitively healthy controls group in the d2 test and longer reaction times in the Cambridge Neuropsychological Test Automated Battery, although the differences were not marked in the latter test. The impairments in basic cognitive processes, such as reaction time and sustained attention, indicate the need to take these functions into account in the test protocols when discriminating between normal aging and early and preclinical dementia processes.

  11. Mapping the early Universe

    International Nuclear Information System (INIS)

    Anon.

    1991-01-01

    From its unique vantage point 900 kilometres above the earth's surface, NASA's Cosmic Background Explorer (COBE) satellite has a privileged view of cosmic background radiation - the remnants of the early (radiation-dominated) Universe which followed the Big Bang some ten Gigayears ago, and possibly some subsequent history. In this way astroparticle physicists get a first peek at the quantum cosmology which moulded the infant Universe

  12. Earthquake Early Warning Systems

    OpenAIRE

    Pei-Yang Lin

    2011-01-01

    Because of Taiwan’s unique geographical environment, earthquake disasters occur frequently in Taiwan. The Central Weather Bureau collated earthquake data from between 1901 and 2006 (Central Weather Bureau, 2007) and found that 97 earthquakes had occurred, of which, 52 resulted in casualties. The 921 Chichi Earthquake had the most profound impact. Because earthquakes have instant destructive power and current scientific technologies cannot provide precise early warnings in advance, earthquake ...

  13. Coaching in Early Mathematics.

    Science.gov (United States)

    Germeroth, Carrie; Sarama, Julie

    2017-01-01

    Falling scores in math have prompted a renewed interest in math instruction at early ages. By their own admission, early childhood educators are generally underprepared and not always comfortable teaching math. Professional development (PD) in early mathematics is widely considered a main way to increase teachers' skills and efficacy (e.g., Guskey, 2000; Hyson & Woods, 2014; Munby, Russell, & Martin, 2001; Piasta, Logan, Pelatti, Capps, & Petrill, 2015; Richardson & Placier, 2001; Sarama, Clements, Wolfe, & Spitler, 2016; Sarama & DiBiase, 2004; Zaslow, 2014). However, it has been documented that stand-alone PD is not as effective in changing practice (e.g., Biancarosa & Bryk, 2011; Garet et al., 2008; Guskey, 2000; Hyson & Woods, 2014; Institute of Medicine and National Research Council, 2015; Joyce & Showers, 2002; Zaslow, 2014). Site-embedded ongoing support in the form of coaching or mentoring has been shown to be critical for successful implementation (Neuman & Cunningham, 2009; Powell, Diamond, Burchinal, & Koehler, 2010). In this chapter, we describe coaching models and abstract characteristics of effective coaching from the research. With this background, we provide an in-depth view of the coaching aspect of two large empirical studies in early mathematics. We introduce the theoretical framework from which the coaching models for these projects were developed and describe the research on which they were based. We then summarize how the planned models were instantiated and challenges to their implementation within each project. In the final section, we summarize what we have learned and described implications and challenges for the field. © 2017 Elsevier Inc. All rights reserved.

  14. Early prevention of obesity

    OpenAIRE

    Claudio Maffeis

    2014-01-01

    Childhood obesity is the metabolic disorder with the highest prevalence in both children and adults. Urgency to treat and prevent childhood obesity is based on the clear evidence that obesity tends to track from childhood to adulthood, is associated to morbidity also in childhood and to long-term mortality. Early life, i.e., intrauterine life and the first two years, is a sensitive window for prevention. Anatomical and functional maturation of the hypothalamic structures devoted to regulating...

  15. Hands of early primates.

    Science.gov (United States)

    Boyer, Doug M; Yapuncich, Gabriel S; Chester, Stephen G B; Bloch, Jonathan I; Godinot, Marc

    2013-12-01

    Questions surrounding the origin and early evolution of primates continue to be the subject of debate. Though anatomy of the skull and inferred dietary shifts are often the focus, detailed studies of postcrania and inferred locomotor capabilities can also provide crucial data that advance understanding of transitions in early primate evolution. In particular, the hand skeleton includes characteristics thought to reflect foraging, locomotion, and posture. Here we review what is known about the early evolution of primate hands from a comparative perspective that incorporates data from the fossil record. Additionally, we provide new comparative data and documentation of skeletal morphology for Paleogene plesiadapiforms, notharctines, cercamoniines, adapines, and omomyiforms. Finally, we discuss implications of these data for understanding locomotor transitions during the origin and early evolutionary history of primates. Known plesiadapiform species cannot be differentiated from extant primates based on either intrinsic hand proportions or hand-to-body size proportions. Nonetheless, the presence of claws and a different metacarpophalangeal [corrected] joint form in plesiadapiforms indicate different grasping mechanics. Notharctines and cercamoniines have intrinsic hand proportions with extremely elongated proximal phalanges and digit rays relative to metacarpals, resembling tarsiers and galagos. But their hand-to-body size proportions are typical of many extant primates (unlike those of tarsiers, and possibly Teilhardina, which have extremely large hands). Non-adapine adapiforms and omomyids exhibit additional carpal features suggesting more limited dorsiflexion, greater ulnar deviation, and a more habitually divergent pollex than observed plesiadapiforms. Together, features differentiating adapiforms and omomyiforms from plesiadapiforms indicate increased reliance on vertical prehensile-clinging and grasp-leaping, possibly in combination with predatory behaviors in

  16. Early Detection Of Cancer

    Directory of Open Access Journals (Sweden)

    V B Bhatnagar

    1987-04-01

    Full Text Available Farly detection of cancer is based upon three fundamental assumptions, firstly that the trea'ment of benign and precancerous lesions reduces the incidence of cancer, secondly, that the treatment of in situ cancers is conducive to total cure and thirdly that early diagnosis and management of invasive cancer ensures be.ter survival. When patient seeks medical advice for vague symptoms, which could however be due to a possible malignant tumour at a particular site, the alert clinician should investigate the patient immediately to exclude cancer. At this stage cancer is usually not significantly advanced. Currently the U. I. C. C. (International Union for Cancer Control} is studying the epidemiology of cancers in various countries The importance of this is two folds : Firstly by focussing attention on a section of population vulnerable to a particular cancer an early detection is facilitated Secondly by changing the causative factors responsible to a particular cancer, the incidence of that cancer can be reduced e. g. reduction in lung cancer following campaigns against ciguette smoking and reductioi in breast cancer after campaigns for advocating breast feeding of infants, lowering fat consumption and encouraging self palpation of breast regularly. Indeed early diagnosis of cancer implies diagnosis of cancer in almost a symptomatic stage It involves motiva’ion of the population towards acquisitio : of knowledge, attitude and practice.. Epidemiologies and clinicians should be able to recognise high risk cases exposed to particular neoplasia and knowledge of alarming symptoms should be pro- pogated for wide publicity through common available media and means. Probable cases should have regular clhrcal examination periodically and relevant investigations including radiological, imaging techniques and Bio-Chemical examination should be undertaken as and when desired Suspicious lesions should be investigated by specific tests including smear cytology

  17. PHOBOS, the Early Years

    Science.gov (United States)

    Stephans, George S. F.; Back, B. B.; Baker, M. D.; Barton, D. S.; Betts, R. R.; Ballintijn, M.; Bickley, A. A.; Bindel, R.; Budzanowski, A.; Busza, W.; Carroll, A.; Decowski, M. P.; Garcia, E.; George, N.; Gulbrandsen, K.; Gushue, S.; Halliwell, C.; Hamblen, J.; Heintzelman, G. A.; Henderson, C.; Hofman, D. J.; Hollis, R. S.; Holynski, R.; Holzman, B.; Iordanova, A.; Johnson, E.; Kane, J. L.; Katzy, J.; Khan, N.; Kucewicz, W.; Kulinich, P.; Kuo, C. M.; Lin, W. T.; Manly, S.; McLeod, D.; Michalowski, J.; Mignerey, A. C.; Nouicer, R.; Olszewski, A.; Pak, R.; Park, I. C.; Pernegger, H.; Reed, C.; Remsberg, L. P.; Reuter, M.; Roland, C.; Roland, G.; Rosenberg, L.; Sagerer, J.; Sarin, P.; Sawicki, P.; Skulski, W.; Steadman, S. G.; Steinberg, P.; Stephans, G. S. F.; Stodulski, M.; Sukhanov, A.; Tang, J.-L.; Teng, R.; Trzupek, A.; Vale, C.; van Nieuwenhuizen, G. J.; Verdier, R.; Wadsworth, B.; Wolfs, F. L. H.; Wosiek, B.; Wozniak, K.; Wuosmaa, A. H.; Wyslouch, B.

    2002-06-01

    The PHOBOS detector, one of the two small experiments at RHIC, focuses on measurements of charged particle multiplicity over almost the full phase space and identified particles near mid-rapidity. Results will be presented from the early RHIC gold--gold runs at nucleon--nucleon center of mass energies of 56 and 130 GeV as well as the recently concluded run at the full RHIC energy of 200 GeV.

  18. Mapping the early Universe

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1991-06-15

    From its unique vantage point 900 kilometres above the earth's surface, NASA's Cosmic Background Explorer (COBE) satellite has a privileged view of cosmic background radiation - the remnants of the early (radiation-dominated) Universe which followed the Big Bang some ten Gigayears ago, and possibly some subsequent history. In this way astroparticle physicists get a first peek at the quantum cosmology which moulded the infant Universe.

  19. Early breast cancer

    International Nuclear Information System (INIS)

    Dongen, J.A. van

    1989-01-01

    The therapy of early breast cancer has been changing during the last decennium. It requires a multi-disciplinary approach and in each of these disciplines improvements have been implemented. The result is that treatment schedules can now be adapted to specific subgroups. In this review early breast cancer is defined as operable disease, using the criteria set out by Haagensen. Emphasis is given to describing the new developments in prognostic criteria, since these form the basis for creating subgroups for specific treatment schedules. Distinction is made between the factors relating to growth rate and those relating to metastatic potential. Data on screening promises a beneficial effect of the implementation of screening in national health care programs. Important shifts are seen in treatment schedules; the place of postoperative radiotherapy after classic ablative treatment is being challenged, whereas it plays a major role in the new breast conserving therapy schedules. The data mentioned in the review suggest that a large proportion of 'operable' cases can be treated with breast conservation but details in the technique of breast conserving therapy are still under investigation. They form a major part of the coming prospective studies in breast cancer. Improvements in reconstruction techniques, creating better cosmetic results, make reconstruction more competitive with breast conserving therapy. The use of chemotherapy and endocrine manipulation in early breast cancer has now been clearly confirmed by the overview technique by the Peto-group, thanks to all efforts of individual trialists together. (orig.)

  20. Fucoidan, a Sulfated Polysaccharide, Inhibits Osteoclast Differentiation and Function by Modulating RANKL Signaling

    Directory of Open Access Journals (Sweden)

    Young Woo Kim

    2014-10-01

    Full Text Available Multinucleated osteoclasts differentiate from hematopoietic progenitors of the monocyte/macrophage lineage. Because of its pivotal role in bone resorption, regulation of osteoclast differentiation is a potential therapeutic approach to the treatment of erosive bone disease. In this study, we have found that fucoidan, a sulfated polysaccharide extracted from brown seaweed, inhibited osteoclast differentiation. In particular, addition of fucoidan into the early stage osteoclast cultures significantly inhibited receptor activator of nuclear factor kappa B (NF-κB ligand (RANKL-induced osteoclast formation, thus suggesting that fucoidan affects osteoclast progenitors. Furthermore, fucoidan significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases (MAPKs such as JNK, ERK, and p38, and also c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. In addition, the activation of NF-κB, which is an upstream transcription factor modulating NFATc1 expression, was alleviated in the fucoidan-treated cells. These results collectively suggest that fucoidan inhibits osteoclastogenesis from bone marrow macrophages by inhibiting RANKL-induced p38, JNK, ERK and NF-κB activation, and by downregulating the expression of genes that partake in both osteoclast differentiation and resorption.

  1. Global phosphotyrosine proteomics identifies PKCδ as a marker of responsiveness to Src inhibition in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Eliot T McKinley

    Full Text Available Sensitive and specific biomarkers of protein kinase inhibition can be leveraged to accelerate drug development studies in oncology by associating early molecular responses with target inhibition. In this study, we utilized unbiased shotgun phosphotyrosine (pY proteomics to discover novel biomarkers of response to dasatinib, a small molecule Src-selective inhibitor, in preclinical models of colorectal cancer (CRC. We performed unbiased mass spectrometry shotgun pY proteomics to reveal the pY proteome of cultured HCT-116 colonic carcinoma cells, and then extended this analysis to HCT-116 xenograft tumors to identify pY biomarkers of dasatinib-responsiveness in vivo. Major dasatinib-responsive pY sites in xenograft tumors included sites on delta-type protein kinase C (PKCδ, CUB-domain-containing protein 1 (CDCP1, Type-II SH2-domain-containing inositol 5-phosphatase (SHIP2, and receptor protein-tyrosine phosphatase alpha (RPTPα. The pY313 site PKCδ was further supported as a relevant biomarker of dasatinib-mediated Src inhibition in HCT-116 xenografts by immunohistochemistry and immunoblotting with a phosphospecific antibody. Reduction of PKCδ pY313 was further correlated with dasatinib-mediated inhibition of Src and diminished growth as spheroids of a panel of human CRC cell lines. These studies reveal PKCδ pY313 as a promising readout of Src inhibition in CRC and potentially other solid tumors and may reflect responsiveness to dasatinib in a subset of colorectal cancers.

  2. Aging Potentiates Lateral but Not Local Inhibition of Orientation Processing in Primary Visual Cortex

    Directory of Open Access Journals (Sweden)

    Zhengchun Wang

    2018-02-01

    Full Text Available Aging-related declines in vision can decrease well-being of the elderly. Concerning early sensory changes as in the primary visual cortex, physiological and behavioral reports seem contradictory. Neurophysiological studies on orientation tuning properties suggested that neuronal changes might come from decreased cortical local inhibition. However, behavioral results either showed no clear deficits in orientation processing in older adults, or proposed stronger surround suppression. Through psychophysical experiments and computational modeling, we resolved these discrepancies by suggesting that lateral inhibition increased in older adults while neuronal orientation tuning widths, related to local inhibition, stayed globally intact across age. We confirmed this later result by re-analyzing published neurophysiological data, which showed no systematic tuning width changes, but instead displayed a higher neuronal noise with aging. These results suggest a stronger lateral inhibition and mixed effects on local inhibition during aging, revealing a more complex picture of age-related effects in the central visual system than people previously thought.

  3. Early intervention as a catalyst for effective early childhood ...

    African Journals Online (AJOL)

    ... of positive attitudes towards children with disabilities in a country like Ghana. ... As Ghana strides towards mainstreaming early childhood education in the quest ... an integrated, inclusive and effective early intervention programme becomes ...

  4. Early Discontinuation of Metformin in Individuals Treated with Inhibitors of Transporters of Metformin

    DEFF Research Database (Denmark)

    Stage, Tore Bjerregaard; Lee, Moa P; Hallas, Jesper

    2016-01-01

    The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132......,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and four negative controls. Increased odds ratio of early discontinuation of metformin was only associated with codeine...... drugs were associated with a decreased risk. These findings indicate that codeine use may be associated with risk of early discontinuation of metformin and could be used as a basis for further investigation....

  5. Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

    Science.gov (United States)

    Bunnell, Bryan E; Escobar, Jillian F; Bair, Kirsten L; Sutton, Mark D; Crane, John K

    2017-01-01

    Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

  6. Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Bryan E Bunnell

    Full Text Available Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

  7. Dopamine inhibits somatolactin gene expression in tilapia pituitary cells through the dopamine D2 receptors.

    Science.gov (United States)

    Jiang, Quan; Lian, Anji; He, Qi

    2016-07-01

    Dopamine (DA) is an important neurotransmitter in the central nervous system of vertebrates and possesses key hypophysiotropic functions. Early studies have shown that DA has a potent inhibitory effect on somatolactin (SL) release in fish. However, the mechanisms responsible for DA inhibition of SL gene expression are largely unknown. To this end, tilapia DA type-1 (D1) and type-2 (D2) receptor transcripts were examined in the neurointermediate lobe (NIL) of the tilapia pituitary by real-time PCR. In tilapia, DA not only was effective in inhibiting SL mRNA levels in vivo and in vitro, but also could abolish pituitary adenylate cyclase-activating polypeptide (PACAP)- and salmon gonadotropin-releasing hormone (sGnRH)-stimulated SL gene expression at the pituitary level. In parallel studies, the specific D2 receptor agonists quinpirole and bromocriptine could mimic the DA-inhibited SL gene expression. Furthermore, the D2 receptor antagonists domperidone and (-)-sulpiride could abolish the SL response to DA or the D2 agonist quinpirole, whereas D1 receptor antagonists SCH23390 and SKF83566 were not effective in this respect. In primary cultures of tilapia NIL cells, D2 agonist quinpirole-inhibited cAMP production could be blocked by co-treatment with the D2 antagonist domperidone and the ability of forskolin to increase cAMP production was also inhibited by quinpirole. Using a pharmacological approach, the AC/cAMP pathway was shown to be involved in quinpirole-inhibited SL mRNA expression. These results provide evidence that DA can directly inhibit SL gene expression at the tilapia pituitary level via D2 receptor through the AC/cAMP-dependent mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Aspartate inhibits Staphylococcus aureus biofilm formation.

    Science.gov (United States)

    Yang, Hang; Wang, Mengyue; Yu, Junping; Wei, Hongping

    2015-04-01

    Biofilm formation renders Staphylococcus aureus highly resistant to conventional antibiotics and host defenses. Four D-amino acids (D-Leu, D-Met, D-Trp and D-Tyr) have been reported to be able to inhibit biofilm formation and disassemble established S. aureus biofilms. We report here for the first time that both D- and L-isoforms of aspartate (Asp) inhibited S. aureus biofilm formation on tissue culture plates. Similar biofilm inhibition effects were also observed against other staphylococcal strains, including S. saprophyticus, S. equorum, S. chromogenes and S. haemolyticus. It was found that Asp at high concentrations (>10 mM) inhibited the growth of planktonic N315 cells, but at subinhibitory concentrations decreased the cellular metabolic activity without influencing cell growth. The decreased cellular metabolic activity might be the reason for the production of less protein and DNA in the matrix of the biofilms formed in the presence of Asp. However, varied inhibition efficacies of Asp were observed for biofilms formed by clinical staphylococcal isolates. There might be mechanisms other than decreasing the metabolic activity, e.g. the biofilm phenotypes, affecting biofilm formation in the presence of Asp. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Simvastatin inhibits Candida albicans biofilm in vitro.

    Science.gov (United States)

    Liu, Geoffrey; Vellucci, Vincent F; Kyc, Stephanie; Hostetter, Margaret K

    2009-12-01

    By inhibiting the conversion of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate, statins impair cholesterol metabolism in humans. We reasoned that statins might similarly interfere with the biosynthesis of ergosterol, the major sterol of the yeast cell membrane. As assessed by spectrophotometric and microscopic analysis, significant inhibition of biofilm production was noted after 16-h incubation with 1, 2.5, and 5 muM simvastatin, concentrations that did not affect growth, adhesion, or hyphal formation by C. albicans in vitro. Higher concentrations (10, 20, and 25 muM simvastatin) inhibited biofilm by >90% but also impaired growth. Addition of exogenous ergosterol (90 muM) overcame the effects of 1 and 2.5 muM simvastatin, suggesting that at least one mechanism of inhibition is interference with ergosterol biosynthesis. Clinical isolates from blood, skin, and mucosal surfaces produced biofilms; biofilms from bloodstream isolates were similarly inhibited by simvastatin. In the absence of fungicidal activity, simvastatin's interruption of a critical step in an essential metabolic pathway, highly conserved from yeast to man, has unexpected effects on biofilm production by a eukaryotic pathogen.

  10. Terbinafine inhibits gap junctional intercellular communication

    International Nuclear Information System (INIS)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-01-01

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca 2+ concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca 2+ concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  11. Terbinafine inhibits gap junctional intercellular communication

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ju Yeun, E-mail: whitewndus@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Yoon, Sei Mee, E-mail: sei_mee@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Department of Integrated OMICS for Biomedical Sciences, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Choi, Eun Ju, E-mail: yureas@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Lee, Jinu, E-mail: jinulee@yonsei.ac.kr [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of)

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca{sup 2+} concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca{sup 2+} concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  12. Infusing Early Childhood Mental Health into Early Intervention Services

    Science.gov (United States)

    Grabert, John C.

    2009-01-01

    This article describes the process of enhancing early childhood mental health awareness and skills in non-mental health staff. The author describes a pilot training model, conducted the U.S. Army's Early Intervention Services, that involved: (a) increasing early childhood mental health knowledge through reflective readings, (b) enhancing…

  13. Raman spectrum reveals Mesenchymal stem cells inhibiting HL60 cells growth

    Science.gov (United States)

    Su, Xin; Fang, Shaoyin; Zhang, Daosen; Zhang, Qinnan; Lu, Xiaoxu; Tian, Jindong; Fan, Jinping; Zhong, Liyun

    2017-04-01

    Though some research results reveals that Mesenchymal stem cells (MSCs) have the ability of inhibiting tumor cells proliferation, it remains controversial about the precise interaction mechanism during MSCs and tumor cells co-culture. In this study, combing Raman spectroscopic data and principle component analysis (PCA), the biochemical changes of MSCs or Human promyelocytic leukemia (HL60) cells during their co-culture were presented. The obtained results showed that some main Raman peaks of HL60 assigned to nucleic acids or proteins were greatly higher in intensity in the late stage of co-culture than those in the early stage of co-culture while they were still lower relative to the control group, implicating that the effect of MSCs inhibiting HL60 proliferation appeared in the early stage but gradually lost the inhibiting ability in the late stage of co-culture. Moreover, some other peaks of HL60 assigned to proteins were decreased in intensity in the early stage of co-culture relative to the control group but rebounded to the level similar to the control group in the late stage, showing that the content and structure changes of these proteins might be generated in the early stage but returned to the original state in the late stage of co-culture. As a result, in the early stage of MSCs-HL60 co-culture, along with the level of Akt phosphorylation of HL60 was lowered relative to its control group, the proliferation rate of HL60 cells was decreased. And in the late stage of co-culture, along with the level of Akt phosphorylation was rebounded, the reverse transfer of Raman peaks within 875-880 cm- 1 appeared, thus MSCs lost the ability to inhibit HL60 growth and HL60 proliferation was increased. In addition, it was observed that the peak at 811 cm- 1, which is a marker of RNA, was higher in intensity in the late stage than that in the control group, indicating that MSCs might be differentiated into myofibroblast-like MSCs. In addition, PCA results also exhibited

  14. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  15. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Schroll, Casper; Hilbert, Lisbeth Rischel

    2009-01-01

    Undesired biofilm formation is a major concern in many areas. In the present study, we investigated biofilm-inhibiting properties of a silver-palladium surface that kills bacteria by generating microelectric fields and electrochemical redox processes. For evaluation of the biofilm inhibition...... efficacy and study of the biofilm inhibition mechanism, the silver-sensitive Escherichia coli J53 and the silver-resistant E. coli J53[pMG101] strains were used as model organisms, and batch and flow chamber setups were used as model systems. In the case of the silver-sensitive strain, the silver......-palladium surfaces killed the bacteria and prevented biofilm formation under conditions of low or high bacterial load. In the case of the silver-resistant strain, the silver-palladium surfaces killed surface-associated bacteria and prevented biofilm formation under conditions of low bacterial load, whereas under...

  16. Inhibition of melanogenesis by Xanthium strumarium L.

    Science.gov (United States)

    Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok

    2012-01-01

    Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3β (GSK3β) and β-catenin. Hence, the influence of X. strumarium stem extract on GSK3β and β-catenin was further investigated. X. strumarium induced GSK3β phosphorylation (inactivation), but the level of β-catenin did not change. Moreover, a specific GSK3β inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3β phosphorylation.

  17. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    Directory of Open Access Journals (Sweden)

    Susan Skanderup Falkenberg

    2012-01-01

    Full Text Available 12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM and collagen- (2.0 μg/mL induced aggregations in human blood. These four species in respective extracts (in brackets were Blechnum chilense (MeOH, Luma apiculata (H2O, Amomyrtus luma (DCM : MeOH 1 : 1 and Cestrum parqui (DCM : MeOH 1 : 1. The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1, and L. apiculata (H2O were substantial and confirmed by inhibition of platelet surface activation markers.

  18. Distractor inhibition: Evidence from lateralized readiness potentials.

    Science.gov (United States)

    Pramme, Lisa; Dierolf, Angelika M; Naumann, Ewald; Frings, Christian

    2015-08-01

    The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object-based selective attention on the level of distractor representations. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Terbinafine inhibits gap junctional intercellular communication.

    Science.gov (United States)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Inhibition of aluminum corrosion using Opuntia extract

    International Nuclear Information System (INIS)

    El-Etre, A.Y.

    2003-01-01

    The inhibitive action of the mucilage extracted from the modified stems of prickly pears, toward acid corrosion of aluminum, is tested using weight loss, thermometry, hydrogen evolution and polarization techniques. It was found that the extract acts as a good corrosion inhibitor for aluminum corrosion in 2.0 M HCl solution. The inhibition action of the extract was discussed in view of Langmuir adsorption isotherm. It was found that the adsorption of the extract on aluminum surface is a spontaneous process. The inhibition efficiency (IE) increases as the extract concentration is increased. The effect of temperature on the IE was studied. It was found that the presence of extract increases the activation energy of the corrosion reaction. Moreover, the thermodynamic parameters of the adsorption process were calculated. It was found also that the Opuntia extract provides a good protection to aluminum against pitting corrosion in chloride ion containing solutions

  1. Mapuche herbal medicine inhibits blood platelet aggregation.

    Science.gov (United States)

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM : MeOH 1 : 1) and Cestrum parqui (DCM : MeOH 1 : 1). The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers.

  2. Early Life Exposures and Cancer

    Science.gov (United States)

    Early-life events and exposures have important consequences for cancer development later in life, however, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges.

  3. History of early atomic clocks

    International Nuclear Information System (INIS)

    Ramsey, N.F.

    2005-01-01

    This review of the history of early atomic clocks includes early atomic beam magnetic resonance, methods of separated and successive oscillatory fields, microwave absorption, optical pumping and atomic masers. (author)

  4. Inhibition of intestinal disaccharidase activity by pentoses

    DEFF Research Database (Denmark)

    Halschou-Jensen, Kia

    on carbohydrate- ingesting enzymes activity in vitro and possible effects on human postprandial blood response. In paper 1 the effects of sugar beet polyphenols from molasses and the potential inhibition of sucrase activity in vitro, was investigated. Two different polyphenol-rich fractions from chromatographic...... separation of molasses from sugar beets and pure ferulic acid were tested. We found no effects of the two fractions of molasses. The pure ferulic acid indicated an inhibition of sucrase in vitr. Both in vitro and in vivo studies have investigated the effects of L-arabinose and D-xylose on carbohydrate...

  5. Sprout inhibition in roots, tubers and bulbs

    International Nuclear Information System (INIS)

    Luna C, P.C.

    1992-05-01

    The treatment with ionizing radiations to low dose impedes that appear sprouts in the tubers (potatoes); bulbs (onion and garlic) and in roots like the ginger and the yucca. The purpose is to inhibit the germination during the process of manipulation and storage, and this way to avoid the lost ones post crop of these products. The radiation dose required to inhibit the germination goes to depend of: the development conditions, the differences of variety, of the storage state of the bulbs and the conditions of cured and storage. (Author)

  6. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    OpenAIRE

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus l...

  7. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  8. Early prevention of obesity

    Directory of Open Access Journals (Sweden)

    Claudio Maffeis

    2014-06-01

    Full Text Available Childhood obesity is the metabolic disorder with the highest prevalence in both children and adults. Urgency to treat and prevent childhood obesity is based on the clear evidence that obesity tends to track from childhood to adulthood, is associated to morbidity also in childhood and to long-term mortality. Early life, i.e., intrauterine life and the first two years, is a sensitive window for prevention. Anatomical and functional maturation of the hypothalamic structures devoted to regulating energy intake and expenditure and body size mainly occurs in the first 1,000 days of life. Therefore, factors affecting the foetal exposition to maternal metabolic environment and early postnatal nutrition are crucial in modulating the definition of the metabolic programming processes in the brain. Maternal diseases, mainly malnutrition for defect or excess, obesity and diabetes, placental disorders and dysfunctions, maternal use of alcohol and drugs, smoking, affect long term metabolic programming of the foetus with lifelong consequences. Similarly, early nutrition contributes to complete the long-term metabolic regulating framework initiated in the uterus. Breastfeeding, adequate weaning, attention to portion size and diet composition are potential tools for reducing the obesity risk later in childhood. Longitudinal randomized controlled studies are needed for exploring the efficacy of obesity prevention strategies initiated after conception.Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

  9. Crowdsourced earthquake early warning

    Science.gov (United States)

    Minson, Sarah E.; Brooks, Benjamin A.; Glennie, Craig L.; Murray, Jessica R.; Langbein, John O.; Owen, Susan E.; Heaton, Thomas H.; Iannucci, Robert A.; Hauser, Darren L.

    2015-01-01

    Earthquake early warning (EEW) can reduce harm to people and infrastructure from earthquakes and tsunamis, but it has not been implemented in most high earthquake-risk regions because of prohibitive cost. Common consumer devices such as smartphones contain low-cost versions of the sensors used in EEW. Although less accurate than scientific-grade instruments, these sensors are globally ubiquitous. Through controlled tests of consumer devices, simulation of an Mw (moment magnitude) 7 earthquake on California’s Hayward fault, and real data from the Mw 9 Tohoku-oki earthquake, we demonstrate that EEW could be achieved via crowdsourcing.

  10. Why Recruits Separate Early

    Science.gov (United States)

    1991-01-01

    our sample were reportedly unable to adjust to the military environment due to social or emotional immaturity. This problem was especially prevalent...Table 9. Table 9 REASONS FOR EARLY SEPARATION 1. Mental health. Phobias , suicide threats and attempts, emotional immaturity, and personality and...hliurfl’lutf t’ htrtiuug tht .’ plinittol piioL’m.9 evIn’ thfll I b’ r i’lli. vre’.Ilv ifao~ , ýI ll.tv ill it](- rv ’: 111nil tln1 (i~..󈧏 4 P A W4.11

  11. Early modern mathematical instruments.

    Science.gov (United States)

    Bennett, Jim

    2011-12-01

    In considering the appropriate use of the terms "science" and "scientific instrument," tracing the history of "mathematical instruments" in the early modern period is offered as an illuminating alternative to the historian's natural instinct to follow the guiding lights of originality and innovation, even if the trail transgresses contemporary boundaries. The mathematical instrument was a well-defined category, shared across the academic, artisanal, and commercial aspects of instrumentation, and its narrative from the sixteenth to the eighteenth century was largely independent from other classes of device, in a period when a "scientific" instrument was unheard of.

  12. Early solar physics

    CERN Document Server

    Meadows, A J

    1970-01-01

    Early Solar Physics reviews developments in solar physics, particularly the advent of solar spectroscopy and the discovery of relationships between the various layers of the solar atmosphere and between the different forms of solar activity. Topics covered include solar observations during 1843; chemical analysis of the solar atmosphere; the spectrum of a solar prominence; and the solar eclipse of December 12, 1871. Spectroscopic observations of the sun are also presented. This book is comprised of 30 chapters and begins with an overview of ideas about the sun in the mid-nineteenth century, fo

  13. Early and late motherhood

    DEFF Research Database (Denmark)

    Christoffersen, Mogens; Lausten, Mette

    2009-01-01

    The study investigates parental child rearing methods, structural factors relating to the family during adolescence geographic segregation, individual resource deficits and social background of first time late live births among 32 to 37 years old women and compare to teenagers before becoming...... economic and social gradient for first-time teenage mothers. Teenagers who had experienced family separation or who were formerly in out-of-home care in particular had an increased risk of early childbearing. Results showed that teenage mothers were in every respect in a more disadvantaged position than...

  14. Early Reading and Concrete Operations.

    Science.gov (United States)

    Polk, Cindy L. Howes; Goldstein, David

    1980-01-01

    Indicated that early readers are more likely to be advanced in cognitive development than are nonearly-reading peers. After one year of formal reading instruction, early readers maintained their advantage in reading achievement. Measures of concrete operations were found to predict reading achievement for early and nonearly readers. (Author/DB)

  15. Early Childhood Workforce Index, 2016

    Science.gov (United States)

    Whitebook, Marcy; McLean, Caitlin; Austin, Lea J. E.

    2016-01-01

    The State of the Early Childhood Workforce (SECW) Initiative is a groundbreaking multi-year project to shine a steady spotlight on the nation's early childhood workforce. The SECW Initiative is designed to challenge entrenched ideas and policies that maintain an inequitable and inadequate status quo for early educators and for the children and…

  16. Early regulation of axolotl limb regeneration.

    Science.gov (United States)

    Makanae, Aki; Satoh, Akira

    2012-10-01

    Amphibian limb regeneration has been studied for a long time. In amphibian limb regeneration, an undifferentiated blastema is formed around the region damaged by amputation. The induction process of blastema formation has remained largely unknown because it is difficult to study the induction of limb regeneration. The recently developed accessory limb model (ALM) allows the investigation of limb induction and reveals early events of amphibian limb regeneration. The interaction between nerves and wound epidermis/epithelium is an important aspect of limb regeneration. During early limb regeneration, neurotrophic factors act on wound epithelium, leading to development of a functional epidermis/epithelium called the apical epithelial cap (AEC). AEC and nerves create a specific environment that inhibits wound healing and induces regeneration through blastema formation. It is suggested that FGF-signaling and MMP activities participate in creating a regenerative environment. To understand why urodele amphibians can create such a regenerative environment and humans cannot, it is necessary to identify the similarities and differences between regenerative and nonregenerative animals. Here we focus on ALM to consider limb regeneration from a new perspective and we also reported that focal adhesion kinase (FAK)-Src signaling controlled fibroblasts migration in axolotl limb regeneration. Copyright © 2012 Wiley Periodicals, Inc.

  17. Finasteride inhibited brain dopaminergic system and open-field behaviors in adolescent male rats.

    Science.gov (United States)

    Li, Li; Kang, Yun-Xiao; Ji, Xiao-Ming; Li, Ying-Kun; Li, Shuang-Cheng; Zhang, Xiang-Jian; Cui, Hui-Xian; Shi, Ge-Ming

    2018-02-01

    Finasteride inhibits the conversion of testosterone to dihydrotestosterone. Because androgen regulates dopaminergic system in the brain, it could be hypothesized that finasteride may inhibit dopaminergic system. The present study therefore investigates the effects of finasteride in adolescent and early developmental rats on dopaminergic system, including contents of dopamine and its metabolites (dihydroxy phenyl acetic acid and homovanillic acid) and tyrosine hydroxylase expressions both at gene and protein levels. Meanwhile, open-field behaviors of the rats are examined because of the regulatory effect of dopaminergic system on the behaviors. Open-field behaviors were evaluated by exploratory and motor behaviors. Dopamine and its metabolites were assayed by liquid chromatography-mass spectrometry. Tyrosine hydroxylase mRNA and protein expressions were determined by real-time qRT-PCR and western blot, respectively. It was found that in adolescent male rats, administration of finasteride at doses of 25 and 50 mg/kg for 14 days dose dependently inhibited open-field behaviors, reduced contents of dopamine and its metabolites in frontal cortex, hippocampus, caudate putamen, nucleus accumbens, and down-regulated tyrosine hydroxylase mRNA and protein expressions in substantia nigra and ventral tegmental area. However, there was no significant change of these parameters in early developmental rats after finasteride treatment. These results suggest that finasteride inhibits dopaminergic system and open-field behaviors in adolescent male rats by inhibiting the conversion of testosterone to dihydrotestosterone, and imply finasteride as a potential therapeutic option for neuropsychiatric disorders associated with hyperactivities of dopaminergic system and androgen. © 2017 John Wiley & Sons Ltd.

  18. Radiation early warning system

    International Nuclear Information System (INIS)

    Schmitzer, C.; Kloesch, W.; Stadtmann, H.

    1993-01-01

    A prototype station for a Radiation Early Warning Network has been designed and set up at the Austrian Research Centre Seibersdorf. This unit was developed to measure all relevant parameters necessary to detect and track radioactive contamination at an early stage. The station consists of the following components: Radiation measuring channel for ambient gamma dose rate. Meteorological measurement channels for air temperature and humidity, wind direction and wind speed, and precipitation. Data processing and storage unit. The system is capable of unattended operation and data acquisition even under adverse environmental conditions. Connection to a central processing platform may be achieved via leased line, dial up over public switched telephone network (PSTN), or radio-frequency transmission. The remote station will continue acquiring and storing data for at least a month, even if the communications link is broken. Multiple stations can be combined to form a network, providing detailed information about radiological and meteorological data at each site. Thus increased ambient radiation levels may be discovered, tracked, and forecasted based on calculations using current and local weather data

  19. Sonority and early words

    DEFF Research Database (Denmark)

    Kjærbæk, Laila; Boeg Thomsen, Ditte; Lambertsen, Claus

    2015-01-01

    Syllables play an important role in children’s early language acquisition, and children appear to rely on clear syllabic structures as a key to word acquisition (Vihman 1996; Oller 2000). However, not all languages present children with equally clear cues to syllabic structure, and since the spec......Syllables play an important role in children’s early language acquisition, and children appear to rely on clear syllabic structures as a key to word acquisition (Vihman 1996; Oller 2000). However, not all languages present children with equally clear cues to syllabic structure, and since...... acquisition therefore presents us with the opportunity to examine how children respond to the task of word learning when the input language offers less clear cues to syllabic structure than usually seen. To investigate the sound structure in Danish children’s lexical development, we need a model of syllable......-29 months. For the two children, the phonetic structure of the first ten words to occur is compared with that of the last ten words to occur before 30 months of age, and with that of ten words in between. Measures related to the sonority envelope, viz. sonority types and in particular sonority rises...

  20. Inhibition of barley grain germination by light

    NARCIS (Netherlands)

    Roth-Bejerano, N.; Meulen, R.M. van der; Wang, M.

    1996-01-01

    Intact grains of barley (Hordeum distichum cv. Triumph) germinated rapidly in the dark or when exposed to brief daily light breaks in the temperature range 15-25°C, although germination proceeded less rapidly at low temperatures. Prolonged illumination (16 h/day) or continuous light inhibited

  1. Probenazole treatment inhibits anthocyanins biosynthesis via ...

    African Journals Online (AJOL)

    It has been found that anthocyanins were accumulated in Arabidopsis under drought or salt stress. In this study, such accumulation was found to be inhibited by external applied probenazole (3-allyloxy-1, 2-benzisothiazole-1,1-dioxide, PBZ), which is the active ingredient in oryzemate used for the protection of rice from ...

  2. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    International Nuclear Information System (INIS)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    Highlights: ► Salinomycin inhibits preadipocyte differentiation into adipocytes. ► Salinomycin inhibits transcriptional regulation of adipogenesis. ► Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  3. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles

    Science.gov (United States)

    Bearne, Stephen L.

    2012-01-01

    Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

  4. Microbial Metabolism and Inhibition Studies of Phenobarbital

    African Journals Online (AJOL)

    Erah

    techniques, high performance liquid chromatography (HPLC), mass spectrometry (MS) ... Keywords: Microbial metabolism, Phenobarbital, Inhibition studies, Rhizopus stolonifer, CYP 2C9, .... 24 h of incubation 0.5 ml of drug solution was ... mode, positive: spray voltage, 3.5 KV: ... Rhizopus stolonifer showed an extra peak at.

  5. Luteoloside Inhibits Proliferation of Human Chronic Myeloid ...

    African Journals Online (AJOL)

    Purpose: To investigate the effects of luteoloside on the proliferation of human chronic ..... Zhang N, Wang D, Zhu Y, Wang J, Lin H. Inhibition ... Han X. Protection of Luteolin-7-O-Glucoside Against ... Hwang YJ, Lee EJ, Kim HR, Hwang KA.

  6. Nickel Inhibits Mitochondrial Fatty Acid Oxidation

    Science.gov (United States)

    Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

    2015-01-01

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

  7. Inhibiting Intuitive Thinking in Mathematics Education

    Science.gov (United States)

    Thomas, Michael O. J.

    2015-01-01

    The papers in this issue describe recent collaborative research into the role of inhibition of intuitive thinking in mathematics education. This commentary reflects on this research from a mathematics education perspective and draws attention to some of the challenges that arise in collaboration between research fields with different cultures,…

  8. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A. [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States); Yap, Sook Fan [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia); Ngeow, Yun Fong [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia); Chin, Khew-Voon, E-mail: khew-voon.chin@utoledo.edu [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  9. Undecylenic Acid Inhibits Morphogenesis of Candida albicans

    OpenAIRE

    McLain, Nealoo; Ascanio, Rhoda; Baker, Carol; Strohaver, Robert A.; Dolan, Joseph W.

    2000-01-01

    Resilient liners are frequently used to treat denture stomatitis, a condition often associated with Candida albicans infections. Of 10 liners tested, 2 were found to inhibit the switch from the yeast form to hyphae and a third was found to stimulate this switch. The inhibitor was determined to be undecylenic acid.

  10. Undecylenic acid inhibits morphogenesis of Candida albicans.

    Science.gov (United States)

    McLain, N; Ascanio, R; Baker, C; Strohaver, R A; Dolan, J W

    2000-10-01

    Resilient liners are frequently used to treat denture stomatitis, a condition often associated with Candida albicans infections. Of 10 liners tested, 2 were found to inhibit the switch from the yeast form to hyphae and a third was found to stimulate this switch. The inhibitor was determined to be undecylenic acid.

  11. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

    Hsieh, Chia-Wen; Cannella, David; Jørgensen, Henning

    2014-01-01

    Biological degradation of biomass on an industrial scale culminates in high concentrations of end products. It is known that the accumulation of glucose and cellobiose, end products of hydrolysis, inhibit cellulases and decrease glucose yields. Aside from these end products, however, other monosa...

  12. Inhibiting Translation One Protein at a Time.

    Science.gov (United States)

    Disney, Matthew D

    2017-06-01

    Historically, translational inhibitors have been confined to anti-bacterials that globally affect translation. Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Junru; Kulkarni, Ashwini [Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Chintala, Madhu [Schering-Plough Research Institute, Kenilworth, New Jersey (United States); Fink, Louis M. [Nevada Cancer Institute, Las Vegas, Nevada (United States); Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.edu [Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas (United States)

    2013-01-01

    Purpose: To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. Methods and Materials: Rats underwent fractionated X-irradiation (5 Gy Multiplication-Sign 9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation. Results: Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups. Conclusion: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.

  14. Polysulfonate suramin inhibits Zika virus infection.

    Science.gov (United States)

    Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

    2017-07-01

    Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Neural Synchrony during Response Production and Inhibition

    Science.gov (United States)

    Müller, Viktor; Anokhin, Andrey P.

    2012-01-01

    Inhibition of irrelevant information (conflict monitoring) and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs) elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG) recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300–600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations. PMID:22745691

  16. WEE1 inhibition sensitizes osteosarcoma to radiotherapy

    International Nuclear Information System (INIS)

    PosthumaDeBoer, Jantine; Würdinger, Thomas; Graat, Harm CA; Beusechem, Victor W van; Helder, Marco N; Royen, Barend J van; Kaspers, Gertjan JL

    2011-01-01

    The use of radiotherapy in osteosarcoma (OS) is controversial due to its radioresistance. OS patients currently treated with radiotherapy generally are inoperable, have painful skeletal metastases, refuse surgery or have undergone an intralesional resection of the primary tumor. After irradiation-induced DNA damage, OS cells sustain a prolonged G 2 cell cycle checkpoint arrest allowing DNA repair and evasion of cell death. Inhibition of WEE1 kinase leads to abrogation of the G 2 arrest and could sensitize OS cells to irradiation induced cell death. WEE1 expression in OS was investigated by gene-expression data analysis and immunohistochemistry of tumor samples. WEE1 expression in OS cell lines and human osteoblasts was investigated by Western blot. The effect of WEE1 inhibition on the radiosensitivity of OS cells was assessed by cell viability and caspase activation analyses after combination treatment. The presence of DNA damage was visualized using immunofluorescence microscopy. Cell cycle effects were investigated by flow cytometry and WEE1 kinase regulation was analyzed by Western blot. WEE1 expression is found in the majority of tested OS tissue samples. Small molecule drug PD0166285 inhibits WEE1 kinase activity. In the presence of WEE1-inhibitor, irradiated cells fail to repair their damaged DNA, and show higher levels of caspase activation. The inhibition of WEE1 effectively abrogates the irradiation-induced G 2 arrest in OS cells, forcing the cells into premature, catastrophic mitosis, thus enhancing cell death after irradiation treatment. We show that PD0166285, a small molecule WEE1 kinase inhibitor, can abrogate the G 2 checkpoint in OS cells, pushing them into mitotic catastrophe and thus sensitizing OS cells to irradiation-induced cell death. This suggests that WEE1 inhibition may be a promising strategy to enhance the radiotherapy effect in patients with OS

  17. Neural synchrony during response production and inhibition.

    Directory of Open Access Journals (Sweden)

    Viktor Müller

    Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

  18. Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives

    International Nuclear Information System (INIS)

    Boehm, Lothar; Roos, Wynand Paul; Serafin, Antonio Mendes

    2003-01-01

    The methylxanthine drug Pentoxifylline is reviewed for new properties which have emerged only relatively recently and for which clinical applications can be expected. After a summary on the established systemic effects of Pentoxifylline on the microcirculation and reduction of tumour anoxia, the role of the drug in the treatment of vasoocclusive disorders, cerebral ischemia, infectious diseases, septic shock and acute respiratory distress, the review focuses on another level of drug action which is based on in vitro observations in a variety of cell lines. Pentoxifylline and the related drug Caffeine are known radiosensitizers especially in p53 mutant cells. The explanation that the drug abrogates the G2 block and shortens repair in G2 by promoting early entry into mitosis is not anymore tenable because enhancement of radiotoxicity requires presence of the drug during irradiation and fails when the drug is added after irradiation at the G2 maximum. Repair assays by measurement of recovery ratios and by delayed plating experiments indeed strongly suggested a role in repair which is now confirmed for Pentoxifylline by constant field gel electrophoresis (CFGE) measurements and for Pentoxifylline and for Caffeine by use of a variety of repair mutants. The picture now emerging shows that Caffeine and Pentoxifylline inhibit homologous recombination by targeting members of the PIK kinase family (ATM and ATR) which facilitate repair in G2. Pentoxifylline induced repair inhibition between irradiation dose fractions to counter interfraction repair has been successfully applied in a model for stereotactic surgery. Another realistic avenue of application of Pentoxifylline in tumour therapy comes from experiments which show that repair events in G2 can be targeted directly by addition of cytotoxic drugs and Pentoxifylline at the G2 maximum. Under these conditions massive dose enhancement factors of up to 80 have been observed suggesting that it may be possible to realise

  19. Cellular transformation by radiation: induction, promotion, and inhibition

    International Nuclear Information System (INIS)

    Borek, C.

    1981-01-01

    Radiation oncogenesis induced in utero in hamsters is expressed at a lower frequency than that induced in vitro. Quantitative studies carried out on hamster embryo cells indicate that neutrons are more effective in their carcinogenic potential than x-rays but also more toxic, that splitting the dose of x-rays at low doses leads to enhanced transformation, but that at high doses protracted radiation has a sparing effect. At all dose ranges survival was increased by protracting the radiation dose, thus suggesting that different repair processes must be involved for survival and transformation. In our qualitative studies, once cells are transformed by radiation, they exhibit a wide range of structural and functional phenotypic changes, some of which are membrane-associated and are expressed within days after induction. Our current studies on nutritional and hormonal influences on radiation transformation indicate the following: Pyrolysate products from broiled protein foods act in synergism with radiation to produce transformation, whereas vitamin A analogs are powerful, preventive agents. Retinoids inhibit both x-ray-induced transformation and its promotion by TPA; these modifications (enhancement by TPA, inhibition by retinoids) are not reflected in sister chromatid exchanges, but are reflected in the level of membrane associated enzymes Na/K ATPase. Whereas retinoids modify late events (expression, promotion), we find that thyroid hormone plays a crucial role in the early phases of radiation and chemically induced transformation. Our recent success in transforming human skin fibroblasts will enable quantitative and qualitative studies of radiation carcinogenesis in a system relevant to man

  20. Parent Ratings of Impulsivity and Inhibition Predict State Testing Scores

    Directory of Open Access Journals (Sweden)

    Rebecca A. Lundwall

    2018-03-01

    Full Text Available One principle of cognitive development is that earlier intervention for educational difficulties tends to improve outcomes such as future educational and career success. One possible way to help students who struggle is to determine if they process information differently. Such determination might lead to clues for interventions. For example, early information processing requires attention before the information can be identified, encoded, and stored. The aim of the present study was to investigate whether parent ratings of inattention, inhibition, and impulsivity, and whether error rate on a reflexive attention task could be used to predict child scores on state standardized tests. Finding such an association could provide assistance to educators in identifying academically struggling children who might require targeted educational interventions. Children (N = 203 were invited to complete a peripheral cueing task (which measures the automatic reorienting of the brain’s attentional resources from one location to another. While the children completed the task, their parents completed a questionnaire. The questionnaire gathered information on broad indicators of child functioning, including observable behaviors of impulsivity, inattention, and inhibition, as well as state academic scores (which the parent retrieved online from their school. We used sequential regression to analyze contributions of error rate and parent-rated behaviors in predicting six academic scores. In one of the six analyses (for science, we found that the improvement was significant from the simplified model (with only family income, child age, and sex as predictors to the full model (adding error rate and three parent-rated behaviors. Two additional analyses (reading and social studies showed near significant improvement from simplified to full models. Parent-rated behaviors were significant predictors in all three of these analyses. In the reading score analysis

  1. Parenting and Child Characteristics in the Prediction of Shame in Early and Middle Childhood

    Science.gov (United States)

    Mills, Rosemary S. L.; Arbeau, Kimberley A.; Lall, Debra I. K.; De Jaeger, Amy E.

    2010-01-01

    We examined individual differences in shame responding in early childhood and predictive relations with shame proneness in middle childhood. Child shame responding, parental shaming, and child temperamental inhibition were assessed at Time 1 (n = 225, aged 3-4 years), shame responding was reassessed at Time 2 (n = 199, aged 5-7 years), and shame…

  2. Temperamental, Parental, and Contextual Contributors to Early-Emerging Internalizing Problems: A New Integrative Analysis Approach

    Science.gov (United States)

    Mills, Rosemary S. L.; Hastings, Paul D.; Helm, Jonathan; Serbin, Lisa A.; Etezadi, Jamshid; Stack, Dale M.; Schwartzman, Alex E.; Li, Hai Hong

    2012-01-01

    This study evaluated a comprehensive model of factors associated with internalizing problems (IP) in early childhood, hypothesizing direct, mediated, and moderated pathways linking child temperamental inhibition, maternal overcontrol and rejection, and contextual stressors to IP. In a novel approach, three samples were integrated to form a large…

  3. Early-Onset Dementia

    DEFF Research Database (Denmark)

    Konijnenberg, Elles; Fereshtehnejad, Seyed-Mohammad; Kate, Mara Ten

    2017-01-01

    BACKGROUND: Early-onset dementia (EOD) is a rare condition, with an often atypical clinical presentation, and it may therefore be challenging to diagnose. Specialized memory clinics vary in the type of patients seen, diagnostic procedures applied, and the pharmacological treatment given. The aim...... of this study was to investigate quality-of-care indicators in subjects with EOD from 3 tertiary memory clinics in 3 European countries. METHODS: We included 1325 newly diagnosed EOD patients, ages 65 years or younger, between January 1, 2007 and December 31, 2013, from the Danish Dementia Registry...... (Rigshospitalet, Copenhagen), the Swedish Dementia Registry ("SveDem", Karolinska University Hospital, Stockholm), and the Amsterdam Dementia Cohort (VU University Medical Center). RESULTS: The frequency of EOD among all dementia patients was significantly lower in Copenhagen (410, 20%) and Stockholm (284, 21...

  4. Response inhibition is modulated by functional cerebral asymmetries for facial expression perception

    Directory of Open Access Journals (Sweden)

    Sebastian eOcklenburg

    2013-11-01

    Full Text Available The efficacy of executive functions is critically modulated by information processing in earlier cognitive stages. For example, initial processing of verbal stimuli in the language-dominant left-hemisphere leads to more efficient response inhibition than initial processing of verbal stimuli in the non-dominant right hemisphere. However, it is unclear whether this organizational principle is specific for the language system, or a general principle that also applies to other types of lateralized cognition. To answer this question, we investigated the neurophysiological correlates of early attentional processes, facial expression perception and response inhibition during tachistoscopic presentation of facial ‘Go’ and ‘Nogo’ stimuli in the left and the right visual field. Participants committed fewer false alarms after Nogo-stimulus presentation in the left compared to the right visual field. This right-hemispheric asymmetry on the behavioral level was also reflected in the neurophysiological correlates of face perception, specifically in a right-sided asymmetry in the N170 amplitude. Moreover, the right-hemispheric dominance for facial expression processing also affected event-related potentials typically related to response inhibition, namely the Nogo-N2 and Nogo-P3. These findings show that an effect of hemispheric asymmetries in early information processing on the efficacy of higher cognitive functions is not limited to left-hemispheric language functions, but can be generalized to predominantly right-hemispheric functions.

  5. An Embodied Account of Early Executive-Function Development

    Science.gov (United States)

    Gottwald, Janna M.; Achermann, Sheila; Marciszko, Carin; Lindskog, Marcus; Gredebäck, Gustaf

    2016-01-01

    The importance of executive functioning for later life outcomes, along with its potential to be positively affected by intervention programs, motivates the need to find early markers of executive functioning. In this study, 18-month-olds performed three executive-function tasks—involving simple inhibition, working memory, and more complex inhibition—and a motion-capture task assessing prospective motor control during reaching. We demonstrated that prospective motor control, as measured by the peak velocity of the first movement unit, is related to infants’ performance on simple-inhibition and working memory tasks. The current study provides evidence that motor control and executive functioning are intertwined early in life, which suggests an embodied perspective on executive-functioning development. We argue that executive functions and prospective motor control develop from a common source and a single motive: to control action. This is the first demonstration that low-level movement planning is related to higher-order executive control early in life. PMID:27765900

  6. Contrasting neural effects of aging on proactive and reactive response inhibition

    NARCIS (Netherlands)

    Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; Rest, van de O.; Cools, Roshan; Aarts, Esther

    2016-01-01

    Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition

  7. Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2006-01-01

    MIS is a member of the TGF family. The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth than either agent alone...

  8. Mullerian Inhibiting Substance (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2004-01-01

    Mullerian Inhibiting Substance (MIS), a member of the TGFB family regulates growth, differentiation, and apoptosis in many cell types In the male embryo, MIS causes regression of the Mullerian duct...

  9. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

    International Nuclear Information System (INIS)

    Mahalingam, Sharada; Gao, Liying; Gonnering, Marni; Helferich, William; Flaws, Jodi A.

    2016-01-01

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.

  10. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Mahalingam, Sharada, E-mail: mahalin2@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Gao, Liying, E-mail: lgao@uiuc.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Gonnering, Marni, E-mail: mgonne2@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States); Helferich, William, E-mail: helferic@illinois.edu [Department of Food Science and Human Nutrition, University of Illinois, 905 S. Goodwin, Urbana, IL 61801 (United States); Flaws, Jodi A., E-mail: jflaws@illinois.edu [Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, 2001 S. Lincoln Ave, Urbana, IL 61802 (United States)

    2016-03-15

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24 h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. - Highlights: • Equol exposure inhibits antral follicle growth. • Equol exposure increases follicle atresia. • Equol exposure inhibits sex steroid hormone levels. • Equol exposure inhibits mRNA levels of certain steroidogenic enzymes.

  11. Proactive modulation of long-interval intracortical inhibition during response inhibition

    Science.gov (United States)

    Cowie, Matthew J.; MacDonald, Hayley J.; Cirillo, John

    2016-01-01

    Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABAB receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a “default” nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective “brake” is applied. PMID:27281744

  12. Event-related fields evoked by vocal response inhibition: a comparison of younger and older adults.

    Science.gov (United States)

    Castro-Meneses, Leidy J; Johnson, Blake W; Sowman, Paul F

    2016-06-01

    The current study examined event-related fields (ERFs) evoked by vocal response inhibition in a stimulus-selective stop-signal task. We compared inhibition-related ERFs across a younger and an older group of adults. Behavioural results revealed that stop-signal reaction times (RTs), go-RTs, ignore-stop RTs and failed stop RTs were longer in the older, relative to the younger group by 38, 123, 149 and 116 ms, respectively. The amplitude of the ERF M2 peak (approximately 200 ms after the stop signal) evoked on successful stop trials was larger compared to that evoked on both failed stop and ignore-stop trials. The M4 peak (approximately 450 ms after stop signal) was of larger amplitude in both successful and failed stops compared to ignore-stop trials. In the older group, the M2, M3 and M4 peaks were smaller in amplitude and peaked later in time (by 24, 50 and 76 ms, respectively). We demonstrate that vocal response inhibition-related ERFs exhibit a similar temporal evolution to those previously described for manual response inhibition: an early peak at 200 ms (i.e. M2) that differentiates successful from failed stopping, and a later peak (i.e. M4) that is consistent with a neural marker of response checking and error processing. Across groups, our data support a more general decline of stimulus processing speed with age.

  13. Inhibition of chondroitin sulfate glycosaminoglycans incorporation affected odontoblast differentiation in cultured embryonic mouse molars.

    Science.gov (United States)

    Liu, Lipei; Chen, Weiting; Li, Lefeng; Xu, Fangfang; Jiang, Beizhan

    2017-12-01

    Chondroitin sulfate proteoglycan (CSPG) is an important component of extracellular matrix (ECM), it is composed of a core protein and one or more chondroitin sulfate glycosaminoglycan side chains (CS-GAGs). To investigate the roles of its CS-GAGs in dentinogenesis, the mouse mandibular first molar tooth germs at early bell stage were cultivated with or without β-xyloside. As expected, the CS-GAGs were inhibited on their incorporation to CSPGs by β-xyloside, accompanied by the change of morphology of the cultured tooth germs. The histological results and the transmission electron microscopy (TEM) investigation indicated that β-xyloside exhibited obvious inhibiting effects on odontoblasts differentiation compared with the control group. Meanwhile the results of immunohistochemistry, in situ hybridization and quantitative RT-PCR for type I collagen, dentin matrix acidic phosphoprotein 1 and dentin sialophosphoprotein, the products of differentiated odontoblasts, further proved that odontoblasts differentiation was inhibited. Collagen fibers detected in TEM decreased and arranged in disorder as well. Thus we conclude that the inhibition of CS-GAGs incorporation to CSPGs can affect odontoblast differentiation in cultured embryonic mouse molars.

  14. Studies on Inhibition of Proliferation of Enterovirus-71 by Compound YZ-LY-0.

    Science.gov (United States)

    Yang, Qingzhan; Jie, Qing; Shaw, Neil; Li, Lei; Rao, Zihe; Yin, Zheng; Lou, Zhiyong

    2015-01-01

    In recent years, hand-foot-and-mouth disease (HFMD), which is caused by Enteroviruses, has emerged as a serious illness. It affects mainly children under the age of five and results in high fatality rates. Enterovirus 71 (EV71) is the main causative agent of HFMD in China and currently there are no effective anti-viral drugs available to treat HFMD. In the present study, we screened compounds for inhibition of proliferation of EV71. Compound YZ-LY-0 stalled the life cycle of EV71. The inhibitor exhibited EC50 value of 0.29 μm against SK-EV006 strain of EV71. Notably, YZ-LY-0 had low cytotoxicity (CC50 > 100 μM) and a high selectivity index (over 300) in Vero and RD cells. YZ-LY-0 in combination with an EV71 RdRp inhibitor or an entry inhibitor showed an antagonistic effect at very low concentrations. However, at higher concentrations the inhibitors exhibited a synergistic effect in inhibiting viral replication. Preliminary results on investigation of the mechanism of inhibition indicate that YZ-LY-0 does not block the entry of the virus in the host cell, but instead inhibits an early stage of EV71 replication. Our studies provide a potential clinical therapeutic option against EV71 infections and suggest that a combined application of YZ-LY-0 with other inhibitors could be more effective in the treatment of HFMD.

  15. Study of early pregnancy factor (EPF) in equine (Equus caballus).

    Science.gov (United States)

    Ohnuma, K; Yokoo, M; Ito, K; Nambo, Y; Miyake, Y I; Komatsu, M; Takahashi, J

    2000-03-01

    Early pregnancy factor (EPF) is an immunosuppressive protein detected in the early pregnancy serum. We have already reported that we developed the rosette inhibition test for mare EPF and detected EPF in thoroughbreds. The aim of this study was to determine whether or not our method could be used clinically. The rosette inhibition test for equine EPF was carried out on serum from six nonpregnant and six pregnant Shetland ponies, a female and a male Chinese pony, and four nonpregnant and 13 pregnant thoroughbred mares. In the thoroughbreds sera were collected during the pregnancy period. Furthermore, we measured progesterone and detected pregnant mare serum gonadotrophin (PMSG) in order to confirm pregnancy of the Chinese pony 3 and 6 months after mating. In the nonpregnant Shetland ponies, the rosette inhibition titre (RIT) was 6.0+/-1.0 and EPF was negative. In contrast, in the pregnant ponies, the RIT was 9.2+/-0.4 and EPF was positive. Based on these results, we diagnosed pregnancy of the Chinese pony. The RIT of the female Chinese pony (3 months after mating) was above 10 and EPF was positive. Furthermore, we detected PMSG and progesterone in the serum of this pony. EPF appeared in the maternal blood circulation at 24-72 hr after mating, it was detected until the second trimester, and after that it disappeared from the maternal serum. The pony's EPF was detected by using the same rosette inhibition test as in the thoroughbred and was present from 24 to 72 hr after mating until the second trimester. The results indicated that our method was useful for pregnancy diagnosis of Equine.

  16. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

    Energy Technology Data Exchange (ETDEWEB)

    Voss, Kelsey; Amaya, Moushimi [National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA (United States); Mueller, Claudius [Center for Applied Proteomics and Personalized Medicine, George Mason University, 10900 University Boulevard, Manassas, VA (United States); Roberts, Brian [Leidos Health Life Sciences, 5202 Presidents Court, Suite 110, Frederick, MD (United States); Kehn-Hall, Kylene; Bailey, Charles [National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA (United States); Petricoin, Emanuel [Center for Applied Proteomics and Personalized Medicine, George Mason University, 10900 University Boulevard, Manassas, VA (United States); Narayanan, Aarthi, E-mail: anaraya1@gmu.edu [National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA (United States)

    2014-11-15

    New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. - Highlights: • VEEV infection activated multiple components of the ERK signaling cascade. • Inhibition of ERK activation using Ag-126 inhibited VEEV multiplication. • Activation of ERK by Ceramide C6 increased infectious titers of TC-83. • Ag-126 inhibited virulent strains of all New World alphaviruses. • Ag-126 treatment increased percent survival of infected cells.

  17. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

    International Nuclear Information System (INIS)

    Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius; Roberts, Brian; Kehn-Hall, Kylene; Bailey, Charles; Petricoin, Emanuel; Narayanan, Aarthi

    2014-01-01

    New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. - Highlights: • VEEV infection activated multiple components of the ERK signaling cascade. • Inhibition of ERK activation using Ag-126 inhibited VEEV multiplication. • Activation of ERK by Ceramide C6 increased infectious titers of TC-83. • Ag-126 inhibited virulent strains of all New World alphaviruses. • Ag-126 treatment increased percent survival of infected cells

  18. Manipulating early pig embryos.

    Science.gov (United States)

    Niemann, H; Reichelt, B

    1993-01-01

    On the basis of established surgical procedures for embryo recovery and transfer, the early pig embryo can be subjected to various manipulations aimed at a long-term preservation of genetic material, the generation of identical multiplets, the early determination of sex or the alteration of the genetic make-up. Most of these procedures are still at an experimental stage and despite recent considerable progress are far from practical application. Normal piglets have been obtained after cryopreservation of pig blastocysts hatched in vitro, whereas all attempts to freeze embryos with intact zona pellucida have been unsuccessful. Pig embryos at the morula and blastocyst stage can be bisected microsurgically and the resulting demi-embryos possess a high developmental potential in vitro, whereas their development in vivo is impaired. Pregnancy rates are similar (80%) but litter size is reduced compared with intact embryos and twinning rate is approximately 2%. Pig blastomeres isolated from embryos up to the 16-cell stage can be grown in culture and result in normal blastocysts. Normal piglets have been born upon transfer of blastocysts derived from isolated eight-cell blastomeres, clearly underlining the totipotency of this developmental stage. Upon nuclear transfer the developmental capacity of reconstituted pig embryos is low and culture. Sex determination can be achieved either by separation of X and Y chromosome bearing spermatozoa by flow cytometry or by analysing the expression of the HY antigen in pig embryos from the eight-cell to morula stage. Microinjection of foreign DNA has been successfully used to alter growth and development of transgenic pigs, and to produce foreign proteins in the mammary gland or in the bloodstream, indicating that pigs can be used as donors for valuable human pharmaceutical proteins. Another promising area of gene transfer is the increase of disease resistance in transgenic lines of pigs. Approximately 30% of pig spermatozoa bind

  19. Cell Cycle Inhibition To Treat Sleeping Sickness

    Directory of Open Access Journals (Sweden)

    Conrad L. Epting

    2017-09-01

    Full Text Available African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR, which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens.

  20. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... on individual cellulases hydrolyzing insoluble cellulose remains insufficient. Such knowledge is necessary to pinpoint and quantify inhibitory weak-links in cellulose hydrolysis, but has proven challenging to come by. Here we show that product inhibition of mono-component cellulases hydrolyzing unmodified...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...

  1. How x rays inhibit amphibian limb regeneration

    International Nuclear Information System (INIS)

    Maden, M.; Wallace, H.

    1976-01-01

    The effects of an inhibiting dose of 2,000 rad of x-rays on the regenerating limbs of axolotl larvae have been examined in a histological and cytological study. Particular attention was paid to the mitotic indices of normal and irradiated epidermal and blastemal cells. Both the characteristic pattern of epidermal mitotic stimulation which normally follows amputation and the later increase in blastemal mitoses are suppressed by irradiation. In most cells the effects are permanent, but in a small proportion a mitotic delay is induced and upon subsequent division chromosome damage in the form of micronuclei is revealed. Thus irradiated cells which do divide almost certainly die. These results are discussed in relation to other theories of x-ray inhibition of regeneration with particular reference to the view that irradiated cells can be reactivated

  2. Theobromine inhibits sensory nerve activation and cough.

    Science.gov (United States)

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

  3. Extinction Generates Outcome-Specific Conditioned Inhibition.

    Science.gov (United States)

    Laurent, Vincent; Chieng, Billy; Balleine, Bernard W

    2016-12-05

    Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL); inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippocampus (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Fermentation of lignocellulosic hydrolysates: Inhibition and detoxification

    Energy Technology Data Exchange (ETDEWEB)

    Palmqvist, E.

    1998-02-01

    The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds produced during hydrolysis. Evaluation of the effect of various biological, physical and chemical detoxification treatments by fermentation assays using Saccharomyces cerevisiae was used to characterise inhibitors. Inhibition of fermentation was decreased after removal of the non-volatile compounds, pre-fermentation by the filamentous fungus Trichoderma reesei, treatment with the lignolytic enzyme laccase, extraction with ether, and treatment with alkali. Yeast growth in lignocellulosic hydrolysates was inhibited below a certain fermentation pH, most likely due to high concentrations of undissociated weak acids. The effect of individual compounds were studied in model fermentations. Furfural is reduced to furfuryl alcohol by yeast dehydrogenases, thereby affecting the intracellular redox balance. As a result, acetaldehyde accumulated during furfural reduction, which most likely contributed to inhibition of growth. Acetic acid (10 g 1{sup -1}) and furfural (3 g 1{sup -1}) interacted antagonistically causing decreased specific growth rate, whereas no significant individual or interaction effects were detected by the lignin-derived compound 4-hydroxybenzoic acid (2 g 1{sup -1}). By maintaining a high cell mass density in the fermentor, the process was less sensitive to inhibitors affecting growth and to fluctuations in fermentation pH, and in addition the depletion rate of bioconvertible inhibitors was increased. A theoretical ethanol yield and high productivity was obtained in continuous fermentation of spruce hydrolysate when the cell mass concentration was maintained at a high level by applying cell recirculation 164 refs, 16 figs, 5 tabs

  5. Osthole inhibits bone metastasis of breast cancer

    OpenAIRE

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-01-01

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potent...

  6. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    OpenAIRE

    Chin-Feng Chan; Ching-Cheng Huang; Ming-Yuan Lee; Yung-Sheng Lin

    2014-01-01

    Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  7. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    Directory of Open Access Journals (Sweden)

    Chin-Feng Chan

    2014-08-01

    Full Text Available Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  8. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    DEFF Research Database (Denmark)

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

    2011-01-01

    Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

  9. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Petr Dobes

    2013-05-01

    Full Text Available Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE and/or, butyrylcholinesterase (BChE, the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was −6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.

  10. Inhibition of methane production by Methanobacterium formicicum

    Energy Technology Data Exchange (ETDEWEB)

    Hobson, P N; Shaw, B G

    1976-01-01

    The effects of volatile fatty acids, ammonia and copper on methane production by growing cultures of Methanobacterium formicicum were studied. Acetate and butyrate were not inhibitory, but propionate was inhibitory above certain concentrations, as was ammonia. Copper was inhibitory, but inhibitory concentrations are difficult to define as varying amounts may be precipitated as the sulphide. The results are compared with those from piggery-waste digesters and it is suggested that failure of farm-waste digesters from such inhibitions is unlikely.

  11. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  12. Inhibition of enveloped viruses infectivity by curcumin.

    Directory of Open Access Journals (Sweden)

    Tzu-Yen Chen

    Full Text Available Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter than for the pseudorabies virus (approximately 180 nm and the vaccinia virus (roughly 335 × 200 × 200 nm. These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses.

  13. Imitation inhibition in children with Tourette syndrome.

    Science.gov (United States)

    Brandt, Valerie Cathérine; Moczydlowski, Agnes; Jonas, Melanie; Boelmans, Kai; Bäumer, Tobias; Brass, Marcel; Münchau, Alexander

    2017-08-12

    Echopraxia, that is, the open and automatic imitation of other peoples' actions, is common in patients with Gilles de la Tourette syndrome, autism spectrum disorder, and also those with frontal lobe lesions. While systematic reaction time tasks have confirmed increased automatic imitation in the latter two groups, adult patients with Tourette syndrome appear to compensate for automatic imitation tendencies by an overall slowing in response times. However, whether children with Tourette syndrome are already able to inhibit automatic imitation tendencies has not been investigated. Fifteen children with Tourette syndrome and 15 healthy children (aged 7-12 years) performed an imitation inhibition paradigm. Participants were asked to respond to an auditory cue by lifting their index finger or their little finger. Participants were simultaneously presented with either compatible or incompatible visual stimuli. Overall responses in children with Tourette syndrome were slower than in healthy children. Although responses were faster in compatible than in incompatible trials in both groups, this 'interference effect' was smaller in children with Tourette syndrome. Children with Tourette syndrome have a smaller interference effect than healthy children, indicating an enhanced ability to behaviourally control automatic imitation tendencies at the cost of reacting slower. The results suggest that children with Tourette syndrome already employ different or additional inhibition strategies compared to healthy children. © 2017 The British Psychological Society.

  14. Inhibition of Enveloped Viruses Infectivity by Curcumin

    Science.gov (United States)

    Wen, Hsiao-Wei; Ou, Jun-Lin; Chiou, Shyan-Song; Chen, Jo-Mei; Wong, Min-Liang; Hsu, Wei-Li

    2013-01-01

    Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 × 200 × 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID:23658730

  15. Scaling Up Cortical Control Inhibits Pain

    Directory of Open Access Journals (Sweden)

    Jahrane Dale

    2018-05-01

    Full Text Available Summary: Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain. : Dale et al. find that acute pain increases activity levels in the prefrontal cortex. Chronic pain reduces both basal spontaneous and pain-evoked activity in this region, whereas neurostimulation to restore basal activities can in turn enhance nociception-evoked prefrontal activities to inhibit pain. Keywords: chronic pain, neuromodulation, prefrontal cortex, PFC, cortical gain control

  16. Pharmacological inhibition of feline immunodeficiency virus (FIV).

    Science.gov (United States)

    Mohammadi, Hakimeh; Bienzle, Dorothee

    2012-05-01

    Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses and causes an acquired immunodeficiency syndrome (AIDS) in domestic and non-domestic cats worldwide. Genome organization of FIV and clinical characteristics of the disease caused by the virus are similar to those of human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes and macrophages, and their replication cycle in infected cells is analogous. Due to marked similarity in genomic organization, virus structure, virus replication and disease pathogenesis of FIV and HIV, infection of cats with FIV is a useful tool to study and develop novel drugs and vaccines for HIV. Anti-retroviral drugs studied extensively in HIV infection have targeted different steps of the virus replication cycle: (1) inhibition of virus entry into susceptible cells at the level of attachment to host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus membrane with the cell membrane; (3) blockade of reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and viral DNA integration into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite much success of anti-retroviral therapy slowing disease progression in people, similar therapy has not been thoroughly investigated in cats. In this article we review current pharmacological approaches and novel targets for anti-lentiviral therapy, and critically assess potentially suitable applications against FIV infection in cats.

  17. Wnt signaling inhibits CTL memory programming.

    Science.gov (United States)

    Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra; Li, Lei

    2013-12-01

    Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Response inhibition in motor conversion disorder.

    Science.gov (United States)

    Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A; Hallett, Mark

    2013-05-01

    Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society. Copyright © 2013 Movement Disorder Society.

  19. The Kinetics of Carrier Transport Inhibition

    DEFF Research Database (Denmark)

    Rosenberg, T.; Wilbrandt, Robert Walter

    1962-01-01

    The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing with the subst......The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing...... with the substrate for the enzyme or the carrier or for both, competing with the carrier for the enzyme, or non-competitive) and in the ability of penetrating the membrane. Experiments are reported on the inhibition of glucose and fructose transport across the human red cell membrane by phlorizine, phloretine...... and polyphloretinephosphate. The results of the analysis for these inhibitors indicate a substrate competitive mode of action. The effect of reversing the transport direction by interchanging the substrate concentration has been treated for the case of a non-penetrating substrate competitive inhibitor in the external medium...

  20. Trace element inhibition of phytase activity.

    Science.gov (United States)

    Santos, T; Connolly, C; Murphy, R

    2015-02-01

    Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.

  1. Chloroquine inhibits accessory cell presentation of soluble natural and synthetic protein antigens

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1984-01-01

    We have studied the in vitro effect of the lysosomotrophic agent, chloroquine, on the presentation of soluble protein antigens by guinea pig accessory cells. Chloroquine inhibited the capacity of antigen-pulsed accessory cells to stimulate proliferation in appropriately primed T cells. The effect...... was time- and dose-dependent. A brief treatment solely of the accessory cells with the drug compromised their ability to stimulate primed T cells in a subsequent culture provided the accessory cells were treated with chloroquine before their exposure to the antigen. These results suggest that chloroquine...... acts on an early event in the antigen handling by accessory cells. Chloroquine is a well known inhibitor of lysosomal proteolysis, and it is likely that its effect on antigen presentation is caused by an inhibition of antigen degradation....

  2. Angiotensin-converting enzyme inhibition improves cardiac fatty acid metabolism in patients with congestive heart failure.

    Science.gov (United States)

    Yamauchi, S; Takeishi, Y; Minamihaba, O; Arimoto, T; Hirono, O; Takahashi, H; Miyamoto, T; Nitobe, J; Nozaki, N; Tachibana, H; Watanabe, T; Fukui, A; Kubota, I

    2003-08-01

    This study aimed to examine whether angiotensin-converting enzyme (ACE) inhibition improved cardiac fatty acid metabolism in patients with congestive heart failure (CHF). Myocardial 123I-beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP) imaging was performed in 25 patients with CHF and in 10 control subjects. Myocardial 123I-BMIPP images were obtained 30 min and 4 h after tracer injection. The heart-to-mediastinum (H/M) ratio of 123I-BMIPP uptake and the washout rate of 123I-BMIPP from the myocardium were calculated. Patients were given enalapril for 6 months, and 123I-BMIPP imaging was repeated. H/M ratios on early and delayed images were lower in CHF patients than in normal controls (Pacid metabolism by ACE inhibition may represent a new mechanism for the beneficial effect of this therapy in heart failure.

  3. EARLY ENTRANCE COPRODUCTION PLANT

    Energy Technology Data Exchange (ETDEWEB)

    John S. Abughazaleh; Mushtaq Ahmed; Ashok Anand; John H. Anderson; Charles Benham; Fred D. Brent; Thomas E. Chance; William K. Davis; Raymond F. Drnevich; Larry Hall; Ming He; Stephen A. Lang; David Mintner; Wendy Moore; Jimmy O. Ong; George Potoczniak; Adela G. Sanchez; Charles H. Schrader; Lalit S. Shah; Kalapi D. Sheth; Phil J. Shires; Rae Song

    2001-05-17

    The overall objective of this project is the three-phase development of an Early Entrance Coproduction Plant (EECP) that produces at least one product from at least two of the following three categories: Electric power (or heat); Fuels; and Chemicals. The objective is to have these products produced by technologies capable of using synthesis gas derived from coal and/or some other carbonaceous feedstock, such as petroleum coke. The objective of Phase I was to determine the feasibility and define the concept for the EECP located at a specific site and to develop a Research, Development, and Testing (RD and T) Plan for implementation in Phase II. This objective has now been accomplished. A specific site, Motiva Refinery in Port Arthur, Texas, has been selected as the location best suited for the EECP. The accomplishments of Phase I are discussed in detail in this Phase I Concept Report. A RD and T Plan and a preliminary project financing plan have been developed and are submitted separately from this report.

  4. The Early Experiments

    Science.gov (United States)

    Garvey, Gerald

    2013-04-01

    Stuart Freedman obtained his PhD at Berkley with an experimental thesis providing very strong evidence against theories requiring local hidden variables. He then came to Princeton in 1972 and began collaboration on a search for second-class currents. These measurements are quite difficult as the effects are the order of 1%, demonstrating Freedman's drive to take on hard but important experiments. After carrying out some relatively standard nuclear physics measurements he moved on to Stanford in 1976. There, Freedman was involved in identifying measurements sensitive to the existence of light axions. He also carried out searches for various exotica that might be produced from cosmic rays or the SLAC beam stop. During this time he was collaborating with us at Argonne investigating nuclear parity violation and time-like axial beta decay. In 1982 Freedman came to Argonne where he worked on fundamental issues in neutron beta decay. He also initiated what was to become one of his trademarks, demonstrating that surprising peaks in the e^+-e^- spectrum observed in very heavy ion collisions were spurious. He further launched his first neutrino oscillation experiment. This period of early research was marked by a remarkable diversity of subject matter and approach.

  5. Early diagnosis of leptospirosis

    Directory of Open Access Journals (Sweden)

    Andrea Babic-Erceg

    2014-06-01

    Full Text Available A 25-years old man from Zagreb, Croatia, was admitted to the University Hospital for Infectious Diseases four days after the onset of symptoms such as fever, intense pain in the calves and anuria. The patient owned a rabbit and, before the onset of the disease, repaired some rubber pipes damaged by rodents. At admission, he had a severe clinical picture with fever, hypotension, jaundice, immobility, and pain in leg muscles. Treatment with ceftriaxone was initiated in combination with volume restitution. Renal failure soon ensued. Consequently continuous venovenous hemodiaphiltration therapy was performed. Due to acute respiratory distress syndrome, the patient was mechanically ventilated. The patient’s condition gradually improved and he recovered fully from multi-organ failure. Diagnosis was confirmed by a microscopic agglutination test (MAT covering 15 leptospira serovars and real-time polymerase-chain reaction (PCR. The first serum sample taken on day 6 tested negative for leptospira, while PCR showed positive results for leptospiral DNA. The second serum sample taken on day 13 tested positive for serovar Canicola serogroup Canicola, serovar Patoc, serovar Grippotyphosa serogroup Grippotyphosa and serovar Tarassovi serogroup Tarassovi (titre 4000, 4000, 1000 and 2000, respectively, while PCR was negative. This report highlights the benefits of combining MAT and PCR methods in early diagnosis of leptospirosis.

  6. EARLY ENTRANCE COPRODUCTION PLANT

    International Nuclear Information System (INIS)

    William K. Davis

    2001-01-01

    The overall objective of this project is the three phase development of an Early Entrance Coproduction Plant (EECP) which produces at least one product from at least two of the following three categories: (1) electric power (or heat), (2) fuels, and (3) chemicals. The objective is to have these products produced by technologies capable of using synthesis gas derived from coal and/or other carbonaceous feedstocks. The objective of Phase I is to determine the feasibility and define the concept for the EECP located at a specific site; develop a Research, Development, and Testing (RD and T) Plan for implementation in Phase II; and prepare a Preliminary Project Financing Plan. The objective of Phase II is to implement the work as outlined in the Phase I RD and T Plan to enhance the development and commercial acceptance of coproduction technology that produces high-value products, particularly those that are critical to our domestic fuel and power requirements. The project will resolve critical knowledge and technology gaps on the integration of gasification and downstream processing to coproduce some combination of power, fuels, and chemicals from coal and/or other carbonaceous feedstocks. The objective of Phase III is to develop an engineering design package and a financing plan for an EECP located at a specific site. The project's intended result is to provide the necessary technical, economic, and environmental information needed by industry to move the EECP forward to detailed design, construction, and operation

  7. Is credit for early action credible early action?

    International Nuclear Information System (INIS)

    Rolfe, C.; Michaelowa, A.; Dutschke, M.

    1999-12-01

    Credit for early action as a tool for greenhouse gas emissions reduction is compared with various market instruments as a means of narrowing the gap between projected emissions and those of the Kyoto Protocol. Market instruments work by creating a market price for emissions and use the market to encourage reductions at the lowest price, which is done by placing limits on greenhouse gas emissions and allowing the market to decide where reductions occur, or by imposing a carbon tax or emissions charge. While they can be applied within a sector, they are usually used to encourage reductions throughout the economy or across large sectors. Credit for early action also creates an incentive for emissions reductions throughout the economy or at least across many sectors. Credit for early action tools do not work by either imposing a carbon tax or emissions charge or placing limits on emissions, rather they promise that entities that take action against greenhouse gases prior to the imposition of a carbon tax or emissions limits will receive a credit against future taxes or limits. An overview is provided of the Kyoto Protocol and the rationale for taking early action, and a review is included of the theory and specific proposals for market instruments and credit for early action. A comparative analysis is provided of these approaches by examining their relative efficiency, environmental effectiveness, and impacts on the redistribution of wealth. Credit for early action is viewed as problematic on a number of counts and is seen as an interim strategy for imposition while political support for market instruments develop. The environmental effectiveness of credit for early action is very difficult to predict, and credit for early action programs do not yield the lowest cost emissions reductions. Credit for early action programs will not achieve compliance with the Kyoto Protocol at the lowest cost, and credits for early action will increase the compliance costs for those who

  8. Inhibition of Breast Cancer Metastasis by Heregulin-Beta 1

    National Research Council Canada - National Science Library

    Yu, Dihua

    1999-01-01

    The major goal of this Idea proposal is to determine whether and how HRG-Beta1 inhibits breast cancer metastasis and to identify the functional domains that are sufficient for inhibition of breast cancer metastasis...

  9. A specific bioassay for the inhibition of flowering.

    Science.gov (United States)

    Blake, J

    1972-06-01

    A bioassay for the inhibition of flowering involving the in vitro culture of excised, partially-induced, apices of Viscaria candida is described. This bioassay has been used to detect flowering inhibition in extracts from Kalanchoe blossfeldiana.

  10. Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide

    International Nuclear Information System (INIS)

    Altmann, S.E.; Jones, J.C.; Schultz-Cherry, S.; Brandt, C.R.

    2009-01-01

    Concerns about the possible use of Variola virus, the causative agent of smallpox, as a weapon for bioterrorism have led to renewed efforts to identify new antivirals against orthopoxviruses. We identified a peptide, EB, which inhibited infection by Vaccinia virus with an EC 50 of 15 μM. A control peptide, EBX, identical in composition to EB but differing in sequence, was inactive (EC 50 > 200 μM), indicating sequence specificity. The inhibition was reversed upon removal of the peptide, and EB treatment had no effect on the physical integrity of virus particles as determined by electron microscopy. Viral adsorption was unaffected by the presence of EB, and the addition of EB post-entry had no effect on viral titers or on early gene expression. The addition of EB post-adsorption resulted in the inhibition of β-galactosidase expression from an early viral promoter with an EC 50 of 45 μM. A significant reduction in virus entry was detected in the presence of the peptide when the number of viral cores released into the cytoplasm was quantified. Electron microscopy indicated that 88% of the virions remained on the surface of cells in the presence of EB, compared to 37% in the control (p < 0.001). EB also blocked fusion-from-within, suggesting that virus infection is inhibited at the fusion step. Analysis of EB derivatives suggested that peptide length may be important for the activity of EB. The EB peptide is, to our knowledge, the first known small molecule inhibitor of Vaccinia virus entry.

  11. Motor training reduces surround inhibition in the motor cortex.

    Science.gov (United States)

    Akkad, Haya; Di Stasio, Flavio; Tibold, Robert; Kassavetis, Panagiotis; Rothwell, John C; Edwards, Mark J

    2016-06-01

    Surround inhibition (SI) is thought to facilitate focal contraction of a hand muscle by keeping nearby muscles silent. Unexpectedly, SI is reduced in skilled pianists. We tested whether repeated practice of focal contraction in non-pianists could reduce SI. Motor-evoked potentials were elicited by transcranial magnetic stimulation in the relaxed abductor digiti minimi randomly at the onset and 5s after offset of a 2s focal contraction (10% maximum) of the first dorsal interosseous (FDI). Over 5 blocks of 40 trials participants obtained points for increasing contraction speed and stability in FDI. In a final block, the interval between contractions was varied randomly to increase attention to the task. Over the first 5 blocks, SI declined as performance (points scored) improved. In the final "attention" block SI increased towards baseline without affecting performance. Although SI may be useful during the early stages of learning, skilled focal finger movement does not require SI to prevent activity in non-involved muscles. This could be due to better targeting of the excitatory command to move. Results from the final block suggest that increased attention can re-engage SI when task parameters change. SI is not necessary for successful focal contraction, but may contribute during learning and during attention to task. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Experimental studies on the plasma bullet propagation and its inhibition

    International Nuclear Information System (INIS)

    Karakas, Erdinc; Laroussi, Mounir

    2010-01-01

    Plasma bullets generated by atmospheric pressure low temperature plasma jets have recently been an active research topic due to their unique properties and their enhanced plasma chemistry. In this paper, experimental insights into the plasma bullet lifetime and its velocity are reported. Data obtained from intensified charge-coupled device camera and time-resolved optical emission spectroscopy (OES) elucidated the existence of a weakly ionized channel between the plasma bullet and its source (such as the plasma pencil). Factors responsible for the inhibition of the propagation of the bullet, such as low helium mole fraction, the magnitude of the applied voltage, and the secondary discharge ignition time, are also revealed. A new technique is discussed to accurately measure the plasma bullet velocity, using time-resolved OES. This new technique shows that during its lifetime the plasma bullet goes through launching, propagation, and ending phases. In addition, it is noted that the plasma bullet exhibits an unstable behavior at the early beginning and late ending of the propagation.

  13. Inhibition of Staphylococcus epidermidis Biofilm by Trimethylsilane Plasma Coating

    Science.gov (United States)

    Ma, Yibao; Jones, John E.; Ritts, Andrew C.; Yu, Qingsong

    2012-01-01

    Biofilm formation on implantable medical devices is a major impediment to the treatment of nosocomial infections and promotes local progressive tissue destruction. Staphylococcus epidermidis infections are the leading cause of biofilm formation on indwelling devices. Bacteria in biofilms are highly resistant to antibiotic treatment, which in combination with the increasing prevalence of antibiotic resistance among human pathogens further complicates treatment of biofilm-related device infections. We have developed a novel plasma coating technology. Trimethylsilane (TMS) was used as a monomer to coat the surfaces of 316L stainless steel and grade 5 titanium alloy, which are widely used in implantable medical devices. The results of biofilm assays demonstrated that this TMS coating markedly decreased S. epidermidis biofilm formation by inhibiting the attachment of bacterial cells to the TMS-coated surfaces during the early phase of biofilm development. We also discovered that bacterial cells on the TMS-coated surfaces were more susceptible to antibiotic treatment than their counterparts in biofilms on uncoated surfaces. These findings suggested that TMS coating could result in a surface that is resistant to biofilm development and also in a bacterial community that is more sensitive to antibiotic therapy than typical biofilms. PMID:22964248

  14. Flavonoids Inhibit the Respiratory Burst of Neutrophils in Mammals

    Directory of Open Access Journals (Sweden)

    Milan Ciz

    2012-01-01

    Full Text Available Neutrophils represent the front-line defence cells in protecting organisms against infection and play an irreplaceable role in the proper performance of the immune system. As early as within the first minutes of stimulation, neutrophilic NADPH oxidase is activated, and cells release large quantities of highly toxic reactive oxygen species (ROS. These oxidants can be highly toxic not only for infectious agents but also for neighboring host tissues. Since flavonoids exhibit antioxidant and anti-inflammatory effects, they are subjects of interest for pharmacological modulation of ROS production. The present paper summarizes contemporary knowledge on the effects of various flavonoids on the respiratory burst of mammalian neutrophils. It can be summarized that the inhibitory effects of flavonoids on the respiratory burst of phagocytes are mediated via inhibition of enzymes involved in cell signaling as well as via modulation of redox status. However, the effects of flavonoids are even more complex, and several sites of action, depending upon the flavonoid structure and way of application, are included.

  15. Differential effects of cognitive inhibition and intelligence on creativity

    OpenAIRE

    Benedek, Mathias; Franz, Fabiola; Heene, Moritz; Neubauer, Aljoscha C.

    2012-01-01

    There are different conceptions about how cognitive inhibition is related to creativity. Creativity has either been associated with effective inhibition, or with disinhibition, or with an adaptive engagement of inhibition. In this study, we examined the relationship of cognitive inhibition, assessed by means of the random motor generation task, with different measures of creativity. We also analyzed whether this relation is mediated by intelligence. We generally found a positive correlation o...

  16. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    OpenAIRE

    Ho, Ming-Chou; Li, Ren-Hau; Tang, Tze-Chun

    2011-01-01

    Betel nut (or areca) is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for ob...

  17. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi

    International Nuclear Information System (INIS)

    Arras, G.; Gambella, F.; Demontis, S.; Petretto, A.

    1995-01-01

    An isolate (87) of the bacillus subtilis strains isolated from cold stored citrus fruit 13 proved to inhibit the growth in vitro of the penicillium italicum used in the experiment (from 50.6% to 92.2%) and to inhibit botrytis cinerea (from 65.3% to 95.9%). A further test, superimposing on plates containing PDA strains Nos. 13, 173, and 160, totally inhibited the fungi. Tested in vivo on artificially bruised oranges, they significantly inhibited two fungi

  18. The development of children's inhibition: Does parenting matter?

    OpenAIRE

    Roskam, I.; Stievenart, Marie; Meunier, J.-C.; Noël, M.-P.

    2014-01-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8. years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition ...

  19. Early tetrapod relationships revisited.

    Science.gov (United States)

    Ruta, Marcello; Coates, Michael I; Quicke, Donald L J

    2003-05-01

    In an attempt to investigate differences between the most widely discussed hypotheses of early tetrapod relationships, we assembled a new data matrix including 90 taxa coded for 319 cranial and postcranial characters. We have incorporated, where possible, original observations of numerous taxa spread throughout the major tetrapod clades. A stem-based (total-group) definition of Tetrapoda is preferred over apomorphy- and node-based (crown-group) definitions. This definition is operational, since it is based on a formal character analysis. A PAUP* search using a recently implemented version of the parsimony ratchet method yields 64 shortest trees. Differences between these trees concern: (1) the internal relationships of aïstopods, the three selected species of which form a trichotomy; (2) the internal relationships of embolomeres, with Archeria crassidisca and Pholiderpeton scut collapsed in a trichotomy with a clade formed by Anthracosaurus russelli and Pholiderpeton attheyi; (3) the internal relationships of derived dissorophoids, with four amphibamid species forming an unresolved node with a clade consisting of micromelerpetontids and branchiosaurids and a clade consisting of albanerpetontids plus basal crown-group lissamphibians; (4) the position of albenerpetontids and Eocaecilia micropoda, which form an unresolved node with a trichotomy subtending Karaurus sharovi, Valdotriton gracilis and Triadobatrachus massinoti; (5) the branching pattern of derived diplocaulid nectrideans, with Batrachiderpeton reticulatum and Diceratosaurus brevirostris collapsed in a trichotomy with a clade formed by Diplocaulus magnicornis and Diploceraspis burkei. The results of the original parsimony run--as well as those retrieved from several other treatments of the data set (e.g. exclusion of postcranial and lower jaw data; character reweighting; reverse weighting)--indicate a deep split of early tetrapods between lissamphibian- and amniote-related taxa. Colosteids, Crassigyrinus

  20. Early onset sebaceous carcinoma

    Directory of Open Access Journals (Sweden)

    Kaltreider Sara A

    2011-09-01

    Full Text Available Abstract Background Ocular sebaceous carcinoma can masquerade as benign lesions resulting in delay of diagnosis. Early recognition is even more difficult in young patients where the disease rarely occurs. Here, we provide a clinicopathological correlation of ocular sebaceous carcinoma in a young individual lacking history of hereditary cancer or immunosuppression. Findings A detailed histopathological study including p53 DNA sequencing was performed on an aggressive sebaceous carcinoma presenting in a healthy 32 year-old Caucasian woman. She had no history of retinoblastoma, evidence for a hereditary cancer syndrome, or radiation therapy. However, she potentially was at risk for excessive UV light exposure. A detailed review of the literature is also provided. A moderately well differentiated sebaceous carcinoma was established histopathologically arising from the meibomian gland of the upper eyelid. In most areas, the cytoplasm contained small but distinct Oil-red-O positive vacuoles. Direct sequencing of p53 identified a G:C→A:T mutation at a dipyrimidine site. The mutation results in substitution of arginine for the highly conserved glycine at residue 199 located at the p53 dimer-dimer interface. Energy minimization structural modeling predicts that G199R will neutralize negative charges contributed by nearby inter- and intramonomeric glutamate residues. Discussion This study points to the importance of recognizing that sebaceous carcinoma can occur in young patients with no evidence for hereditary cancer risk or radiation therapy. The G199R substitution is anticipated to alter the stability of the p53 tetrameric complex. The role of UV light in the etiology of sebaceous carcinoma deserves further study. Our findings, taken together with those of others, suggest that different environmental factors could lead to the development of sebaceous carcinoma in different patients.

  1. ROCK inhibition abolishes the establishment of the aquiferous system in Ephydatia muelleri (Porifera, Demospongiae).

    Science.gov (United States)

    Schenkelaars, Quentin; Quintero, Omar; Hall, Chelsea; Fierro-Constain, Laura; Renard, Emmanuelle; Borchiellini, Carole; Hill, April L

    2016-04-15

    The Rho associated coiled-coil protein kinase (ROCK) plays crucial roles in development across bilaterian animals. The fact that the Rho/Rock pathway is required to initiate epithelial morphogenesis and thus to establish body plans in bilaterians makes this conserved signaling pathway key for studying the molecular mechanisms that may control early development of basally branching metazoans. The purpose of this study was to evaluate whether or not the main components of this signaling pathway exist in sponges, and if present, to investigate the possible role of the regulatory network in an early branching non-bilaterian species by evaluating ROCK function during Ephydatia muelleri development. Molecular phylogenetic analyses and protein domain predictions revealed the existence of Rho/Rock components in all studied poriferan lineages. Binding assays revealed that both Y-27632 and GSK429286A are capable of inhibiting Em-ROCK activity in vitro. Treatment with both drugs leads to impairment of growth and formation of the basal pinacoderm layer in the developing sponge. Furthermore, inhibition of Em-Rock prevents the establishment of a functional aquiferous system, including the absence of an osculum. In contrast, no effect of ROCK inhibition was observed in juvenile sponges that already possess a fully developed and functional aquiferous system. Thus, the Rho/Rock pathway appears to be essential for the proper development of the freshwater sponge, and may play a role in various cell behaviors (e.g. cell proliferation, cell adhesion and cell motility). Taken together, these data are consistent with an ancestral function of Rho/Rock signaling in playing roles in early developmental processes and may provide a new framework to study the interaction between Wnt signaling and the Rho/Rock pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Early determinants of mental health

    NARCIS (Netherlands)

    Räikkönen, Katri; Pesonen, Anu-Katriina; Roseboom, Tessa J.; Eriksson, Johan G.

    2012-01-01

    Environmental adversities in pre- and early postnatal life may have life-long consequences. Based upon a series of epidemiological and clinical studies and natural experiments, this review describes how the early life environment may affect psychological functions and mental disorders later in life.

  3. Early Childhood Education in Taiwan.

    Science.gov (United States)

    Barclay, Lisa K.

    1989-01-01

    Describes early childhood education in Taiwan, focusing on living patterns and child care arrangements, the position of the individual within the family and community, and the application of cultural norms to early childhood education. Compares the behavior of Chinese preschool children to that of American preschool children. (RJC)

  4. Cell Analysis and Early Diagnostics

    NARCIS (Netherlands)

    Subramaniam, Vinod; Jones, Val

    2006-01-01

    In an era of aging populations and rising health-care costs, the shift of medical paradigms towards rapid, accurate, early diagnoses of diseases is inevitable. In addition to further development of ultrasensitive in vitro tests, the focus of attention in both diagnostics and the early drug discovery

  5. Early Childhood Inclusion in Spain

    Science.gov (United States)

    Giné, Climent; Balcells-Balcells, Anna; Cañadas, Margarita; Paniagua, Gema

    2016-01-01

    This article describes early childhood inclusion in educational settings in Spain. First, we address the legislative framework of preschool education in Spain and offer a brief analysis of some relevant issues, including the current situation of early childhood education and inclusion at this stage. Second, current policies and practices relating…

  6. Contour detection based on nonclassical receptive field inhibition

    NARCIS (Netherlands)

    Grigorescu, Cosmin; Petkov, Nicolai; Westenberg, Michel A.

    We propose a biologically motivated computational step, called nonclassical receptive field (non-CRF) inhibition, more generally surround inhibition or suppression, to improve contour detection in machine vision. Non-CRF inhibition is exhibited by 80% of the orientation-selective neurons in the

  7. The Effectiveness of Reward and Punishment Contingencies on Response Inhibition

    Science.gov (United States)

    Costantini, Arthur F.; Hoving, Kenneth L.

    1973-01-01

    The relative effectiveness of reward and punishment on the development of response inhibition was evaluated developmentally with kindergarteners and second graders. Removal of positive reinforcers was apparently more effective than reward in producing inhibiting at both age levels. Transfer of inhibition training was also evaluated. (DP)

  8. Effect of Adenine Concentration on the Corrosion Inhibition of Aisi ...

    African Journals Online (AJOL)

    This gave a surface coverage of 0.8956 and corrosion penetration rate of 0.022132mm/yr. Hence, the best adenine concentration for the corrosion inhibition of alloys 304L in 1.0M sulphuric acid solution to obtain optimum inhibition efficiency is 0.011M. Keywords: Corrosion, AISI 304L Steel, Inhibition efficiency, Degree of ...

  9. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi.

    Science.gov (United States)

    Miyazawa, M; Tougo, H; Ishihara, M

    2001-01-01

    Inhibition of acetylcholinesterase (AChE) activity by essential oils of Citrus paradisi (grapefruit pink in USA) was studied. Inhibition of AChE was measured by the colorimetric method. Nootkatone and auraptene were isolated from C. paradisi oil and showed 17-24% inhibition of AChE activity at the concentration of 1.62 microg/mL.

  10. Inhibition and Adsorption impact of Leave Extracts of Cnidoscolus ...

    African Journals Online (AJOL)

    Corrosion inhibition in the presence of alokaloid and non alkaloid extracts of Cnidoscolus aconitifolius in 1M HCl was studied using the weight loss and hydrogen evolution techniques at 303, 313 and 333 K. The results obtained revealed that the inhibition efficiency decreased with increase in temperature. Inhibition ...

  11. A fusion-inhibiting peptide against Rift Valley fever virus inhibits multiple, diverse viruses.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Koehler

    Full Text Available For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III based on the protein sequence and structure. For Rift Valley fever virus (RVFV, the glycoprotein Gc (Class II fusion protein mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus, Class II (Andes virus, or Class III (vesicular stomatitis virus fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors.

  12. [Erythropoiesis and functional characteristics in bone marrow erythroblastic islets during stimulated adn inhibited erythropoiesis].

    Science.gov (United States)

    Rassokhin, A G; Kruglov, D G; Zakharov, Iu M

    2000-01-01

    When erythropiesis is stimulated (acute blood loss) or inhibited (posttransfusion polycythemia), there are early changes in the cytochemical values of erythroblastic islets (EI): in the levels of acid and neutral glucoconjugates and in the activity of nonspecific esterase. A close correlation has been found between the erythropoiesis in EI and its functional characteristics. It is concluded that central macrophages play the key role in the modulation of EI erythropoiesis. It is suggested that EI macrophages are involved in the provision of bioenergetic and reparative processes in EI.

  13. Early diagnosis and early intervention in cerebral palsy

    Directory of Open Access Journals (Sweden)

    Mijna eHadders-Algra

    2014-09-01

    Full Text Available This paper reviews the opportunities and challenges for early diagnosis and early intervention in cerebral palsy (CP. CP describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to disturbances that occurred in the fetal or infant brain. Therefore the paper starts with a summary of relevant information from developmental neuroscience. Most lesions underlying CP occur in the second half of gestation, when developmental activity in the brain reaches its summit. Variations in timing of the damage not only result in different lesions, but also in different neuroplastic reactions and different associated neuropathologies. This turns CP into a heterogeneous entity. This may mean that the best early diagnostics and the best intervention methods may differ for various subgroups of children with CP. Next, the paper addresses possibilities for early diagnosis. It discusses the predictive value of neuromotor and neurological exams, neuro-imaging techniques and neurophysiological assessments. Prediction is best when complementary techniques are used in longitudinal series. Possibilities for early prediction of CP differ for infants admitted to neonatal intensive care and other infants. In the former group best prediction is achieved with the combination of neuro-imaging and the assessment of general movements, in the latter group best prediction is based on carefully documented milestones and neurological assessment. The last part reviews early intervention in infants developing CP. Most knowledge on early intervention is based on studies in high risk infants without CP. In these infants early intervention programs promote cognitive development until preschool age; motor development profits less. The few studies on early intervention in infants developing CP suggest that programs that stimulate all aspects of infant development by means of family coaching are most promising. More research is

  14. Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer.

    Science.gov (United States)

    Patel, Sukeshi; Hurez, Vincent; Nawrocki, Steffan T; Goros, Martin; Michalek, Joel; Sarantopoulos, John; Curiel, Tyler; Mahalingam, Devalingam

    2016-09-13

    Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.

  15. Development of response inhibition in the context of relevant versus irrelevant emotions

    Directory of Open Access Journals (Sweden)

    Margot A Schel

    2013-07-01

    Full Text Available The present study examined the influence of relevant and irrelevant emotions on response inhibition from childhood to early adulthood. Ninety-four participants between 6 and 25 years of age performed two go/nogo tasks with emotional faces (neutral, happy, and fearful as stimuli. In one go/nogo task emotion formed a relevant dimension of the task and in the other go/nogo task emotion was irrelevant and participants had to respond to the color of the faces instead. A special feature of the latter task, in which emotion was irrelevant, was the inclusion of free choice trials, in which participants could freely decide between acting and inhibiting. Results showed a linear increase in response inhibition performance with increasing age both in relevant and irrelevant affective contexts. Relevant emotions had a pronounced influence on performance across age, whereas irrelevant emotions did not. Overall, participants made more false alarms on trials with fearful faces than happy faces, and happy faces were associated with better performance on go trials (higher percentage correct and faster RTs than fearful faces. The latter effect was stronger for young children in terms of accuracy. Finally, during the free choice trials participants did not base their decisions on affective context, confirming that irrelevant emotions do not have a strong impact on inhibition. Together, these findings suggest that across development relevant affective context has a larger influence on response inhibition than irrelevant affective context. When emotions are relevant, a context of positive emotions is associated with better performance compared to a context with negative emotions, especially in young children.

  16. ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Hu, E-mail: austhudong@126.com [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Medical Inspection Center, Anhui University of Science and Technology, Huainan (China); Jing, Wu, E-mail: wujing8008@126.com [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Medical Inspection Center, Anhui University of Science and Technology, Huainan (China); Runpeng, Zhao; Xuewei, Xu; Min, Mu; Ru, Cai [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Yingru, Xing; Shengfa, Ni [Affiliated Cancer Hospital, Anhui University of Science and Technology (China); Rongbo, Zhang [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Medical Inspection Center, Anhui University of Science and Technology, Huainan (China)

    2016-08-19

    In recent years, increasing studies have found that pathogenic Mycobacterium tuberculosis (Mtb) inhibits autophagy, which mediates the anti-mycobacterial response, but the mechanism is not clear. We previously reported that secretory acid phosphatase (SapM) of Mtb can negatively regulate autophagy flux. Recently, another virulence factor of Mtb, early secretory antigenic target 6 (ESAT6), has been found to be involved in inhibiting autophagy, but the mechanism remains unclear. In this study, we show that ESAT6 hampers autophagy flux to boost bacillus Calmette-Guerin (BCG) proliferation and reveals a mechanism by which ESAT6 blocks autophagosome-lysosome fusion in a mammalian target of rapamycin (MTOR)-dependent manner. In both Raw264.7 cells and primary macrophages derived from the murine abdominal cavity (ACM), ESAT6 repressed autophagy flux by interfering with the autophagosome-lysosome fusion, which resulted in an increased load of BCG. Impaired degradation of LC3Ⅱ and SQSTM1 by ESAT6 was related to the upregulated activity of MTOR. Contrarily, inhibiting MTOR with Torin1 removed the ESAT6-induced autophagy block and lysosome dysfunction. Furthermore, in both Raw264.7 and ACM cells, MTOR inhibition significantly suppressed the survival of BCG. In conclusion, our study highlights how ESAT6 blocks autophagy and promotes BCG survival in a way that activates MTOR. - Highlights: • A mechanism for disruping autophagy flux induced by ESAT6. • ESAT6-inhibited autophagy is MTOR-dependent. • ESAT6-boosted BCG is MTOR-dependent.

  17. Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine

    OpenAIRE

    Isayev, Orkhan; Rausch, Vanessa; Bauer, Nathalie; Liu, Li; Fan, Pei; Zhang, Yiyao; Gladkich, Jury; Nwaeburu, Clifford C.; Mattern, Jürgen; Mollenhauer, Martin; Rückert, Felix; Zach, Sebastian; Haberkorn, Uwe; Gross, Wolfgang; Schönsiegel, Frank

    2014-01-01

    According to the cancer stem cell (CSC) hypothesis, the aggressive growth and early metastasis of pancreatic ductal adenocarcinoma (PDA) is due to the activity of CSCs, which are not targeted by current therapies. Otto Warburg suggested that the growth of cancer cells is driven by a high glucose metabolism. Here, we investigated whether glycolysis inhibition targets CSCs and thus may enhance therapeutic efficacy. Four established and 3 primary PDA cell lines, non-malignant cells, and 3 patien...

  18. Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring

    OpenAIRE

    Khalil, Omari S; Pisar, Mazura; Forrest, Caroline M; Vincenten, Maria C J; Darlington, L Gail; Stone, Trevor W

    2014-01-01

    Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developme...

  19. Curcumin inhibits aggregation of alpha-synuclein.

    Science.gov (United States)

    Pandey, Neeraj; Strider, Jeffrey; Nolan, William C; Yan, Sherry X; Galvin, James E

    2008-04-01

    Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

  20. Cannabidiol inhibits angiogenesis by multiple mechanisms.

    Science.gov (United States)

    Solinas, M; Massi, P; Cantelmo, A R; Cattaneo, M G; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, L M; Noonan, D M; Albini, A; Parolaro, D

    2012-11-01

    Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  1. Inhibition of initial adhesion of oral bacteria through a lectin from Bauhinia variegata L. var. variegata expressed in Escherichia coli.

    Science.gov (United States)

    Klafke, G B; Borsuk, S; Gonçales, R A; Arruda, F V S; Carneiro, V A; Teixeira, E H; Coelho da Silva, A L; Cavada, B S; Dellagostin, O A; Pinto, L S

    2013-11-01

    The aim of the present work was to study the in vitro effect of native and recombinant Bauhinia variegata var. variegata lectins in inhibiting early adhesion of Streptococcus mutans, Streptococcus sanguis and Streptococcus sobrinus to experimentally acquired pellicle. Native lectin from B. variegata (BVL) was purified by affinity chromatography of extract of seeds. The recombinant lectin (rBVL-I) was expressed in E. coli strain BL21 (DE3) from a genomic clone encoding the mature B. variegata lectin gene using the vector pAE-bvlI. Recombinant protein deposited in inclusion bodies was solubilized and subsequently purified by affinity chromatography. The rBVL-I was compared to BVL for agglutination of erythrocytes and initial adherence of oral bacteria on a saliva-coated surface. The results revealed that rBVL-I acts similarly to BVL for agglutination of erythrocytes. Both lectins showed adhesion inhibition effect on Step. sanguis, Step. mutans and Step. sobrinus. We report, for the first time, the inhibition of early adhesion of oral bacteria by a recombinant lectin. Our results support the proposed biotechnological application of lectins in a strategy to reduce development of dental caries by inhibiting the initial adhesion and biofilm formation. © 2013 The Society for Applied Microbiology.

  2. Disruptions of working memory and inhibition mediate the association between exposure to institutionalization and symptoms of attention deficit hyperactivity disorder.

    Science.gov (United States)

    Tibu, F; Sheridan, M A; McLaughlin, K A; Nelson, C A; Fox, N A; Zeanah, C H

    2016-02-01

    Young children raised in institutions are exposed to extreme psychosocial deprivation that is associated with elevated risk for psychopathology and other adverse developmental outcomes. The prevalence of attention deficit hyperactivity disorder (ADHD) is particularly high in previously institutionalized children, yet the mechanisms underlying this association are poorly understood. We investigated whether deficits in executive functioning (EF) explain the link between institutionalization and ADHD. A sample of 136 children (aged 6-30 months) was recruited from institutions in Bucharest, Romania, and 72 never institutionalized community children matched for age and gender were recruited through general practitioners' offices. At 8 years of age, children's performance on a number of EF components (working memory, response inhibition and planning) was evaluated. Teachers completed the Health and Behavior Questionnaire, which assesses two core features of ADHD, inattention and impulsivity. Children with history of institutionalization had higher inattention and impulsivity than community controls, and exhibited worse performance on working memory, response inhibition and planning tasks. Lower performances on working memory and response inhibition, but not planning, partially mediated the association between early institutionalization and inattention and impulsivity symptom scales at age 8 years. Institutionalization was associated with decreased EF performance and increased ADHD symptoms. Deficits in working memory and response inhibition were specific mechanisms leading to ADHD in previously institutionalized children. These findings suggest that interventions that foster the development of EF might reduce risk for psychiatric problems in children exposed to early deprivation.

  3. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    Energy Technology Data Exchange (ETDEWEB)

    Jan, Yi-Hua [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Baker, Angela A. [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Mishin, Vladimir [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Department of Environmental Health Science, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2015-10-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  4. Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

    International Nuclear Information System (INIS)

    Jan, Yi-Hua; Richardson, Jason R.; Baker, Angela A.; Mishin, Vladimir; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2015-01-01

    Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.

  5. Saw palmetto ethanol extract inhibits adipocyte differentiation.

    Science.gov (United States)

    Villaverde, Nicole; Galvis, Adriana; Marcano, Adriana; Priestap, Horacio A; Bennett, Bradley C; Barbieri, M Alejandro

    2013-07-01

    The fruits of saw palmetto have been used for the treatment of a variety of urinary and reproductive system problems. In this study we investigated whether the fruit extracts affect in vitro adipogenesis. Saw palmetto ethanol extract inhibited the lipid droplet accumulation by induction media in a dose-dependent manner, and it also attenuated the protein expressions of C-EBPα and PPARγ. Phosphorylation of Erk1/2 and Akt1 were also decreased by saw palmetto ethanol extract. This report suggests that saw palmetto extracts selectively affect the adipocyte differentiation through the modulation of several key factors that play a critical role during adipogenesis.

  6. Irradiation inhibits the regeneration of aneurogenic limbs

    International Nuclear Information System (INIS)

    Wallace, H.; Maden, M.

    1976-01-01

    The developing arms of axolotl larvae from the 2-digit stage onward and the aneurogenic arms of surgically denervated larvae maintained in parabiosis are able to regenerate after amputation. Such regeneration is uniformly inhibited by local irradiation of the arm, whether innervated or not. This demonstration refutes a recent hypothesis that x-rays interfere with a special activity of nerves required for regeneration, and supports the earlier concept that x-rays act directly on those cells which must proliferate to form the regenerated tissues

  7. Inhibition of sulfate reduction in paddy soils

    Energy Technology Data Exchange (ETDEWEB)

    Vamos, R

    1958-12-13

    The hydrogen sulfide formed in waterlogged soils is a serious problem in rice cultivation. It inhibits the uptake of water and nutrients and may even cause root-rot. Results can best be obtained by preventing the formation of hydrogen sulfide. It is formed mainly by reduction of sulfate for which the cellulose-butyric acid fermentation provides the hydrogen source. Addition of ammonium or potassium nitrate prevents the formation of H/sub 2/S. The hydrogen produced by butyric acid fermentation is used to reduce nitrate and consequently cannot be utilized by the sulfate-reducing bacteria as a source of energy. 6 references.

  8. Vaginal Lactobacillus isolates inhibit uropathogenic Escherichia coli.

    OpenAIRE

    Atassi , Fabrice; Brassart , Dominique; Grob , Philipp; Graf , Federico; Servin , Alain ,

    2006-01-01

    The purpose of this study was to investigate the antibacterial activities of Lactobacillus jensenii KS119.1 and KS121.1, and Lactobacillus gasserii KS120.1 and KS124.3 strains isolated from the vaginal microflora of healthy women, against uropathogenic, diffusely adhering Afa/Dr Escherichia coli (Afa/Dr DAEC) strains IH11128 and 7372 involved in recurrent cystitis. We observed that some of the Lactobacillus isolates inhibited the growth and decreased the viability of E. coli IH11128 and 7372....

  9. Research on inhibition of corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Zhang-Hui Yang

    2015-12-01

    Full Text Available Corneal transparency is the basis of the normal physiological functions.However, corneal neovascularization(CNVmay occur in the infection, mechanical and chemical injury or under other pathological conditions,which make the cornea lose original transparency and severe visual impairment. In recent years, along with the development of immunology, molecular biology, biochemistry and other disciplines, there is more in-depth understanding on the CNV, and clinical treatment of CNV has made new breakthroughs. This article provides an overview of the inhibition of CNV.

  10. Na+/K+-ATPase: Activity and inhibition

    Science.gov (United States)

    Čolović, M.; Krstić, D.; Krinulović, K.; Momić, T.; Savić, J.; Vujačić, A.; Vasić, V.

    2009-09-01

    The aim of the study was to give an overview of the mechanism of inhibition of Na+/K+-ATPase activity induced by some specific and non specific inhibitors. For this purpose, the effects of some ouabain like compounds (digoxin, gitoxin), noble metals complexes ([PtCl2DMSO2], [AuCl4]-, [PdCl4]2-, [PdCl(dien)]+, [PdCl(Me4dien)]+), transition metal ions (Cu2+, Zn2+, Fe2+, Co2+), and heavy metal ions (Hg2+, Pb2+, Cd2+) on the activity of Na+/K+-ATPase from rat synaptic plasma membranes (SPM), porcine cerebral cortex and human erythrocytes were discussed.

  11. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  12. A Longitudinal Investigation of Predictors of the Association Between Age 3 and Age 6 Behavioural Inhibition.

    Science.gov (United States)

    Johnson, Victoria C; Olino, Thomas M; Klein, Daniel N; Dyson, Margaret W; Bufferd, Sara J; Durbin, C Emily; Dougherty, Lea R; Hayden, Elizabeth P

    2016-08-01

    Children who exhibit elevated levels of the temperament trait behavioural inhibition (BI) across time may be at greatest risk for anxiety. However, little research has investigated the influence of other temperamental traits, particularly positive emotionality (PE), on the continuity of BI in childhood, nor whether parental overprotection influences associations between early and later child BI. To explore whether PE and overprotection shape associations between early and later BI, this longitudinal study of three-year-olds ( N = 446) followed up at age 6 included tasks tapping child temperament, and parental overprotection was assessed via interview ratings and parent-report. Lower levels of child PE and higher levels of caregiver overprotection at baseline predicted stronger associations between laboratory-assessed BI at ages 3 and 6. Findings elucidate influences shaping the developmental continuity of BI.

  13. Characterization of the tumor-promoting activity of m-chloroperoxybenzoic acid in SENCAR mouse skin and its inhibition by gallotannin, oligomeric proanthocyanidin, and their monomeric units

    Science.gov (United States)

    Guilan Chen; Elisabeth M. Perchellet; Xiao Mei Gao; Fatima K. Johnson; Amy W. Davis; Steven W. Newell; Richard W. Hemingway; Vittorio Bottari; Jean-Pierre Perchellett

    1996-01-01

    m-Chloroperoxybenzoic acid (CPBA). Which induces ornithine decarboxylase activity as much as 12-0- terradecanoyIp horbol-13-acetate (TPA ). was tested for its ability to induce DNA synthesis. bydroperoxide (HPx) production. and tumor promotion in mouse epidermis in vivo. After an early inhibition. CPBA stimulates DNA synthesis. A response which is maintained between 16...

  14. Inhibition of Insulin like growth factor-I expression by chromatographic fraction of Polygonum hydropiper root reduces implantation preference in rat

    Directory of Open Access Journals (Sweden)

    Pranjiv Goswami

    2014-03-01

    Major conclusions: The root of P. hydropiper contains compound(s with capability to modulate transcription and expression of IGF-I in rat uterus during early gestation. Down regulation of IGF-I results suggests that the phytocompound(s work through the ovarian steroid receptor(s resulting in an inhibition of decidual cell reaction and implantation.

  15. Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

    NARCIS (Netherlands)

    Beuningen, H.M. van; Vries-van Melle, M.L. de; Vitters, E.L.; Schreurs, W.; Berg, W.B. van den; Osch, G.J. van; Kraan, P.M. van der

    2014-01-01

    OBJECTIVE: To rescue chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in osteoarthritic conditions by inhibition of protein kinases. METHODS: hMSCs were cultured in pellets. During early chondrogenic differentiation, these were exposed to osteoarthritic synovium-conditioned

  16. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing

    International Nuclear Information System (INIS)

    Tropea, J.E.; Molyneux, R.J.; Kaushal, G.P.; Pan, Y.T.; Mitchell, M.; Elbein, A.D.

    1989-01-01

    Australine is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, the authors tested australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the α-glucosidase amyloglucosidase (50% inhibition at 5.8 μM), but it did not inhibit β-glucosidase, α- or β-mannosidase, or α- or β-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, this alkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc 3 Man 7-9 (GlcNAc) 2 -oligosaccharides

  17. Early Maternal Time Investment and Early Child Outcomes

    OpenAIRE

    Del Bono, Emilia; Francesconi, Marco; Kelly, Yvonne; Sacker, Amanda

    2014-01-01

    Using large longitudinal survey data from the UK Millennium Cohort Study, this paper estimates the relationship between maternal time inputs and early child development. We find that maternal time is a quantitatively important determinant of skill formation and that its effect declines with child age. There is evidence of long-term effects of early maternal time inputs on later outcomes, especially in the case of cognitive skill development. In the case of non-cognitive development, the evide...

  18. EARLY ENTRANCE COPRODUCTION PLANT

    Energy Technology Data Exchange (ETDEWEB)

    Fred D. Brent; Lalit Shah; Earl Berry; Charles H. Schrader; John Anderson; Ming He; James F. Stevens; Centha A. Davis; Michael Henley; Jerome Mayer; Harry Tsang; Jimell Erwin; Jennifer Adams; Michael Tillman; Chris Taylor; Marjan J. Roos; Robert F. Earhart

    2004-01-27

    The overall objective of this project is the three phase development of an Early Entrance Coproduction Plant (EECP) which uses petroleum coke to produce at least one product from at least two of the following three categories: (1) electric power (or heat), (2) fuels, and (3) chemicals using ChevronTexaco's proprietary gasification technology. The objective of Phase I is to determine the feasibility and define the concept for the EECP located at a specific site; develop a Research, Development, and Testing (RD&T) Plan to mitigate technical risks and barriers; and prepare a Preliminary Project Financing Plan. The objective of Phase II is to implement the work as outlined in the Phase I RD&T Plan to enhance the development and commercial acceptance of coproduction technology. The objective of Phase III is to develop an engineering design package and a financing and testing plan for an EECP located at a specific site. The project's intended result is to provide the necessary technical, economic, and environmental information needed by industry to move the EECP forward to detailed design, construction, and operation. The partners in this project are Texaco Energy Systems LLC or TES (a subsidiary of ChevronTexaco), General Electric (GE), Praxair, and Kellogg Brown & Root (KBR) in addition to the U.S. Department of Energy (DOE). TES is providing gasification technology and Fischer-Tropsch (F-T) technology developed by Rentech, GE is providing combustion turbine technology, Praxair is providing air separation technology, and KBR is providing engineering. Each of the EECP subsystems was assessed for technical risks and barriers. A plan was developed to mitigate the identified risks (Phase II RD&T Plan, October 2000). The potential technical and economic risks to the EECP from Task 2.5 can be mitigated by demonstrating that the end-use products derived from the upgrading of the F-T synthesis total liquid product can meet or exceed current specifications for the

  19. DOT1L inhibitor improves early development of porcine somatic cell nuclear transfer embryos

    DEFF Research Database (Denmark)

    Tao, Jia; Zhang, Yu; Zuo, Xiaoyuan

    2017-01-01

    Incomplete epigenetic reprogramming of the genome of donor cells causes poor early and full-term developmental efficiency of somatic cell nuclear transfer (SCNT) embryos. Previous research indicate that inhibition of the histone H3 K79 methyltransferase DOT1L, using a selective pharmacological...... inhibitor EPZ004777 (EPZ), significantly improved reprogramming efficiency during the generation of mouse induced pluripotent stem cells. However, the roles of DOT1L in porcine nuclear transfer-mediated cellular reprogramming are not yet known. Here we showed that DOT1L inhibition via 0.5 nM EPZ treatment...

  20. Early vision and visual attention

    Directory of Open Access Journals (Sweden)

    Gvozdenović Vasilije P.

    2003-01-01

    Full Text Available The question whether visual perception is spontaneous, sudden or is running through several phases, mediated by higher cognitive processes, was raised ever since the early work of Gestalt psychologists. In the early 1980s, Treisman proposed the feature integration theory of attention (FIT, based on the findings of neuroscience. Soon after publishing her theory a new scientific approach appeared investigating several visual perception phenomena. The most widely researched were the key constructs of FIT, like types of visual search and the role of the attention. The following review describes the main studies of early vision and visual attention.

  1. Sprouting inhibition of rhizomes by gamma irradiation

    International Nuclear Information System (INIS)

    Hilmy, Nazly; Chosdu, Rahayu

    1985-01-01

    Sprouting inhibition by gamma irradiation to prolong the storage life of 4 species of rhizomes, namely curcuma domestica, kaemferia galanga, curcuma xanthoriza and curcuma aeruginosa, has been carried out. Two groups of samples were used, freshly harvested rhizomes and fresh rhizomes which have been stored for about two weeks. The samples were packed in a plastic net bag, each contained about 100 grams of rhizomes. Irradiation was carried out at room temperature at the doses of 0, 0.02, 0.04, 0.06, 0.08, 0.10, 0.15, 0.20 and 0.25 kGy. Post irradiation storage was done at room temperature with relative humidity ranging between 85 and 95%. The results showed that irradiation doses of 0.06 to 0.08 kGy was sufficient to inhibit sprouting of freshly harvested rhizomes and prolonged its storage life for 6 weeks, while in the other group sprouting still occured at the dose of 0.25 kGy. Irradiation dose up to 0.25 kGy did not cause significant effect on moisture and volatile oil contents, as well as volatile oil characteristics of the samples. About 50% of weight losses were found either in irradiated or unirradiated samples after being stored for 8 weeks. Odour and texture were evaluated organoleptically while mould growth and insect damage were observed visually. (author)

  2. Inhibition of DNA replication by ultraviolet light

    International Nuclear Information System (INIS)

    Edenberg, H.J.

    1976-01-01

    DNA replication in ultraviolet-irradiated HeLa cells was studied by two different techniques: measurements of the kinetics of semiconservative DNA synthesis, and DNA fiber autoradiography. In examining the kinetics of semiconservative DNA synthesis, density label was used to avoid measuring the incorporation due to repair replication. The extent of inhibition varied with time. After doses of less than 10 J/m 2 the rate was initially depressed but later showed some recovery. After higher doses, a constant, low rate of synthesis was seen for at least the initial 6 h. An analysis of these data indicated that the inhibition of DNA synthesis could be explained by replication forks halting at pyrimidine dimers. DNA fiber autoradiography was used to further characterize replication after ultraviolet irradiation. The average length of labeled segments in irradiated cells increased in the time immediately after irradiation, and then leveled off. This is the predicted pattern if DNA synthesis in each replicon continued at its previous rate until a lesion is reached, and then halted. The frequency of lesions that block synthesis is approximately the same as the frequency of pyrimidine dimers

  3. Soluble Aβ aggregates can inhibit prion propagation.

    Science.gov (United States)

    Sarell, Claire J; Quarterman, Emma; Yip, Daniel C-M; Terry, Cassandra; Nicoll, Andrew J; Wadsworth, Jonathan D F; Farrow, Mark A; Walsh, Dominic M; Collinge, John

    2017-11-01

    Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP C ). Ligands that bind to PrP C can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP C , and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrP C and emphasize the bidirectional nature of the interplay between Aβ and PrP C in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common. © 2017 The Authors.

  4. Ketose induced respiratory inhibition in isolated hepatocytes.

    Science.gov (United States)

    Martínez, P; Carrascosa, J M; Núñez de Castro, I

    1987-06-01

    The addition of 10 mM fructose or 10 mM tagatose to a suspension of hepatocytes caused respiratory inhibition, whereas no change in oxygen uptake was observed following the addition of glucose. However, incubations in the presence of fructose showed a high, aerobic glycolytic activity. Tagatose is phosphorylated to tagatose 1-phosphate but is not further metabolized by cell free liver extract. Moreover, the addition of fructose to glucagon treated cells also caused the Crabtree-like effect. The concentration of adenine nucleotides and inorganic phosphate (Pi) in the mitochondrial and cytosolic compartments during incubation (time 30 min) was determined by the digitonin fractionation procedure. In the presence of 10 mM fructose or tagatose, the total adenine nucleotide pools decreased by 40%; however, glucose produced no change. The addition of ketoses diminished the asymmetric distribution of extramitochondrial (ATP/ADP)e ratio and intramitochondrial (ATP/ADP)i ratio. At the same time the total mitochondrial Pi fell from 17 mM to 6-7 mM. The mitochondrial membrane potential (-161 mV) in the presence of fructose showed no changes during the 30 min experimental period. An increase in the NADH/NAD+ ratio was observed. These results suggest that in hepatocytes the inhibition of respiration is not necessarily linked with the enhanced aerobic glycolysis, by competition for common substrates.

  5. Lactam inhibiting Streptococcus mutans growth on titanium

    Energy Technology Data Exchange (ETDEWEB)

    Xavier, J.G.; Geremias, T.C.; Montero, J.F.D. [Center for Research on Dental Implants (CEPID), School of Dentistry (ODT), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-900 (Brazil); Vahey, B.R. [Herman Ostrow School of Dentistry of USC, 925 W 34 St, Los Angeles, CA 90089 (United States); Benfatti, C.A.M.; Souza, J.C.M.; Magini, R.S. [Center for Research on Dental Implants (CEPID), School of Dentistry (ODT), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-900 (Brazil); Pimenta, A.L., E-mail: andrea@intelab.ufsc.br [Department of Biologia, ERRMECe, Université de Cergy Pontoise, 2, Av. Adolphe Chauvin 95302 Cergy, Pontoise (France); Integrated Laboratories Technologies (InteLab), Dept. Chemical and Food Engineering (EQA), Federal University of Santa Catarina - UFSC, Florianópolis/SC, 88040-970 (Brazil)

    2016-11-01

    The aim of this work was to analyze the activity of novel synthetic lactams on preventing biofilm formation on titanium surfaces. Titanium (Ti6Al4V) samples were exposed to Streptococcus mutans cultures in the presence or absence of a synthetic lactam. After 48 h incubation, planktonic growth was determined by spectrophotometry. Biofilm was evaluated by crystal violet staining and colony forming units (CFU·ml{sup −1}), followed by scanning electron microscopy (SEM). Results showed that the average of adhered viable cells was approximately 1.5 × 10{sup 2} CFU/ml in the presence of lactam and 4 × 10{sup 2} CFU/ml in its absence. This novel compound was considerable active in reducing biofilm formation over titanium surfaces, indicating its potential for the development of antimicrobial drugs targeting the inhibition of the initial stages of bacterial biofilms on dental implants abutments. - Highlights: • A novel synthetic compound is tested on preventing biofilm formation on titanium surfaces • Biofilm inhibition has been achieved on titanium surfaces containing the novel compound. • Planktonic growth of S. mutans was not affected by the presence of lactams on titanium.

  6. Universal water-dilutable inhibited protective lubricants

    International Nuclear Information System (INIS)

    Mamtseva, M.V.; Kardash, N.V.; Latynina, M.B.

    1993-01-01

    In the interest of environmental protection, improvement of working conditions, and reduced fire hazard in production operations, water-based protective lubricants are now available in a wide assortment, and the production volume has increased greatly. The term water-dilutable inhibited protective lubricants (WDIPL) means water-soluble, water-emulsifiable, or water-dispersible products with the dual function of reducing friction and wear and protecting metal surfaces against corrosion for specified periods of time. According to the standard Unified System of Protection Against Corrosion and Aging (COST 9.103-78), WDIPLs are classed as products for the temporary corrosion protection of metals and end-items. In the general class of WDIPLs one can identify water-dilutable combination corrosion inhibitors, film-forming inhibited petroleum compositions (FIPC-d), detergent-preservative fluids, operational-preservative lubricating-cooling process compounds (ICPC), and, finally, universal multifunctional products. Combined corrosion inhibitors may consist of water-soluble organic and inorganic compounds; water/oil and oil-soluble surfactants - corrosion inhibitors of the chemisorption type or donor and/or acceptor types; shielding inhibitors of the adsorption type; and fast-acting water-displacing components. 23 refs

  7. Salinomycin, A Polyether Ionophoric Antibiotic, Inhibits Adipogenesis

    Science.gov (United States)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy. PMID:23123626

  8. Structural basis of kynurenine 3-monooxygenase inhibition.

    Science.gov (United States)

    Amaral, Marta; Levy, Colin; Heyes, Derren J; Lafite, Pierre; Outeiro, Tiago F; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S

    2013-04-18

    Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.

  9. PD-1 checkpoint inhibition: Toxicities and management.

    Science.gov (United States)

    Hahn, Andrew W; Gill, David M; Agarwal, Neeraj; Maughan, Benjamin L

    2017-12-01

    With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Platelets Inhibit Migration of Canine Osteosarcoma Cells.

    Science.gov (United States)

    Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

    2017-01-01

    The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

  11. Kaempferol inhibits thrombosis and platelet activation.

    Science.gov (United States)

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  12. Lactam inhibiting Streptococcus mutans growth on titanium

    International Nuclear Information System (INIS)

    Xavier, J.G.; Geremias, T.C.; Montero, J.F.D.; Vahey, B.R.; Benfatti, C.A.M.; Souza, J.C.M.; Magini, R.S.; Pimenta, A.L.

    2016-01-01

    The aim of this work was to analyze the activity of novel synthetic lactams on preventing biofilm formation on titanium surfaces. Titanium (Ti6Al4V) samples were exposed to Streptococcus mutans cultures in the presence or absence of a synthetic lactam. After 48 h incubation, planktonic growth was determined by spectrophotometry. Biofilm was evaluated by crystal violet staining and colony forming units (CFU·ml −1 ), followed by scanning electron microscopy (SEM). Results showed that the average of adhered viable cells was approximately 1.5 × 10 2 CFU/ml in the presence of lactam and 4 × 10 2 CFU/ml in its absence. This novel compound was considerable active in reducing biofilm formation over titanium surfaces, indicating its potential for the development of antimicrobial drugs targeting the inhibition of the initial stages of bacterial biofilms on dental implants abutments. - Highlights: • A novel synthetic compound is tested on preventing biofilm formation on titanium surfaces • Biofilm inhibition has been achieved on titanium surfaces containing the novel compound. • Planktonic growth of S. mutans was not affected by the presence of lactams on titanium.

  13. Periostin Limits Tumor Response to VEGFA Inhibition.

    Science.gov (United States)

    Keklikoglou, Ioanna; Kadioglu, Ece; Bissinger, Stefan; Langlois, Benoît; Bellotti, Axel; Orend, Gertraud; Ries, Carola H; De Palma, Michele

    2018-03-06

    Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA + stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  14. Heat enhances radiation inhibition of wound healing

    International Nuclear Information System (INIS)

    Twomey, P.; Hill, S.; Joiner, M.; Hobson, B.; Denekamp, J.

    1987-01-01

    To study the effect of hyperthermia on the inhibition of healing by radiation, the authors used 2 models of wound tensile strength in mice. In one, tensile strength of 1 cm strips of wounded skin was measured. In the other, strength was measured on 2 by 1 by .3 cm surgical prosthetic sponges of polyvinyl alcohol which has been cut, resutured, and implanted subcutaneously. Granulation tissue grows into the pores of the sponges which gradually fill with collagen. Tensile strength in both models was measured on day 14 using a constant strain extensiometer. The wounds were given graduated doses of ortho-voltage radiation with or without hyperthermia. Maximum radiation sensitivity occurred during the period of rapid neovascularization in the first 5 days after wounding, when a loss of 80% in wound strength occurred with doses less than 20 gray. For single radiation doses given 48 hours after wounding, the authors found a steep dose-response curve with half maximum reduction in strength occurring in both models at approximately 10 gray. Hyperthermia was produced in two ways. Skin wounds were heated in a circulating water bath. In the sponge model, more uniform heating occurs with an RF generator scaled to the mouse. At a dose of 43 C for 30 minutes, no inhibition of healing by heat alone was found. However the combination of heat and radiation produced definite enhancement of radiation damage, with thermal enhancement ratios of up to 1.9 being observed

  15. Periostin Limits Tumor Response to VEGFA Inhibition

    Directory of Open Access Journals (Sweden)

    Ioanna Keklikoglou

    2018-03-01

    Full Text Available Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs under extended vascular-endothelial growth factor A (VEGFA blockade are dependent on periostin (POSTN, a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2, an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs.

  16. Acute drug treatment in the early C. elegans embryo.

    Directory of Open Access Journals (Sweden)

    Ana Carvalho

    Full Text Available Genetic and genome-wide RNAi approaches available in C. elegans, combined with tools for visualizing subcellular events with high-resolution, have led to increasing adoption of the early C. elegans embryo as a model for mechanistic and functional genomic analysis of cellular processes. However, a limitation of this system has been the impermeability of the embryo eggshell, which has prevented the routine use of small molecule inhibitors. Here, we present a method to permeabilize and immobilize embryos for acute inhibitor treatment in conjunction with live imaging. To identify a means to permeabilize the eggshell, we used a dye uptake assay to screen a set of 310 candidate genes defined by a combination of bioinformatic criteria. This screen identified 20 genes whose inhibition resulted in >75% eggshell permeability, and 3 that permeabilized embryos with minimal deleterious effects on embryo production and early embryonic development. To mount permeabilized embryos for acute drug addition in conjunction with live imaging, we combined optimized inhibition of one of these genes with the use of a microfabricated chamber that we designed. We demonstrate that these two developments enable the temporally controlled introduction of inhibitors for mechanistic studies. This method should also open new avenues of investigation by allowing profiling and specificity-testing of inhibitors through comparison with genome-wide phenotypic datasets.

  17. Alpha oscillations and early stages of visual encoding

    Directory of Open Access Journals (Sweden)

    Wolfgang eKlimesch

    2011-05-01

    Full Text Available For a long time alpha oscillations have been functionally linked to the processing of visual information. Here we propose an new theory about the functional meaning of alpha. The central idea is that synchronized alpha reflects a basic processing mode that controls access to information stored in a complex long-term memory system, which we term knowledge system (KS in order to emphasize that it comprises not only declarative memories but any kind of knowledge comprising also procedural information. Based on this theoretical background, we assume that during early stages of perception, alpha ‘directs the flow of information’ to those neural structures which represent information that is relevant for encoding. The physiological function of alpha is interpreted in terms of inhibition. We assume that alpha enables access to stored information by inhibiting task irrelevant neuronal structures and by timing cortical activity in task relevant neuronal structures. We discuss a variety findings showing that evoked alpha and phase locking reflect successful encoding of global stimulus features in an early poststimulus interval of about 0 - 150 ms.

  18. Inhibition by acrolein of light-induced stomatal opening through inhibition of inward-rectifying potassium channels in Arabidopsis thaliana.

    Science.gov (United States)

    Islam, Md Moshiul; Ye, Wenxiu; Matsushima, Daiki; Khokon, Md Atiqur Rahman; Munemasa, Shintaro; Nakamura, Yoshimasa; Murata, Yoshiyuki

    2015-01-01

    Acrolein is a reactive α,β-unsaturated aldehyde derived from lipid peroxides, which are produced in plants under a variety of stress. We investigated effects of acrolein on light-induced stomatal opening using Arabidopsis thaliana. Acrolein inhibited light-induced stomatal opening in a dose-dependent manner. Acrolein at 100 μM inhibited plasma membrane inward-rectifying potassium (Kin) channels in guard cells. Acrolein at 100 μM inhibited Kin channel KAT1 expressed in a heterologous system using Xenopus leaves oocytes. These results suggest that acrolein inhibits light-induced stomatal opening through inhibition of Kin channels in guard cells.

  19. Bovine Lactoferrin and Lactoferricin, a Peptide Derived from Bovine Lactoferrin, Inhibit Tumor Metastasis in Mice

    Science.gov (United States)

    Watanabe, Shikiko; Watanabe, Ryosuke; Hata, Katsusuke; Shimazaki, Kei–ichi; Azuma, Ichiro

    1997-01-01

    We investigated the effect of a bovine milk protein, lactoferrin (LF–B), and a pepsin–generated peptide of LF–B, lactoferricin (Lfcin–B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16–BL6 melanoma and L5178Y–ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo–lactoferrin (apo–LF–B, 1 mg/mouse) and Lfcin–B (0.5 mg/monse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y–ML25 cells. However, human apo–lactoferrin (apo–LF–H) and bovine holo–lactoferrin (holo–LF–B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y–ML25 cells. Similarly, the s.c. administration of apo–LF–B as well as Lfcin–B, but not apo–LF–H and holo–LF–B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16–BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor–induced angiogenesis, both apo–LF–B and Lfcin–B inhibited the number of tumor–induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long–term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo–LF–B significantly suppressed the growth of B16–BL6 cells throughout the examination period, whereas Lfcin–B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16–BL6 melanoma cells, multiple administration of both apo–LF–B and Lfcin–B into tumor–bearing mice significantly inhibited lung metastasis produced by B16–BL6 cells, though only apo–LF–B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo–LF–B and Lfcin–B inhibit tumor metastasis through different

  20. The Ayurvedic plant Bacopa Monnieri inhibits inflammatory pathways in the brain

    Science.gov (United States)

    Nemetchek, Michelle D.; Stierle, Andrea A.; Stierle, Donald B.; Lurie, Diana I.

    2016-01-01

    Ethnopharmacological Relevance Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a “medhya rasayana”, an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNF-α and IL-6. However, less is known regarding the anti-inflammatory activity of Bacopa in the brain. Aim Of The Study The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied. Materials And Methods Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-α and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease. Results The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-α and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay. Conclusions Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits

  1. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain.

    Science.gov (United States)

    Nemetchek, Michelle D; Stierle, Andrea A; Stierle, Donald B; Lurie, Diana I

    2017-02-02

    Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a "medhya rasayana", an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNF-α and IL-6. However, less is known regarding the anti-inflammatory activity of Bacopa in the brain. The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied. Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-α and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease. The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-α and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay. Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits enzymes associated with inflammation in the brain. Thus, Bacopa can limit inflammation in the

  2. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

    Science.gov (United States)

    Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

    2015-02-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

  3. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  4. Ketoconazole inhibits the cellular uptake of anandamide via inhibition of FAAH at pharmacologically relevant concentrations.

    Directory of Open Access Journals (Sweden)

    Emmelie Björklund

    Full Text Available The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA.The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 µM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component of 34 µM.The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

  5. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis.

    Science.gov (United States)

    Li, Qingli; Lambrechts, Mark J; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Yin, Rutie; Xi, Mingrong; You, Zongbing

    2013-01-01

    Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy.

  6. FAA Loran early implementation project

    Science.gov (United States)

    1990-03-01

    The Early Implementation Project (EIP), established by FAA Administrator Admiral : Donald C. Engen, was the initial step in the process of Loran integration into the : National Airsace System (NAS). The EIP was designed to give the FAA and the Loran ...

  7. Hypertension presenting early in pregnancy

    OpenAIRE

    Melvin, Audrey; Kinsley, Brendan

    2015-01-01

    Key Clinical Message Paraganglioma in pregnancy is an exceedingly rare and potentially life?threatening diagnosis. It is important that the clinicians consider secondary causes when women present with hypertension in early pregnancy.

  8. Early onset type 2 diabetes

    DEFF Research Database (Denmark)

    Bo, A; Thomsen, R W; Nielsen, J S

    2018-01-01

    was more frequent and meeting physical activity recommendations less likely in persons with early-onset type 2 DM. CONCLUSIONS: We found a clear age-gradient, with increasing prevalence of clinical and behavioural risk factors the younger the onset age of type 2 DM. Younger persons with early-onset type 2......AIM: To examine the association between early onset of type 2 diabetes (DM) and clinical and behavioural risk factors for later diabetes complications. METHODS: We conducted a cross-sectional study of 5115 persons with incident type 2 DM enrolled during 2010-2015 in the Danish Centre for Strategic...... Research in Type 2 Diabetes-cohort. We compared risk factors at time of diagnosis among those diagnosed at ≤45 years (early-onset) with diagnosis age 46-55, 56-65 (average-onset = reference), 66-75, and >75 years (late-onset). Prevalence ratios (PRs) were computed using Poisson regression. RESULTS: Poor...

  9. [Early management of cerebrovascular accidents].

    Science.gov (United States)

    Libot, Jérômie; Guillon, Benoit

    2013-01-01

    A cerebrovascular accident requires urgent diagnosis and treatment.The management of a stroke must be early and adapted in order to improve the overall clinical outcome and lower the risk of mortality.

  10. Early Identification of Reading Difficulties

    DEFF Research Database (Denmark)

    Poulsen, Mads; Nielsen, Anne-Mette Veber; Juul, Holger

    2017-01-01

    Early screening for reading difficulties before the onset of instruction is desirable because it allows intervention that is targeted at prevention rather than remediation of reading difficulties. However, early screening may be too inaccurate to effectively allocate resources to those who need...... them. The present study compared the accuracy of early screening before the onset of formal reading instruction with late screening six months into the first year of instruction. The study followed 164 Danish students from the end of Grade 0 to the end of Grade 2. Early screening included measures...... of phonemic awareness, rapid naming, letter knowledge, paired associate learning, and reading. Late screening included only reading. Results indicated that reading measures improved substantially as predictors over the first six months of Grade 1, to the point where late reading measures alone provided...

  11. Early Retiree Reinsurance Program Reports

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Early Retiree Reinsurance Program (ERRP) was established by section 1102 of the Patient Protection and Affordable Care Act (the Affordable Care Act) enacted on...

  12. Timed Synaptic Inhibition Shapes NMDA Spikes, Influencing Local Dendritic Processing and Global I/O Properties of Cortical Neurons

    Directory of Open Access Journals (Sweden)

    Michael Doron

    2017-11-01

    Full Text Available The NMDA spike is a long-lasting nonlinear phenomenon initiated locally in the dendritic branches of a variety of cortical neurons. It plays a key role in synaptic plasticity and in single-neuron computations. Combining dynamic system theory and computational approaches, we now explore how the timing of synaptic inhibition affects the NMDA spike and its associated membrane current. When impinging on its early phase, individual inhibitory synapses strongly, but transiently, dampen the NMDA spike; later inhibition prematurely terminates it. A single inhibitory synapse reduces the NMDA-mediated Ca2+ current, a key player in plasticity, by up to 45%. NMDA spikes in distal dendritic branches/spines are longer-lasting and more resilient to inhibition, enhancing synaptic plasticity at these branches. We conclude that NMDA spikes are highly sensitive to dendritic inhibition; sparse weak inhibition can finely tune synaptic plasticity both locally at the dendritic branch level and globally at the level of the neuron’s output.

  13. Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-β1 from prostate cancer cells

    International Nuclear Information System (INIS)

    Stanley, Gwenaelle; Harvey, Kevin; Slivova, Veronika; Jiang Jiahua; Sliva, Daniel

    2005-01-01

    Ganoderma lucidum (G. lucidum) is a popular medicinal mushroom that has been used as a home remedy for the general promotion of health and longevity in East Asia. The dried powder of G. lucidum, which was recommended as a cancer chemotherapy agent in traditional Chinese medicine, is currently popularly used worldwide in the form of dietary supplements. We have previously demonstrated that G. lucidum induces apoptosis, inhibits cell proliferation, and suppresses cell migration of highly invasive human prostate cancer cells PC-3. However, the molecular mechanism(s) responsible for the inhibitory effects of G. lucidum on the prostate cancer cells has not been fully elucidated. In the present study, we examined the effect of G. lucidum on angiogenesis related to prostate cancer. We found that G. lucidum inhibits the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells. These effects are caused by the inhibition of constitutively active AP-1 in prostate cancer cells, resulting in the down-regulation of secretion of VEGF and TGF-β1 from PC-3 cells. Thus, G. lucidum modulates the phosphorylation of Erk1/2 and Akt kinases in PC-3 cells, which in turn inhibits the activity of AP-1. In summary, our results suggest that G. lucidum inhibits prostate cancer-dependent angiogenesis by modulating MAPK and Akt signaling and could have potential therapeutic use for the treatment of prostate cancer

  14. EARLY ENTRANCE COPRODUCTION PLANT

    Energy Technology Data Exchange (ETDEWEB)

    Fred D. Brent; Lalit Shah; Earl Berry; Charles H. Schrader; John Anderson; J. Erwin; Matthew G. Banks; Terry L. Ullman

    2004-01-12

    The overall objective of this project is the three phase development of an Early Entrance Coproduction Plant (EECP) which uses petroleum coke to produce at least one product from at least two of the following three categories: (1) electric power (or heat), (2) fuels, and (3) chemicals using ChevronTexaco's proprietary gasification technology. The objective of Phase I is to determine the feasibility and define the concept for the EECP located at a specific site; develop a Research, Development, and Testing (RD&T) Plan to mitigate technical risks and barriers; and prepare a Preliminary Project Financing Plan. The objective of Phase II is to implement the work as outlined in the Phase I RD&T Plan to enhance the development and commercial acceptance of coproduction technology. The objective of Phase III is to develop an engineering design package and a financing and testing plan for an EECP located at a specific site. The project's intended result is to provide the necessary technical, economic, and environmental information needed by industry to move the EECP forward to detailed design, construction, and operation. The partners in this project are Texaco Energy Systems LLC or TES (a subsidiary of ChevronTexaco), General Electric (GE), Praxair, and Kellogg Brown & Root (KBR) in addition to the U.S. Department of Energy (DOE). TES is providing gasification technology and Fischer-Tropsch (F-T) technology developed by Rentech, GE is providing combustion turbine technology, Praxair is providing air separation technology, and KBR is providing engineering. Each of the EECP subsystems was assessed for technical risks and barriers. A plan was developed to mitigate the identified risks (Phase II RD&T Plan, October 2000). Phase II RD&T Task 2.6 identified as potential technical risks to the EECP the fuel/engine performance and emissions of the F-T diesel fuel products. Hydrotreating the neat F-T diesel product reduces potentially reactive olefins, oxygenates, and acids

  15. Early Intervention in Bipolar Disorder.

    Science.gov (United States)

    Vieta, Eduard; Salagre, Estela; Grande, Iria; Carvalho, André F; Fernandes, Brisa S; Berk, Michael; Birmaher, Boris; Tohen, Mauricio; Suppes, Trisha

    2018-05-01

    Bipolar disorder is a recurrent disorder that affects more than 1% of the world population and usually has its onset during youth. Its chronic course is associated with high rates of morbidity and mortality, making bipolar disorder one of the main causes of disability among young and working-age people. The implementation of early intervention strategies may help to change the outcome of the illness and avert potentially irreversible harm to patients with bipolar disorder, as early phases may be more responsive to treatment and may need less aggressive therapies. Early intervention in bipolar disorder is gaining momentum. Current evidence emerging from longitudinal studies indicates that parental early-onset bipolar disorder is the most consistent risk factor for bipolar disorder. Longitudinal studies also indicate that a full-blown manic episode is often preceded by a variety of prodromal symptoms, particularly subsyndromal manic symptoms, therefore supporting the existence of an at-risk state in bipolar disorder that could be targeted through early intervention. There are also identifiable risk factors that influence the course of bipolar disorder, some of them potentially modifiable. Valid biomarkers or diagnosis tools to help clinicians identify individuals at high risk of conversion to bipolar disorder are still lacking, although there are some promising early results. Pending more solid evidence on the best treatment strategy in early phases of bipolar disorder, physicians should carefully weigh the risks and benefits of each intervention. Further studies will provide the evidence needed to finish shaping the concept of early intervention. AJP AT 175 Remembering Our Past As We Envision Our Future April 1925: Interpretations of Manic-Depressive Phases Earl Bond and G.E. Partridge reviewed a number of patients with manic-depressive illness in search of a unifying endo-psychic conflict. They concluded that understanding either phase of illness was "elusive" and

  16. Early vision and visual attention

    OpenAIRE

    Gvozdenović Vasilije P.

    2003-01-01

    The question whether visual perception is spontaneous, sudden or is running through several phases, mediated by higher cognitive processes, was raised ever since the early work of Gestalt psychologists. In the early 1980s, Treisman proposed the feature integration theory of attention (FIT), based on the findings of neuroscience. Soon after publishing her theory a new scientific approach appeared investigating several visual perception phenomena. The most widely researched were the key constru...

  17. Early diagnosis of breast cancer

    International Nuclear Information System (INIS)

    Semiglazov, V.F.

    1989-01-01

    Modern data are presentd on epidemology etiopathogensis and statistics of breast cancer. Home and international clinical and histological classifications is given. Much attention is paid to the methods for early diagnosis of pretumor diseases and breast cancer: clinical roentgenomammography, thrmography and computerized tomomammography. The role of self-examination in cancer early detection has been analyzed. Special attention is paid to system of detection of minimal and unpalpable form of breast cancer, screening of these tumors. 113 refs.; 60 figs.; 6 tabs

  18. Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells.

    Science.gov (United States)

    Ge, Peng-Fei; Zhang, Ji-Zhou; Wang, Xiao-Fei; Meng, Fan-Kai; Li, Wen-Chen; Luan, Yong-Xin; Ling, Feng; Luo, Yi-Nan

    2009-07-01

    The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G(2)/M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G(2)/M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.Acta Pharmacologica Sinica (2009) 30: 1046-1052; doi: 10.1038/aps.2009.71.

  19. Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

    Directory of Open Access Journals (Sweden)

    Chaonan Sun

    Full Text Available The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER homeostatic state and result in ER stress (ERS, subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05. Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.

  20. Early presentation of primary glioblastoma.

    Science.gov (United States)

    Faguer, R; Tanguy, J-Y; Rousseau, A; Clavreul, A; Menei, P

    2014-08-01

    Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. [Autism: An early neurodevelopmental disorder].

    Science.gov (United States)

    Bonnet-Brilhault, F

    2017-04-01

    With approximately 67 million individuals affected worldwide, autism spectrum disorder (ASD) is the fastest growing neurodevelopmental disorder (United Nations, 2011), with a prevalence estimated to be 1/100. In France ASD affects approximately 600,000 individuals (from childhood to adulthood, half of whom are also mentally retarded), who thus have a major handicap in communication and in adapting to daily life, which leads autism to be recognized as a national public health priority. ASD is a neurodevelopmental disorder that affects several domains (i.e., socio-emotional, language, sensori-motor, executive functioning). These disorders are expressed early in life with an age of onset around 18 months. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. The clinical picture is characterized by impairments in social interaction and communication and the presence of restrictive and repetitive behaviors (DSM-5, ICD-10). However, in addition to these two main dimensions there is significant comorbidity between ASD and other neurodevelopmental disorders such as attention deficit hyperactivity disorder or with genetic and medical conditions. One of the diagnostic features of ASD is its early emergence: symptoms must begin in early childhood for a diagnosis to be given. Due to brain plasticity, early interventions are essential to facilitate clinical improvement. Therefore, general practitioners and pediatricians are on the front line to detect early signs of ASD and to guide both medical explorations and early rehabilitation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Inhibition of glycogen synthase kinase-3 reduces extension of the axonal leading process by destabilizing microtubules in cerebellar granule neurons.

    Science.gov (United States)

    Inami, Yoshihiro; Omura, Mitsuru; Kubota, Kenta; Konishi, Yoshiyuki

    2018-07-01

    Recent studies have uncovered various molecules that play key roles in neuronal morphogenesis. Nevertheless, the mechanisms underlying the neuron-type-dependent regulation of morphogenesis remain unknown. We have previously reported that inhibition of glycogen synthase kinase-3 (GSK3) markedly reduced axonal length of cerebellar granule neurons (CGNs) in a neuron-type-dependent manner. In the present study, we investigated the mechanisms by which the growth of CGN axons was severely suppressed upon GSK3 inhibition. Using time-lapse imaging of cultured CGNs at early morphogenesis, we found that extension of the leading process was severely inhibited by the pharmacological inhibition of GSK3. The rate of somal migration was also reduced with a GSK3 inhibitor in dissociated culture as well as in microexplant culture. In addition, CGNs ectopically expressed with a catalytically inactive mutant of GSK3 exhibited a migration defect in vivo. In axonal leading processes of CGNs, detyrosination and acetylation of α-tubulin, which are known to correlate with microtubule stability, were decreased by GSK3 inhibition. A photoconversion analysis found that inhibition of GSK3 increases the turnover of microtubules. Furthermore, in the presence of paclitaxel, a microtubule-stabilizing reagent, inhibition of GSK3 recovered the axonal leading process extension that was reduced by paclitaxel. Our results suggest that GSK3 supports the extension of axonal processes by stabilizing microtubules, contrary to its function in other neuron-types, lending mechanical insight into neuron-type-dependent morphological regulation. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Cyclophilin A potentiates TRIM5α inhibition of HIV-1 nuclear import without promoting TRIM5α binding to the viral capsid.

    Directory of Open Access Journals (Sweden)

    Mallori Burse

    Full Text Available The host immunophilin cyclophilin A (CypA binds to the capsid protein (CA of HIV-1 and regulates its infectivity. Depending on the target cell type, CypA can either promote or inhibit HIV-1 infection. The ability of CypA to promote HIV-1 infection has been extensively studied and linked to several steps in early replication including uncoating, reverse transcription and nuclear import. By contrast, the mechanism by which CypA inhibits infection is less well understood. We investigated the mechanism by which CypA potentiates restriction of HIV-1 by the tripartite motif-containing protein 5 (TRIM5α. Depletion of TRIM5α in the African green monkey cell line Vero, resulted in a loss of inhibition of infection by CypA, demonstrating that inhibition by CypA is mediated by TRIM5α. Complementary genetic and biochemical assays failed to demonstrate an ability of CypA to promote binding of TRIM5α to the viral capsid. TRIM5α inhibits HIV-1 reverse transcription in a proteasome-dependent manner; however, we observed that inhibition of proteasome activity did not reduce the ability of CypA to inhibit infection, suggesting that CypA acts at a step after reverse transcription. Accordingly, we observed a CypA-dependent reduction in the accumulation of nuclear HIV-1 DNA, indicating that CypA specifically promotes TRIM5α inhibition of HIV-1 nuclear import. We also observed that the ability of CypA to inhibit HIV-1 infection is abolished by amino acid substitutions within the conserved CPSF6-binding surface in CA. Our results indicate that CypA inhibits HIV-1 infection in Vero cells not by promoting TRIM5α binding to the capsid but by blocking nuclear import of the HIV-1 preintegration complex.

  4. Changes in nucleosome repeat lengths precede replication in the early replicating metallothionein II gene region of cells synchronized in early S phase

    International Nuclear Information System (INIS)

    D'Anna, J.A.; Tobey, R.A.

    1989-01-01

    Previous investigations showed that inhibition of DNA synthesis by hydroxyurea, aphidicolin, or 5-fluorodeoxyuridine produced large changes in the composition and nucleosome repeat lengths of bulk chromatin. There the authors report results of investigations to determine whether the changes in nucleosome repeat lengths might be localized in the initiated replicons, as postulated. In most experiments, Chinese hamster (line CHO) cells were synchronized in G1, or they were synchronized in early S phase by allowing G1 cells to enter S phase in medium containing 1 mM hydroxyurea or 5 μg mL -1 aphidicolin, a procedure believed to produce an accumulation of initiated replicons that arise from normally early replicating DNA. Measurements of nucleosome repeat lengths of bulk chromatin, the early replicating unexpressed metallothionein II (MTII) gene region, and a later replicating repeated sequence indicate that the changes in repeat lengths occur preferentially in the early replicating MTII gene region as G1 cells enter and become synchronized in early S phase. During that time, the MTII gene region is not replicated nor is there any evidence for induction of MTII messenger RNA. Thus, the results are consistent with the hypothesis that changes in chromatin structure occur preferentially in the early replicating (presumably initiated) replicons at initiation or that changes in chromatin structure can precede replication during inhibition of DNA synthesis. The shortened repeat lengths that precede MTII replication are, potentially, reversible, because they become elongated when the synchronized early S-phase cells are released to resume cell cycle progression

  5. Inhibition of autophagy enhances SMI-4a-induced growth inhibition ...

    African Journals Online (AJOL)

    admin

    years [1]. It is associated with early metastasis, poor prognosis, very low 5-year survival rate, and .... nude mice (Charles River Laboratories). ... 2016-13). All experimental procedures involving animals were performed according to the ...

  6. Structural basis for alpha fetoprotein-mediated inhibition of caspase-3 activity in hepatocellular carcinoma cells.

    Science.gov (United States)

    Lin, Bo; Zhu, Mingyue; Wang, Wenting; Li, Wei; Dong, Xu; Chen, Yi; Lu, Yan; Guo, Junli; Li, Mengsen

    2017-10-01

    Alpha-fetoprotein (AFP) is an early serum growth factor in the foetal liver development and hepatic carcinogenesis; However, the precise biological role of cytoplasmic AFP remains elusive. Although we recently demonstrated that cytoplasmic AFP might interact with caspase-3 and inhibit the signal transduction of apoptosis in human hepatocellular carcinoma (HCC) cells, the details of this interaction are not clear. To reveal the molecular relationship between AFP and caspase-3, we performed molecular docking, co-immunoprecipitation (Co-IP), laser confocal microscopy, site-directed mutagenesis and functional experiments to analyse the key amino acid residues in the binding site of caspase-3. The results of Co-IP, laser confocal microscopy and functional analyses were consistent with the computational model. We also used the model to explain why AFP cannot bind to caspase-8. These results provide the molecular basis for the AFP-mediated inhibition of caspase-3 activity in HCC cells. Altogether, we found that AFP interacts with caspase-3 through precise amino acids, namely loop-4 residues Glu-248, Asp-253 and His-257. The results further demonstrated that AFP plays a critical role in the inhibition of the apoptotic signal transduction that mediated by caspase-3. Thus, AFP might represent a novel biotarget for the therapy of HCC patients. © 2017 UICC.

  7. Inhibition of corneal neovascularization by recombinant adenovirus-mediated sFlk-1 expression

    International Nuclear Information System (INIS)

    Yu Hui; Wu Jihong; Li Huiming; Wang Zhanli; Chen Xiafang; Tian Yuhua; Yi Miaoying; Ji Xunda; Ma Jialie; Huang Qian

    2007-01-01

    The interaction of vascular endothelial growth factor (VEGF) and its receptors (Flt-1, Flk-1/KDR) is correlated with neovascularization in the eyes. Therefore, blocking the binding of VEGF and the corresponding receptor has become critical for inhibiting corneal neovascularization. In this study, we have expressed the cDNA for sFlk-1 under the control of cytomegalovirus immediate-early promoter (CMV) from an E1/partial E3 deleted replication defective recombinant adenovirus, and Ad.sflk-1 expression was determined by Western blotting. We have shown that conditioned media from Ad.sflk-1-infected ARPE-19 cells significantly reduced VEGF-induced human umbilical vein endothelial cells (HUVEC) and murine endothelial cells (SVEC) proliferation in vitro compared with the control vector. In vivo, adenoviral vectors expressing green fluorescent protein alone (Ad.GFP) were utilized to monitor gene transfer to the cornea. Moreover, in the models of corneal neovascularization, the injection of Ad.sflk-1 (10 8 PFU) into the anterior chamber could significantly inhibit angiogenic changes compared with Ad.null-injected and vehicle-injected models. Immunohistochemical analysis showed that corneal endothelial cells and corneal stroma of cauterized rat eyes were efficiently transduced and expressed sFlk-1. These results not only support that adenoviral vectors are capable of high-level transgene expression but also demonstrate that Ad.sflk-1 gene therapy might be a feasible approach for inhibiting the development of corneal neovascularization

  8. A pilot study of combined working memory and inhibition training for children with AD/HD.

    Science.gov (United States)

    Johnstone, Stuart J; Roodenrys, Steven; Phillips, Elise; Watt, Annele J; Mantz, Sharlene

    2010-03-01

    Building on recent favourable outcomes using working memory (WM) training, this study examined the behavioural and physiological effect of concurrent computer-based WM and inhibition training for children with attention-deficit hyperactivity disorder (AD/HD). Using a double-blind active-control design, 29 children with AD/HD completed a 5-week at-home training programme and pre- and post-training sessions which included the assessment of overt behaviour, resting EEG, as well as task performance, skin conductance level and event-related potentials (ERPs) during a Go/Nogo task. Results indicated that after training, children from the high-intensity training condition showed reduced frequency of inattention and hyperactivity symptoms. Although there were trends for improved Go/Nogo performance, increased arousal and specific training effects for the inhibition-related N2 ERP component, they failed to reach standard levels of statistical significance. Both the low- and high-intensity conditions showed resting EEG changes (increased delta, reduced alpha and theta activity) and improved early attention alerting to Go and Nogo stimuli, as indicated by the N1 ERP component, post-training. Despite limitations, this preliminary work indicates the potential for cognitive training that concurrently targets the interrelated processes of WM and inhibition to be used as a treatment for AD/HD.

  9. Neural correlates of saccadic inhibition in healthy elderly and patients with amnestic mild cognitive impairment

    Science.gov (United States)

    Alichniewicz, K. K.; Brunner, F.; Klünemann, H. H.; Greenlee, M. W.

    2013-01-01

    Performance on tasks that require saccadic inhibition declines with age and altered inhibitory functioning has also been reported in patients with Alzheimer's disease. Although mild cognitive impairment (MCI) is assumed to be a high-risk factor for conversion to AD, little is known about changes in saccadic inhibition and its neural correlates in this condition. Our study determined whether the neural activation associated with saccadic inhibition is altered in persons with amnestic mild cognitive impairment (aMCI). Functional magnetic resonance imaging (fMRI) revealed decreased activation in parietal lobe in healthy elderly persons compared to young persons and decreased activation in frontal eye fields in aMCI patients compared to healthy elderly persons during the execution of anti-saccades. These results illustrate that the decline in inhibitory functions is associated with impaired frontal activation in aMCI. This alteration in function might reflect early manifestations of AD and provide new insights in the neural activation changes that occur in pathological ageing. PMID:23898312

  10. Inhibition of β-catenin-mediated transactivation by flavanone in AGS gastric cancer cells

    International Nuclear Information System (INIS)

    Park, Chi Hoon; Hahm, Eun Ryeong; Lee, Ju Hyung; Jung, Kyung Chae; Yang, Chul Hak

    2005-01-01

    Recently, data which prove that Wnt pathway activation may be an early event in multistep carcinogenesis in the stomach have been accumulating. We examined the effect of flavanone against β-catenin/Tcf signaling in AGS gastric cancer cells. Reporter gene assay showed that flavanone inhibited β-catenin/Tcf signaling efficiently. In addition, the inhibition of β-catenin/Tcf signaling by flavanone in HEK293 cells transiently transfected with constitutively mutant β-catenin gene, whose product is not phosphorylated by GSK3β, indicates that its inhibitory mechanism was related to β-catenin itself or downstream components. To investigate the precise inhibitory mechanism, we performed immunofluorescence, Western blot, and EMSA. As a result, our data revealed that there is no change of β-catenin distribution and of nuclear β-catenin levels through flavanone. In addition, the binding of Tcf complexes to DNA is not influenced by flavanone. The β-catenin/Tcf transcriptional target gene cyclinD1 was downregulated by flavanone. These data suggest that flavanone inhibits the transcription of β-catenin/Tcf responsive genes, by modulating Tcf activity without disrupting β-catenin/Tcf complex formation

  11. Contextual startle responses moderate the relation between behavioral inhibition and anxiety in middle childhood.

    Science.gov (United States)

    Barker, Tyson V; Reeb-Sutherland, Bethany; Degnan, Kathryn A; Walker, Olga L; Chronis-Tuscano, Andrea; Henderson, Heather A; Pine, Daniel S; Fox, Nathan A

    2015-11-01

    Behavioral inhibition (BI), a temperament characterized in early childhood by wariness and avoidance of novelty, is a risk factor for anxiety disorders. An enhanced startle response has been observed in adolescents characterized with BI in childhood, particularly when they also manifest concurrent symptoms of anxiety. However, no prior study has examined relations among BI, startle responsivity, and anxiety in a prospective manner. Data for the present study were from a longitudinal study of infant temperament. Maternal reports and observations of BI were assessed at ages 2 and 3. At age 7, participants completed a startle procedure, while electromyography was collected, where participants viewed different colors on a screen that were associated with either the delivery of an aversive stimulus (i.e., puff of air to the larynx; threat cue) or the absence of the aversive stimulus (i.e., safety cue). Parental reports of child anxiety were collected when children were 7 and 9 years of age. Results revealed that startle responses at age 7 moderated the relation between early BI and 9-year anxiety. These findings provide insight into one potential mechanism that may place behaviorally inhibited children at risk for anxiety. © 2015 Society for Psychophysiological Research.

  12. Dietary intake of high-dose biotin inhibits spermatogenesis in young rats.

    Science.gov (United States)

    Sawamura, Hiromi; Ikeda, Chieko; Shimada, Ryoko; Yoshii, Yui; Watanabe, Toshiaki

    2015-02-01

    To characterize a new function of the water-soluble vitamin, biotin, in reproduction and early growth in mammals, the effects of high dietary doses of biotin on early spermatogenesis were biochemically and histologically investigated in male rats. Weaned rats were fed a CE-2 (control) diet containing 0.00004% biotin, or a control diet supplemented with 0.01%, 0.1%, or 1.0% biotin. Pair-fed rats were fed a control diet that was equal in calories to the amount ingested by the 1.0% biotin group, because food intake was decreased in the 1.0% biotin group. Food intake and body weight gain were lower in the 1.0% biotin group than in the control group. The kidney, brain and testis weights were significantly lower in the 1.0% biotin group than in the pair-fed group after 6 weeks of feeding. The accumulation of biotin in the liver and testis increased in a dose-dependent manner. In the 1.0% biotin group, the number of mature sperm was markedly lower, that of sperm with morphologically abnormal heads, mainly consisting of round heads, had increased. In addition, the development of seminiferous tubules was inhibited, and few spermatogonia and no spermatocytes were histologically observed. These results demonstrated that the long-term intake of high-dose biotin inhibited spermatogenesis in young male rats. © 2014 Japanese Teratology Society.

  13. Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11.

    Science.gov (United States)

    Li, Manqing; Kao, Elaine; Gao, Xia; Sandig, Hilary; Limmer, Kirsten; Pavon-Eternod, Mariana; Jones, Thomas E; Landry, Sebastien; Pan, Tao; Weitzman, Matthew D; David, Michael

    2012-11-01

    In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.

  14. LIF inhibits osteoblast differentiation at least in part by regulation of HAS2 and its product hyaluronan.

    Science.gov (United States)

    Falconi, Dominic; Aubin, Jane E

    2007-08-01

    LIF arrests osteogenesis in fetal rat calvaria cells in a differentiation stage-specific manner. Differential display identified HAS2 as a LIF-induced gene and its product, HA, modulated osteoblast differentiation similarly to LIF. Our data suggest that LIF arrests osteoblast differentiation by altering HA content of the extracellular matrix. Leukemia inhibitory factor (LIF) elicits both anabolic and catabolic effects on bone. We previously showed in the fetal rat calvaria (RC) cell system that LIF inhibits osteoblast differentiation at the late osteoprogenitor/early osteoblast stage. To uncover potential molecular mediators of this inhibitory activity, we used a positive-negative genome-wide differential display screen to identify LIF-induced changes in the developing osteoblast transcriptome. Although LIF signaling is active throughout the RC cell proliferation-differentiation sequence, only a relatively small number of genes, in several different functional clusters, are modulated by LIF specifically during the LIF-sensitive inhibitory time window. Based on their known and predicted functions, most of the LIF-regulated genes identified are plausible candidates to be involved in the LIF-induced arrest of osteoprogenitor differentiation. To test this hypothesis, we further analyzed the function of one of the genes identified, hyaluronan synthase 2 (HAS2), in the LIF-induced inhibition. Synthesis of hyaluronan (HA), the product of HAS enzymatic activity, was stimulated by LIF and mimicked the HAS2 expression profile, with highest expression in early/proliferative and late/maturing cultures and lowest levels in intermediate/late osteoprogenitor-early osteoblast cultures. Exogenously added high molecular weight HA, the product of HAS2, dose-dependently inhibited osteoblast differentiation, with pulse-treatment effective in the same differentiation stage-specific inhibitory window as seen with LIF. In addition, however, pulse treatment with HA in early cultures

  15. Inhibition of nitric oxide synthesis enhances leukocyte rolling and adhesion in human microvasculature

    Directory of Open Access Journals (Sweden)

    Hossain Mokarram

    2012-07-01

    Full Text Available Abstract Background Nitric oxide (NO is a multifunctional signaling molecule that regulates important cellular events in inflammation including leukocyte recruitment. Previous studies have shown that pharmacological inhibition of NO synthesis induces leukocyte recruitment in various in vitro and animal models. However, it is not known whether NO modulation has similar effects on leukocyte-endothelial cell interactions within the human microvasculature. The present study explored the effect of systemic L-NAME treatment on leukocyte recruitment in the SCID-hu mouse model. Methods Human skin xenografts were transplanted in SCID mice to study human leukocyte dynamics in human vasculature. Early events of human leukocyte recruitment in human vasculature were studied using intravital microscopy. NO synthesis was pharmacologically inhibited using NG-nitro-L-arginine methyl ester (L-NAME. Immunohistochemical analysis was performed to elucidate E-selectin expression in human xenograft skin. Human neutrophil-endothelial cell interactions were also studied in an in vitro flow chamber assay system. P- and E-selectin expression on cultured human umbilical vein endothelial cells (HUVECs was measured using ELISA. Platelet-activating factor (PAF synthesis was detected using a TLC-based assay. Results L-NAME treatment significantly enhanced the rolling and adhesion of human leukocytes to the human vasculature. Functional blocking of P- and E-selectins significantly inhibited rolling but not adhesion induced by inhibition of NO synthesis. Systemic L-NAME treatment enhanced E-selectin expression in human xenograft skin. L-NAME treatment significantly enhanced P- and E-selectin expression on HUVECs. L-NAME treatment did not significantly modify neutrophil rolling or adhesion to HUVECs indicating that L-NAME−induced subtle P- and E-selectin expression was insufficient to elicit dynamic neutrophil-HUVEC interactions in vitro. Moreover, synthesis of endothelial

  16. A novel approach to inhibit bone resorption

    DEFF Research Database (Denmark)

    Panwar, Preety; Søe, Kent; Guido, Rafael VC

    2016-01-01

    BACKGROUND AND PURPOSE: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other...... pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. EXPERIMENTAL APPROACH: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho......-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation. Cell cultures, Western blot, light and scanning electron microscopy as well as energy dispersive X-ray spectroscopy, molecular modelling and enzymatic assays were used to evaluate the inhibitors. KEY...

  17. Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

    Science.gov (United States)

    Kim, Bo-Young; Son, Yonghae; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

    2016-09-23

    27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Isoform-specific inhibition of cyclophilins.

    Science.gov (United States)

    Daum, Sebastian; Schumann, Michael; Mathea, Sebastian; Aumüller, Tobias; Balsley, Molly A; Constant, Stephanie L; de Lacroix, Boris Féaux; Kruska, Fabian; Braun, Manfred; Schiene-Fischer, Cordelia

    2009-07-07

    Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.

  19. Inhibition of cellular oxidation by fluoride

    Energy Technology Data Exchange (ETDEWEB)

    Borei, H

    1945-01-01

    An attempt has been made to investigate the inhibition by fluoride of the oxidative processes which occur in the cell by way of the cytochrome oxidase-cytochrome system. Some chemical and physical properties of the fluoride ion are discussed, together with certain quantitative methods for the determination of fluoride. An exhaustive review of the literature concerning the effect of fluoride on enzymic processes has been compiled. The experiments have shown that the point of the attack by fluoride is to be found among the cytochromes. The inhibitory mechanism appears to be such that the haemoprotein is prevented from taking part in the preceding and succeeding links in the reaction chain. The blocking action leaves the prosthetic group of the haemoprotein completely unchanged. The experimental results indicate the formation of a fluorophosphoprotein complex, analogous to that found in the case of enolase. Magnesium may possibly play a part in this process.

  20. Inhibition of Neurogenesis by Zika virus Infection.

    Science.gov (United States)

    Ahmad, Fahim; Siddiqui, Amna; Kamal, Mohammad A; Sohrab, Sayed S

    2018-02-01

    The association between Zika virus infection and neurological disorder has raised urgent global alarm. The ongoing epidemic has triggered quick responses in the scientific community. The first case of Zika virus was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of travel-associated Zika virus infection have also been reported in the United States. Zika virus is primarily transmitted by mosquito belongs to the genus Aedes that are widely distributed throughout the world including the Southern United States. Additionally, the virus can also be transmitted from males to females by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and development of microcephaly in their unborn babies. This finding is a cause for grave concern since microcephaly is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicate that Zika virus infection affects the growth of fetal neural progenitor cells and cerebral neurons that results in malformation of cerebral cortex leading to microcephaly. Recently, it has been reported that Zika virus infection deregulates the signaling pathway of neuronal cell and inhibit the neurogenesis resulting into dementia. In this review we have discussed about the information about cellular and molecular mechanisms in neurodegeneration of human neuronal cells and inhibit the neurogenesis. Additionally, this information will be very helpful further not only in neuro-scientific research but also designing and development of management strategies for microcephaly and other mosquito borne disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.