WorldWideScience

Sample records for policies mediating brain

  1. Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration.

    Science.gov (United States)

    Kempuraj, Duraisamy; Thangavel, Ramasamy; Selvakumar, Govindhasamy P; Zaheer, Smita; Ahmed, Mohammad E; Raikwar, Sudhanshu P; Zahoor, Haris; Saeed, Daniyal; Natteru, Prashant A; Iyer, Shankar; Zaheer, Asgar

    2017-01-01

    Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1-42 (Aβ1-42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can

  2. Brain sites mediating corticosteroid feedback inhibition of stimulated ACTH secretion

    International Nuclear Information System (INIS)

    Jacobson, L.

    1989-01-01

    There is substantial evidence that the brain mediates stress-induced and circadian increases in ACTH secretion and that corticosteroid concentrations which normalize basal plasma ACTH are insufficient to normalize ACTH responses to circadian or stressful stimuli in adrenalectomized rats. To identify brain sites mediating corticosteroid inhibition of stimulated ACTH secretion, two approaches were used. The first compared brain [ 14 C]-2-deoxyglucose uptake in rats with differential ACTH responses to stress. Relative to sham-adrenalectomized (SHAM) rats, adrenalectomized rats replaced with low, constant corticosterone levels via a subcutaneous corticosterone pellet (B-PELLET) exhibited elevated and prolonged ACTH responses to a variety of stimuli. Adrenalectomized rate given a circadian corticosterone rhythm via corticosterone in their drinking water exhibited elevated ACTH levels immediately after stress, but unlike B-PELLET rats, terminated stress induced ACTH secretion normally relative to SHAMS. Therefore, the abnormal ACTH responses to stress in B-PELLET rats were due to the lack of both circadian variations and stress-induced increases in corticosterone. Hypoxia was selected as a standardized stimulus for correlating brain [ 14 C]-2-deoxyglucose uptake with ACTH secretion. In intact rats, increases in plasma ACTH and decreases in arterial PO 2 correlated with the severity of hypoxia at arterial PCO 2 below 60 mm Hg. Hypoxia PELLET vs. SHAM rats. However, in preliminary experiments, although hypoxia increased brain 2-deoxyglucose uptake in most brain regions, plasma ACTH correlated poorly with 2-deoxyglucose uptake at 12% and 10% O 2

  3. The Chinese brain drain and policy options.

    Science.gov (United States)

    Chang, P; Deng, Z

    1992-01-01

    The authors discuss the growing problem caused by the increasing reluctance of Chinese receiving higher education overseas to return to China following completion of their studies. They note that the Tiananmen incident of June 1989 exacerbated this problem. The policy options open to the Chinese government are reviewed.

  4. Brain mediators of the effects of noxious heat on pain.

    Science.gov (United States)

    Atlas, Lauren Y; Lindquist, Martin A; Bolger, Niall; Wager, Tor D

    2014-08-01

    Recent human neuroimaging studies have investigated the neural correlates of either noxious stimulus intensity or reported pain. Although useful, analyzing brain relationships with stimulus intensity and behavior separately does not address how sensation and pain are linked in the central nervous system. In this study, we used multi-level mediation analysis to identify brain mediators of pain--regions in which trial-by-trial responses to heat explained variability in the relationship between noxious stimulus intensity (across 4 levels) and pain. This approach has the potential to identify multiple circuits with complementary roles in pain genesis. Brain mediators of noxious heat effects on pain included targets of ascending nociceptive pathways (anterior cingulate, insula, SII, and medial thalamus) and also prefrontal and subcortical regions not associated with nociceptive pathways per se. Cluster analysis revealed that mediators were grouped into several distinct functional networks, including the following: somatosensory, paralimbic, and striatal-cerebellar networks that increased with stimulus intensity; and 2 networks co-localized with "default mode" regions in which stimulus intensity-related decreases mediated increased pain. We also identified "thermosensory" regions that responded to increasing noxious heat but did not predict pain reports. Finally, several regions did not respond to noxious input, but their activity predicted pain; these included ventromedial prefrontal cortex, dorsolateral prefrontal cortex, cerebellar regions, and supplementary motor cortices. These regions likely underlie both nociceptive and non-nociceptive processes that contribute to pain, such as attention and decision-making processes. Overall, these results elucidate how multiple distinct brain systems jointly contribute to the central generation of pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  5. Moving Policy Forward: "Brain Drain" as a Wicked Problem

    Science.gov (United States)

    Logue, Danielle

    2009-01-01

    The mobility of scientists and the concerns surrounding "brain drain" are not new. Even in the Ptolemic dynasty, the first king set out to attract and influence the movements of scholars to shift the centre of learning from Athens to Alexandria. Yet after all this time, there is still much policy discourse and debate focused on attempting to…

  6. Receptor-Mediated Endocytosis and Brain Delivery of Therapeutic Biologics

    Directory of Open Access Journals (Sweden)

    Guangqing Xiao

    2013-01-01

    Full Text Available Transport of macromolecules across the blood-brain-barrier (BBB requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn in regulating the efflux of Immunoglobulin G (IgG from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed.

  7. Brain structure mediates the association between height and cognitive ability.

    Science.gov (United States)

    Vuoksimaa, Eero; Panizzon, Matthew S; Franz, Carol E; Fennema-Notestine, Christine; Hagler, Donald J; Lyons, Michael J; Dale, Anders M; Kremen, William S

    2018-05-11

    Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.

  8. mTHPC-mediated photodynamic diagnosis of malignant brain tumors

    International Nuclear Information System (INIS)

    Zimmermann, A.

    2001-03-01

    Radical tumor resection is the basis for prolonged survival of patients suffering from malignant brain tumors such as glioblastoma multiform. We have carried out a phase II study involving 22 patients with malignant brain tumors to assess the feasibility and the effectiveness of the combination of intraoperative photodynamic diagnosis (PDD) and fluorescence-guided resection (FGR) mediated by the second generation photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC). In addition, intraoperative photodynamic therapy (PDT) was performed. Several commercially available fluorescence diagnostic systems were investigated for their applicability for clinical practice. We have adapted and optimized a diagnostic system which includes a surgical microscope, an excitation light source (filtered to 370-440 nm), a video camera detection system, and a spectrometer for clear identification of the mTHPC fluorescence emission at 652 nm. Especially in regions of faint fluorescence it turned out to be essential to maximize the spectral information by optimizing and matching the spectral properties of all components, such as excitation source, camera and color filters. In summary, based on 138 tissue samples derived from 22 tumor specimens we have been able to achieve a sensitivity of 87.9 % and a specificity of 95.7 %. This study demonstrates that mTHPC-mediated intraoperative fluorescence-guided resection followed by photodynamic therapy is a feasible concept. (author)

  9. LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid-β

    OpenAIRE

    Kanekiyo, Takahisa; Liu, Chia-Chen; Shinohara, Mitsuru; Li, Jie; Bu, Guojun

    2012-01-01

    Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer’s disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-...

  10. Tracing the Policy Mediation Process in the Implementation of a Change in the Life Sciences Curriculum

    Science.gov (United States)

    Singh-Pillay, Asheena; Alant, Busisiwe

    2015-01-01

    This paper accounts for the enacted realities of curriculum reform in South Africa, in particular the mediation of curriculum change. Curriculum implementation is viewed as a complex networked process of transforming or mediating policy into classroom practice. The fact that curriculum implementation is seen as problematic requires attention for…

  11. Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction.

    Science.gov (United States)

    Micevych, Paul E; Mermelstein, Paul G; Sinchak, Kevin

    2017-11-01

    Over the past few years our understanding of estrogen signaling in the brain has expanded rapidly. Estrogens are synthesized in the periphery and in the brain, acting on multiple receptors to regulate gene transcription, neural function, and behavior. Various estrogen-sensitive signaling pathways often operate in concert within the same cell, increasing the complexity of the system. In females, estrogen concentrations fluctuate over the estrous/menstrual cycle, dynamically modulating estrogen receptor (ER) expression, activity, and trafficking. These dynamic changes influence multiple behaviors but are particularly important for reproduction. Using the female rodent model, we review our current understanding of estradiol signaling in the regulation of sexual receptivity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Priming media stereotypes reduces support for social welfare policies: the mediating role of empathy.

    Science.gov (United States)

    Johnson, James D; Olivo, Nelgy; Gibson, Nathan; Reed, William; Ashburn-Nardo, Leslie

    2009-04-01

    Two experiments involving White participants tested the influence of media-based priming of Black stereotypes on support for government policy that assisted Black versus White persons-in-need. Experiment 1 showed that priming the "Black criminal" stereotype through exposure to photographs of Blacks looting after Hurricane Katrina reduced policy support for Black evacuees-in-need but did not influence support responses toward White evacuees-in-need. Experiment 2 showed that priming the "promiscuous Black female" stereotype through exposure to sexual rap music reduced policy support for a Black pregnant woman-in-need but did not influence support responses toward a White pregnant woman-in-need. Further tests of mediated moderation demonstrated that in both experiments, the interactive influence of priming Black stereotypes and race of persons-in-need on policy support was mediated by empathic responding.

  13. Blood brain barrier permeability and tPA-mediated neurotoxicity

    Science.gov (United States)

    Nassar, Taher; Yarovoi, Sergey; Rayan, Anwar; Lamensdorf, Itschak; Karakoveski, Michael; Vadim, Polianski; Fanne, Rami Abu; Jamal, Mahmud; Cines, Douglas B.; Higazi, Abd Al-Roof

    2015-01-01

    Tissue type plasminogen activator (tPA) induces neuronal apoptosis, disrupt the blood-brain-barrier (BBB), and promotes dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA. Our data show that intravenous administration of human tPA to rats increases BBB permeability through a non-catalytic process, which is associated with reversible neurotoxicity, brain damage, edema, mortality and contributes significantly to its brief therapeutic window. Furthermore, our data show that inhibiting the effect of tPA on BBB function without affecting its catalytic activity, improves outcome and significantly extends its therapeutic window in mechanical as well as thromboembolic models of stroke. PMID:20060006

  14. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

    Directory of Open Access Journals (Sweden)

    Nadine Ruderisch

    2017-10-01

    Full Text Available Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ antibodies and secretase inhibitors. However, the blood-brain barrier (BBB limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

  15. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

    Institute of Scientific and Technical Information of China (English)

    Tingting Lin; Ergang Liu; Huining He; Meong Cheol Shin; Cheol Moon; Victor C.Yang; Yongzhuo Huang

    2016-01-01

    Brain delivery of macromolecular therapeutics(e.g., proteins) remains an unsolved problem because of the formidable blood–brain barrier(BBB). Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs,new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways(e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion), a low molecular weight protamine(LMWP) cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides(CPP)have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP–proteins are able to effectively penetrate into the brain after intranasal administration.The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases.

  16. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

    Directory of Open Access Journals (Sweden)

    Tingting Lin

    2016-07-01

    Full Text Available Brain delivery of macromolecular therapeutics (e.g., proteins remains an unsolved problem because of the formidable blood–brain barrier (BBB. Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs, new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways (e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion, a low molecular weight protamine (LMWP cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides (CPP have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP–proteins are able to effectively penetrate into the brain after intranasal administration. The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases.

  17. The Mediation of Representative Council of Learners Policy in Western Cape Schools--1997 to 2003

    Science.gov (United States)

    Carr, Ivan; Williams, Clarence

    2009-01-01

    We investigated how education policy was mediated at a representative number of Western Cape schools, from 1997 to 2003, using the structure, symbolic, human resource and political frames of Bolman and Deal (1997) as the basis of the investigation. The investigation produced diverse research findings. At the one end there were a majority of…

  18. Pharmacologic Effects in vivo in Brain by Vector-Mediated Peptide Drug Delivery

    Science.gov (United States)

    Bickel, Ulrich; Yoshikawa, Takayoshi; Landaw, Elliot M.; Faull, Kym F.; Pardridge, William M.

    1993-04-01

    Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 μg/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.

  19. Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM-Mediated Protection of Ischemic Brain.

    Directory of Open Access Journals (Sweden)

    Chi-Hsin Lin

    Full Text Available The protective value of neuron-derived conditioned medium (NCM in cerebral ischemia and the underlying mechanism(s responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO animal model, we discovered that ischemia/reperfusion (I/R-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFβ1, NT-3 and GDNF and p-ERK dependent manner. Brain injection with TGFβ1, NT3, GDNF and ERK agonist (DADS alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1β release from GOSD-treated microglia and limit the infiltration of IL-β-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1β can inhibit the glutamate-mediated neurotoxicity and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFβ1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation.

  20. Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior.

    Science.gov (United States)

    Mackey, Scott; Chaarani, Bader; Kan, Kees-Jan; Spechler, Philip A; Orr, Catherine; Banaschewski, Tobias; Barker, Gareth; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Cattrell, Anna; Conrod, Patricia J; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Paillère Martinot, Marie-Laure; Artiges, Eric; Nees, Frauke; Papadopoulos-Orfanos, Dimitri; Poustka, Luise; Smolka, Michael N; Jurk, Sarah; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Althoff, Robert R; Garavan, Hugh

    2017-08-15

    Individual differences in impulsivity and early adversity are known to be strong predictors of adolescent antisocial behavior. However, the neurobiological bases of impulsivity and their relation to antisocial behavior and adversity are poorly understood. Impulsivity was estimated with a temporal discounting task. Voxel-based morphometry was used to determine the brain structural correlates of temporal discounting in a large cohort (n = 1830) of 14- to 15-year-old children. Mediation analysis was then used to determine whether the volumes of brain regions associated with temporal discounting mediate the relation between adverse life events (e.g., family conflict, serious accidents) and antisocial behaviors (e.g., precocious sexual activity, bullying, illicit substance use). Greater temporal discounting (more impulsivity) was associated with 1) lower volume in frontomedial cortex and bilateral insula and 2) greater volume in a subcortical region encompassing the ventral striatum, hypothalamus and anterior thalamus. The volume ratio between these cortical and subcortical regions was found to partially mediate the relation between adverse life events and antisocial behavior. Temporal discounting is related to regions of the brain involved in reward processing and interoception. The results support a developmental imbalance model of impulsivity and are consistent with the idea that negative environmental factors can alter the developing brain in ways that promote antisocial behavior. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  1. Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

    Directory of Open Access Journals (Sweden)

    van Doorn Ruben

    2012-06-01

    Full Text Available Abstract Background The sphingosine 1-phosphate (S1P receptor modulator FTY720P (Gilenya® potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P5 largely contributes to the maintenance of brain endothelial barrier function. Methods We analyzed the expression of S1P5 in human post-mortem tissues using immunohistochemistry. The function of S1P5 at the BBB was assessed in cultured human brain endothelial cells (ECs using agonists and lentivirus-mediated knockdown of S1P5. Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. Results We show that activation of S1P5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. Conclusion Our

  2. Hormonally-mediated Epigenetic Changes to Steroid Receptors in the Developing Brain: Implications for Sexual Differentiation

    Science.gov (United States)

    Nugent, Bridget M.; Schwarz, Jaclyn M.; McCarthy, Margaret M.

    2010-01-01

    The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiol-induced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain. PMID:20800064

  3. Consistency and Variation in School-Level Youth Sports Traumatic Brain Injury Policy Content.

    Science.gov (United States)

    Coxe, Kathryn; Hamilton, Kelsey; Harvey, Hosea H; Xiang, Joe; Ramirez, Marizen R; Yang, Jingzhen

    2018-03-01

    The purpose of the study was to examine the consistency and variation in content of high school written traumatic brain injury (TBI) policies in relation to the three key tenets of youth sports TBI laws. A content analysis was conducted on written TBI policies retrieved from 71 high schools currently participating in High School Reporting Information Online. Each policy was independently analyzed by two trained coders. The number and percent of the policies reflecting the three key tenets of state youth sports TBI laws were described and compared on policy enforcement (i.e., strictness of language), policy description (i.e., details and definitions of the requirements), and policy implementation steps (i.e., specific steps for implementing the requirements). Direct quotes were identified to support quantitative findings. All 71 high school TBI policies contained at least two of the three main TBI law tenets, where 98.6% (n = 70) included the return to play tenet, 83.1% (n = 59) included the removal from play tenet, and 59.2% (n = 42) specified the distribution of TBI information sheets to student-athletes and their parents. Nearly half of the policies (49.3%, n = 35) required parents' signature while only 39.4% (n = 28) required students' signature on the TBI information sheet. The language exhibited wide variance across the 71 TBI policies regarding policy enforcement, policy description, and policy implementation specifications. All 71 TBI policies covered at least two of the three youth sports TBI law tenets, but with considerable variation. Future research should assess variations by schools within the same state and their impact on TBI rates in school athletics. Copyright © 2017 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  4. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response.

    Science.gov (United States)

    Stengel, Andreas; Taché, Yvette F

    2017-01-01

    Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates-in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis-other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  5. Decreased α1-adrenergic receptor-mediated inositide hydrolysis in neurons from hypertensive rat brain

    International Nuclear Information System (INIS)

    Feldstein, J.B.; Gonzales, R.A.; Baker, S.P.; Sumners, C.; Crews, F.T.; Raizada, M.K.

    1986-01-01

    The expression of α 1 -adrenergic receptors and norepinephrine (NE)-stimulated hydrolysis of inositol phospholipid has been studied in neuronal cultures from the brains of normotensive (Wistar-Kyoto, WKY) and spontaneously hypertensive (SH) rats. Binding of 125 I-1-[β-(4-hydroxyphenyl)-ethyl-aminomethyl] tetralone (HEAT) to neuronal membranes was 68-85% specific and was rapid. Competition-inhibition experiments with various agonists and antagonists suggested that 125 I-HEAT bound selectively to α 1 -adrenergic receptors. Specific binding of 125 I-HEAT to neuronal membranes from SH rat brain cultures was 30-45% higher compared with binding in WKY normotensive controls. This increase was attributed to an increase in the number of α 1 -adrenergic receptors on SH rat brain neurons. Incubation of neuronal cultures of rat brain from both strains with NE resulted in a concentration-dependent stimulation of release of inositol phosphates, although neurons from SH rat brains were 40% less responsive compared with WKY controls. The decrease in responsiveness of SH rat brain neurons to NE, even though the α 1 -adrenergic receptors are increased, does not appear to be due to a general defect in membrane receptors and postreceptor signal transduction mechanisms. This is because neither the number of muscarinic-cholinergic receptors nor the carbachol-stimulated release of inositol phosphates is different in neuronal cultures from the brains of SH rats compared with neuronal cultures from the brains of WKY rats. These observations suggest that the increased expression of α 1 -adrenergic receptors does not parallel the receptor-mediated inositol phosphate hydrolysis in neuronal cultures from SH rat brain

  6. Migraine with aura and silent brain infarcts lack of mediation of patent foramen ovale.

    Science.gov (United States)

    Calviere, L; Tall, P; Massabuau, P; Bonneville, F; Larrue, V

    2013-12-01

    Population-based studies have shown a heightened prevalence of clinically silent brain infarcts in subjects who have migraine with aura (MA). We sought to determine whether this association could be confirmed in young patients with cryptogenic ischemic stroke, and explored the role of patent foramen ovale (PFO) as a potential underlying mechanism. Patients were selected from a registry of young patients consecutively treated for ischemic stroke in a tertiary university hospital among those without definite cause of stroke. Patients with PFO were matched for age and gender with patients with normal atrial septum. Migraine and MA were evaluated after patient selection and matching. Silent brain infarcts were independently evaluated on MRI. We included 100 patients [60 men; mean age (SD), 44.8 years (8.3)], 50 patients with PFO. We found silent brain infarcts in 36 patients and MA in 13 patients. MA was more frequent in patients with silent brain infarcts than in patients without silent brain infarcts (25.0% vs. 6.3%; OR, 5; 95% CI, 1.4-17.6; P = 0.01). Traditional cardiovascular risk factors were not associated with silent brain infarcts. PFO was neither associated with MA (OR, 1.7; 95% CI, 0.5-5.3) nor silent brain infarcts (OR, 0.7; 95% CI, 0.3-1.5). The association of MA with silent brain infarcts was not altered after adjustment for PFO. Findings suggest that silent brain infarcts in young patients with cryptogenic stroke is associated with MA. We found no evidence for a mediating effect of PFO on this association. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

  7. Cellular mechanisms of estradiol-mediated sexual differentiation of the brain.

    Science.gov (United States)

    Wright, Christopher L; Schwarz, Jaclyn S; Dean, Shannon L; McCarthy, Margaret M

    2010-09-01

    Gonadal steroids organize the developing brain during a perinatal sensitive period and have enduring consequences for adult behavior. In male rodents testicular androgens are aromatized in neurons to estrogens and initiate multiple distinct cellular processes that ultimately determine the masculine phenotype. Within specific brain regions, overall cell number and dendritic morphology are the principal targets for hormonal organization. Recent advances have been made in elucidating the cellular mechanisms by which the neurological underpinnings of sexually dimorphic physiology and behavior are determined. These include estradiol-mediated prostaglandin synthesis, presynaptic release of glutamate, postsynaptic changes in glutamate receptors and changes in cell adhesion molecules. Sex differences in cell death are mediated by hormonal modulation of survival and death factors such as TNFalpha and Bcl-2/BAX. Copyright 2010 Elsevier Ltd. All rights reserved.

  8. Brain activation to negative stimuli mediates a relationship between adolescent marijuana use and later emotional functioning

    OpenAIRE

    Heitzeg, Mary M.; Cope, Lora M.; Martz, Meghan E.; Hardee, Jillian E.; Zucker, Robert A.

    2015-01-01

    This work investigated the impact of heavy marijuana use during adolescence on emotional functioning, as well as the brain functional mediators of this effect. Participants (n = 40) were recruited from the Michigan Longitudinal Study (MLS). Data on marijuana use were collected prospectively beginning in childhood as part of the MLS. Participants were classified as heavy marijuana users (n = 20) or controls with minimal marijuana use. Two facets of emotional functioning—negative emotionality a...

  9. Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics

    Science.gov (United States)

    Chen, Shuo; Weitemier, Adam Z.; Zeng, Xiao; He, Linmeng; Wang, Xiyu; Tao, Yanqiu; Huang, Arthur J. Y.; Hashimotodani, Yuki; Kano, Masanobu; Iwasaki, Hirohide; Parajuli, Laxmi Kumar; Okabe, Shigeo; Teh, Daniel B. Loong; All, Angelo H.; Tsutsui-Kimura, Iku; Tanaka, Kenji F.; Liu, Xiaogang; McHugh, Thomas J.

    2018-02-01

    Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

  10. The Effect of Environmental Policy by Considering the Mediating Role of Customer Satisfaction and Loyalty

    OpenAIRE

    Safshekan, Sedigheh

    2014-01-01

    ABSTRACT: This thesis aimed to explore the effects of environmental policies (EP) on three dependent variables including customer satisfaction (CS), customer loyalty (CL) and market performance (MP). It also investigated the effects of employing EP on hotel market performance by considering the mediating role of customer satisfaction and customer loyalty in this relationship. Through a quantitative research method, a survey questionnaire administered to international tourists and managers of ...

  11. Gender, intoxication and the developing brain: Problematisations of drinking among young adults in Australian alcohol policy.

    Science.gov (United States)

    Manton, Elizabeth; Moore, David

    2016-05-01

    In this article, we draw on recent scholarly work in the poststructuralist analysis of policy to consider how policy itself functions as a key site in the constitution of alcohol 'problems', and the political implications of these problematisations. We do this by examining Australian alcohol policy as it relates to young adults (18-24 years old). Our critical analysis focuses on three national alcohol policies (1990, 2001 and 2006) and two Victorian state alcohol policies (2008 and 2013), which together span a 25-year period. We argue that Australian alcohol policies have conspicuously ignored young adult men, despite their ongoing over-representation in the statistical 'evidence base' on alcohol-related harm, while increasingly problematising alcohol consumption amongst other population subgroups. We also identify the development of a new problem representation in Australian alcohol policy, that of 'intoxication' as the leading cause of alcohol-related harm and rising hospital admissions, and argue that changes in the classification and diagnosis of intoxication may have contributed to its prioritisation and problematisation in alcohol policy at the expense of other forms of harm. Finally, we draw attention to how preliminary and inconclusive research on the purported association between binge drinking and brain development in those under 25 years old has been mobilised prematurely to support calls to increase the legal purchasing age from 18 to 21 years. Our critical analysis of the treatment of these three issues - gender, intoxication, and brain development - is intended to highlight the ways in which policy functions as a key site in the constitution of alcohol 'problems'. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.

    Directory of Open Access Journals (Sweden)

    Choong-Wan Woo

    2015-01-01

    Full Text Available Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS, an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.

  13. Progesterone mediates brain functional connectivity changes during the menstrual cycle - A pilot resting state MRI study

    Directory of Open Access Journals (Sweden)

    Katrin eArelin

    2015-02-01

    Full Text Available The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral DLPFC and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal rs-fMRI design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.

  14. β2-Adrenergic Receptor-Mediated HIF-1α Upregulation Mediates Blood Brain Barrier Damage in Acute Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Yanyun Sun

    2017-08-01

    Full Text Available Disruption of the blood brain barrier (BBB within the thrombolytic time window is an antecedent event to intracerebral hemorrhage in ischemic stroke. Our recent studies showed that 2-h cerebral ischemia induced BBB damage in non-infarcted area and secreted matrix metalloproteinase-2 (MMP-2 accounted for this disruption. However, the factors that affect MMP-2 secretion and regulate BBB damage remains unknown. Since hypoxia-inducible factor-1 alpha (HIF-1α was discovered as a mater regulator in hypoxia, we sought to investigate the roles of HIF-1α in BBB damage as well as the factors regulating HIF-1α expression in the ischemic brain. in vivo rat middle cerebral artery occlusion (MCAO and in vitro oxygen glucose deprivation (OGD models were used to mimic ischemia. Pretreatment with HIF-1α inhibitor YC-1 significantly inhibited 2-h MCAO-induced BBB damage, which was accompanied by suppressed occludin degradation and vascular endothelial growth factor (VEGF mRNA upregulation. Interestingly, β2-adrenergic receptor (β2-AR antagonist ICI 118551 attenuated ischemia-induced BBB damage by regulating HIF-1α expression. Double immunostaining showed that HIF-1α was upregulated in ischemic neurons but not in astrocytes andendothelial cells. Of note, HIF-1α inhibition with inhibitor YC-1 or siRNA significantly prevented OGD-induced VEGF upregulation as well as the secretion of VEGF and MMP-2 in neurons. More importantly, blocking β2-AR with ICI 118551 suppressedHIF-1α upregulation in ischemic neurons and attenuated occludin degradation induced by the conditioned media of OGD-treatedneurons. Taken together, blockade of β2-AR-mediated HIF-1α upregulation mediates BBB damage during acute cerebral ischemia. These findings provide new mechanistic understanding of early BBB damage in ischemic stroke and may help reduce thrombolysis-related hemorrhagic complications.

  15. Brain's reward circuits mediate itch relief. a functional MRI study of active scratching.

    Directory of Open Access Journals (Sweden)

    Alexandru D P Papoiu

    Full Text Available Previous brain imaging studies investigating the brain processing of scratching used an exogenous intervention mimicking scratching, performed not by the subjects themselves, but delivered by an investigator. In real life, scratching is a conscious, voluntary, controlled motor response to itching, which is directed to the perceived site of distress. In this study we aimed to visualize in real-time by brain imaging the core mechanisms of the itch-scratch cycle when scratching was performed by subjects themselves. Secondly, we aimed to assess the correlations between brain patterns of activation and psychophysical ratings of itch relief or pleasurability of scratching. We also compared the patterns of brain activity evoked by self-scratching vs. passive scratching. We used a robust tridimensional Arterial Spin Labeling fMRI technique that is less sensitive to motion artifacts: 3D gradient echo and spin echo (GRASE--Propeller. Active scratching was accompanied by a higher pleasurability and induced a more pronounced deactivation of the anterior cingulate cortex and insula, in comparison with passive scratching. A significant involvement of the reward system including the ventral tegmentum of the midbrain, coupled with a mechanism deactivating the periaqueductal gray matter (PAG, suggests that itch modulation operates in reverse to the mechanism known to suppress pain. Our findings not only confirm a role for the central networks processing reward in the pleasurable aspects of scratching, but also suggest they play a role in mediating itch relief.

  16. Brain death determination: the imperative for policy and legal initiatives in Sub-Saharan Africa.

    Science.gov (United States)

    Waweru-Siika, Wangari; Clement, Meredith Edwards; Lukoko, Lilian; Nadel, Simon; Rosoff, Philip M; Naanyu, Violet; Kussin, Peter S

    2017-05-01

    The concept of brain death (BD), defined as irreversible loss of function of the brain including the brainstem, is accepted in the medical literature and in legislative policy worldwide. However, in most of Sub-Saharan Africa (SSA) there are no legal guidelines regarding BD. Hypothetical scenarios based on our collective experience are presented which underscore the consequences of the absence of BD policies in resource-limited countries (RLCs). Barriers to the development of BD laws exist in an RLC such as Kenya. Cultural, ethnic, and religious diversity creates a complex perspective about death challenging the development of uniform guidelines for BD. The history of the medical legal process in the USA provides a potential way forward. Uniform guidelines for legislation at the state level included special consideration for ethnic or religious preferences in specific states. In SSA, medical and social consensus on the definition of BD is a prerequisite for the development BD legislation. Legislative policy will (1) limit prolonged and futile interventions; (2) mitigate the suffering of families; (3) standardise clinical practice; and (4) facilitate better allocation of scarce critical care resources in RLCs. There is a clear-cut need for these policies, and previous successful policies can serve to guide these efforts.

  17. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.

    Science.gov (United States)

    Kanekiyo, Takahisa; Liu, Chia-Chen; Shinohara, Mitsuru; Li, Jie; Bu, Guojun

    2012-11-14

    Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer's disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in cerebrovasculature, in particular in vascular smooth muscle cells. Previous studies have indicated a role of LRP1 in endothelial cells in transcytosing Aβ out of the brain across the BBB; however, whether this represents a significant pathway for brain Aβ clearance remains controversial. Here, we demonstrate that Aβ can be cleared locally in the cerebrovasculature by an LRP1-dependent endocytic pathway in smooth muscle cells. The uptake and degradation of both endogenous and exogenous Aβ were significantly reduced in LRP1-suppressed human brain vascular smooth muscle cells. Conditional deletion of Lrp1 in vascular smooth muscle cell in amyloid model APP/PS1 mice accelerated brain Aβ accumulation and exacerbated Aβ deposition as amyloid plaques and CAA without affecting Aβ production. Our results demonstrate that LRP1 is a major Aβ clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to Aβ accumulation. These studies establish critical functions of the cerebrovasculature system in Aβ metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA.

  18. Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Olszewski, Pawel K., E-mail: olsze005@umn.edu [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Minnesota Obesity Center, Saint Paul, MN 55108 (United States); Fredriksson, Robert; Eriksson, Jenny D. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Mitra, Anaya [Department of Food Science and Nutrition, Saint Paul, MN 55108 (United States); Radomska, Katarzyna J. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Gosnell, Blake A. [Department of Food Science and Nutrition, Saint Paul, MN 55108 (United States); Solvang, Maria N. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Levine, Allen S. [Minnesota Obesity Center, Saint Paul, MN 55108 (United States); Department of Food Science and Nutrition, Saint Paul, MN 55108 (United States); Schioeth, Helgi B. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden)

    2011-05-13

    Highlights: {yields} The majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto. {yields} The level of colocalization is similar in the male and female brain. {yields} Fto overexpression in hypothalamic neurons increases oxytocin mRNA levels by 50%. {yields} Oxytocin does not affect Fto expression through negative feedback mechanisms. -- Abstract: Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.

  19. Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression

    International Nuclear Information System (INIS)

    Olszewski, Pawel K.; Fredriksson, Robert; Eriksson, Jenny D.; Mitra, Anaya; Radomska, Katarzyna J.; Gosnell, Blake A.; Solvang, Maria N.; Levine, Allen S.; Schioeth, Helgi B.

    2011-01-01

    Highlights: → The majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto. → The level of colocalization is similar in the male and female brain. → Fto overexpression in hypothalamic neurons increases oxytocin mRNA levels by 50%. → Oxytocin does not affect Fto expression through negative feedback mechanisms. -- Abstract: Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.

  20. The mediating role of social workers in the implementation of regional policies targeting energy poverty

    International Nuclear Information System (INIS)

    Scarpellini, Sabina; Sanz Hernández, M. Alexia; Llera-Sastresa, Eva; Aranda, Juan A.; López Rodríguez, María Esther

    2017-01-01

    This paper aims to provide a socio-political reflection of the role played by social workers in regional policies and of the real needs of households affected by energy poverty. The paper also examines the impact of technical-specialised training on the ability of social workers to prevent and mitigate conditions of household energy poverty in Europe. The adoption of a research-action-participation methodological framework and a training research approach has permitted the opinions of social workers to be collected through surveys, and their central role in implementing regional policies to be highlighted. The conclusions obtained have made possible the construction of a self-diagnosis and data-collection tool which increases the ability of social workers to mediate and implement urgent mitigation measures for energy poverty. Finally, regional policies which aim to mitigate household energy poverty are examined from the professional perspective of social workers. - Highlights: • Social workers play a mediating role in the certification of household energy poverty. • Specific training for social workers contributes to the prevention of energy poverty. • National wide regulation would enable the implementation of equitable measures for energy poverty. • It is recommendable to define progressive subsidies depending on the level of energy vulnerability of the households.

  1. Body distributioin of RGD-mediated liposome in brain-targeting drug delivery.

    Science.gov (United States)

    Qin, Jing; Chen, DaWei; Hu, Haiyang; Qiao, MingXi; Zhao, XiuLi; Chen, Baoyu

    2007-09-01

    RGD conjugation liposomes (RGD-liposomes) were evaluated for brain-targeting drug delivery. The flow cytometric in vitro study demonstrated that RGD-liposomes could bind to monocytes and neutrophils effectively. Ferulic acid (4-hydroxy-3-methoxycinnamic, FA) was loaded into liposomes. Rats were subjected to intrastriatal microinjections of 100 units of human recombinant IL-1beta to produce brain inflammation and caudal vein injection of three formulations (FA solution, FA liposome and RGD-coated FA liposome). Animals were sacrificed 15, 30, 60 and 120 min after administration to study the body distribution of the FA in the three formulations. HPLC was used to determine the concentration of FA in vivo with salicylic acid as internal standard. The results of body distribution indicated that RGD-coated liposomes could be mediated into the brain with a 6-fold FA concentration compared to FA solution and 3-fold in comparison to uncoated liposome. Brain targeted delivery was achieved and a reduction in dosage might be allowed.

  2. Implications of astrocytes in mediating the protective effects of Selective Estrogen Receptor Modulators upon brain damage

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2015-04-01

    Full Text Available Selective Estrogen Receptor Modulators (SERMs are steroidal or non-steroidal compounds that are already used in clinical practice for the treatment of breast cancer, osteoporosis and menopausal symptoms. While SERMs actions in the breast, bone, and uterus have been well characterized, their actions in the brain are less well understood. Previous works have demonstrated the beneficial effects of SERMs in different chronic neurodegenerative diseases like Alzheimer, Parkinson’s disease and Multiple sclerosis, as well as acute degeneration as stroke and traumatic brain injury. Moreover, these compounds exhibit similar protective actions as those of estradiol in the Central Nervous System, overt any secondary effect. For these reasons, in the past few years, there has been a growing interest in the neuroprotective effects exerted directly or indirectly by SERMs in the SNC. In this context, astrocytes play an important role in the maintenance of brain metabolism, and antioxidant support to neurons, thus indicating that better protection of astrocytes are an important asset targeting neuronal protection. Moreover, various clinical and experimental studies have reported that astrocytes are essential for the neuroprotective effects of SERMs during neuronal injuries, as these cells express different estrogen receptors in cell membrane, demonstrating that part of SERMs effects upon injury may be mediated by astrocytes. The present work highlights the current evidence on the protective mechanisms of SERMs, such as tamoxifen and raloxifene, in the SNC, and their modulation of astrocytic properties as promising therapeutic targets during brain damage.

  3. Mediating Education Policy: Making up the "Anti-Politics" of Third-Sector Participation in Public Education

    Science.gov (United States)

    Williamson, Ben

    2014-01-01

    This article examines the participation of "third-sector" organisations in public education in England. These organisations act as a cross-sectoral policy network made up of new kinds of policy experts: mediators and brokers with entrepreneurial careers in ideas. They have sought to make education reform thinkable, intelligible and…

  4. Anti-Amyloid-?-Mediated Positron Emission Tomography Imaging in Alzheimer's Disease Mouse Brains

    OpenAIRE

    McLean, Daniel; Cooke, Michael J.; Wang, Yuanfei; Green, David; Fraser, Paul E.; George-Hyslop, Peter St; Shoichet, Molly S.

    2012-01-01

    Antibody-mediated imaging of amyloid β (Aβ) in Alzheimer's disease (AD) offers a promising strategy to detect and monitor specific Aβ species, such as oligomers, that have important pathological and therapeutic relevance. The major current limitation of antibodies as a diagnostic and imaging device is poor blood-brain-barrier permeability. A classical anti-Aβ antibody, 6E10, is modified with 10 kDa polyethylene glycol (PEG) and a positron emitting isotope, Copper-64 (t(½) = 12.7 h), and intra...

  5. Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat.

    Science.gov (United States)

    Anselmi, L; Toti, L; Bove, C; Travagli, R A

    2017-11-01

    Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1 ) assess the gastric effects of brain stem DA application, 2 ) identify the DA receptor subtype, and, 3 ) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway. Copyright © 2017 the American Physiological Society.

  6. Receptor-mediated transcytosis of cyclophilin B through the blood-brain barrier.

    Science.gov (United States)

    Carpentier, M; Descamps, L; Allain, F; Denys, A; Durieux, S; Fenart, L; Kieda, C; Cecchelli, R; Spik, G

    1999-07-01

    Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein mainly located in intracellular vesicles and secreted in biological fluids. In previous works, we demonstrated that CyPB interacts with T lymphocytes and enhances in vitro cellular incorporation and activity of CsA. In addition to its immunosuppressive activity, CsA is able to promote regeneration of damaged peripheral nerves. However, the crossing of the drug from plasma to neural tissue is restricted by the relative impermeability of the blood-brain barrier. To know whether CyPB might also participate in the delivery of CsA into the brain, we have analyzed the interactions of CyPB with brain capillary endothelial cells. First, we demonstrated that CyPB binds to two types of binding sites present at the surface of capillary endothelial cells from various species of tissues. The first type of binding sites (K(D) = 300 nM; number of sites = 3 x 10(6)) is related to interactions with negatively charged compounds such as proteoglycans. The second type of binding sites, approximately 50,000 per cell, exhibits a higher affinity for CyPB (K(D) = 15 nM) and is involved in an endocytosis process, indicating it might correspond to a functional receptor. Finally, the use of an in vitro model of blood-brain barrier allowed us to demonstrate that CyPB is transcytosed by a receptor-mediated pathway (flux = 16.5 fmol/cm2/h). In these conditions, CyPB did not significantly modify the passage of CsA, indicating that it is unlikely to provide a pathway for CsA brain delivery.

  7. Feedback control policies employed by people using intracortical brain-computer interfaces

    Science.gov (United States)

    Willett, Francis R.; Pandarinath, Chethan; Jarosiewicz, Beata; Murphy, Brian A.; Memberg, William D.; Blabe, Christine H.; Saab, Jad; Walter, Benjamin L.; Sweet, Jennifer A.; Miller, Jonathan P.; Henderson, Jaimie M.; Shenoy, Krishna V.; Simeral, John D.; Hochberg, Leigh R.; Kirsch, Robert F.; Bolu Ajiboye, A.

    2017-02-01

    Objective. When using an intracortical BCI (iBCI), users modulate their neural population activity to move an effector towards a target, stop accurately, and correct for movement errors. We call the rules that govern this modulation a ‘feedback control policy’. A better understanding of these policies may inform the design of higher-performing neural decoders. Approach. We studied how three participants in the BrainGate2 pilot clinical trial used an iBCI to control a cursor in a 2D target acquisition task. Participants used a velocity decoder with exponential smoothing dynamics. Through offline analyses, we characterized the users’ feedback control policies by modeling their neural activity as a function of cursor state and target position. We also tested whether users could adapt their policy to different decoder dynamics by varying the gain (speed scaling) and temporal smoothing parameters of the iBCI. Main results. We demonstrate that control policy assumptions made in previous studies do not fully describe the policies of our participants. To account for these discrepancies, we propose a new model that captures (1) how the user’s neural population activity gradually declines as the cursor approaches the target from afar, then decreases more sharply as the cursor comes into contact with the target, (2) how the user makes constant feedback corrections even when the cursor is on top of the target, and (3) how the user actively accounts for the cursor’s current velocity to avoid overshooting the target. Further, we show that users can adapt their control policy to decoder dynamics by attenuating neural modulation when the cursor gain is high and by damping the cursor velocity more strongly when the smoothing dynamics are high. Significance. Our control policy model may help to build better decoders, understand how neural activity varies during active iBCI control, and produce better simulations of closed-loop iBCI movements.

  8. Brain activation to negative stimuli mediates a relationship between adolescent marijuana use and later emotional functioning.

    Science.gov (United States)

    Heitzeg, Mary M; Cope, Lora M; Martz, Meghan E; Hardee, Jillian E; Zucker, Robert A

    2015-12-01

    This work investigated the impact of heavy marijuana use during adolescence on emotional functioning, as well as the brain functional mediators of this effect. Participants (n=40) were recruited from the Michigan Longitudinal Study (MLS). Data on marijuana use were collected prospectively beginning in childhood as part of the MLS. Participants were classified as heavy marijuana users (n=20) or controls with minimal marijuana use. Two facets of emotional functioning-negative emotionality and resiliency (a self-regulatory mechanism)-were assessed as part of the MLS at three time points: mean age 13.4, mean age 19.6, and mean age 23.1. Functional neuroimaging data during an emotion-arousal word task were collected at mean age 20.2. Negative emotionality decreased and resiliency increased across the three time points in controls but not heavy marijuana users. Compared with controls, heavy marijuana users had less activation to negative words in temporal, prefrontal, and occipital cortices, insula, and amygdala. Activation of dorsolateral prefrontal cortex to negative words mediated an association between marijuana group and later negative emotionality. Activation of the cuneus/lingual gyrus mediated an association between marijuana group and later resiliency. Results support growing evidence that heavy marijuana use during adolescence affects later emotional outcomes. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Brain activation to negative stimuli mediates a relationship between adolescent marijuana use and later emotional functioning

    Directory of Open Access Journals (Sweden)

    Mary M. Heitzeg

    2015-12-01

    Full Text Available This work investigated the impact of heavy marijuana use during adolescence on emotional functioning, as well as the brain functional mediators of this effect. Participants (n = 40 were recruited from the Michigan Longitudinal Study (MLS. Data on marijuana use were collected prospectively beginning in childhood as part of the MLS. Participants were classified as heavy marijuana users (n = 20 or controls with minimal marijuana use. Two facets of emotional functioning—negative emotionality and resiliency (a self-regulatory mechanism—were assessed as part of the MLS at three time points: mean age 13.4, mean age 19.6, and mean age 23.1. Functional neuroimaging data during an emotion-arousal word task were collected at mean age 20.2. Negative emotionality decreased and resiliency increased across the three time points in controls but not heavy marijuana users. Compared with controls, heavy marijuana users had less activation to negative words in temporal, prefrontal, and occipital cortices, insula, and amygdala. Activation of dorsolateral prefrontal cortex to negative words mediated an association between marijuana group and later negative emotionality. Activation of the cuneus/lingual gyrus mediated an association between marijuana group and later resiliency. Results support growing evidence that heavy marijuana use during adolescence affects later emotional outcomes.

  10. Identification and Sensitivity Analysis for Average Causal Mediation Effects with Time-Varying Treatments and Mediators: Investigating the Underlying Mechanisms of Kindergarten Retention Policy.

    Science.gov (United States)

    Park, Soojin; Steiner, Peter M; Kaplan, David

    2018-06-01

    Considering that causal mechanisms unfold over time, it is important to investigate the mechanisms over time, taking into account the time-varying features of treatments and mediators. However, identification of the average causal mediation effect in the presence of time-varying treatments and mediators is often complicated by time-varying confounding. This article aims to provide a novel approach to uncovering causal mechanisms in time-varying treatments and mediators in the presence of time-varying confounding. We provide different strategies for identification and sensitivity analysis under homogeneous and heterogeneous effects. Homogeneous effects are those in which each individual experiences the same effect, and heterogeneous effects are those in which the effects vary over individuals. Most importantly, we provide an alternative definition of average causal mediation effects that evaluates a partial mediation effect; the effect that is mediated by paths other than through an intermediate confounding variable. We argue that this alternative definition allows us to better assess at least a part of the mediated effect and provides meaningful and unique interpretations. A case study using ECLS-K data that evaluates kindergarten retention policy is offered to illustrate our proposed approach.

  11. Neural Computations Mediating One-Shot Learning in the Human Brain

    Science.gov (United States)

    Lee, Sang Wan; O’Doherty, John P.; Shimojo, Shinsuke

    2015-01-01

    Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI) data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively “switched” on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a “switch,” turning on and off one-shot learning as required. PMID:25919291

  12. Anti-amyloid-β-mediated positron emission tomography imaging in Alzheimer's disease mouse brains.

    Directory of Open Access Journals (Sweden)

    Daniel McLean

    Full Text Available Antibody-mediated imaging of amyloid β (Aβ in Alzheimer's disease (AD offers a promising strategy to detect and monitor specific Aβ species, such as oligomers, that have important pathological and therapeutic relevance. The major current limitation of antibodies as a diagnostic and imaging device is poor blood-brain-barrier permeability. A classical anti-Aβ antibody, 6E10, is modified with 10 kDa polyethylene glycol (PEG and a positron emitting isotope, Copper-64 (t(½ = 12.7 h, and intravenously delivered to the TgCRND8 mouse model of Alzheimer's disease. Modification of 6E10 with PEG (6E10-PEG increases accumulation of 6E10 in brain tissue in both TgCRND8 and wild type control animals. 6E10-PEG differentiates TgCRND8 animals from wild type controls using positron emission tomography (PET and provides a framework for using antibodies to detect pathology using non-invasive medical imaging techniques.

  13. Serotonin: A mediator of the gut-brain axis in multiple sclerosis.

    Science.gov (United States)

    Malinova, Tsveta S; Dijkstra, Christine D; de Vries, Helga E

    2017-11-01

    The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a microbial-modulated neurotransmitter (NT) as a showcase to demonstrate that NTs regulated by the gut microbiome are potent candidates for mediators of the gut-brain axis in demyelinating disorders. Methods, Results, and Conclusion: Our comprehensive overview of literature provides evidence that 5-HT levels in the gut are controlled by the microbiome, both via secretion and through regulation of metabolites. In addition, we demonstrate that the gut microbiome can influence the formation of the serotonergic system (SS) in the brain. We also show that SS alterations have been related to MS directly-altered expression of 5-HT transporters in central nervous system (CNS) and indirectly-beneficial effects of 5-HT modulating drugs on the course of the disease and higher prevalence of depression in patients with MS. Finally, we discuss briefly the role of other microbiome-modulated NTs such as γ-aminobutyric acid and dopamine in MS to highlight a new direction for future research aiming to relate microbiome-regulated NTs to demyelinating disorders.

  14. Neural computations mediating one-shot learning in the human brain.

    Directory of Open Access Journals (Sweden)

    Sang Wan Lee

    2015-04-01

    Full Text Available Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively "switched" on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a "switch," turning on and off one-shot learning as required.

  15. Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain.

    Science.gov (United States)

    Harro, Jaanus; Kanarik, Margus; Kaart, Tanel; Matrov, Denis; Kõiv, Kadri; Mällo, Tanel; Del Río, Joaquin; Tordera, Rosa M; Ramirez, Maria J

    2014-07-01

    The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy.

    Science.gov (United States)

    Sullan, Molly J; Asken, Breton M; Jaffee, Michael S; DeKosky, Steven T; Bauer, Russell M

    2018-01-01

    Traumatic brain injury (TBI) is an increasingly important issue among veterans, athletes and the general public. Difficulties with sleep onset and maintenance are among the most commonly reported symptoms following injury, and sleep debt is associated with increased accumulation of beta amyloid (Aβ) and phosphorylated tau (p-tau) in the interstitial space. Recent research into the glymphatic system, a lymphatic-like metabolic clearance mechanism in the central nervous system (CNS) which relies on cerebrospinal fluid (CSF), interstitial fluid (ISF), and astrocytic processes, shows that clearance is potentiated during sleep. This system is damaged in the acute phase following mTBI, in part due to re-localization of aquaporin-4 channels away from astrocytic end feet, resulting in reduced potential for waste removal. Long-term consequences of chronic dysfunction within this system in the context of repetitive brain trauma and insomnia have not been established, but potentially provide one link in the explanatory chain connecting repetitive TBI with later neurodegeneration. Current research has shown p-tau deposition in perivascular spaces and along interstitial pathways in chronic traumatic encephalopathy (CTE), pathways related to glymphatic flow; these are the main channels by which metabolic waste is cleared. This review addresses possible links between mTBI-related damage to glymphatic functioning and physiological changes found in CTE, and proposes a model for the mediating role of sleep disruption in increasing the risk for developing CTE-related pathology and subsequent clinical symptoms following repetitive brain trauma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Dissociable brain systems mediate vicarious learning of stimulus-response and action-outcome contingencies.

    Science.gov (United States)

    Liljeholm, Mimi; Molloy, Ciara J; O'Doherty, John P

    2012-07-18

    Two distinct strategies have been suggested to support action selection in humans and other animals on the basis of experiential learning: a goal-directed strategy that generates decisions based on the value and causal antecedents of action outcomes, and a habitual strategy that relies on the automatic elicitation of actions by environmental stimuli. In the present study, we investigated whether a similar dichotomy exists for actions that are acquired vicariously, through observation of other individuals rather than through direct experience, and assessed whether these strategies are mediated by distinct brain regions. We scanned participants with functional magnetic resonance imaging while they performed an observational learning task designed to encourage either goal-directed encoding of the consequences of observed actions, or a mapping of observed actions to conditional discriminative cues. Activity in different parts of the action observation network discriminated between the two conditions during observational learning and correlated with the degree of insensitivity to outcome devaluation in subsequent performance. Our findings suggest that, in striking parallel to experiential learning, neural systems mediating the observational acquisition of actions may be dissociated into distinct components: a goal-directed, outcome-sensitive component and a less flexible stimulus-response component.

  18. GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain.

    Science.gov (United States)

    Reddy, Doodipala Samba

    2018-01-01

    Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus. Recently, a consensus neurosteroid pharmacophore model has been proposed at extrasynaptic δGABA-A receptors based on structure-activity relationship for functional activation of tonic currents and seizure protection. Aside from anticonvulsant actions, neurosteroids have been found to be powerful anxiolytic and anesthetic agents. Neurosteroids and Zn 2+ have preferential affinity for δ-containing receptors. Thus, Zn 2+ can prevent neurosteroid activation of extrasynaptic δGABA-A receptor-mediated tonic inhibition. Recently, we demonstrated that Zn 2+ selectively inhibits extrasynaptic δGABA-A receptors and thereby fully prevents AP activation of tonic inhibition and seizure protection. We confirmed that neurosteroids exhibit greater sensitivity at extrasynaptic δGABA-A receptors. Overall, extrasynaptic GABA-A receptors are primary mediators of tonic inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurological disorders. © 2018 Elsevier Inc. All rights reserved.

  19. Symptom severity and life satisfaction in brain injury: The mediating role of disability acceptance and social self-efficacy.

    Science.gov (United States)

    Ditchman, Nicole; Sung, Connie; Easton, Amanda B; Johnson, Kristina S; Batchos, Elisabeth

    2017-01-01

    Although the negative impact of symptom severity on subjective well-being outcomes has been established among individuals with brain injury, the mediating and protective role that positive human traits might have on this relationship has not been adequately explored. The purpose of this study was to examine the impact of social self-efficacy and disability acceptance on the relationship between symptom severity and life satisfaction among individuals with brain injury. Hierarchical regression analysis and correlation techniques were used to test a hypothesized dual-mediation model of life satisfaction in a sample of 105 adults with acquired brain injury. Results indicated that social self-efficacy and disability acceptance fully mediated the relationship between symptom severity and life satisfaction, lending support for a dual-mediation model with disability acceptance being the strongest contributor. These findings suggest there may be considerable value for rehabilitation providers to develop strengths-based service strategies and/or specialized intervention programs that focus on capitalizing these positive human traits to promote life satisfaction and well-being for clients with brain injury. Implications for clinical practice and future research direction are also discussed.

  20. Nanoparticle-mediated transcriptional modification enhances neuronal differentiation of human neural stem cells following transplantation in rat brain.

    Science.gov (United States)

    Li, Xiaowei; Tzeng, Stephany Y; Liu, Xiaoyan; Tammia, Markus; Cheng, Yu-Hao; Rolfe, Andrew; Sun, Dong; Zhang, Ning; Green, Jordan J; Wen, Xuejun; Mao, Hai-Quan

    2016-04-01

    Strategies to enhance survival and direct the differentiation of stem cells in vivo following transplantation in tissue repair site are critical to realizing the potential of stem cell-based therapies. Here we demonstrated an effective approach to promote neuronal differentiation and maturation of human fetal tissue-derived neural stem cells (hNSCs) in a brain lesion site of a rat traumatic brain injury model using biodegradable nanoparticle-mediated transfection method to deliver key transcriptional factor neurogenin-2 to hNSCs when transplanted with a tailored hyaluronic acid (HA) hydrogel, generating larger number of more mature neurons engrafted to the host brain tissue than non-transfected cells. The nanoparticle-mediated transcription activation method together with an HA hydrogel delivery matrix provides a translatable approach for stem cell-based regenerative therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Social Competence in Childhood Brain Tumor Survivors: Feasibility and Preliminary Outcomes of a Peer-Mediated Intervention

    Science.gov (United States)

    Devine, Katie A.; Bukowski, William M.; Sahler, Olle Jane Z.; Ohman-Strickland, Pamela; Smith, Tristram H.; Lown, E. Anne; Patenaude, Andrea Farkas; Korones, David N.; Noll, Robert B.

    2016-01-01

    Objective Evaluate the acceptability, feasibility, and preliminary outcomes of a peer-mediated intervention to improve social competence of brain tumor survivors and classmates. Methods Twelve childhood brain tumor survivors and 217 classroom peers in intervention (n = 8) or comparison (n = 4) classrooms completed measures of social acceptance and reputation at two time points in the year. The intervention (5–8 sessions over 4–6 weeks) taught peer leaders skills for engaging classmates. Individual and classroom outcomes were analyzed with ANCOVA. Results Recruitment rates of families of brain tumor survivors (81%) and schools (100%) were adequate. Peer leaders reported satisfaction with the intervention. Preliminary outcome data trended toward some benefit in increasing the number of friend nominations for survivors of brain tumors but no changes in other peer-reported metrics. Preliminary results also suggested some positive effects on classroom levels of victimization and rejection. Conclusions A peer-mediated intervention was acceptable to families of brain tumor survivors and feasible to implement in schools. Findings warrant a larger trial to evaluate improvements for children with brain tumors and their peers. PMID:27355881

  2. Refugee flow or brain-drain? The humanitarian policy and post-Tiananmen mainland Chinese immigration to Canada.

    Science.gov (United States)

    Liu X-f

    1997-03-01

    "The humanitarian policy that the Canadian government implemented in response to the 1989 Tiananmen Square crackdown changed a migration system primarily based on personal networks into a brain drain. Post-Tiananmen mainland Chinese immigrants (MCIs) were better educated than those arriving in Canada previously. Among the post-Tiananmen MCIs, those who landed under the policy were better educated than those landing in other categories. The analysis suggests that post-Tiananmen MCIs represented a brain-drain rather than a refugee flow, that the humanitarian policy implicitly contained ideological and human capital concerns in addition to humanitarian concerns, and that Canada benefited from the policy by obtaining human capital as well as satisfying its humanitarian obligations and ideological aspirations." excerpt

  3. Mapping glucose-mediated gut-to-brain signalling pathways in humans.

    Science.gov (United States)

    Little, Tanya J; McKie, Shane; Jones, Richard B; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G; McLaughlin, John T

    2014-08-01

    Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. Copyright © 2014. Published by Elsevier Inc.

  4. Mapping glucose-mediated gut-to-brain signalling pathways in humans☆

    Science.gov (United States)

    Little, Tanya J.; McKie, Shane; Jones, Richard B.; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G.; McLaughlin, John T.

    2014-01-01

    Objectives Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental design Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250 ml) of: 1 M glucose + predosing with dexloxiglumide (CCK1 receptor antagonist), 1 M glucose + placebo, or 0.9% saline (control) + placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observations Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose + dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Conclusions Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. PMID:24685436

  5. Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery.

    Science.gov (United States)

    Volak, Adrienn; LeRoy, Stanley G; Natasan, Jeya Shree; Park, David J; Cheah, Pike See; Maus, Andreas; Fitzpatrick, Zachary; Hudry, Eloise; Pinkham, Kelsey; Gandhi, Sheetal; Hyman, Bradley T; Mu, Dakai; GuhaSarkar, Dwijit; Stemmer-Rachamimov, Anat O; Sena-Esteves, Miguel; Badr, Christian E; Maguire, Casey A

    2018-05-16

    The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.

  6. Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain.

    Science.gov (United States)

    Wu, Shih-Ying; Chen, Cherry C; Tung, Yao-Sheng; Olumolade, Oluyemi O; Konofagou, Elisa E

    2015-08-28

    Lipid-shelled microbubbles have been used in ultrasound-mediated drug delivery. The physicochemical properties of the microbubble shell could affect the delivery efficiency since they determine the microbubble mechanical properties, circulation persistence, and dissolution behavior during cavitation. Therefore, the aim of this study was to investigate the shell effects on drug delivery efficiency in the brain via blood-brain barrier (BBB) opening in vivo using monodisperse microbubbles with different phospholipid shell components. The physicochemical properties of the monolayer were varied by using phospholipids with different hydrophobic chain lengths (C16, C18, and C24). The dependence on the molecular size and acoustic energy (both pressure and pulse length) were investigated. Our results showed that a relatively small increase in the microbubble shell rigidity resulted in a significant increase in the delivery of 40-kDa dextran, especially at higher pressures. Smaller (3kDa) dextran did not show significant difference in the delivery amount, suggesting that the observed shell effect was molecular size-dependent. In studying the impact of acoustic energy on the shell effects, it was found that they occurred most significantly at pressures causing microbubble destruction (450kPa and 600kPa); by increasing the pulse length to deliver the 40-kDa dextran, the difference between C16 and C18 disappeared while C24 still achieved the highest delivery efficiency. These indicated that the acoustic energy could be used to modulate the shell effects. The acoustic cavitation emission revealed the physical mechanisms associated with different shells. Overall, lipid-shelled microbubbles with long hydrophobic chain length could achieve high delivery efficiency for larger molecules especially with high acoustic energy. Our study, for the first time, offered evidence directly linking the microbubble monolayer shell with their efficacy for drug delivery in vivo. Copyright © 2015

  7. Characterization of GABA/sub A/ receptor-mediated 36chloride uptake in rat brain synaptoneurosomes

    International Nuclear Information System (INIS)

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-01-01

    γ-Aminobutyric acid (GABA) receptor-mediated 36 chloride ( 36 Cl - ) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36 Cl - uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36 Cl - uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36 Cl - uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br - >Cl - ≥NO 3 - >I - ≥SCN - >>C 3 H 5 OO - ≥ClO 4 - >F - , consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl - channel. 43 references, 4 figures, 3 tables

  8. The Politics of the Great Brain Race: Public Policy and International Student Recruitment in Australia, Canada, England and the USA

    Science.gov (United States)

    Sá, Creso M.; Sabzalieva, Emma

    2018-01-01

    As the number of globally mobile students has expanded, governments are assumed to be consistently and intentionally competing for talent, in what has been called a "great brain race". While the notion of competition has become dominant, there is little evidence on long-term policy dynamics in this field, not only across jurisdictions…

  9. Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model.

    Directory of Open Access Journals (Sweden)

    Habib Baghirov

    Full Text Available The treatment of brain diseases is hindered by the blood-brain barrier (BBB preventing most drugs from entering the brain. Focused ultrasound (FUS with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma.

  10. Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

    Science.gov (United States)

    Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

    2018-01-01

    The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

  11. HMGB1 mediates endogenous TLR2 activation and brain tumor regression.

    Directory of Open Access Journals (Sweden)

    James F Curtin

    2009-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive primary brain tumor that carries a 5-y survival rate of 5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, which is due to brain immune privilege, tumor immune evasion, and a paucity of dendritic cells (DCs within the central nervous system. Herein we uncovered a novel pathway for the activation of an effective anti-GBM immune response mediated by high-mobility-group box 1 (HMGB1, an alarmin protein released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2 signaling on bone marrow-derived GBM-infiltrating DCs.Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad expressing Fms-like tyrosine kinase 3 ligand (Flt3L and thymidine kinase (TK delivered into the tumor mass, we demonstrated that CD4(+ and CD8(+ T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. We then proceeded to identify the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating mDCs. We demonstrated that HMGB1 was released from dying tumor cells, in response to Ad-TK (+ gancyclovir [GCV] treatment. Increased levels of HMGB1 were also detected in the serum of tumor-bearing Ad-Flt3L/Ad-TK (+GCV-treated mice. Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti

  12. Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport

    International Nuclear Information System (INIS)

    Kumagai, A.K.; Eisenberg, J.B.; Pardridge, W.M.

    1987-01-01

    Cationized albumin (pI greater than 8), unlike native albumin (pI approximately 4), enters cerebrospinal fluid (CSF) rapidly from blood. This suggests that a specific uptake mechanism for cationized albumin may exist at the brain capillary wall, i.e. the blood-brain barrier. Isolated bovine brain capillaries rapidly bound cationized [ 3 H]albumin and approximately 70% of the bound radioactivity was resistant to mild acid wash, which is assumed to represent internalized peptide. Binding was saturable and a Scatchard plot gave a maximal binding capacity (Ro) = 5.5 +/- 0.7 micrograms/mgp (79 +/- 10 pmol/mgp), and a half-saturation constant (KD) = 55 +/- 8 micrograms/ml (0.8 +/- 0.1 microM). The binding of cationized [ 3 H]albumin (pI = 8.5-9) was inhibited by protamine, protamine sulfate, and polylysine (molecular weight = 70,000) with a Ki of approximately 3 micrograms/ml for all three proteins. The use of cationized albumin in directed delivery of peptides through the blood-brain barrier was examined by coupling [ 3 H]beta-endorphin to unlabeled cationized albumin (pI = 8.5-9) using the bifunctional reagent, N-succinimidyl 3-(2-pyridyldithio)proprionate. The [ 3 H]beta-endorphin-cationized albumin chimeric peptide was rapidly bound and endocytosed by isolated bovine brain capillaries, and this was inhibited by unlabeled cationized albumin but not by unconjugated beta-endorphin or native bovine albumin. Cationized albumin provides a new tool for studying absorptive-mediated endocytosis at the brain capillary and may also provide a vehicle for directed drug delivery through the blood-brain barrier

  13. Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport

    Energy Technology Data Exchange (ETDEWEB)

    Kumagai, A.K.; Eisenberg, J.B.; Pardridge, W.M.

    1987-11-05

    Cationized albumin (pI greater than 8), unlike native albumin (pI approximately 4), enters cerebrospinal fluid (CSF) rapidly from blood. This suggests that a specific uptake mechanism for cationized albumin may exist at the brain capillary wall, i.e. the blood-brain barrier. Isolated bovine brain capillaries rapidly bound cationized (/sup 3/H)albumin and approximately 70% of the bound radioactivity was resistant to mild acid wash, which is assumed to represent internalized peptide. Binding was saturable and a Scatchard plot gave a maximal binding capacity (Ro) = 5.5 +/- 0.7 micrograms/mgp (79 +/- 10 pmol/mgp), and a half-saturation constant (KD) = 55 +/- 8 micrograms/ml (0.8 +/- 0.1 microM). The binding of cationized (/sup 3/H)albumin (pI = 8.5-9) was inhibited by protamine, protamine sulfate, and polylysine (molecular weight = 70,000) with a Ki of approximately 3 micrograms/ml for all three proteins. The use of cationized albumin in directed delivery of peptides through the blood-brain barrier was examined by coupling (/sup 3/H)beta-endorphin to unlabeled cationized albumin (pI = 8.5-9) using the bifunctional reagent, N-succinimidyl 3-(2-pyridyldithio)proprionate. The (/sup 3/H)beta-endorphin-cationized albumin chimeric peptide was rapidly bound and endocytosed by isolated bovine brain capillaries, and this was inhibited by unlabeled cationized albumin but not by unconjugated beta-endorphin or native bovine albumin. Cationized albumin provides a new tool for studying absorptive-mediated endocytosis at the brain capillary and may also provide a vehicle for directed drug delivery through the blood-brain barrier.

  14. The brain cytoplasmic RNA BC1 regulates dopamine D-2 receptor-mediated transmission in the striatum

    OpenAIRE

    Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; De Chiara, Valentina; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

    2007-01-01

    Dopamine D-2 receptor (D2DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D-2 receptors in this brain area are essentially obscure. We have studied the physiological responses of the D2DR stimulations in mice...

  15. Mediatization

    DEFF Research Database (Denmark)

    Hjarvard, Stig

    2017-01-01

    Mediatization research shares media effects studies' ambition of answering the difficult questions with regard to whether and how media matter and influence contemporary culture and society. The two approaches nevertheless differ fundamentally in that mediatization research seeks answers...... to these general questions by distinguishing between two concepts: mediation and mediatization. The media effects tradition generally considers the effects of the media to be a result of individuals being exposed to media content, i.e. effects are seen as an outcome of mediated communication. Mediatization...... research is concerned with long-term structural changes involving media, culture, and society, i.e. the influences of the media are understood in relation to how media are implicated in social and cultural changes and how these processes come to create new conditions for human communication and interaction...

  16. Proinflammatory Adhesion Molecules Facilitate Polychlorinated Biphenyl–Mediated Enhancement of Brain Metastasis Formation

    OpenAIRE

    Sipos, Eszter; Chen, Lei; András, Ibolya E.; Wrobel, Jagoda; Zhang, Bei; Pu, Hong; Park, Minseon; Eum, Sung Yong; Toborek, Michal

    2012-01-01

    Polychlorinated biphenyls (PCBs) are environmental toxicants that cause vascular inflammation and facilitate the development of brain metastases. The crucial event in metastasis formation is adhesion of blood-borne tumor cells to the vascular endothelium, followed by their transcapillary migration. The aim of the present study was to examine the mechanisms of PCB118-induced brain metastasis formation at the blood-brain barrier level with the focus on tumor cell adhesion to the brain endotheli...

  17. The effects of poverty on childhood brain development: the mediating effect of caregiving and stressful life events.

    Science.gov (United States)

    Luby, Joan; Belden, Andy; Botteron, Kelly; Marrus, Natasha; Harms, Michael P; Babb, Casey; Nishino, Tomoyuki; Barch, Deanna

    2013-12-01

    IMPORTANCE The study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This study was conducted at an academic research unit at the Washington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of a magnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to-needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of children's white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained using magnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain

  18. Expression of Shiga toxin 2e glycosphingolipid receptors of primary porcine brain endothelial cells and toxin-mediated breakdown of the blood-brain barrier.

    Science.gov (United States)

    Meisen, Iris; Rosenbrück, Regina; Galla, Hans-Joachim; Hüwel, Sabine; Kouzel, Ivan U; Mormann, Michael; Karch, Helge; Müthing, Johannes

    2013-06-01

    Shiga toxin (Stx) 2e, released by certain Stx-producing Escherichia coli, is presently the best characterized virulence factor responsible for pig edema disease, which is characterized by hemorrhagic lesions, neurological disorders and often fatal outcomes. Although Stx2e-mediated brain vascular injury is the key event in development of neurologic signs, the glycosphingolipid (GSL) receptors of Stx2e and toxin-mediated impairment of pig brain endothelial cells have not been investigated so far. Here, we report on the detailed structural characterization of Stx2e receptors globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), which make up the major neutral GSLs in primary porcine brain capillary endothelial cells (PBCECs). Various Gb3Cer and Gb4Cer lipoforms harboring sphingenine (d18:1) or sphinganine (d18:0) and mostly a long-chain fatty acid (C20-C24) were detected. A notable batch-to-batch heterogeneity of primary endothelial cells was observed regarding the extent of ceramide hydroxylation of Gb3Cer or Gb4Cer species. Gb3Cer, Gb4Cer and sphingomyelin preferentially distribute to detergent-resistant membrane fractions and can be considered lipid raft markers in PBCECs. Moreover, we employed an in vitro model of the blood-brain barrier (BBB), which exhibited strong cytotoxic effects of Stx2e on the endothelial monolayer and a rapid collapse of the BBB. These data strongly suggest the involvement of Stx2e in cerebral vascular damage with resultant neurological disturbance characteristic of edema disease.

  19. Teacher Verbal Aggressiveness and Credibility Mediate the Relationship between Teacher Technology Policies and Perceived Student Learning

    Science.gov (United States)

    Finn, Amber N.; Ledbetter, Andrew M.

    2014-01-01

    In this study, we extend previous work on teacher technology policies by refining the teacher technology policies instrument to account for the technology purpose (social, academic) and type (cell phone, laptop/tablet), and examine a model of teacher technology policies and perceived learning. We found that students are more sensitive to policies…

  20. Nonspatial intermodal selective attention is mediated by sensory brain brain areas: Evidence from event-related potential.

    NARCIS (Netherlands)

    Talsma, D.; Kok, A.

    2001-01-01

    Focuses on the question of whether inter-and intramodal forms of attention are reflected in activation of the same or different brain areas. ERPs were recorded while Ss (aged 18-41 yrs) were presented a random sequence of visual and auditory stimuli. They were instructed to attend to nonspatial

  1. Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.

    Science.gov (United States)

    Baumann, Michael H; Bulling, Simon; Benaderet, Tova S; Saha, Kusumika; Ayestas, Mario A; Partilla, John S; Ali, Syed F; Stockner, Thomas; Rothman, Richard B; Sandtner, Walter; Sitte, Harald H

    2014-05-01

    Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.

  2. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia

    Science.gov (United States)

    2013-01-01

    Background Hypoxia induces microglial activation which causes damage to the developing brain. Microglia derived inflammatory mediators may contribute to this process. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation and cytokines production in brain injuries; however, its role in hypoxic injury remains uncertain. We investigate here TLR4 expression and its roles in neuroinflammation in neonatal rats following hypoxic injury. Methods One day old Wistar rats were subjected to hypoxia for 2 h. Primary cultured microglia and BV-2 cells were subjected to hypoxia for different durations. TLR4 expression in microglia was determined by RT-PCR, western blot and immunofluorescence staining. Small interfering RNA (siRNA) transfection and antibody neutralization were employed to downregulate TLR4 in BV-2 and primary culture. mRNA and protein expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS) was assessed. Reactive oxygen species (ROS), nitric oxide (NO) and NF-κB levels were determined by flow cytometry, colorimetric and ELISA assays respectively. Hypoxia-inducible factor-1 alpha (HIF-1α) mRNA and protein expression was quantified and where necessary, the protein expression was depleted by antibody neutralization. In vivo inhibition of TLR4 with CLI-095 injection was carried out followed by investigation of inflammatory mediators expression via double immunofluorescence staining. Results TLR4 immunofluorescence and protein expression in the corpus callosum and cerebellum in neonatal microglia were markedly enhanced post-hypoxia. In vitro, TLR4 protein expression was significantly increased in both primary microglia and BV-2 cells post-hypoxia. TLR4 neutralization in primary cultured microglia attenuated the hypoxia-induced expression of TNF-α, IL-1β and iNOS. siRNA knockdown of TLR4 reduced hypoxia-induced upregulation of TNF-α, IL-1β, iNOS, ROS and NO in BV-2 cells. TLR4

  3. Neuropeptides as mediators of the early-life impact on the brain; implications for alcohol use disorders

    Directory of Open Access Journals (Sweden)

    Ingrid eNylander

    2012-07-01

    Full Text Available The brain is constantly exposed to external and internal input and to function in an ever-changing environment we are dependent on processes that enable the brain to adapt to new stimuli. Exposure to postnatal environmental stimuli can interfere with vital adaption processes and cause long-term changes in physiological function and behaviour. Early-life alterations in brain function may result in impaired ability to adapt to new situations, in altered sensitivity to challenges later in life and thereby mediate risk or protection for psychopathology such as alcohol use disorders (AUD. In clinical research the studies of mechanisms, mediators and causal relation between early environmental factors and vulnerability to AUD are restricted and attempts are made to find valid animal models for studies of the early-life influence on the brain. This review focuses on rodent models and the effects of adverse and naturalistic conditions on peptide networks within the brain and pituitary gland. Importantly, the consequences of alcohol addiction are not discussed but rather neurobiological alterations that can cause risk consumption and vulnerability to addiction. The article reviews earlier results and includes new data with emphasis on endogenous opioid peptides but also oxytocin and vasopressin. These peptides are vital for developmental processes and it is hypothesized that early-life changes in peptide networks may interfere with neuronal processes and thereby contribute the individual vulnerability for AUD. The summarized results indicate a link between early-life rearing conditions, opioids and ethanol consumption and that the ethanol-induced effects and the treatment with opioid antagonists later in life are dependent on early-life experiences. Endogenous opioids are therefore of interest to further study in the early-life impact on individual differences in vulnerability to AUD and treatment outcome.

  4. Reorganization of functional brain networks mediates the improvement of cognitive performance following real-time neurofeedback training of working memory.

    Science.gov (United States)

    Zhang, Gaoyan; Yao, Li; Shen, Jiahui; Yang, Yihong; Zhao, Xiaojie

    2015-05-01

    Working memory (WM) is essential for individuals' cognitive functions. Neuroimaging studies indicated that WM fundamentally relied on a frontoparietal working memory network (WMN) and a cinguloparietal default mode network (DMN). Behavioral training studies demonstrated that the two networks can be modulated by WM training. Different from the behavioral training, our recent study used a real-time functional MRI (rtfMRI)-based neurofeedback method to conduct WM training, demonstrating that WM performance can be significantly improved after successfully upregulating the activity of the target region of interest (ROI) in the left dorsolateral prefrontal cortex (Zhang et al., [2013]: PloS One 8:e73735); however, the neural substrate of rtfMRI-based WM training remains unclear. In this work, we assessed the intranetwork and internetwork connectivity changes of WMN and DMN during the training, and their correlations with the change of brain activity in the target ROI as well as with the improvement of post-training behavior. Our analysis revealed an "ROI-network-behavior" correlation relationship underlying the rtfMRI training. Further mediation analysis indicated that the reorganization of functional brain networks mediated the effect of self-regulation of the target brain activity on the improvement of cognitive performance following the neurofeedback training. The results of this study enhance our understanding of the neural basis of real-time neurofeedback and suggest a new direction to improve WM performance by regulating the functional connectivity in the WM related networks. © 2014 Wiley Periodicals, Inc.

  5. GLUT2-mediated glucose uptake and availability are required for embryonic brain development in zebrafish.

    Science.gov (United States)

    Marín-Juez, Rubén; Rovira, Mireia; Crespo, Diego; van der Vaart, Michiel; Spaink, Herman P; Planas, Josep V

    2015-01-01

    Glucose transporter 2 (GLUT2; gene name SLC2A2) has a key role in the regulation of glucose dynamics in organs central to metabolism. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, its role in the brain is not well understood. To decipher the role of GLUT2 in brain development, we knocked down slc2a2 (glut2), the functional ortholog of human GLUT2, in zebrafish. Abrogation of glut2 led to defective brain organogenesis, reduced glucose uptake and increased programmed cell death in the brain. Coinciding with the observed localization of glut2 expression in the zebrafish hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a but not those expressing neurod. Specificity of the morphant phenotype was demonstrated by the restoration of brain organogenesis, whole-embryo glucose uptake, brain apoptosis, and expression of proneural markers in rescue experiments. These results indicate that glut2 has an essential role during brain development by facilitating the uptake and availability of glucose and support the involvement of glut2 in brain glucose sensing.

  6. Socialization of prosocial behavior: Gender differences in the mediating role of child brain volume

    NARCIS (Netherlands)

    R. Kok (Renske); P.J. Prinzie (Peter); M.J. Bakermans-Kranenburg (Marian); F.C. Verhulst (Frank); T.J.H. White (Tonya); H.W. Tiemeier (Henning); M.H. van IJzendoorn (Rien)

    2017-01-01

    textabstractEvidence has been accumulating for the impact of normal variation in caregiving quality on brain morphology in children, but the question remains whether differences in brain volume related to early caregiving translate to behavioral implications. In this longitudinal population-based

  7. Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

    Czech Academy of Sciences Publication Activity Database

    Zakharov, S.; Kotíková, K.; Nurieva, O.; Hlušička, J.; Kačer, P.; Urban, P.; Vaněčková, M.; Seidl, Z.; Diblík, P.; Kuthan, P.; Navrátil, Tomáš; Pelclová, D.

    2017-01-01

    Roč. 55, č. 4 (2017), s. 249-259 ISSN 1556-3650 Institutional support: RVO:61388955 Keywords : brain damage * leukotrienes * methanol poisoning * Neuroinflammation * nontraumatic brain injury * sequelae of poisoning Subject RIV: CG - Electrochemistry OBOR OECD: Electrochemistry (dry cells, batteries, fuel cells, corrosion metals, electrolysis) Impact factor: 3.677, year: 2016

  8. Ultrasound-mediated drug delivery to the brain: principles, progress and prospects

    NARCIS (Netherlands)

    Dasgupta, I.; Liu, M.; Ojha, T.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

    2016-01-01

    The blood–brain barrier (BBB) limits drug delivery to the central nervous system. When combined with microbubbles, ultrasound can transiently permeate blood vessels in the brain. This approach, which can be referred to as sonoporation or sonopermeabilization, holds significant promise for shuttling

  9. Mediated Ciphertext-Policy Attribute-Based Encryption and Its Application

    NARCIS (Netherlands)

    Ibraimi, L.; Petkovic, M.; Nikova, S.I.; Hartel, Pieter H.; Jonker, Willem; Youm, Heung Youl; Yung, Moti

    2009-01-01

    In Ciphertext-Policy Attribute-Based Encryption (CP-ABE), a user secret key is associated with a set of attributes, and the ciphertext is associated with an access policy over attributes. The user can decrypt the ciphertext if and only if the attribute set of his secret key satisfies the access

  10. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation.

    Directory of Open Access Journals (Sweden)

    Kirsten Ridder

    2014-06-01

    Full Text Available Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.

  11. Antioxidant mediated response of Scoparia dulcis in noise-induced redox imbalance and immunohistochemical changes in rat brain.

    Science.gov (United States)

    Wankhar, Wankupar; Srinivasan, Sakthivel; Rajan, Ravindran; Sheeladevi, Rathinasamy

    2017-01-19

    Noise has been regarded as an environmental/occupational stressor that causes damages to both auditory and non-auditory organs. Prolonged exposure to these mediators of stress has often resulted in detrimental effect, where oxidative/nitrosative stress plays a major role. Hence, it would be appropriate to examine the possible role of free radicals in brain discrete regions and the "antioxidants" mediated response of S. dulcis. Animals were subjected to noise stress for 15 days (100 dB/4 hours/day) and estimation of endogenous free radical and antioxidant activity were carried out on brain discrete regions (the cerebral cortex, cerebellum, brainstem, striatum, hippocampus and hypothalamus). The result showed that exposure to noise could alleviate endogenous free radical generation and altered antioxidant status in brain discrete regions when compared to that of the control groups. This alleviated free radical generation (H 2 O 2 and NO) is well supported by an upregulated protein expression on immunohistochemistry of both iNOS and nNOS in the cerebral cortex on exposure to noise stress. These findings suggest that increased free radical generation and altered anti-oxidative status can cause redox imbalance in the brain discrete regions. However, free radical scavenging activity of the plant was evident as the noise exposed group treated with S. dulcis[200 mg/(kg·b·w)] displayed a therapeutic effect by decreasing the free radical level and regulate the anti-oxidative status to that of control animals. Hence, it can be concluded that the efficacy of S. dulcis could be attributed to its free radical scavenging activity and anti-oxidative property.

  12. Salt-Induced Hypertension in a Mouse Model of Liddle's Syndrome is Mediated by Epithelial Sodium Channels in the Brain

    Science.gov (United States)

    Van Huysse, James W.; Amin, Md. Shahrier; Yang, Baoli; Leenen, Frans H. H.

    2012-01-01

    Neural precursor cell expressed and developmentally downregulated 4-2 protein (Nedd4-2) facilitates the endocytosis of epithelial Na channels (ENaC). Both mice and humans with a loss of regulation of ENaC by Nedd4-2 have salt-induced hypertension. ENaC is also expressed in the brain, where it is critical for hypertension on high salt diet in salt-sensitive rats. In the present studies we assessed whether Nedd4-2 knockout (−/−) mice have: 1) increased brain ENaC; 2) elevated CSF sodium on high salt diet; and 3) enhanced pressor responses to CSF sodium and hypertension on high salt diet, both mediated by brain ENaC. Prominent choroid plexus and neuronal ENaC staining was present in −/− but not in wild-type (W/T) mice. In chronically instrumented mice, intracerebroventricular (icv) infusion of Na-rich aCSF increased MAP 3-fold higher in −/− than W/T. Icv infusion of the ENaC blocker benzamil abolished this enhancement. In telemetered −/− mice on high salt diet (8% NaCl), CSF [Na+], MAP and HR increased significantly, MAP by 30-35 mmHg. These MAP and HR responses were largely prevented by icv benzamil, but only to a minor extent by sc benzamil at the icv rate. We conclude that increased ENaC expression in the brain of Nedd 4-2 −/− mice mediates their hypertensive response to high salt diet, by causing increased sodium levels in the CSF as well as hyper-responsiveness to CSF sodium. These findings highlight the possible causative contribution of CNS ENaC in the etiology of salt-induced hypertension. PMID:22802227

  13. Turning brain drain into brain circulation. Immigration policies can be a ticket for scientific talent to recirculate among countries

    International Nuclear Information System (INIS)

    Parthasarathi, A.

    2006-01-01

    In the 1960s and 1970s, the flow of scientists, engineers and medical personnel from developing to industrialised nations was thought to have almost entirely negative consequences for the source countries, affecting their university staffing and availability of industrial personnel. Recently, however, there has been growing emphasis on reverse flows of knowledge and skills, and of money the migrants send home. What was once termed brain drain is now seen as brain circulation, but this has blurred important issues affecting most developing countries. Countries can benefit when emigrants return home with accumulated skills and experience. But a large part of the evidence for this comes from the experiences of South Korea and Taiwan, China. There, returning emigrants were attracted to fill key roles in what were already advanced research and development environments. In other words, the pre-existence of considerable 'absorptive capacity' appears to be a necessary condition for significant reverse migration

  14. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum.

    Science.gov (United States)

    Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; De Chiara, Valentina; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

    2007-08-15

    Dopamine D(2) receptor (D(2)DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D(2) receptors in this brain area are essentially obscure. We have studied the physiological responses of the D(2)DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D(2)-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D(2) receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB(1) receptors was intact in the striatum of BC1 knock-out (KO) mice despite D(2) and CB(1) receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D(2)-mediated transmission. Because D(2)DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D(2)DR indirectly, probably regulating translation of molecules involved in D(2)DR turnover and/or stability.

  15. Adeno-associated virus vector-mediated transduction in the cat brain.

    Science.gov (United States)

    Vite, Charles H; Passini, Marco A; Haskins, Mark E; Wolfe, John H

    2003-10-01

    Adeno-associated virus (AAV) vectors are capable of delivering a therapeutic gene to the mouse brain that can result in long-term and widespread protein production. However, the human infant brain is more than 1000 times larger than the mouse brain, which will make the treatment of global neurometabolic disorders in children more difficult. In this study, we evaluated the ability of three AAV serotypes (1,2, and 5) to transduce cells in the cat brain as a model of a large mammalian brain. The human lysosomal enzyme beta-glucuronidase (GUSB) was used as a reporter gene, because it can be distinguished from feline GUSB by heat stability. The vectors were injected into the cerebral cortex, caudate nucleus, thalamus, corona radiata, internal capsule, and centrum semiovale of 8-week-old cats. The brains were evaluated for gene expression using in situ hybridization and enzyme histochemistry 10 weeks after surgery. The AAV2 vector was capable of transducing cells in the gray matter, while the AAV1 vector resulted in greater transduction of the gray matter than AAV2 as well as transduction of the white matter. AAV5 did not result in detectable transduction in the cat brain.

  16. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

    Science.gov (United States)

    Deane, Rashid; Singh, Itender; Sagare, Abhay P.; Bell, Robert D.; Ross, Nathan T.; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J.; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E.; Miller, Benjamin L.; Zlokovic, Berislav V.

    2012-01-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

  17. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    OpenAIRE

    Andreas Stengel; Yvette F. Taché; Yvette F. Taché

    2017-01-01

    Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a br...

  18. Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

    Science.gov (United States)

    Perneczky, R; Drzezga, A; Diehl-Schmid, J; Schmid, G; Wohlschläger, A; Kars, S; Grimmer, T; Wagenpfeil, S; Monsch, A; Kurz, A

    2006-09-01

    Functional imaging studies report that higher education is associated with more severe pathology in patients with Alzheimer's disease, controlling for disease severity. Therefore, schooling seems to provide brain reserve against neurodegeneration. To provide further evidence for brain reserve in a large sample, using a sensitive technique for the indirect assessment of brain abnormality (18F-fluoro-deoxy-glucose-positron emission tomography (FDG-PET)), a comprehensive measure of global cognitive impairment to control for disease severity (total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery) and an approach unbiased by predefined regions of interest for the statistical analysis (statistical parametric mapping (SPM)). 93 patients with mild Alzheimer's disease and 16 healthy controls underwent 18F-FDG-PET imaging of the brain. A linear regression analysis with education as independent and glucose utilisation as dependent variables, adjusted for global cognitive status and demographic variables, was conducted in SPM2. The regression analysis showed a marked inverse association between years of schooling and glucose metabolism in the posterior temporo-occipital association cortex and the precuneus in the left hemisphere. In line with previous reports, the findings suggest that education is associated with brain reserve and that people with higher education can cope with brain damage for a longer time.

  19. Cre Fused with RVG Peptide Mediates Targeted Genome Editing in Mouse Brain Cells In Vivo.

    Science.gov (United States)

    Zou, Zhiyuan; Sun, Zhaolin; Li, Pan; Feng, Tao; Wu, Sen

    2016-12-14

    Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. However, whether RVG can be used for genome editing in the brain has not been reported. In this work, we combined RVG with Cre recombinase for bacterial expression. The purified RVG-Cre protein cut plasmids in vitro and traversed cell membranes in cultured Neuro2a cells. By tail vein-injecting RVG-Cre into Cre reporter mouse lines mTmG and Rosa26 lacZ , we demonstrated that RVG-Cre could target brain cells and achieve targeted somatic genome editing in adult mice. This direct delivery of the gene-editing enzyme protein into mouse brains with RVG is much safer than plasmid- or viral-based methods, holding promise for further applications in the treatment of various brain diseases.

  20. [Paradoxical brain embolism mediated through a pulmonary arteriovenous malformation with hereditary hemorrhagic telangiectasia in a Japanese patient].

    Science.gov (United States)

    Takeda, June; Todo, Kenichi; Yamamoto, Shiro; Yamagami, Hiroshi; Kawamoto, Michi; Kohara, Nobuo

    2012-01-01

    We report a case of paradoxical brain embolism mediated through a pulmonary arteriovenous malformation (PAVM) with hereditary hemorrhagic telangiectasia (HHT). A 25-year-old right handed man was admitted to our hospital after sudden headache and visual field abnormality. In neurologic examinations, he had left superior-quadrantanopsia. Laboratory findings showed iron deficiency anemia. Diffusion weighted images disclosed a high-signal-intensity area in the right occipito-temporal lobe, and intraarterial digital subtraction cerebral angiography revealed occlusion of the right posterior cerebral artery. Transesophageal echocardiography revealed continuous right-to-left shunt. We confirmed his history of spontaneous recurrent epistaxis and the first-degree relatives with epistaxis or PAVM. A contrast enhanced CT scan of the chest revealed a PAVM. The diagnosis of paradoxical brain embolism mediated through the PAVM with HHT was, thus, established. The PAVM was occluded by using embolization coils successfully. In Asian countries, the prevalence of PAVM with HHT is thought to be lower than in European countries. We should carefully take medical and family histories, especially epistaxis, in a young stroke patient.

  1. Theory of mind mediates the prospective relationship between abnormal social brain network morphology and chronic behavior problems after pediatric traumatic brain injury.

    Science.gov (United States)

    Ryan, Nicholas P; Catroppa, Cathy; Beare, Richard; Silk, Timothy J; Crossley, Louise; Beauchamp, Miriam H; Yeates, Keith Owen; Anderson, Vicki A

    2016-04-01

    Childhood and adolescence coincide with rapid maturation and synaptic reorganization of distributed neural networks that underlie complex cognitive-affective behaviors. These regions, referred to collectively as the 'social brain network' (SBN) are commonly vulnerable to disruption from pediatric traumatic brain injury (TBI); however, the mechanisms that link morphological changes in the SBN to behavior problems in this population remain unclear. In 98 children and adolescents with mild to severe TBI, we acquired 3D T1-weighted MRIs at 2-8 weeks post-injury. For comparison, 33 typically developing controls of similar age, sex and education were scanned. All participants were assessed on measures of Theory of Mind (ToM) at 6 months post-injury and parents provided ratings of behavior problems at 24-months post-injury. Severe TBI was associated with volumetric reductions in the overall SBN package, as well as regional gray matter structural change in multiple component regions of the SBN. When compared with TD controls and children with milder injuries, the severe TBI group had significantly poorer ToM, which was associated with more frequent behavior problems and abnormal SBN morphology. Mediation analysis indicated that impaired theory of mind mediated the prospective relationship between abnormal SBN morphology and more frequent chronic behavior problems. Our findings suggest that sub-acute alterations in SBN morphology indirectly contribute to long-term behavior problems via their influence on ToM. Volumetric change in the SBN and its putative hub regions may represent useful imaging biomarkers for prediction of post-acute social cognitive impairment, which may in turn elevate risk for chronic behavior problems. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  2. [Liposome-mediated glial growth factor 2 gene therapy in brain injury: an experimental study with rats].

    Science.gov (United States)

    Xue, Ya-jun; Dong, Yan; Han, Xi; Wei, Mei-yang; Ge, Jun-hui; Cai, Ru-jue; Hu, Guo-han; Luo, Chun; Zhu, Cheng; Lu, Yi-cheng

    2006-09-05

    hippocampus of the treatment group was 102 +/- 11, significantly more than those of the vector control group and liposome group (67 +/- 8 and 58 +/- 9 respectively, both P < 0.01). Higher level of immunoreactivity with MBP was also detected in the cortex in the rats of the treatment group. Cationic liposome-mediated GGF2 gene therapy effectively promotes the recovery of brain injury.

  3. Optimism and the brain: trait optimism mediates the protective role of the orbitofrontal cortex gray matter volume against anxiety.

    Science.gov (United States)

    Dolcos, Sanda; Hu, Yifan; Iordan, Alexandru D; Moore, Matthew; Dolcos, Florin

    2016-02-01

    Converging evidence identifies trait optimism and the orbitofrontal cortex (OFC) as personality and brain factors influencing anxiety, but the nature of their relationships remains unclear. Here, the mechanisms underlying the protective role of trait optimism and of increased OFC volume against symptoms of anxiety were investigated in 61 healthy subjects, who completed measures of trait optimism and anxiety, and underwent structural scanning using magnetic resonance imaging. First, the OFC gray matter volume (GMV) was associated with increased optimism, which in turn was associated with reduced anxiety. Second, trait optimism mediated the relation between the left OFC volume and anxiety, thus demonstrating that increased GMV in this brain region protects against symptoms of anxiety through increased optimism. These results provide novel evidence about the brain-personality mechanisms protecting against anxiety symptoms in healthy functioning, and identify potential targets for preventive and therapeutic interventions aimed at reducing susceptibility and increasing resilience against emotional disturbances. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  4. Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

    Directory of Open Access Journals (Sweden)

    Brandi D Freeman

    2016-03-01

    Full Text Available Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

  5. Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain.

    Directory of Open Access Journals (Sweden)

    Hiroaki Mochizuki

    2011-05-01

    Full Text Available Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II, an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM and No distributive disjunction (Nod, remains unaltered. Genetic analyses of kinesin light chain (Klc and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations.Unc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of

  6. Silica nanoparticles mediated neuronal cell death in corpus striatum of rat brain: implication of mitochondrial, endoplasmic reticulum and oxidative stress

    Science.gov (United States)

    Parveen, Arshiya; Rizvi, Syed Husain Mustafa; Mahdi, Farzana; Tripathi, Sandeep; Ahmad, Iqbal; Shukla, Rajendra K.; Khanna, Vinay K.; Singh, Ranjana; Patel, Devendra K.; Mahdi, Abbas Ali

    2014-11-01

    Extensive uses of silica nanoparticles (SiNPs) in biomedical and industrial fields have increased the risk of exposure, resulting concerns about their safety. We focussed on some of the safety aspects by studying neurobehavioural impairment, oxidative stress (OS), neurochemical and ultrastructural changes in corpus striatum (CS) of male Wistar rats exposed to 80-nm SiNPs. Moreover, its role in inducing mitochondrial and endoplasmic reticulum (ER) stress-mediated neuronal apoptosis was also investigated. The results demonstrated impairment in neurobehavioural indices, and a significant increase in lipid peroxide levels (LPO), hydrogen peroxide (H2O2), superoxide (O2 -) and protein carbonyl content, whereas there was a significant decrease in the activities of the enzymes, manganese superoxide dismutase (Mn SOD), glutathione peroxidase (GPx), catalase (CAT) and reduced glutathione (GSH) content, suggesting impaired antioxidant defence system. Protein (cytochrome c, Bcl-2, Bax, p53, caspase-3, caspase 12 and CHOP/Gadd153) and mRNA (Bcl-2, Bax, p53 and CHOP/Gadd153, cytochrome c) expression studies of mitochondrial and ER stress-related apoptotic factors suggested that both the cell organelles were involved in OS-mediated apoptosis in treated rat brain CS. Moreover, electron microscopic studies clearly showed mitochondrial and ER dysfunction. In conclusion, the result of the study suggested that subchronic SiNPs' exposure has the potential to alter the behavioural activity and also to bring about changes in biochemical, neurochemical and ultrastructural profiles in CS region of rat brain. Furthermore, we also report SiNPs-induced apoptosis in CS, through mitochondrial and ER stress-mediated signalling.

  7. Does multitasking mediate the relationships between episodic memory, attention, executive functions and apathetic manifestations in traumatic brain injury?

    Science.gov (United States)

    Arnould, Annabelle; Rochat, Lucien; Dromer, Emilie; Azouvi, Philippe; Van der Linden, Martial

    2018-03-01

    Apathy is frequently described in patients with traumatic brain injury (TBI); its negative consequences particularly affect functional independence. Among apathetic manifestations, lack of initiative and lack of interest have mainly been associated with cognitive impairments. However, few studies have been conducted to precisely identify the underlying cognitive processes. Our aims were (1) to determine the best predictor of apathy from among several cognitive processes, including episodic memory and attention/executive mechanisms and multitasking, and (2) to examine to what extent multitasking could mediate the relationships between specific cognitive processes and lack of initiative/interest. Seventy participants (34 patients with TBI matched with 36 control participants) were given a questionnaire to assess anxio-depressive symptoms, four tasks to assess specific cognitive processes, and one task to assess real-life multitasking. Participants' relatives completed an apathy questionnaire. Multitasking, as assessed by the number of goals not achieved, was the only significant predictor of apathetic manifestations. In addition, the mediation analyses revealed that multitasking performance mediated the relationships between verbal episodic memory and lack of initiative/interest, whereas executive and attentional functions were only indirectly related to lack of initiative/interest due to their significant impacts on multitasking. These results shed new light on the aetiology of apathetic manifestations in patients with TBI, indicating how specific cognitive deficits are expressed in real-life multitasking, and consequently, how they may lead to the development and/or maintenance of apathetic manifestations. © 2016 The British Psychological Society.

  8. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    Directory of Open Access Journals (Sweden)

    Andreas Stengel

    2017-04-01

    Full Text Available Corticotropin-releasing factor (CRF is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  9. Local Irrigation Management Institutions Mediate Changes Driven by External Policy and Market Pressures in Nepal and Thailand

    Science.gov (United States)

    Bastakoti, Ram C.; Shivakoti, Ganesh P.; Lebel, Louis

    2010-09-01

    This article assesses the role of local institutions in managing irrigation water use. Fifty irrigation systems in each country were studied in Nepal and Thailand to compare the influence of local institutions on performance of irrigation systems amid changes in external policy and market pressures. Nepal’s new irrigation policy after the re-instatement of multiparty democracy in 1990 emphasized participatory irrigation management transferring the management responsibility from state authorities to water users. The water user associations of traditional farmer-managed irrigation systems were formally recognized by requiring registration with related state authorities. In Thailand also government policies encouraged people’s participation in irrigation management. Today water users are directly involved in management of even some large irrigation systems at the level of tertiary canals. Traditional communal irrigation systems in northern Thailand received support for system infrastructure improvement but have faced increased interference from government. In Thailand market development supported diversification in farming practices resulting in increased areas under high water-demanding commercial crops in the dry season. In contrast, the command areas of most irrigation systems in Nepal include cereal-based subsistence farming with only one-third having commercial farming. Cropping intensities are higher in Nepal than in Thailand reflecting, in part, differences in availability of land and management. In both countries local institutions play an important role in maintaining the performance of irrigation systems as external drivers and local contexts change. Local institutions have provided alternative options for irrigation water use by mediating external pressures.

  10. Mediating Policy-Relevant Evidence at Speed: Are Systematic Reviews of Systematic Reviews a Useful Approach?

    Science.gov (United States)

    Caird, Jenny; Sutcliffe, Katy; Kwan, Irene; Dickson, Kelly; Thomas, James

    2015-01-01

    When swift, accurate appraisal of evidence is required to inform policy concerning broad research questions, and budgetary constraints limit the employment of large research teams, researchers face a significant challenge which is sometimes met by reviewing existing systematic reviews. In this paper we highlight the challenges inherent in the…

  11. Literacy Assessment That Counts: Mediating, Interpreting and Contesting Translocal Policy in a Primary School

    Science.gov (United States)

    Kerkham, Lyn; Nixon, Helen

    2014-01-01

    In Australia, as in many western education systems over the last two decades, discourses of accountability and performativity have reshaped education policy that has in turn reorganised the work of school leaders and teachers. One of the effects of this reorganisation is increased attention to the production, analysis and display of student…

  12. Augmenting brain metabolism to increase macro- and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging.

    Science.gov (United States)

    Loos, Ben; Klionsky, Daniel J; Wong, Esther

    2017-09-01

    Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging. Mechanisms to enhance neuronal surveillance to improve neuronal proteostasis have a direct impact on promoting neuronal health and forestalling age-related decline in brain function. Autophagy is a lysosomal degradative pathway pivotal for neuronal protein quality control. Different types of autophagic mechanisms participate in protein handling in neurons. Macroautophagy targets misfolded and aggregated proteins in autophagic vesicles to the lysosomes for destruction, while chaperone-mediated autophagy (CMA) degrades specific soluble cytosolic proteins delivered to the lysosomes by chaperones. Dysfunctions in macroautophagy and CMA contribute to proteo- and neuro-toxicity associated with neurodegeneration and aging. Thus, augmenting or preserving both autophagic mechanisms pose significant benefits in delaying physiological and pathological neuronal demises. Recently, life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise have shown to enhance both autophagy and brain health. However, to what extent these interventions affect neuronal autophagy to promote brain fitness remains largely unclear. Here, we review the functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. In doing so, we provide novel insights and integrated evidence for a potential adjuvant therapeutic strategy to intervene in the neuronal decline in neurodegenerative diseases by controlling both macroautophagy and CMA fluxes favorably. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Role of Department of Defense Policies in Identifying Traumatic Brain Injuries Among Deployed US Service Members, 2001-2016.

    Science.gov (United States)

    Agimi, Yll; Regasa, Lemma Ebssa; Ivins, Brian; Malik, Saafan; Helmick, Katherine; Marion, Donald

    2018-05-01

    To examine the role of Department of Defense policies in identifying theater-sustained traumatic brain injuries (TBIs). We conducted a retrospective study of 48 172 US military service members who sustained their first lifetime TBIs between 2001 and 2016 while deployed to Afghanistan or Iraq. We used multivariable negative binomial models to examine the changes in TBI incidence rates following the introduction of Department of Defense policies. Two Army policies encouraging TBI reporting were associated with an increase of 251% and 97% in TBIs identified following their implementation, respectively. Among airmen, the introduction of TBI-specific screening questions to the Post-Deployment Health Assessment was associated with a 78% increase in reported TBIs. The 2010 Department of Defense Directive Type Memorandum 09-033 was associated with another increase of 80% in the likelihood of being identified with a TBI among soldiers, a 51% increase among sailors, and a 124% increase among Marines. Department of Defense and service-specific policies introduced between 2006 and 2013 significantly increased the number of battlefield TBIs identified, successfully improving the longstanding problem of underreporting of TBIs.

  14. Theranastic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, Gerrit; van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO)

  15. Theranostic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, G; Van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO)

  16. Nonspatial intermodal selective attention is mediated by sensory brain areas: Evidence from event-related potential.

    NARCIS (Netherlands)

    Talsma, D.; Kok, A.

    2001-01-01

    Focuses on the question of whether inter-and intramodal forms of attention are reflected in activation of the same or different brain areas. ERPs were recorded while Ss (aged 18-41 yrs) were presented a random sequence of visual and auditory stimuli. They were instructed to attend to nonspatial

  17. Nonspatial intermodal selective attention is mediated by sensory brain areas: Evidence from event-related potentials

    NARCIS (Netherlands)

    Talsma, D.; Kok, Albert

    2001-01-01

    The present study focuses on the question of whether inter- and intramodal forms of attention are reflected in activation of the same or different brain areas. ERPs were recorded while subjects were presented a random sequence of visual and auditory stimuli. They were instructed to attend to

  18. Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Barry W. Festoff

    2017-01-01

    Full Text Available Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer’s disease (AD in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i the presence/absence of AD, (ii the risk of developing AD, (iii the progression of AD, or (iv AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons is universally present. Current consensus is that the earlier the diagnosis, the better the chance to develop treatments that influence disease progression. In this article we provide a detailed review and analysis of the role of the blood-brain barrier (BBB and damage-associated molecular patterns (DAMPs as well as coagulation molecules in the onset and progression of these neurodegenerative disorders.

  19. Hydrogen inhalation ameliorated mast cell mediated brain injury after ICH in mice

    Science.gov (United States)

    Manaenko, Anatol; Lekic, Tim; Ma, Qingyi; Zhang, John H.; Tang, Jiping

    2012-01-01

    OBJECTIVE Hydrogen inhalation was neuroprotective in several brain injury models. Its mechanisms are believed to be related to anti-oxidative stress. We investigated the potential neurovascular protective effect of hydrogen inhalation especially effect on mast cell activation in a mouse model of intracerebral hemorrhage (ICH). DESIGN Controlled in vivo laboratory study. SETTING Animal research laboratory SUBJECTS 171, 8 weeks old male CD-1 mice were used. INTERVENTIONS Collagenase-induced ICH model in 8 weeks old, male, CD-1 mice was used. Hydrogen was administrated via spontaneous inhalation. The blood-brain barrier (BBB) permeability and neurological deficits were investigated at 24 and 72 hours after ICH. Mast cell activation was evaluated by Western blot and immuno-staining. The effects of hydrogen inhalation on mast cell activation were confirmed in an autologous blood injection model ICH. MEASURMENT AND MAIN RESULTS At 24 and 72 hours post-ICH, animals showed BBB disruption, brain edema, neurological deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated BBB disruption and improved neurobehavioral function. CONCLUSION Activation of mast cells following ICH contributed to increase of BBB permeability and brain edema. Hydrogen inhalation preserved BBB disruption by prevention of mast cell activation after ICH. PMID:23388512

  20. Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1

    Science.gov (United States)

    2013-01-01

    Background Emerging studies have demonstrated that pretreatment with electroacupuncture (EA) induces significant tolerance to focal cerebral ischemia. The present study seeks to determine the involvement of monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified novel modulator of inflammatory reactions, in the cerebral neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of EA pretreatment-induced ischemic brain tolerance. Methods Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes in male C57BL/6 mice and MCPIP1 knockout mice. Transcription and expression of MCPIP1 gene was monitored by qRT-PCR, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, proinflammatory cytokines and leukocyte infiltration in brain and NF-κB signaling were evaluated after ischemia/reperfusion. Results MCPIP1 protein and mRNA levels significantly increased specifically in mouse brain undergoing EA pretreatment. EA pretreatment significantly attenuated the infarct volume, neurological deficits, upregulation of proinflammatory cytokines and leukocyte infiltration in the brain of wild-type mice after MCAO compared with that of the non-EA group. MCPIP1-deficient mice failed to evoke EA pretreatment-induced tolerance compared with that of the control MCPIP1 knockout group without EA treatment. Furthermore, the activation of NF-κB signaling was significantly reduced in EA-pretreated wild-type mice after MCAO compared to that of the non-EA control group and MCPIP1-deficient mice failed to confer the EA pretreatment-induced inhibition of NF-κB signaling after MCAO. Conclusions Our data demonstrated that MCPIP1 deficiency caused significant lack of EA pretreatment-induced cerebral protective effects after MCAO compared with the control group and that MCPIP1 is

  1. Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain.

    Science.gov (United States)

    Fujikake, Kazuma; Sawada, Masato; Hikita, Takao; Seto, Yayoi; Kaneko, Naoko; Herranz-Pérez, Vicente; Dohi, Natsuki; Homma, Natsumi; Osaga, Satoshi; Yanagawa, Yuchio; Akaike, Toshihiro; García-Verdugo, Jose Manuel; Hattori, Mitsuharu; Sobue, Kazuya; Sawamoto, Kazunobu

    2018-05-09

    In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and in vivo loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB. SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts

  2. Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

    Science.gov (United States)

    Sebastiani, Anne; Granold, Matthias; Ditter, Anja; Sebastiani, Philipp; Gölz, Christina; Pöttker, Bruno; Luh, Clara; Schaible, Eva-Verena; Radyushkin, Konstantin; Timaru-Kast, Ralph; Werner, Christian; Schäfer, Michael K; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

    2016-02-01

    The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation

  3. Heuristic and optimal policy computations in the human brain during sequential decision-making.

    Science.gov (United States)

    Korn, Christoph W; Bach, Dominik R

    2018-01-23

    Optimal decisions across extended time horizons require value calculations over multiple probabilistic future states. Humans may circumvent such complex computations by resorting to easy-to-compute heuristics that approximate optimal solutions. To probe the potential interplay between heuristic and optimal computations, we develop a novel sequential decision-making task, framed as virtual foraging in which participants have to avoid virtual starvation. Rewards depend only on final outcomes over five-trial blocks, necessitating planning over five sequential decisions and probabilistic outcomes. Here, we report model comparisons demonstrating that participants primarily rely on the best available heuristic but also use the normatively optimal policy. FMRI signals in medial prefrontal cortex (MPFC) relate to heuristic and optimal policies and associated choice uncertainties. Crucially, reaction times and dorsal MPFC activity scale with discrepancies between heuristic and optimal policies. Thus, sequential decision-making in humans may emerge from integration between heuristic and optimal policies, implemented by controllers in MPFC.

  4. Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression.

    Science.gov (United States)

    Layé, S; Gheusi, G; Cremona, S; Combe, C; Kelley, K; Dantzer, R; Parnet, P

    2000-07-01

    The present study was designed to determine the role of endogenous brain interleukin (IL)-1 in the anorexic response to lipopolysaccharide (LPS). Intraperitoneal administration of LPS (5-10 microgram/mouse) induced a dramatic, but transient, decrease in food intake, associated with an enhanced expression of proinflammatory cytokine mRNA (IL-1beta, IL-6, and tumor necrosis factor-alpha) in the hypothalamus. This dose of LPS also increased plasma levels of IL-1beta. Intracerebroventricular pretreatment with IL-1 receptor antagonist (4 microgram/mouse) attenuated LPS-induced depression of food intake and totally blocked the LPS-induced enhanced expression of proinflammatory cytokine mRNA measured in the hypothalamus 1 h after treatment. In contrast, LPS-induced increases in plasma levels of IL-1beta were not altered. These findings indicate that endogenous brain IL-1 plays a pivotal role in the development of the hypothalamic cytokine response to a systemic inflammatory stimulus.

  5. Brain structural properties predict psychologically mediated hypoalgesia in an 8-week sham acupuncture treatment for migraine.

    Science.gov (United States)

    Liu, Jixin; Mu, Junya; Liu, Qianqian; Dun, Wanghuan; Zhang, Ming; Tian, Jie

    2017-09-01

    Neuroimaging studies described brain structural changes that comprise the mechanisms underlying individual differences in migraine development and maintenance. However, whether such interindividual variability in migraine was observed in a pretreatment scan is a predisposition for subsequent hypoalgesia to placebo treatment that remains largely unclear. Using T1-weighted imaging, we investigated this issue in 50 healthy controls (HC) and 196 patients with migraine without aura (MO). An 8-week double-blinded, randomized, placebo-controlled acupuncture was used, and we only focused on the data from the sham acupuncture group. Eighty patients participated in an 8-weeks sham acupuncture treatment, and were subdivided (50% change in migraine days from baseline) into recovering (MOr) and persisting (MOp) patients. Optimized voxel-based morphometry (VBM) and functional connectivity analysis were performed to evaluate brain structural and functional changes. At baseline, MOp and MOr had similar migraine activity, anxiety and depression; reduced migraine days were accompanied by decreased anxiety in MOr. In our findings, the MOr group showed a smaller volume in the left medial prefrontal cortex (mPFC), and decreased mPFC-related functional connectivity was found in the default mode network. Additionally, the reduction in migraine days after placebo treatment was significantly associated with the baseline gray matter volume of the mPFC which could also predict post-treatment groups with high accuracy. It indicated that individual differences for the brain structure in the pain modulatory system at baseline served as a substrate on how an individual facilitated or diminished hypoalgesia responses to placebo treatment in migraineurs. Hum Brain Mapp 38:4386-4397, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. Hormonally-mediated Epigenetic Changes to Steroid Receptors in the Developing Brain: Implications for Sexual Differentiation

    OpenAIRE

    Nugent, Bridget M.; Schwarz, Jaclyn M.; McCarthy, Margaret M.

    2010-01-01

    The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigeneti...

  7. MAPK and pro-inflammatory mediators in the walls of brain blood vessels following cerebral ischemia

    OpenAIRE

    Maddahi, Aida

    2012-01-01

    INTRODUCTION Stroke is a serious neurological disease which may lead to death and severe disability [1, 2]. There are two major types of stroke: ischemic and hemorrhagic stroke. Both are associated with disruption of blood flow to a part of the brain with rapid depletion of cellular energy and oxygen, resulting in ionic disturbances and eventually neuronal cell death [3]. The pathologic process that develops after stroke is divided into acute (within hours), sub-acute (hours to days), ...

  8. Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX

    Directory of Open Access Journals (Sweden)

    Hangjun Ruan

    1999-11-01

    Full Text Available The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE, which can be activated through hypoxia-inducible factor-1 (HIF-1. We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

  9. Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety

    Directory of Open Access Journals (Sweden)

    Karina Soares de Oliveira

    Full Text Available ABSTRACT Anxiety and obsessive-compulsive related disorders are highly prevalent and disabling disorders for which there are still treatment gaps to be explored. Fear is a core symptom of these disorders and its learning is highly dependent on the activity of the neurotrophin brain-derived neurotrophic factor (BDNF. Should BDNF-mediated fear learning be considered a target for the development of novel treatments for anxiety and obsessive-compulsive related disorders? We review the evidence that suggests that BDNF expression is necessary for the acquisition of conditioned fear, as well as for the recall of its extinction. We describe the findings related to fear learning and genetic/epigenetic manipulation of Bdnf expression in animals and BDNF allelic variants in humans. Later, we discuss how manipulation of BDNF levels represents a promising potential treatment target that may increase the benefits of therapies that extinguish previously conditioned fear.

  10. BNCT of intracerebral melanoma. Enhanced survival and cure following Cereport mediated opening of the blood-brain barrier

    International Nuclear Information System (INIS)

    Barth, R.F.; Yang, W.; Bartus, R.T.; Rotaru, J.H.; Ferketich, A.K.; Moeschberger, M.L.; Nawrocky, M.M.; Coderre, J.A.

    2000-01-01

    Cereport is a bradykinin analogue that produces a transient, pharmacologically mediated opening of the blood-brain barrier (BBB). The present study was designed to determine if Cereport could enhance the delivery of BPA and the efficacy of BNCT in nude rats bearing intracerebral implants of the human MRA 27 melanoma. Animals that received intracarotid (i.c.) injection of Cereport and i.c. BPA had a mean survival time of 115 d compared to 82 d without Cereport, 42 d for i.v. BPA with Cereport and 31 d for irradiated controls. The combination of i.c. Cereport and BPA produced a 400% increase in the life span with 35% long-term survivors (>180 d). (author)

  11. Vasoactive intestinal peptide is a local mediator in a gut-brain neural axis activating intestinal gluconeogenesis.

    Science.gov (United States)

    De Vadder, F; Plessier, F; Gautier-Stein, A; Mithieux, G

    2015-03-01

    Intestinal gluconeogenesis (IGN) promotes metabolic benefits through activation of a gut-brain neural axis. However, the local mediator activating gluconeogenic genes in the enterocytes remains unknown. We show that (i) vasoactive intestinal peptide (VIP) signaling through VPAC1 receptor activates the intestinal glucose-6-phosphatase gene in vivo, (ii) the activation of IGN by propionate is counteracted by VPAC1 antagonism, and (iii) VIP-positive intrinsic neurons in the submucosal plexus are increased under the action of propionate. These data support the role of VIP as a local neuromodulator released by intrinsic enteric neurons and responsible for the induction of IGN through a VPAC1 receptor-dependent mechanism in enterocytes. © 2015 John Wiley & Sons Ltd.

  12. Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction.

    Directory of Open Access Journals (Sweden)

    Letitia D Jones

    Full Text Available The number of HIV-1 positive individuals developing some form of HIV-associated neurocognitive disorder (HAND is increasing. In these individuals, the integrity of the blood-brain barrier (BBB is compromised due to an increase in exposure to pro-inflammatory mediators, viral proteins, and virus released from infected cells. It has been shown that soluble CD40L (sCD40L is released upon platelet activation and is an important mediator of the pathogenesis of HAND but the underlying mechanisms are unclear, emphasizing the need of an effective animal model. Here, we have utilized a novel animal model in which wild-type (WT mice were infected with EcoHIV; a derivative of HIV-1 that contains a substitution of envelope protein gp120 with that of gp80 derived from murine leukemia virus-1 (MuLV-1. As early as two-weeks post-infection, EcoHIV led to increased permeability of the BBB associated with decreased expression of tight junction protein claudin-5, in CD40L and platelet activation-dependent manner. Treatment with an antiplatelet drug, eptifibatide, in EcoHIV-infected mice normalized BBB function, sCD40L release and platelet activity, thus implicating platelet activation and platelet-derived CD40L in virally induced BBB dysfunction. Our results also validate and underscore the importance of EcoHIV infection mouse model as a tool to explore therapeutic targets for HAND.

  13. Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-κB-mediated inflammatory responses.

    Directory of Open Access Journals (Sweden)

    Ruo-Bing Guo

    Full Text Available Paeoniflorin (PF, the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2 and 5-LOX in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

  14. Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-κB-mediated inflammatory responses.

    Science.gov (United States)

    Guo, Ruo-Bing; Wang, Guo-Feng; Zhao, An-Peng; Gu, Jun; Sun, Xiu-Lan; Hu, Gang

    2012-01-01

    Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

  15. Repetitive Hyperbaric Oxygenation Attenuates Reactive Astrogliosis and Suppresses Expression of Inflammatory Mediators in the Rat Model of Brain Injury

    Directory of Open Access Journals (Sweden)

    Irena Lavrnja

    2015-01-01

    Full Text Available The exact mechanisms by which treatment with hyperbaric oxygen (HBOT exerts its beneficial effects on recovery after brain injury are still unrevealed. Therefore, in this study we investigated the influence of repetitive HBOT on the reactive astrogliosis and expression of mediators of inflammation after cortical stab injury (CSI. CSI was performed on male Wistar rats, divided into control, sham, and lesioned groups with appropriate HBO. The HBOT protocol was as follows: 10 minutes of slow compression, 2.5 atmospheres absolute (ATA for 60 minutes, and 10 minutes of slow decompression, once a day for 10 consecutive days. Data obtained using real-time polymerase chain reaction, Western blot, and immunohistochemical and immunofluorescence analyses revealed that repetitive HBOT applied after the CSI attenuates reactive astrogliosis and glial scarring, and reduces expression of GFAP (glial fibrillary acidic protein, vimentin, and ICAM-1 (intercellular adhesion molecule-1 both at gene and tissue levels. In addition, HBOT prevents expression of CD40 and its ligand CD40L on microglia, neutrophils, cortical neurons, and reactive astrocytes. Accordingly, repetitive HBOT, by prevention of glial scarring and limiting of expression of inflammatory mediators, supports formation of more permissive environment for repair and regeneration.

  16. Framing Tobacco Dependence as a "Brain Disease": Implications for Policy and Practice.

    Science.gov (United States)

    Morphett, Kylie; Carter, Adrian; Hall, Wayne; Gartner, Coral

    2017-07-01

    Like other forms of drug dependence, tobacco dependence is increasingly being described as a "chronic brain disease." The potential consequences of this medical labelling have been examined in relation to other addictions, but the implications for tobacco control have been neglected. Some have posited that biomedical conceptions of addiction will reduce stigma and increase uptake of efficacious treatments. Others have countered that it could increase stigma, reduce treatment seeking, and deter unassisted quitting. We explored how smokers respond to the labelling of smoking as a brain disease. Semi-structured interviews with 29 Australian smokers recruited using purposive sampling. Thematic analysis was used to analyze the results. Most participants questioned the accuracy of the brain disease label as applied to smoking. They believed that smoking was not a chronic disease because they perceived smoking to be an individual's choice. In addition, many believed that this label would increase the stigma that they already felt and, did not want to adopt a "sick role" in relation to their smoking. Describing smoking as a brain disease is more likely to alienate smokers than to engage them in quitting. The application of overly medical labels of smoking are inconsistent with smokers own conceptualizations of their smoking, and may have unintended consequences if they are widely disseminated in healthcare settings or antismoking campaigns. The participants in this project believed that biomedical labels of smoking as a "brain disease" or a "chronic disease" were discordant their existing understandings of their smoking. Explanations of addiction that downplay or ignore the role of choice and autonomy risk being perceived as irrelevant by smokers, and could lead to suspicion of health professionals or an unwillingness to seek treatment. © The Author 2017. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights

  17. Dopaminergic differentiation of human neural stem cells mediated by co-cultured rat striatal brain slices

    DEFF Research Database (Denmark)

    Anwar, Mohammad Raffaqat; Andreasen, Christian Maaløv; Lippert, Solvej Kølvraa

    2008-01-01

    differentiation, we co-cultured cells from a human neural forebrain-derived stem cell line (hNS1) with rat striatal brain slices. In brief, coronal slices of neonatal rat striatum were cultured on semiporous membrane inserts placed in six-well trays overlying monolayers of hNS1 cells. After 12 days of co......Properly committed neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. To establish a setting for identification of secreted neural compounds promoting dopaminergic...

  18. Recombinant Adeno-Associated Virus-Mediated microRNA Delivery into the Postnatal Mouse Brain Reveals a Role for miR-134 in Dendritogenesis in Vivo

    DEFF Research Database (Denmark)

    Christensen, Mette; Larsen, Lars A; Kauppinen, Sakari

    2010-01-01

    delivery of microRNAs in vivo by use of recombinant adeno-associated virus (rAAV). rAAV-mediated overexpression of miR-134 in neurons of the postnatal mouse brain provided evidence for a negative role of miR-134 in dendritic arborization of cortical layer V pyramidal neurons in vivo, thereby confirming...

  19. Targeting brains, producing responsibilities: the use of neuroscience within British social policy.

    Science.gov (United States)

    Broer, Tineke; Pickersgill, Martyn

    2015-05-01

    Concepts and findings 'translated' from neuroscientific research are finding their way into UK health and social policy discourse. Critical scholars have begun to analyse how policies tend to 'misuse' the neurosciences and, further, how these discourses produce unwarranted and individualizing effects, rooted in middle-class values and inducing guilt and anxiety. In this article, we extend such work while simultaneously departing from the normative assumptions implied in the concept of 'misuse'. Through a documentary analysis of UK policy reports focused on the early years, adolescence and older adults, we examine how these employ neuroscientific concepts and consequently (re)define responsibility. In the documents analysed, responsibility was produced in three different but intersecting ways: through a focus on optimisation, self-governance, and vulnerability. Our work thereby adds to social scientific examinations of neuroscience in society that show how neurobiological terms and concepts can be used to construct and support a particular imaginary of citizenship and the role of the state. Neuroscience may be leveraged by policy makers in ways that (potentially) reduce the target of their intervention to the soma, but do so in order to expand the outcome of the intervention to include the enhancement of society writ large. By attending as well to more critical engagements with neuroscience in policy documents, our analysis demonstrates the importance of being mindful of the limits to the deployment of a neurobiological idiom within policy settings. Accordingly, we contribute to increased empirical specificity concerning the impacts and translation of neuroscientific knowledge in contemporary society whilst refusing to take for granted the idea that the neurosciences necessarily have a dominant role (to play). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

    Science.gov (United States)

    Taliaz, Dekel; Loya, Assaf; Gersner, Roman; Haramati, Sharon; Chen, Alon; Zangen, Abraham

    2011-03-23

    Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

  1. VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

    International Nuclear Information System (INIS)

    Sun, Jinqiao; Sha, Bin; Zhou, Wenhao; Yang, Yi

    2010-01-01

    This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

  2. NF-kB as a mediator of brain inflammation in AD.

    Science.gov (United States)

    Hong, Jin Tae

    2017-08-07

    Alzheimer's disease is the most common form of dementia. It is characterized by beta-amyloid peptide fibrils which are extracellular deposition of a specific protein, and is accompanied by extensive neuroinflammation. Various studies show the presence of a number of inflammation markers in the AD brain: elevated inflammatory cytokines and chemokines, and an accumulation of activated microglia in the damaged regions. NF-kB is a redox of transcriptional factors, and it is known to be located in the genes involved in amyloidogenesis and inflammation. Epidemiological studies have shown that NF-kB is elevated in the AD patient brain, and long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between NF-kB and AD pathogenesis. This study is (1) to assess the association between NF-kB activity and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD with NF-kB inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury

    DEFF Research Database (Denmark)

    Cnossen, Maryse C; Huijben, Jilske A; van der Jagt, Mathieu

    2017-01-01

    BACKGROUND: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management......, and it was pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. RESULTS: The survey was completed by 66 centers (97% response rate). Centers were mainly academic....... There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as using a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas...

  4. Functional connections between activated and deactivated brain regions mediate emotional interference during externally directed cognition.

    Science.gov (United States)

    Di Plinio, Simone; Ferri, Francesca; Marzetti, Laura; Romani, Gian Luca; Northoff, Georg; Pizzella, Vittorio

    2018-04-24

    Recent evidence shows that task-deactivations are functionally relevant for cognitive performance. Indeed, higher cognitive engagement has been associated with higher suppression of activity in task-deactivated brain regions - usually ascribed to the Default Mode Network (DMN). Moreover, a negative correlation between these regions and areas actively engaged by the task is associated with better performance. DMN regions show positive modulation during autobiographical, social, and emotional tasks. However, it is not clear how processing of emotional stimuli affects the interplay between the DMN and executive brain regions. We studied this interplay in an fMRI experiment using emotional negative stimuli as distractors. Activity modulations induced by the emotional interference of negative stimuli were found in frontal, parietal, and visual areas, and were associated with modulations of functional connectivity between these task-activated areas and DMN regions. A worse performance was predicted both by lower activity in the superior parietal cortex and higher connectivity between visual areas and frontal DMN regions. Connectivity between right inferior frontal gyrus and several DMN regions in the left hemisphere was related to the behavioral performance. This relation was weaker in the negative than in the neutral condition, likely suggesting less functional inhibitions of DMN regions during emotional processing. These results show that both executive and DMN regions are crucial for the emotional interference process and suggest that DMN connections are related to the interplay between externally-directed and internally-focused processes. Among DMN regions, superior frontal gyrus may be a key node in regulating the interference triggered by emotional stimuli. © 2018 Wiley Periodicals, Inc.

  5. Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells.

    Science.gov (United States)

    Prasad, Pankaj; Mittal, Shivani Arora; Chongtham, Jonita; Mohanty, Sujata; Srivastava, Tapasya

    2017-06-01

    Activation of pluripotency regulatory circuit is an important event in solid tumor progression and the hypoxic microenvironment is known to enhance the stemness feature of some cells. The distinct population of cancer stem cells (CSCs)/tumor initiating cells exist in a niche and augment invasion, metastasis, and drug resistance. Previously, studies have reported global hypomethylation and site-specific aberrant methylation in gliomas along with other epigenetic modifications as important contributors to genomic instability during glioma progression. Here, we have demonstrated the role of hypoxia-mediated epigenetic modifications in regulating expression of core pluripotency factors, OCT4 and NANOG, in glioma cells. We observe hypoxia-mediated induction of demethylases, ten-eleven-translocation (TET) 1 and 3, but not TET2 in our cell-line model. Immunoprecipitation studies reveal active demethylation and direct binding of TET1 and 3 at the Oct4 and Nanog regulatory regions. Tet1 and 3 silencing assays further confirmed induction of the pluripotency pathway involving Oct4, Nanog, and Stat3, by these paralogues, although with varying degrees. Knockdown of Tet1 and Tet3 inhibited the formation of neurospheres in hypoxic conditions. We observed independent roles of TET1 and TET3 in differentially regulating pluripotency and differentiation associated genes in hypoxia. Overall, this study demonstrates an active demethylation in hypoxia by TET1 and 3 as a mechanism of Oct4 and Nanog overexpression thus contributing to the formation of CSCs in gliomas. Stem Cells 2017;35:1468-1478. © 2017 AlphaMed Press.

  6. EG-17SUV420-MEDIATED HETEROCHROMATIN CHANGES IN PEDIATRIC BRAIN CANCERS

    Science.gov (United States)

    Van Meter, Timothy E.; Terry, Jocelyn; Rockwell, Nathan; Goggin, Sarah; Nethala, Priya; Khan, Asadullah

    2014-01-01

    Silencing mechanisms play a role in genomic stability by maintaining condensed, non-active regions of the genome. SUV420 enzymes contain a SET domain conferring methyltransferase activity toward histones. The Histone H4 lysine 20 trimethylation (H4K20me3) mark maintained by SUV420H2 is associated with heterochromatin formation and gene silencing, whereas the dimethylated mark (H4K20me2) is associated with DNA repair. In studies of epigenetic factors in large patient cohorts with ependymoma, it was found that SUV420H2 expression was lost or diminished in patients with reciprocal increases in prognostic markers such as hTERT. To better understand the normal function of Suv4-20H1/H2 enzyme in neural progenitors, and pathological changes in cancers, a variety of differentiation paradigms were used. The NT2D1 neurally restricted cell line, and BGO1V and H9 human embryonic stem cells (ESCs), and differentiated progeny, were used alongside tumors to better understand enzyme targets and functional outcomes (e.g.,lineage, differentiation, regional chromatin modifications). Lineage stages were verified with stage-specific markers by immunofluorescence and qPCR. Suv4-20 H1 and H2 were present in ESCs and neural progenitors and decreased thereafter. RNAi knockdown of SUV420 enzymes led to decreased H4K20 methylation in cancer cells. DNA methylation microarrays and ChIP-PCR suggest 1) that SUV420 is not regulated by DNA methylation in ependymomas; 2) that active chromatin marks such as H3K4 dimethylation are enriched near the transcriptional start site in the SUV420H2 gene, and 3) that hTERT is hyper-methylated at specific CpG islands and histones in a tumor sub-group-specific manner. This data supports the hypothesis that Suv4-20H2 is highly active in progenitor cells and functionally lost in some brain cancers. These studies begin to elucidate coincident mechanisms of gene silencing active in neural progenitors that may be altered in a subset of pediatric brain cancers.

  7. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons

    Science.gov (United States)

    Murphy, Diane D.; Cole, Nelson B.; Segal, Menahem

    1998-01-01

    Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons. PMID:9736750

  8. Brain-derived neurotrophic factor mediates cognitive improvements following acute exercise.

    Science.gov (United States)

    Borror, Andrew

    2017-09-01

    The mechanisms causing improved cognition following acute exercise are poorly understood. This article proposes that brain-derived neurotrophic factor (BDNF) is the main factor contributing to improved cognition following exercise. Additionally, it argues that cerebral blood flow (CBF) and oxidative stress explain the release of BDNF from cerebral endothelial cells. One way to test these hypotheses is to block endothelial function and measure the effect on BDNF levels and cognitive performance. The CBF and oxidative stress can also be examined in relationship to BDNF using a multiple linear regression. If these hypotheses are true, there would be a linear relationship between CBF+oxidative stress and BDNF levels as well as between BDNF levels and cognitive performance. The novelty of these hypotheses comes from the emphasis on the cerebral endothelium and the interplay between BDNF, CBF, and oxidative stress. If found to be valid, these hypotheses would draw attention to the cerebral endothelium and provide direction for future research regarding methods to optimize BDNF release and enhance cognition. Elucidating these mechanisms would provide direction for expediting recovery in clinical populations, such as stroke, and maintaining quality of life in the elderly. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. CD44v6 regulates growth of brain tumor stem cells partially through the AKT-mediated pathway.

    Directory of Open Access Journals (Sweden)

    Mayumi Jijiwa

    Full Text Available Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6 in BTSC of a subset of glioblastoma multiforme (GBM. Patients with CD44(high GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44(high GBM but not from CD44(low GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN, increased expression of phosphorylated AKT in CD44(high GBM, but not in CD44(low GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKT pathway.

  10. Structural white-matter connections mediating distinct behavioral components of spatial neglect in right brain-damaged patients.

    Science.gov (United States)

    Vaessen, Maarten J; Saj, Arnaud; Lovblad, Karl-Olof; Gschwind, Markus; Vuilleumier, Patrik

    2016-04-01

    Spatial neglect is a neuropsychological syndrome in which patients fail to perceive and orient to stimuli located in the space contralateral to the lesioned hemisphere. It is characterized by a wide heterogeneity in clinical symptoms which can be grouped into distinct behavioral components correlating with different lesion sites. Moreover, damage to white-matter (WM) fiber tracts has been suggested to disconnect brain networks that mediate different functions associated with spatial cognition and attention. However, it remains unclear what WM pathways are associated with functionally dissociable neglect components. In this study we examined nine patients with a focal right hemisphere stroke using a series of neuropsychological tests and diffusion tensor imaging (DTI) in order to disentangle the role of specific WM pathways in neglect symptoms. First, following previous work, the behavioral test scores of patients were factorized into three independent components reflecting perceptual, exploratory, and object-centered deficits in spatial awareness. We then examined the structural neural substrates of these components by correlating indices of WM integrity (fractional anisotropy) with the severity of deficits along each profile. Several locations in the right parietal and frontal WM correlated with neuropsychological scores. Fiber tracts projecting from these locations indicated that posterior parts of the superior longitudinal fasciculus (SLF), as well as nearby callosal fibers connecting ipsilateral and contralateral parietal areas, were associated with perceptual spatial deficits, whereas more anterior parts of SLF and inferior fronto-occipital fasciculus (IFOF) were predominantly associated with object-centered deficits. In addition, connections between frontal areas and superior colliculus were found to be associated with the exploratory deficits. Our results provide novel support to the view that neglect may result from disconnection lesions in distributed

  11. Socially-mediated differences in brain monoamines in rainbow trout: effects of trace metal contaminants

    International Nuclear Information System (INIS)

    Sloman, Katherine A.; Lepage, Olivier; Rogers, Joseph T.; Wood, Chris M.; Winberg, Svante

    2005-01-01

    Monoaminergic systems play a crucial role in linking behaviour and physiology. Here the physiological and behavioural effects of metal exposure in relation to monoaminergic systems were considered by exposing rainbow trout dyads, demonstrating stable dominance relationships, to cadmium or lead. Fish exposed to 4 μg l -1 cadmium accumulated more cadmium at the gill than fish held in control water. Fish exposed to 7 μg l -1 cadmium had higher gill, liver and kidney cadmium concentrations. No significant lead accumulation was seen after exposure to 46 μg l -1 for 48 h but exposure to 325 μg l -1 lead caused an increase in gill, liver and kidney lead concentrations. Brain accumulation of both cadmium and lead was only seen after exposure to the highest concentrations. Exposure to 4 or 7 μg l -1 cadmium, or 46 or 325 μg l -1 lead for 48 h did not disrupt established dominance hierarchies. As expected with this stable behavioural situation, in control pairs, animals of different social status displayed different physiological profiles. Subordinate fish had higher concentrations of circulating plasma cortisol and telencephalic 5-hydroxyindoleacetic acid/5-hydroxytryptamine (serotonin) (5-HIAA/5-HT) ratios. However, these physiological profiles were affected by metal exposure, with a trend towards higher serotonergic activity in dominant fish. Dominants exposed to 325 μg l -1 lead had significantly higher hypothalamic 5-HIAA/5-HT ratios when compared with subordinates. The results demonstrate that if stable social hierarchies are established in control water they may not be affected by exposure to cadmium and lead although physiological changes may be evident

  12. Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

    Directory of Open Access Journals (Sweden)

    Alnawaz Rehemtulla

    2002-01-01

    Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

  13. Socially-mediated differences in brain monoamines in rainbow trout: effects of trace metal contaminants

    Energy Technology Data Exchange (ETDEWEB)

    Sloman, Katherine A. [School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth, Devon PL4 8AA (United Kingdom)]. E-mail: katherine.sloman@plymouth.ac.uk; Lepage, Olivier [Evolutionary Biology Centre, Department of Comparative Physiology, Uppsala University, Norbyvaegen 18A, SE-752 36 Uppsala (Sweden); Rogers, Joseph T. [Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., L8S 4K1 (Canada); Wood, Chris M. [Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., L8S 4K1 (Canada); Winberg, Svante [Evolutionary Biology Centre, Department of Comparative Physiology, Uppsala University, Norbyvaegen 18A, SE-752 36 Uppsala (Sweden)

    2005-02-10

    Monoaminergic systems play a crucial role in linking behaviour and physiology. Here the physiological and behavioural effects of metal exposure in relation to monoaminergic systems were considered by exposing rainbow trout dyads, demonstrating stable dominance relationships, to cadmium or lead. Fish exposed to 4 {mu}g l{sup -1} cadmium accumulated more cadmium at the gill than fish held in control water. Fish exposed to 7 {mu}g l{sup -1} cadmium had higher gill, liver and kidney cadmium concentrations. No significant lead accumulation was seen after exposure to 46 {mu}g l{sup -1} for 48 h but exposure to 325 {mu}g l{sup -1} lead caused an increase in gill, liver and kidney lead concentrations. Brain accumulation of both cadmium and lead was only seen after exposure to the highest concentrations. Exposure to 4 or 7 {mu}g l{sup -1} cadmium, or 46 or 325 {mu}g l{sup -1} lead for 48 h did not disrupt established dominance hierarchies. As expected with this stable behavioural situation, in control pairs, animals of different social status displayed different physiological profiles. Subordinate fish had higher concentrations of circulating plasma cortisol and telencephalic 5-hydroxyindoleacetic acid/5-hydroxytryptamine (serotonin) (5-HIAA/5-HT) ratios. However, these physiological profiles were affected by metal exposure, with a trend towards higher serotonergic activity in dominant fish. Dominants exposed to 325 {mu}g l{sup -1} lead had significantly higher hypothalamic 5-HIAA/5-HT ratios when compared with subordinates. The results demonstrate that if stable social hierarchies are established in control water they may not be affected by exposure to cadmium and lead although physiological changes may be evident.

  14. Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system.

    Science.gov (United States)

    Ren, Huixia; Luo, Chuanming; Feng, Yanqing; Yao, Xiaoli; Shi, Zhe; Liang, Fengyin; Kang, Jing X; Wan, Jian-Bo; Pei, Zhong; Su, Huanxing

    2017-01-01

    Impairment of amyloid-β (Aβ) clearance leads to Aβ accumulation in the brain during the development of Alzheimer's disease (AD). Strategies that can restore or improve the clearance function hold great promise in delaying or preventing the onset of AD. Here, we show that n-3 polyunsaturated fatty acids (PUFAs), by use of fat-1 transgenic mice and oral administration of fish oil, significantly promote interstitial Aβ clearance from the brain and resist Aβ injury. Such beneficial effects were abolished in Aqp4-knockout mice, suggesting that the AQP4-dependent glymphatic system is actively involved in the promoting the effects of n-3 PUFAs on the clearance of extracellular Aβ. Imaging on clarified brain tissues clearly displayed that n-3 PUFAs markedly inhibit the activation of astrocytes and protect the AQP4 polarization in the affected brain region after Aβ injection. The results of the present study prove a novel mechanism by which n-3 PUFAs exert protective roles in reducing Aβ accumulation via mediating the glymphatic system function.-Ren, H., Luo, C., Feng, Y., Yao, X., Shi, Z., Liang, F., Kang, J. X., Wan, J.-B., Pei, Z., Su, H. Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system. © FASEB.

  15. Astrocytes mediated the nootropic and neurotrophic effects of Sarsasapogenin-AA13 via upregulating brain-derived neurotrophic factor.

    Science.gov (United States)

    Dong, Dong; Mao, Yu; Huang, Cui; Jiao, Qian; Pan, Hui; Ma, Lei; Wang, Rui

    2017-01-01

    Rhizoma Anemarrhena , a widely used traditional Chinese medicine, has previously been shown to have neuroprotective effect. Sarsasapogenin-AA13 (AA13) is a novel synthetic derivative of Sarsasapogenin, which is extracted from Rhizoma Anemarrhena . The aim of this study is to investigate the nootropic and neurotrophic effects of AA13 and underlying mechanisms. In vitro , cell viability of rat primary astrocytes treated with AA13 and neurons cultured with conditioned medium of AA13-treated rat primary astrocytes was tested by MTT assays. In vivo , a pharmacological model of cognitive impairment induced by scopolamine was employed and spatial memory of the mice was assessed by Morris water maze. This study found that AA13 increased cell viability of primary astrocytes and AA13-treated astrocyte-conditioned medium enhanced the survival rate of primary neurons. Interestingly, AA13 markedly enhanced the level of BDNF in astrocytes. Furthermore, AA13 (6 mg/kg) improved the cognitive deficits in animal models (p<0.05) and BDNF and PSD95 levels were increased in brain. Therefore, we hypothesize that AA13 exerts nootropic and neurotrophic activities through astrocytes mediated upregulation of BDNF secretion. The results suggest that AA13 could be a potential compound for cognitive impairment after further research.

  16. Right frontal pole cortical thickness and social competence in children with chronic traumatic brain injury: cognitive proficiency as a mediator.

    Science.gov (United States)

    Levan, Ashley; Baxter, Leslie; Kirwan, C Brock; Black, Garrett; Gale, Shawn D

    2015-01-01

    To examine the association between right frontal pole cortical thickness, social competence, and cognitive proficiency in children participants with a history of chronic traumatic brain injury (TBI). Twenty-three children (65% male; M age = 12.8 years, SD = 2.3 years) at least 1 year post-injury (M = 3.3 years, SD = 1.7 years) were evaluated with the Cognitive Proficiency Index (CPI) from the Wechsler Intelligence Scale for Children, 4th Edition, and their caregiver completed the Child Behavior Checklist. Social competence was evaluated with the Social Competence and Social Problems subscales from the Child Behavior Checklist. Right frontal pole cortical thickness was calculated via FreeSurfer from high-resolution 3-dimensional T1 magnetic resonance imaging scans. Direct effect of right frontal pole cortical thickness on social competence was significant (β = 14.09, SE = 4.6, P Right frontal pole cortical thickness significantly predicted CPI (β = 18.44, SE = 4.9, P right frontal lobe cortical integrity and social competence in pediatric participants with chronic TBI may be mediated through cognitive proficiency.

  17. The mediator-modulator brain system in minks exposed to radiation factors of the Chernobyl NPP 10-km zone

    International Nuclear Information System (INIS)

    Mishunina, T.M.; Kalinskaya, L.N.; Pil'kevich, L.I.; Kononenko, V.Ya.; Ryasenko, V.I.; Bogdanova, T.I.

    1996-01-01

    The paper is devoted to the study of the activity of the important metabolizing mediators/modulators of the central nervous system: adenosine, angiotensin and GABA as well as specific bonding of 14 C-GABA by synaptic membranes of brain structures in minks who were in the 10-km zone of the Chernobyl NPP from 0.5 months to 3 years. Adenosine deaminase, angiotensin converting enzyme and glutamate decarboxylase activities endured significant changes in the hypothalamus, striatum, hippocampus, cerebellum, cerebral, cortex, medulla oblongata and midbrain of minks; the direction and the extent of manifestation of those changes depend on the term of animals' stay in the zone. The GABA reception in the cerebral cortex and medulla oblongata increased significantly and progressively with the prolongation of exposure to radiation. It is concluded that the variety of changes, their regional-specificity and dependence on exposure of animals to the radiation factors of the Chernobyl NPP 10-km zone may induce development of serious complications not only in nervous but in some other systems

  18. Peptide carrier-mediated non-covalent delivery of unmodified cisplatin, methotrexate and other agents via intravenous route to the brain.

    Directory of Open Access Journals (Sweden)

    Gobinda Sarkar

    Full Text Available BACKGROUND: Rapid pre-clinical evaluation of chemotherapeutic agents against brain cancers and other neurological disorders remains largely unattained due to the presence of the blood-brain barrier (BBB, which limits transport of most therapeutic compounds to the brain. A synthetic peptide carrier, K16ApoE, was previously developed that enabled transport of target proteins to the brain by mimicking a ligand-receptor system. The peptide carrier was found to generate transient BBB permeability, which was utilized for non-covalent delivery of cisplatin, methotrexate and other compounds to the brain. APPROACH: Brain delivery of the chemotherapeutics and other agents was achieved either by injecting the carrier peptide and the drugs separately or as a mixture, to the femoral vein. A modification of the method comprised injection of K16ApoE pre-mixed with cetuximab, followed by injection of a 'small-molecule' drug. PRINCIPAL FINDINGS: Seven-of-seven different small molecules were successfully delivered to the brain via K16ApoE. Depending on the method, brain uptake with K16ApoE was 0.72-1.1% for cisplatin and 0.58-0.92% for methotrexate (34-50-fold and 54-92 fold greater for cisplatin and methotrexate, respectively, with K16ApoE than without. Visually intense brain-uptake of Evans Blue, Light Green SF and Crocein scarlet was also achieved. Direct intracranial injection of EB show locally restricted distribution of the dye in the brain, whereas K16ApoE-mediated intravenous injection of EB resulted in the distribution of the dye throughout the brain. Experiments with insulin suggest that ligand-receptor signaling intrinsic to the BBB provides a natural means for passive transport of some molecules across the BBB. SIGNIFICANCE: The results suggest that the carrier peptide can non-covalently transport various chemotherapeutic agents to the brain. Thus, the method offers an avenue for pre-clinical evaluation of various small and large therapeutic molecules

  19. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion

    International Nuclear Information System (INIS)

    Thomas, Elaine R.; Dunfee, Rebecca L.; Stanton, Jennifer; Bogdan, Derek; Taylor, Joann; Kunstman, Kevin; Bell, Jeanne E.; Wolinsky, Steven M.; Gabuzda, Dana

    2007-01-01

    HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion

  20. Using Brain Imaging for Lie Detection: Where Science, Law and Research Policy Collide

    Science.gov (United States)

    Langleben, Daniel D.; Moriarty, Jane Campbell

    2012-01-01

    Progress in the use of functional magnetic resonance imaging (fMRI) of the brain to evaluate deception and differentiate lying from truth-telling has created anticipation of a breakthrough in the search for technology-based methods of lie detection. In the last few years, litigants have attempted to introduce fMRI lie detection evidence in courts. This article weighs in on the interdisciplinary debate about the admissibility of such evidence, identifying the missing pieces of the scientific puzzle that need to be completed if fMRI-based lie detection is to meet the standards of either legal reliability or general acceptance. We believe that the Daubert’s “known error rate” is the key concept linking the legal and scientific standards. We posit that properly-controlled clinical trials are the most convincing means to determine the error rates of fMRI-based lie detection and confirm or disprove the relevance of the promising laboratory research on this topic. This article explains the current state of the science and provides an analysis of the case law in which litigants have sought to introduce fMRI lie detection. Analyzing the myriad issues related to fMRI lie detection, the article identifies the key limitations of the current neuroimaging of deception science as expert evidence and explores the problems that arise from using scientific evidence before it is proven scientifically valid and reliable. We suggest that courts continue excluding fMRI lie detection evidence until this potentially useful form of forensic science meets the scientific standards currently required for adoption of a medical test or device. Given a multitude of stakeholders and, the charged and controversial nature and the potential societal impact of this technology, goodwill and collaboration of several government agencies may be required to sponsor impartial and comprehensive clinical trials that will guide the development of forensic fMRI technology. PMID:23772173

  1. Mediation and Due Process Procedures in Special Education: An Analysis of State Policies. Final Report. Project FORUM.

    Science.gov (United States)

    Ahearn, Eileen M.

    This survey of 50 states and 3 of 10 non-state U.S. jurisdictions concerning state due process procedures focuses mainly on the use of mediation as a form of dispute resolution that offers an alternative to due process hearings in special education. A background section discusses the definition of mediation and the mediation process. Survey…

  2. Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry.

    Science.gov (United States)

    Sawada, Yoshikazu; Izumida, Yoshihiko; Takeuchi, Yoshinori; Aita, Yuichi; Wada, Nobuhiro; Li, EnXu; Murayama, Yuki; Piao, Xianying; Shikama, Akito; Masuda, Yukari; Nishi-Tatsumi, Makiko; Kubota, Midori; Sekiya, Motohiro; Matsuzaka, Takashi; Nakagawa, Yoshimi; Sugano, Yoko; Iwasaki, Hitoshi; Kobayashi, Kazuto; Yatoh, Shigeru; Suzuki, Hiroaki; Yagyu, Hiroaki; Kawakami, Yasushi; Kadowaki, Takashi; Shimano, Hitoshi; Yahagi, Naoya

    2017-11-04

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Policy-relevant behaviours predict heavier drinking and mediate the relationship with age, gender and education status: Analysis from the International Alcohol Control study.

    Science.gov (United States)

    Casswell, Sally; Huckle, Taisia; Wall, Martin; Parker, Karl; Chaiyasong, Surasak; Parry, Charles D H; Viet Cuong, Pham; Gray-Phillip, Gaile; Piazza, Marina

    2018-02-21

    To investigate behaviours related to four alcohol policy variables (policy-relevant behaviours) and demographic variables in relation to typical quantities of alcohol consumed on-premise in six International Alcohol Control study countries. General population surveys with drinkers using a comparable survey instrument and data analysed using path analysis in an overall model and for each country. typical quantities per occasion consumed on-premise; gender, age; years of education, prices paid, time of purchase, time to access alcohol and liking for alcohol advertisements. In the overall model younger people, males and those with fewer years of education consumed larger typical quantities. Overall lower prices paid, later time of purchase and liking for alcohol ads predicted consuming larger typical quantities; this was found in the high-income countries, less consistently in the high-middle-income countries and not in the low middle-income country. Three policy-relevant behaviours (prices paid, time of purchase, liking for alcohol ads) mediated the relationships between age, gender, education and consumption in high-income countries. International Alcohol Control survey data showed a relationship between policy-relevant behaviours and typical quantities consumed and support the likely effect of policy change (trading hours, price and restrictions on marketing) on heavier drinking. The path analysis also revealed policy-relevant behaviours were significant mediating variables between the effect of age, gender and educational status on consumption. However, this relationship is clearest in high-income countries. Further research is required to understand better how circumstances in low-middle-income countries impact effects of policies. © 2018 The Authors Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.

  4. (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain.

    Science.gov (United States)

    Knoll, J; Yoneda, F; Knoll, B; Ohde, H; Miklya, I

    1999-12-01

    1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (-)Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. 2. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (-)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in 0.18 micromol 1(-1) concentration the impulse propagation mediated release of [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14) M concentration. In rats (-)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance.

  5. (−)1-(Benzofuran-2-yl)-2-propylaminopentane, [(−)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain

    Science.gov (United States)

    Knoll, Joseph; Yoneda, Fumio; Knoll, Berta; Ohde, Hironori; Miklya, Ildikó

    1999-01-01

    The brain constituents β-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain (‘catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (−)Deprenyl (Selegiline) and (−)1-phenyl-2-propylaminopentane [(−)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property.By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (−)1-(benzofuran-2-yl)-2-propylaminopentane [(−)BPAP] was selected as a potential follower of (−)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain.(−)BPAP significantly enhanced in 0.18 μmol 1−1 concentration the impulse propagation mediated release of [3H]-noradrenaline and [3H]-dopamine and in 36 nmol 1−1 concentration the release of [3H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10−12–10−14 M (−)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of β-amyloid in 10−14 M concentration. In rats (−)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 μg kg−1 s.c. In the shuttle box, (−)BPAP in rats was about 130 times more potent than (−)deprenyl in antagonizing tetrabenazine induced inhibition of performance. PMID:10588928

  6. A narrative review of the empirical evidence on public attitudes on brain death and vital organ transplantation: the need for better data to inform policy.

    Science.gov (United States)

    Shah, Seema K; Kasper, Kenneth; Miller, Franklin G

    2015-04-01

    Vital organ transplantation is premised on 'the dead donor rule': donors must be declared dead according to medical and legal criteria prior to donation. However, it is controversial whether individuals diagnosed as 'brain dead' are really dead in accordance with the established biological conception of death-the irreversible cessation of the functioning of the organism as a whole. A basic understanding of brain death is also relevant for giving valid, informed consent to serve as an organ donor. There is therefore a need for reliable empirical data on public understanding of brain death and vital organ transplantation. We conducted a review of the empirical literature that identified 43 articles with approximately 18,603 study participants. These data demonstrate that participants generally do not understand three key issues: (1) uncontested biological facts about brain death, (2) the legal status of brain death and (3) that organs are procured from brain dead patients while their hearts are still beating and before their removal from ventilators. These data suggest that, despite scholarly claims of widespread public support for organ donation from brain dead patients, the existing data on public attitudes regarding brain death and organ transplantation reflect substantial public confusion. Our review raises questions about the validity of consent for vital organ transplantation and suggests that existing data are of little assistance in developing policy proposals for organ transplantation from brain dead patients. New approaches to rigorous empirical research with educational components and evaluations of understanding are urgently needed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  7. Oxcarbazepine causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.

    Science.gov (United States)

    Song, Y; Zhong, M; Cai, F-C

    2018-01-01

    Anti-epileptic drugs (AEDs) are the main methods for treatment of neonatal seizures; however, a few AEDs may cause developing brain damage of neonate. This study aims to investigate effects of oxcarbazepine (OXC) on developing brain damage of neonatal rats. Both of neonatal and adult rats were divided into 6 groups, including Control, OXC 187.5 mg/kg, OXC 281.25 mg/kg, OXC 375 mg/kg group, LEV and PHT group. Body weight and brain weight were evaluated. Hematoxylin and eosin (HE) and Nissl staining were used to observe neurocyte morphology and Nissl bodies, respectively. Apoptosis was examined using TUNEL assay, and caspase 8 activity was evaluated using spectrophotometer method. Cytochrome C-release was evaluated using flow cytometry. Western blot was used to examine Bax and Bcl-2 expression. OXC 375 mg/kg treatment significantly decreased brain weight compared to Control group in neonatal rats (P5 rats) (pOxcarbazepine at a concentration of 281.25 mg/kg or more causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.

  8. Neuroprotection by biodegradable PAMAM ester (e-PAM-R)-mediated HMGB1 siRNA delivery in primary cortical cultures and in the postischemic brain.

    Science.gov (United States)

    Kim, Il-Doo; Lim, Chae-Moon; Kim, Jung-Bin; Nam, Hye Yeong; Nam, Kihoon; Kim, Seung-Woo; Park, Jong-Sang; Lee, Ja-Kyeong

    2010-03-19

    Although RNA interference (RNAi)-mediated gene silencing provides a powerful strategy for modulating specific gene functions, difficulties associated with siRNA delivery have impeded the development of efficient therapeutic applications. In particular, the efficacy of siRNA delivery into neurons has been limited by extremely low transfection efficiencies. e-PAM-R is a biodegradable arginine ester of PAMAM dendrimer, which is readily degradable under physiological conditions (pH 7.4, 37 degrees C). In the present study, we investigated the efficiency of siRNA delivery by e-PAM-R in primary cortical cultures and in rat brain. e-PAM-R/siRNA complexes showed high transfection efficiencies and low cytotoxicities in primary cortical cultures. Localization of fluorescence-tagged siRNA revealed that siRNA was delivered not only into the nucleus and cytoplasm, but also along the processes of the neuron. e-PAM-R/siRNA complex-mediated target gene reduction was observed in over 40% of cells and it was persistent for over 48 h. The potential use of e-PAM-R was demonstrated by gene knockdown after transfecting High mobility group box-1 (HMGB1, a novel cytokine-like molecule) siRNA into H(2)O(2)- or NMDA-treated primary cortical cultures. In these cells, HMGB1 siRNA delivery successfully reduced both basal and H(2)O(2)- or NMDA-induced HMGB1 levels, and as a result of that, neuronal cell death was significantly suppressed in both cases. Furthermore, we showed that e-PAM-R successfully delivered HMGB1 siRNA into the rat brain, wherein HMGB1 expression was depleted in over 40% of neurons and astrocytes of the normal brain. Moreover, e-PAM-R-mediated HMGB1 siRNA delivery notably reduced infarct volume in the postischemic rat brain, which is generated by occluding the middle cerebral artery for 60 min. These results indicate that e-PAM-R, a novel biodegradable nonviral gene carrier, offers an efficient means of transfecting siRNA into primary neuronal cells and in the brain and of

  9. p75 neurotrophin receptor cleavage by α- and γ-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells.

    Science.gov (United States)

    Forsyth, Peter A; Krishna, Niveditha; Lawn, Samuel; Valadez, J Gerardo; Qu, Xiaotao; Fenstermacher, David A; Fournier, Michelle; Potthast, Lisa; Chinnaiyan, Prakash; Gibney, Geoffrey T; Zeinieh, Michele; Barker, Philip A; Carter, Bruce D; Cooper, Michael K; Kenchappa, Rajappa S

    2014-03-21

    Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.

  10. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  11. Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of 11C-labeled topotecan using small-animal positron emission tomography

    International Nuclear Information System (INIS)

    Yamasaki, Tomoteru; Fujinaga, Masayuki; Kawamura, Kazunori; Hatori, Akiko; Yui, Joji; Nengaki, Nobuki; Ogawa, Masanao; Yoshida, Yuichiro; Wakizaka, Hidekatsu; Yanamoto, Kazuhiko; Fukumura, Toshimitsu; Zhang Mingrong

    2011-01-01

    Introduction: Topotecan (TPT) is a camptothecin derivative and is an anticancer drug working as a topoisomerase-I-specific inhibitor. But TPT cannot penetrate through the blood-brain barrier. In this study, we synthesized a new positron emission tomography (PET) probe, [ 11 C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [ 11 C]TPT using small-animal PET. Methods: [ 11 C]TPT was synthesized by the reaction of a desmethyl precursor with [ 11 C]CH 3 I. In vitro study using [ 11 C]TPT was carried out in MES-SA and doxorubicin-resistant MES-SA/Dx5 cells in the presence or absence of elacridar, a specific inhibitor for Pgp and BCRP. The biodistribution of [ 11 C]TPT was determined using small-animal PET and the dissection method in mice. Results: The transport of [ 11 C]TPT to the extracellular side was determined in MES-SA/Dx5 cells exhibiting the expressions of Pgp and BCRP at high levels. This transport was inhibited by coincubation with elacridar. In Mdr1a/b -/- Bcrp1 -/- mice, PET results indicated that the brain uptake of [ 11 C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [ 11 C]TPT in wild-type mice was increased by treatment with elacridar. The radioactivity in the brain of elacridar-treated mice was maintained at a certain level after the injection of [ 11 C]TPT, although the radioactivity in the blood decreased with time. Conclusions: We demonstrated the increase of brain penetration of [ 11 C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.

  12. Middle Managers' Experience of Policy Implementation and Mediation in the Context of the Scottish Quality Enhancement Framework

    Science.gov (United States)

    Saunders, Murray; Sin, Cristina

    2015-01-01

    This paper analyses how middle managers perform and experience their role in enacting policy in Scottish higher education institutions. The policy focus is the quality enhancement framework (QEF) for learning and teaching in higher education, which was launched in 2003. The data-set was collected between 2008 and 2010, during the evaluation of the…

  13. Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

    Science.gov (United States)

    Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

    2016-11-01

    Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

  14. Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

    Directory of Open Access Journals (Sweden)

    Rodríguez-Muñoz María

    2009-03-01

    Full Text Available Abstract Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than

  15. Antisense-mediated isoform switching of steroid receptor coactivator-1 in the central nucleus of the amygdala of the mouse brain

    Directory of Open Access Journals (Sweden)

    Zalachoras Ioannis

    2013-01-01

    Full Text Available Abstract Background Antisense oligonucleotide (AON-mediated exon skipping is a powerful tool to manipulate gene expression. In the present study we investigated the potential of exon skipping by local injection in the central nucleus of the amygdala (CeA of the mouse brain. As proof of principle we targeted the splicing of steroid receptor coactivator-1 (SRC-1, a protein involved in nuclear receptor function. This nuclear receptor coregulator exists in two splice variants (SRC-1a and SRC-1e which display differential distribution and opposing activities in the brain, and whose mRNAs differ in a single SRC-1e specific exon. Methods For proof of principle of feasibility, we used immunofluorescent stainings to study uptake by different cell types, translocation to the nucleus and potential immunostimulatory effects at different time points after a local injection in the CeA of the mouse brain of a control AON targeting human dystrophin with no targets in the murine brain. To evaluate efficacy we designed an AON targeting the SRC-1e-specific exon and with qPCR analysis we measured the expression ratio of the two splice variants. Results We found that AONs were taken up by corticotropin releasing hormone expressing neurons and other cells in the CeA, and translocated into the cell nucleus. Immune responses after AON injection were comparable to those after sterile saline injection. A successful shift of the naturally occurring SRC-1a:SRC-1e expression ratio in favor of SRC-1a was observed, without changes in total SRC-1 expression. Conclusions We provide a proof of concept for local neuropharmacological use of exon skipping by manipulating the expression ratio of the two splice variants of SRC-1, which may be used to study nuclear receptor function in specific brain circuits. We established that exon skipping after local injection in the brain is a versatile and useful tool for the manipulation of splice variants for numerous genes that are relevant

  16. p75 Neurotrophin Receptor Cleavage by α- and γ-Secretases Is Required for Neurotrophin-mediated Proliferation of Brain Tumor-initiating Cells*

    Science.gov (United States)

    Forsyth, Peter A.; Krishna, Niveditha; Lawn, Samuel; Valadez, J. Gerardo; Qu, Xiaotao; Fenstermacher, David A.; Fournier, Michelle; Potthast, Lisa; Chinnaiyan, Prakash; Gibney, Geoffrey T.; Zeinieh, Michele; Barker, Philip A.; Carter, Bruce D.; Cooper, Michael K.; Kenchappa, Rajappa S.

    2014-01-01

    Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target. PMID:24519935

  17. Leptin Mediate High Fat Diet Sensitization of Angiotensin II-elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation

    Science.gov (United States)

    Xue, Baojian; Yu, Yang; Zhang, Zhongming; Guo, Fang; Beltz, Terry G.; Thunhorst, Robert L.; Felder, Robert B.; Johnson, Alan Kim

    2016-01-01

    Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin (Ang) II administration that is mediated at least in part by increased activity of brain renin-angiotensin system (RAS) and proinflammatory cytokines (PICs). The present study tested whether leptin mediates this HFD-induced sensitization of Ang II-elicited hypertension by interacting with brain RAS and PICs mechanisms. Rats fed a HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels and mRNA expression of leptin and its receptors in the lamina terminalis (LT) and hypothalamic paraventricular nucleus (PVN). Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of Ang II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the AT1-R antagonist irbesartan, the TNF-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the RAS and PICs in the LT and PVN. The leptin antagonist and the inhibitors of AT1-R, TNF-α synthesis and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by leptin through upregulation of central RAS and PICs. PMID:27021010

  18. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    Science.gov (United States)

    Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

    2014-01-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

  19. Estradiol receptors mediate estradiol-induced inhibition of mitochondrial Ca^{2+} efflux in rat caudate nucleus and brain stem

    OpenAIRE

    PETROVIC, SNJEZANA; MILOSEVIC, MAJA; RISTIC-MEDIC, DANIJELA; VELICKOVIC, NATASA; DRAKULIC, DUNJA; GRKOVIC, IVANA; HORVAT, ANICA

    2015-01-01

    Our earlier studies found that in vitro estradiol modulates mitochondrial Ca2+ transport in discrete brain regions. The present study examined the role of estradiol receptors (ERs) in estradiol-induced inhibition of Ca^{2+} efflux from synaptosomal mitochondria isolated from rat caudate nuclei and brain stems. Radioactively labeled CaCl_2 (0.6?0.75 µCi ^45CaCl_{2}) was used for Ca^{2+} transport monitoring. The results revealed that in the presence of ER antagonist 7\\alpha,17ß-[9[(4,4,5,5,5-...

  20. [Mediator processes in the brain structures in the late periods after external and combined exposure to ionizing radiation].

    Science.gov (United States)

    Taĭts, M Iu; Dudina, T V; Kandybo, T S; Elkina, A I

    1990-01-01

    In experiments with mature Wistar male rats it was shown that X-radiation of 12.9 mCi/kg and the combined effect of X-rays and 131I of 6.5 mCi/kg changed the rate of mediator processes in the structures responsible for the hypothalamic function regulation. At remote times (6 months) following irradiation differences were observed in the discoordination of mediator interrelations associated with the peculiarities of the indirect effect of external and combined irradiation implemented via endocrine mechanism system.

  1. Health Data Sharing Preferences of Consumers: Public Policy and Legal Implications of Consumer-Mediated Data Management

    Science.gov (United States)

    Moon, Lisa A.

    2017-01-01

    An individual's choice to share or have control of the sharing or withholding of their personal health information is one of the most significant public policy challenges associated with electronic information exchange. There were four aims of this study. First, to describe predictors of health data sharing preferences of consumers. Second, to…

  2. Solid lipid nanoparticles carrying chemotherapeutic drug across the blood-brain barrier through insulin receptor-mediated pathway.

    Science.gov (United States)

    Kuo, Yung-Chih; Shih-Huang, Chun-Yuan

    2013-09-01

    Carmustine (BCNU)-loaded solid lipid nanoparticles (SLNs) were grafted with 83-14 monoclonal antibody (MAb) (83-14 MAb/BCNU-SLNs) and applied to the brain-targeting delivery. Human brain-microvascular endothelial cells (HBMECs) incubated with 83-14 MAb/BCNU-SLNs were stained to demonstrate the interaction between the nanocarriers and expressed insulin receptors (IRs). The results revealed that the particle size of 83-14 MAb/BCNU-SLNs decreased with an increasing weight percentage of Dynasan 114 (DYN). Storage at 4 °C for 6 weeks slightly deformed the colloidal morphology. In addition, poloxamer 407 on 83-14 MAb/BCNU-SLNs induced cytotoxicity to RAW264.7 cells and inhibited phagocytosis by RAW264.7 cells. An increase in the weight percentage of DYN from 0% to 67% slightly reduced the viability of RAW264.7 cells and promoted phagocytosis. Moreover, the transport ability of 83-14 MAb/BCNU-SLNs across the blood-brain barrier (BBB) in vitro enhanced with an increasing weight percentage of Tween 80. 83-14 MAb on MAb/BCNU-SLNs stimulated endocytosis by HBMECs via IRs and enhanced the permeability of BCNU across the BBB. 83-14 MAb/BCNU-SLNs can be a promising antitumor drug delivery system for transporting BCNU to the brain.

  3. Morus alba leaf extract mediates neuroprotection against glyphosate-induced toxicity and biochemical alterations in the brain.

    Science.gov (United States)

    Rebai, Olfa; Belkhir, Manel; Boujelben, Adnen; Fattouch, Sami; Amri, Mohamed

    2017-04-01

    Recent studies demonstrate that glyphosate exposure is associated with oxidative stress and some neurological disorders such as Parkinson's pathology. Therefore, phytochemicals, in particular phenolic compounds, have attracted increasing attention as potential agents for neuroprotection. In the present study, we investigate the impact of glyphosate on the rat brain following i.p. injection and the possible molecular target of neuroprotective activity of the phenolic fraction from Morus alba leaf extract (MALE) and its ability to reduce oxidative damage in the brain. Wistar rats from 180 to 240 g were i.p. treated with a single dose of glyphosate (100 mg kg -1 b.w.) or MALE (100 μg mL -1  kg -1 b.w.) for 2 weeks. Brain homogenates were used to evaluate neurotoxicity induced by the pesticide. For this, biochemical parameters were measured. Data shows that MALE regulated oxidative stress and counteracted glyphosate-induced deleterious effects and oxidative damage in the brain, as it abrogated LDH, protein carbonyls, and malonyldialdehyde. MALE also appears to be able to scavenge H 2 O 2 levels, maintain iron and Ca 2+ homeostasis, and increase SOD activity. Thus, in vivo results showed that mulberry leaf extract is a potent protector against glyphosate-induced toxicity, and its protective effect could result from synergism or antagonism between the various bioactive phenolic compounds in the acetonic fraction from M. alba leaf extract.

  4. Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

    Directory of Open Access Journals (Sweden)

    Wang X

    2014-10-01

    Full Text Available Xiang Wang,1 Ping Liu,1 Weixiao Yang,1 Lu Li,1 Peijing Li,2 Zheng Liu,1 Zhongxiong Zhuo,1 Yunhua Gao1 1Department of Ultrasound, Xinqiao Hospital of the Third Military Medical University, Chongqing, 2Department of Ultrasound, General Hospital of the Jinan Military Area, Jinan, People’s Republic of China Abstract: Methotrexate (MTX is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 µm in diameter was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 µg/g > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 µg/g > MTX alone (6.97±0.75 µg/g > MTX-liposome-coupled microbubbles (2.92±0.39 µg/g. Therefore

  5. Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study.

    Science.gov (United States)

    Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-04-28

    Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo-DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS-induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD±Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically-relevant concentrations of doxorubicin (4.8±0.5μg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10μl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo-DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was

  6. Development, Characterization, and Implementation of a System for Focused Ultrasound-Mediated Blood-Brain Barrier Opening in Mice

    Science.gov (United States)

    Valdez, Michael Aaron

    The blood-brain barrier BBB refers to the set of specialized endothelial cells that line the vasculature in the brain and effectively control movement of molecules into and out of the brain. While necessary for proper brain function, the BBB blocks 98% of drugs from entering the brain and is the most significant barrier to developing therapies for neurodegenerative diseases. Active transport allows some specific molecules to cross the BBB, but therapeutic development using this route has had limited success. A number of techniques have been used to bypass the BBB, but are often highly invasive and ineffective. Over the last two decades, a minimally invasive technique to transiently open the BBB has been under development that utilizes transcranial focused ultrasound (FUS) in combination with intravascular microbubble contrast agents. This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS). Because of the utility of mouse models of neurological disease and the exploratory nature of MRgFUS, systems that allow BBB opening in mice are a useful and necessary tool to develop and evaluate this method for clinical application. In this dissertation project, a custom built, cost-effective FUS system for opening the BBB in mice was developed, with the objective of using this device to deliver therapeutics to the brain. Being a custom device, it was necessary to evaluate the ultrasound output, verify in vivo safety, and anticipate the therapeutic effect. The scope of the work herein consists of the design, construction, and evaluation of system that fulfills these requirements. The final constructed system cost was an order of magnitude less than any commercially available MRgFUS system. At this low price point, the hardware could allow the implementation of the methodology in many more research areas than previously possible. Additionally, to anticipate the

  7. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain

    Directory of Open Access Journals (Sweden)

    Iyaswamy Ashok

    2014-01-01

    Full Text Available Aspartame, an artificial sweetener, is very widely used in many foods and beverages. But there are controversies about its metabolite which is marked for its toxicity. Hence it is believed to be unsafe for human use. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether or not chronic aspartame (FDA approved Daily Acceptable Intake (ADI,40 mg/kg bwt administration could release methanol, and whether or not it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. To mimic the human methanol metabolism, Methotrexate (MTX-treated Wistar strain male albino rats were used and after the oral administration of aspartame, the effects were studied along with controls and MTX-treated controls. Aspartame exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, lipid peroxidation levels, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and catalase activity in (aspartame MTX-treated animals and with a significant decrease in reduced glutathione, glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic marker Bax showed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain.

  8. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain.

    Science.gov (United States)

    Ashok, Iyaswamy; Sheeladevi, Rathinasamy

    2014-01-01

    Aspartame, an artificial sweetener, is very widely used in many foods and beverages. But there are controversies about its metabolite which is marked for its toxicity. Hence it is believed to be unsafe for human use. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether or not chronic aspartame (FDA approved Daily Acceptable Intake (ADI),40 mg/kg bwt) administration could release methanol, and whether or not it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. To mimic the human methanol metabolism, Methotrexate (MTX)-treated Wistar strain male albino rats were used and after the oral administration of aspartame, the effects were studied along with controls and MTX-treated controls. Aspartame exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, lipid peroxidation levels, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and catalase activity in (aspartame MTX)-treated animals and with a significant decrease in reduced glutathione, glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic marker Bax showed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain.

  9. Active Targeted Macrophage-mediated Delivery of Catalase to Affected Brain Regions in Models of Parkinson's Disease.

    Science.gov (United States)

    Zhao, Yuling; Haney, Matthew J; Mahajan, Vivek; Reiner, Benjamin C; Dunaevsky, Anna; Mosley, R Lee; Kabanov, Alexander V; Gendelman, Howard E; Batrakova, Elena V

    2011-09-10

    We previously demonstrated that monocyte-macrophage based drug delivery can be applied to a spectrum of infectious, neoplastic, and degenerative disorders. In particular, bone marrow-derived macrophages (BMM) loaded with nano formulated catalase, "nanozyme", were shown to attenuate neuro inflammation and nigrostriatal degeneration in rodent models of Parkinson's disease (PD). Nonetheless, the pharmacokinetics and biodistribution of BMM-incorporated nanozyme has not been explored. To this end, we now demonstrate that BMM, serving as a "depot" for nanozyme, increased area under the curve(AUC), half-life, and mean residence time in blood circulation of the protein when compared to the nanozyme administered alone. Accordingly, bioavailability of the nanozyme for the brain, spleen, kidney, and liver was substantially increased. Importantly, nanozyme-loaded BMM targeted diseased sites and improved transport across the blood brain barrier. This was seen specifically in affected brain subregions in models of PD. Engaging natural immune cells such as monocyte-macrophages as drug carriers provides a new perspective for therapeutic delivery for PD and also likely a range of other inflammatory and degenerative diseases.

  10. BOLD fMRI of C-Fiber Mediated Nociceptive Processing in Mouse Brain in Response to Thermal Stimulation of the Forepaws.

    Directory of Open Access Journals (Sweden)

    Simone C Bosshard

    Full Text Available Functional magnetic resonance imaging (fMRI in rodents enables non-invasive studies of brain function in response to peripheral input or at rest. In this study we describe a thermal stimulation paradigm using infrared laser diodes to apply noxious heat to the forepaw of mice in order to study nociceptive processing. Stimulation at 45 and 46°C led to robust BOLD signal changes in various brain structures including the somatosensory cortices and the thalamus. The BOLD signal amplitude scaled with the temperature applied but not with the area irradiated by the laser beam. To demonstrate the specificity of the paradigm for assessing nociceptive signaling we administered the quaternary lidocaine derivative QX-314 to the forepaws, which due to its positive charge cannot readily cross biological membranes. However, upon activation of TRPV1 channels following the administration of capsaicin the BOLD signal was largely abolished, indicative of a selective block of the C-fiber nociceptors due to QX-314 having entered the cells via the now open TRPV1 channels. This demonstrates that the cerebral BOLD response to thermal noxious paw stimulation is specifically mediated by C-fibers.

  11. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting.

    Science.gov (United States)

    Liang, Qingning; Zhong, Ling; Zhang, Jialiang; Wang, Yu; Bornstein, Stefan R; Triggle, Chris R; Ding, Hong; Lam, Karen S L; Xu, Aimin

    2014-12-01

    Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor α (PPARα) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARα KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARα KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  12. Sex- and brain region-specific patterns of gene expression associated with socially-mediated puberty in a eusocial mammal.

    Directory of Open Access Journals (Sweden)

    Mariela Faykoo-Martinez

    Full Text Available The social environment can alter pubertal timing through neuroendocrine mechanisms that are not fully understood; it is thought that stress hormones (e.g., glucocorticoids or corticotropin-releasing hormone influence the hypothalamic-pituitary-gonadal axis to inhibit puberty. Here, we use the eusocial naked mole-rat, a unique species in which social interactions in a colony (i.e. dominance of a breeding female suppress puberty in subordinate animals. Removing subordinate naked mole-rats from this social context initiates puberty, allowing for experimental control of pubertal timing. The present study quantified gene expression for reproduction- and stress-relevant genes acting upstream of gonadotropin-releasing hormone in brain regions with reproductive and social functions in pre-pubertal, post-pubertal, and opposite sex-paired animals (which are in various stages of pubertal transition. Results indicate sex differences in patterns of neural gene expression. Known functions of genes in brain suggest stress as a key contributing factor in regulating male pubertal delay. Network analysis implicates neurokinin B (Tac3 in the arcuate nucleus of the hypothalamus as a key node in this pathway. Results also suggest an unappreciated role for the nucleus accumbens in regulating puberty.

  13. Neuroanatomical circuitry between kidney and rostral elements of brain: a virally mediated transsynaptic tracing study in mice.

    Science.gov (United States)

    Zhou, Ye-Ting; He, Zhi-Gang; Liu, Tao-Tao; Feng, Mao-Hui; Zhang, Ding-Yu; Xiang, Hong-Bing

    2017-02-01

    The identity of higher-order neurons and circuits playing an associative role to control renal function is not well understood. We identified specific neural populations of rostral elements of brain regions that project multisynaptically to the kidneys in 3-6 days after injecting a retrograde tracer pseudorabies virus (PRV)-614 into kidney of 13 adult male C57BL/6J strain mice. PRV-614 infected neurons were detected in a number of mesencephalic (e.g. central amygdala nucleus), telencephalic regions and motor cortex. These divisions included the preoptic area (POA), dorsomedial hypothalamus (DMH), lateral hypothalamus, arcuate nucleus (Arc), suprachiasmatic nucleus (SCN), periventricular hypothalamus (PeH), and rostral and caudal subdivision of the paraventricular nucleus of the hypothalamus (PVN). PRV-614/Tyrosine hydroxylase (TH) double-labeled cells were found within DMH, Arc, SCN, PeH, PVN, the anterodorsal and medial POA. A subset of neurons in PVN that participated in regulating sympathetic outflow to kidney was catecholaminergic or serotonergic. PRV-614 infected neurons within the PVN also contained arginine vasopressin or oxytocin. These data demonstrate the rostral elements of brain innervate the kidney by the neuroanatomical circuitry.

  14. Chronic alcoholism-mediated impairment in the medulla oblongata: a mechanism of alcohol-related mortality in traumatic brain injury?

    Science.gov (United States)

    Lai, Xiao-ping; Yu, Xiao-jun; Qian, Hong; Wei, Lai; Lv, Jun-yao; Xu, Xiao-hu

    2013-01-01

    Alcohol-related traumatic brain injury (TBI) is a common condition in medical and forensic practice, and results in high prehospital mortality. We investigated the mechanism of chronic alcoholism-related mortality by examining the effects of alcohol on the synapses of the medulla oblongata in a rat model of TBI. Seventy adult male Sprague-Dawley rats were randomly assigned to either ethanol (EtOH) group, EtOH-TBI group, or control groups (water group, water-TBI group). To establish chronic alcoholism model, rats in the EtOH group were given EtOH twice daily (4 g/kg for 2 weeks and 6 g/kg for another 2 weeks). The rats also received a minor strike on the occipital tuberosity with an iron pendulum. Histopathologic and ultrastructure changes and the numerical density of the synapses in the medulla oblongata were examined. Expression of postsynaptic density-95 (PSD-95) in the medulla oblongata was measured by ELISA. Compared with rats in the control group, rats in the chronic alcoholism group showed: (1) minor axonal degeneration; (2) a significant decrease in the numerical density of synapses (p Chronic alcoholism induces significant synapse loss and axonal impairment in the medulla oblongata and renders the brain more susceptible to TBI. The combined effects of chronic alcoholism and TBI induce significant synapse and axon impairment and result in high mortality.

  15. Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults.

    Science.gov (United States)

    Ehlers, Diane K; Daugherty, Ana M; Burzynska, Agnieszka Z; Fanning, Jason; Awick, Elizabeth A; Chaddock-Heyman, Laura; Kramer, Arthur F; McAuley, Edward

    2017-01-01

    Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness. Methods: Participants were 247 older adults (65.4 ± 4.6 years-old) enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance ( n = 69), Strength/Stretching/Stability ( n = 70), Walk ( n = 54), and Walk Plus ( n = 54). All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus) before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework. Results: Perceived social support increased ( p = 0.003), while stress ( p loneliness ( p = 0.001) decreased over the intervention. Increased social support directly (-0.63, p loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44). However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0.02). Further, individuals with larger baseline PFC volumes experienced greater reductions in stress due

  16. Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults

    Directory of Open Access Journals (Sweden)

    Diane K. Ehlers

    2017-04-01

    Full Text Available Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness.Methods: Participants were 247 older adults (65.4 ± 4.6 years-old enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance (n = 69, Strength/Stretching/Stability (n = 70, Walk (n = 54, and Walk Plus (n = 54. All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework.Results: Perceived social support increased (p = 0.003, while stress (p < 0.001, and loneliness (p = 0.001 decreased over the intervention. Increased social support directly (−0.63, p < 0.01 and indirectly, through decreased stress (−0.10, p = 0.02, predicted decreased loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44. However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0

  17. Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

    Science.gov (United States)

    Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

    2018-02-01

    OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

  18. Opioid receptor subtypes mediating the noise-induced decreases in high-affinity choline uptake in the rat brain.

    Science.gov (United States)

    Lai, H; Carino, M A

    1992-07-01

    Acute (20 min) exposure to 100-dB white noise elicits a naltrexone-sensitive decrease in sodium-dependent high-affinity choline uptake in the frontal cortex and hippocampus of the rat. In the present study, the subtypes of opioid receptors involved were investigated by pretreating rats with microinjection of specific opioid-receptor antagonists into the lateral cerebroventricle before noise exposure. We found that the noise-induced decrease in high-affinity choline uptake in the hippocampus was blocked by pretreatment with either mu-, delta-, or kappa-opioid-receptor antagonists, whereas the effect of noise on frontal cortical high-affinity choline uptake was blocked by a mu- and delta- but not by a kappa-antagonist. These data further confirm the role of endogenous opioids in mediating the effects of noise on central cholinergic activity and indicate that different neural mechanisms are involved in the effects of noise on the frontal cortical and hippocampal cholinergic systems.

  19. Mediation in matters of environmental policy and industrial project planning. Theory and case reports; Umweltmediation in Theorie und Anwendung

    Energy Technology Data Exchange (ETDEWEB)

    Oppermann, B.; Langer, K.

    2000-07-01

    The guidebook is intended for regional or local decision-making bodies from industry and society, politics and administration involved in the planning, organisation and performance of public hearings in the context of industrial project planning, technology assessment and compliance with environmental policy and requirements. Participation of the public and conflict resolution are essential aspects of the guidebook which is one in a series of existing and planned publications on a variety of issues of public interest. (orig./CB) [German] Im Bereich technik- und umeltrelevanter Planungen werden immer haeufiger neue Formen der Buergerbeteiligung diskutiert. Die Akademie fuer Technikfolgenabschaetzung in Baden-Wuerttemberg hat es sich seit einigen Jahren zur Aufgabe gemacht, innovative Verfahren der diskursiven Verstaendigung und Konfliktloesung zu erproben und weiterzuentwickeln. Es zeigte sich, dass ein grosser Bedarf nach allgemeinverstaendlichen Praxisanleitungen besteht, so dass die Akademie begonnen hat, Praxis-Leitfaeden z.B. fuer regionale und lokale Entscheidungstraeger aus Politik, Verwaltung, Wirtschaft und Gesellschaft zu erarbeiten, als Hilfestellung bei Planung, Organisation und Durchfuehrung der vorgeschriebenen Verfahren. Neben dem vorliegenden Leitfaden sind auch weitere zu anderen Themen schon erschienen oder in Planung. (orig./CB)

  20. Interest mediation and policy formulation in the European Union. Influence of transnational technology-oriented agreements on European policy in the field of carbon capture and storage. Advances in systems analysis 3

    International Nuclear Information System (INIS)

    Schenk, Olga

    2013-01-01

    decision-making system and ii) the level of the organizational development of TOA. The research interest of the project addresses the interest mediation processes in a specific policy sector. The goal of the research project is to contribute to the study of the influence of transnational organizations at policy-making in a specific policy sector of the EU. The organizations that are included into the unit of analysis do not have any formal decisionmaking authority in the decision-making system of the EU. They are assumed to influence the actors which are in possession of such authority. The focus of the project is directed at scope of the influence of the transnational organizations and the factors that explain the variation of their influence. The PhD project contributes to the research fields Interest Mediation in the Multi-Level System of the EU and Global Environmental Governance. The research project was developed in cooperation between the Department for Political Science of the RWTH-Aachen University and the Department of Systems Analysis and Technology Evaluation of the Forschungszentrum Juelich.

  1. Interest mediation and policy formulation in the European Union. Influence of transnational technology-oriented agreements on European policy in the field of carbon capture and storage. Advances in systems analysis 3

    Energy Technology Data Exchange (ETDEWEB)

    Schenk, Olga

    2013-10-01

    in the political decision-making system and ii) the level of the organizational development of TOA. The research interest of the project addresses the interest mediation processes in a specific policy sector. The goal of the research project is to contribute to the study of the influence of transnational organizations at policy-making in a specific policy sector of the EU. The organizations that are included into the unit of analysis do not have any formal decisionmaking authority in the decision-making system of the EU. They are assumed to influence the actors which are in possession of such authority. The focus of the project is directed at scope of the influence of the transnational organizations and the factors that explain the variation of their influence. The PhD project contributes to the research fields Interest Mediation in the Multi-Level System of the EU and Global Environmental Governance. The research project was developed in cooperation between the Department for Political Science of the RWTH-Aachen University and the Department of Systems Analysis and Technology Evaluation of the Forschungszentrum Juelich.

  2. Parallel neural pathways in higher visual centers of the Drosophila brain that mediate wavelength-specific behavior

    Directory of Open Access Journals (Sweden)

    Hideo eOtsuna

    2014-02-01

    Full Text Available Compared with connections between the retinae and primary visual centers, relatively less is known in both mammals and insects about the functional segregation of neural pathways connecting primary and higher centers of the visual processing cascade. Here, using the Drosophila visual system as a model, we demonstrate two levels of parallel computation in the pathways that connect primary visual centers of the optic lobe to computational circuits embedded within deeper centers in the central brain. We show that a seemingly simple achromatic behavior, namely phototaxis, is under the control of several independent pathways, each of which is responsible for navigation towards unique wavelengths. Silencing just one pathway is enough to disturb phototaxis towards one characteristic monochromatic source, whereas phototactic behavior towards white light is not affected. The response spectrum of each demonstrable pathway is different from that of individual photoreceptors, suggesting subtractive computations. A choice assay between two colors showed that these pathways are responsible for navigation towards, but not for the detection itself of, the monochromatic light. The present study provides novel insights about how visual information is separated and processed in parallel to achieve robust control of an innate behavior.

  3. Constructive episodic simulation of the future and the past: distinct subsystems of a core brain network mediate imagining and remembering.

    Science.gov (United States)

    Addis, Donna Rose; Pan, Ling; Vu, Mai-Anh; Laiser, Noa; Schacter, Daniel L

    2009-09-01

    Recent neuroimaging studies demonstrate that remembering the past and imagining the future rely on the same core brain network. However, findings of common core network activity during remembering and imagining events and increased activity during future event simulation could reflect the recasting of past events as future events. We experimentally recombined event details from participants' own past experiences, thus preventing the recasting of past events as imagined events. Moreover, we instructed participants to imagine both future and past events in order to disambiguate whether future-event-specific activity found in previous studies is related specifically to prospection or a general demand of imagining episodic events. Using spatiotemporal partial-least-squares (PLS), a conjunction contrast confirmed that even when subjects are required to recombine details into imagined events (and prevented from recasting events), significant neural overlap between remembering and imagining events is evident throughout the core network. However, the PLS analysis identified two subsystems within the core network. One extensive subsystem was preferentially associated with imagining both future and past events. This finding suggests that regions previously associated with future events, such as anterior hippocampus, medial prefrontal cortex and inferior frontal gyrus, support processes general to imagining events rather than specific to prospection. This PLS analysis also identified a subsystem, including hippocampus, parahippocampal gyrus and extensive regions of posterior visual cortex that was preferentially engaged when remembering past events rich in contextual and visuospatial detail.

  4. Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

    International Nuclear Information System (INIS)

    Ji, Jian-feng; Ji, Sheng-jun; Sun, Rui; Li, Kun; Zhang, Yuan; Zhang, Li-yuan; Tian, Ye

    2014-01-01

    Highlights: •Forced exercise can ameliorate WBI induced cognitive impairment in our rat model. •Mature BDNF plays an important role in the effects of forced exercise. •Exercise may be a possible treatment of the radiation-induced cognitive impairment. -- Abstract: Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non

  5. Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Jian-feng; Ji, Sheng-jun; Sun, Rui; Li, Kun; Zhang, Yuan; Zhang, Li-yuan; Tian, Ye, E-mail: dryetian@hotmail.com

    2014-01-10

    Highlights: •Forced exercise can ameliorate WBI induced cognitive impairment in our rat model. •Mature BDNF plays an important role in the effects of forced exercise. •Exercise may be a possible treatment of the radiation-induced cognitive impairment. -- Abstract: Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non

  6. Analgesia produced by exposure to 2450-MHz radiofrequency radiation (RFR) is mediated by brain mu- and kappa-opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Salomon, G.; Park, E.J.; Quock, R.M. (Univ. of Illinois, Rockford (United States))

    1992-02-26

    This study was conducted to identify the opioid receptor subtype(s) responsible for RFR-induced analgesia. Male Swiss Webster mice, 20-25 g, were exposed to 20 mW/cm{sup 2} RFR in a 2,450-MHz waveguide system for 10 min, then tested 15 min later in the abdominal constriction paradigm which detects {mu}- and {kappa}-opioid activity. Immediately following RFR exposure, different groups of mice were pretreated intracerebroventricularly with different opioid receptor blockers with selectivity for {mu}- or {kappa}-opioid receptors. Results show that RFR-induced analgesia was attenuated by higher but not lower doses of the non-selective antagonist naloxone, but the selective {mu}-opioid antagonist {beta}-funaltrexamine and by the selective {kappa}-opioid antagonist norbinaltorphimine. RFR-induced analgesia was also reduced by subcutaneous pretreatment with 5.0 mg/kg of the {mu}-/{kappa}-opioid antagonist({minus})-5,9-diethyl-{alpha}-5,9-dialkyl-2{prime}-hydroxy-6,7-benzomorphan(MR-2266). These findings suggest that RFR-induced analgesia may be mediated by both {mu}- and {kappa}-opioid mechanisms.

  7. Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals.

    Science.gov (United States)

    Pozdnyakova, Natalia; Pastukhov, Artem; Dudarenko, Marina; Galkin, Maxim; Borysov, Arsenii; Borisova, Tatiana

    2016-03-31

    Nanodiamonds are one of the most perspective nano-sized particles with superb physical and chemical properties, which are mainly composed of carbon sp(3) structures in the core with sp(2) and disorder/defect carbons on the surface. The research team recently demonstrated neuromodulatory properties of carbon nanodots with other than nanodiamonds hybridization types, i.e., sp(2) hybridized graphene islands and diamond-like sp(3) hybridized elements. In this study, neuroactive properties of uncoated nanodiamonds produced by detonation synthesis were assessed basing on their effects on transporter-mediated uptake and the ambient level of excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), in isolated rat brain nerve terminals. It was shown that nanodiamonds in a dose-dependent manner attenuated the initial velocity of Na(+)-dependent transporter-mediated uptake and accumulation of L-[(14)C]glutamate and [(3)H]GABA by nerve terminals and increased the ambient level of these neurotransmitters. Also, nanodiamonds caused a weak reduction in acidification of synaptic vesicles and depolarization of the plasma membrane of nerve terminals. Therefore, despite different types of hybridization in nanodiamonds and carbon dots, they exhibit very similar effects on glutamate and GABA transport in nerve terminals and this common feature of both nanoparticles is presumably associated with their nanoscale size. Observed neuroactive properties of pure nanodiamonds can be used in neurotheranostics for simultaneous labeling/visualization of nerve terminals and modulation of key processes of glutamate- and GABAergic neurotransmission. In comparison with carbon dots, wider medical application involving hypo/hyperthermia, external magnetic fields, and radiolabel techniques can be perspective for nanodiamonds.

  8. The Safety and Feasibility of Image-Guided BrainPath-Mediated Transsulcul Hematoma Evacuation: A Multicenter Study.

    Science.gov (United States)

    Labib, Mohamed A; Shah, Mitesh; Kassam, Amin B; Young, Ronald; Zucker, Lloyd; Maioriello, Anthony; Britz, Gavin; Agbi, Charles; Day, J D; Gallia, Gary; Kerr, Robert; Pradilla, Gustavo; Rovin, Richard; Kulwin, Charles; Bailes, Julian

    2017-04-01

    Subcortical injury resulting from conventional surgical management of intracranial hemorrhage may counteract the potential benefits of hematoma evacuation. To evaluate the safety and potential benefits of a novel, minimally invasive approach for clot evacuation in a multicenter study. The integrated approach incorporates 5 competencies: (1) image interpretation and trajectory planning, (2) dynamic navigation, (3) atraumatic access system (BrainPath, NICO Corp, Indianapolis, Indiana), (4) extracorporeal optics, and (5) automated atraumatic resection. Twelve neurosurgeons from 11 centers were trained to use this approach through a continuing medical education-accredited course. Demographical, clinical, and radiological data of patients treated over 2 years were analyzed retrospectively. Thirty-nine consecutive patients were identified. The median Glasgow Coma Scale (GCS) score at presentation was 10 (range, 5-15). The thalamus/basal ganglion regions were involved in 46% of the cases. The median hematoma volume and depth were 36 mL (interquartile range [IQR], 27-65 mL) and 1.4 cm (IQR, 0.3-2.9 cm), respectively. The median time from ictus to surgery was 24.5 hours (IQR, 16-66 hours). The degree of hematoma evacuation was ≥90%, 75% to 89%, and 50% to 74% in 72%, 23%, and 5.0% of the patients, respectively. The median GCS score at discharge was 14 (range, 8-15). The improvement in GCS score was statistically significant ( P < .001). Modified Rankin Scale data were available for 35 patients. Fifty-two percent of those patients had a modified Rankin Scale score of ≤2. There were no mortalities. The approach was safely performed in all patients with a relatively high rate of clot evacuation and functional independence. Copyright © 2016 by the Congress of Neurological Surgeons

  9. Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans.

    Directory of Open Access Journals (Sweden)

    Michael P O'Donnell

    2018-02-01

    Full Text Available Animals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2 controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-β and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via a PDF-2/PDFR-1 neuropeptide signaling-dependent pathway. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL associated with these traits. Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state.

  10. Lesions of entorhinal cortex produce a calpain-mediated degradation of brain spectrin in dentate gyrus. I. Biochemical studies.

    Science.gov (United States)

    Seubert, P; Ivy, G; Larson, J; Lee, J; Shahi, K; Baudry, M; Lynch, G

    1988-09-06

    Lesions of the rat entorhinal cortex cause extensive synaptic restructuring and perturbation of calcium regulation in the dentate gyrus of hippocampus. Calpain is a calcium-activated protease which has been implicated in degenerative phenomena in muscles and in peripheral nerves. In addition, calpain degrades several major structural neuronal proteins and has been proposed to play a critical role in the morphological changes observed following deafferentation. In this report we present evidence that lesions of the entorhinal cortex produce a marked increase in the breakdown of brain spectrin, a substrate for calpain, in the dentate gyrus. Two lines of evidence indicate that this effect is due to calpain activation: (i) the spectrin breakdown products observed following the lesion are indistinguishable from calpain-generated spectrin fragments in vitro; and (ii) their appearance can be reduced by prior intraventricular in fusion of leupeptin, a calpain inhibitor. Levels of spectrin breakdown products are increased as early as 4 h post-lesion, reach maximal values at 2 days, and remain above normal to some degree for at least 27 days. In addition, a small but significant increase in spectrin proteolysis is also observed in the hippocampus contralateral to the lesioned side in the first week postlesion. At 2 days postlesion the total spectrin immunoreactivity (native polypeptide plus breakdown products) increases by 40%, suggesting that denervation of the dentate gyrus produces not only an increased rate of spectrin degradation but also an increased rate of spectrin synthesis. These results indicate that calpain activation and spectrin degradation are early biochemical events following deafferentation and might well participate in the remodelling of postsynaptic structures. Finally, the magnitude of the observed effects as well as the stable nature of the breakdown products provide a sensitive assay for neuronal pathology.

  11. A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain.

    Science.gov (United States)

    Ishimoto, Hiroshi; Wang, Zhe; Rao, Yi; Wu, Chun-Fang; Kitamoto, Toshihiro

    2013-01-01

    The biological actions of steroid hormones are mediated primarily by their cognate nuclear receptors, which serve as steroid-dependent transcription factors. However, steroids can also execute their functions by modulating intracellular signaling cascades rapidly and independently of transcriptional regulation. Despite the potential significance of such "non-genomic" steroid actions, their biological roles and the underlying molecular mechanisms are not well understood, particularly with regard to their effects on behavioral regulation. The major steroid hormone in the fruit fly Drosophila is 20-hydroxy-ecdysone (20E), which plays a variety of pivotal roles during development via the nuclear ecdysone receptors. Here we report that DopEcR, a G-protein coupled receptor for ecdysteroids, is involved in activity- and experience-dependent plasticity of the adult central nervous system. Remarkably, a courtship memory defect in rutabaga (Ca²⁺/calmodulin-responsive adenylate cyclase) mutants was rescued by DopEcR overexpression or acute 20E feeding, whereas a memory defect in dunce (cAMP-specific phosphodiestrase) mutants was counteracted when a loss-of-function DopEcR mutation was introduced. A memory defect caused by suppressing dopamine synthesis was also restored through enhanced DopEcR-mediated ecdysone signaling, and rescue and phenocopy experiments revealed that the mushroom body (MB)--a brain region central to learning and memory in Drosophila--is critical for the DopEcR-dependent processing of courtship memory. Consistent with this finding, acute 20E feeding induced a rapid, DopEcR-dependent increase in cAMP levels in the MB. Our multidisciplinary approach demonstrates that DopEcR mediates the non-canonical actions of 20E and rapidly modulates adult conditioned behavior through cAMP signaling, which is universally important for neural plasticity. This study provides novel insights into non-genomic actions of steroids, and opens a new avenue for genetic

  12. A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain.

    Directory of Open Access Journals (Sweden)

    Hiroshi Ishimoto

    Full Text Available The biological actions of steroid hormones are mediated primarily by their cognate nuclear receptors, which serve as steroid-dependent transcription factors. However, steroids can also execute their functions by modulating intracellular signaling cascades rapidly and independently of transcriptional regulation. Despite the potential significance of such "non-genomic" steroid actions, their biological roles and the underlying molecular mechanisms are not well understood, particularly with regard to their effects on behavioral regulation. The major steroid hormone in the fruit fly Drosophila is 20-hydroxy-ecdysone (20E, which plays a variety of pivotal roles during development via the nuclear ecdysone receptors. Here we report that DopEcR, a G-protein coupled receptor for ecdysteroids, is involved in activity- and experience-dependent plasticity of the adult central nervous system. Remarkably, a courtship memory defect in rutabaga (Ca²⁺/calmodulin-responsive adenylate cyclase mutants was rescued by DopEcR overexpression or acute 20E feeding, whereas a memory defect in dunce (cAMP-specific phosphodiestrase mutants was counteracted when a loss-of-function DopEcR mutation was introduced. A memory defect caused by suppressing dopamine synthesis was also restored through enhanced DopEcR-mediated ecdysone signaling, and rescue and phenocopy experiments revealed that the mushroom body (MB--a brain region central to learning and memory in Drosophila--is critical for the DopEcR-dependent processing of courtship memory. Consistent with this finding, acute 20E feeding induced a rapid, DopEcR-dependent increase in cAMP levels in the MB. Our multidisciplinary approach demonstrates that DopEcR mediates the non-canonical actions of 20E and rapidly modulates adult conditioned behavior through cAMP signaling, which is universally important for neural plasticity. This study provides novel insights into non-genomic actions of steroids, and opens a new avenue for

  13. Different populations of prostaglandin EP3 receptor-expressing preoptic neurons project to two fever-mediating sympathoexcitatory brain regions.

    Science.gov (United States)

    Nakamura, Y; Nakamura, K; Morrison, S F

    2009-06-30

    The central mechanism of fever induction is triggered by an action of prostaglandin E(2) (PGE(2)) on neurons in the preoptic area (POA) through the EP3 subtype of prostaglandin E receptor. EP3 receptor (EP3R)-expressing POA neurons project directly to the dorsomedial hypothalamus (DMH) and to the rostral raphe pallidus nucleus (rRPa), key sites for the control of thermoregulatory effectors. Based on physiological findings, we hypothesize that the febrile responses in brown adipose tissue (BAT) and those in cutaneous vasoconstrictors are controlled independently by separate neuronal pathways: PGE(2) pyrogenic signaling is transmitted from EP3R-expressing POA neurons via a projection to the DMH to activate BAT thermogenesis and via another projection to the rRPa to increase cutaneous vasoconstriction. In this case, DMH-projecting and rRPa-projecting neurons would constitute segregated populations within the EP3R-expressing neuronal group in the POA. Here, we sought direct anatomical evidence to test this hypothesis with a double-tracing experiment in which two types of the retrograde tracer, cholera toxin b-subunit (CTb), conjugated with different fluorophores were injected into the DMH and the rRPa of rats and the resulting retrogradely labeled populations of EP3R-immunoreactive neurons in the POA were identified with confocal microscopy. We found substantial numbers of EP3R-immunoreactive neurons in both the DMH-projecting and the rRPa-projecting populations. However, very few EP3R-immunoreactive POA neurons were labeled with both the CTb from the DMH and that from the rRPa, although a substantial number of neurons that were not immunoreactive for EP3R were double-labeled with both CTbs. The paucity of the EP3R-expressing neurons that send collaterals to both the DMH and the rRPa suggests that pyrogenic signals are sent independently to these caudal brain regions from the POA and that such pyrogenic outputs from the POA reflect different control mechanisms for BAT

  14. Exposure to traffic-generated air pollutants mediates alterations in brain microvascular integrity in wildtype mice on a high-fat diet.

    Science.gov (United States)

    Suwannasual, Usa; Lucero, JoAnn; McDonald, Jacob D; Lund, Amie K

    2018-01-01

    Air pollution-exposure is associated with detrimental outcomes in the central nervous system (CNS) such as cerebrovascular disorders, including stroke, and neurodegenerative diseases. While the mechanisms of these CNS-related outcomes involved have not been fully elucidated, exposure to traffic-generated air pollutants has been associated with altered blood brain barrier (BBB) integrity and permeability. The current study investigated whether inhalation exposure to mixed vehicle emissions (MVE) alters cerebral microvascular integrity in healthy 3 mo old C57BL/6 mice, as well as whether exposure-mediated effects were exacerbated by a high-fat (HF) vs. low-fat (LF) diet. Mice on each diet were randomly assigned to be exposed to either filtered air (FA) or MVE [100PM/m 3 vehicle emissions mixture: 30µg PM/m 3 gasoline engine + 70µg PM/m 3 diesel engine emissions; median size ~ 60nm; particle mass size distribution median of ~ 1µm (range: diet, results in altered BBB integrity and increased ox-LDL signaling in the cerebral vasculature in a wildtype animal model. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back

    Directory of Open Access Journals (Sweden)

    Roberto Coccurello

    2018-04-01

    Full Text Available Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on “old” and “new” players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin, and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of “feeding center,” we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin

  16. Social isolation mediated anxiety like behavior is associated with enhanced expression and regulation of BDNF in the female mouse brain.

    Science.gov (United States)

    Kumari, Anita; Singh, Padmanabh; Baghel, Meghraj Singh; Thakur, M K

    2016-05-01

    Adverse early life experience is prominent risk factors for numerous psychiatric illnesses, including mood and anxiety disorders. It imposes serious long-term costs on the individual as well as health and social systems. Hence, developing therapies that prevent the long-term consequences of early life stress is of utmost importance, and necessitates a better understanding of the mechanisms by which early life stress triggers long-lasting alterations in gene expression and behavior. Post-weaning isolation rearing of rodents models the behavioral consequences of adverse early life experiences in humans and it is reported to cause anxiety like behavior which is more common in case of females. Therefore, in the present study, we have studied the impact of social isolation of young female mice for 8weeks on the anxiety like behavior and the underlying molecular mechanism. Elevated plus maze and open field test revealed that social isolation caused anxiety like behavior. BDNF, a well-known molecule implicated in the anxiety like behavior, was up-regulated both at the message and protein level in cerebral cortex by social isolation. CREB-1 and CBP, which play a crucial role in BDNF transcription, were up-regulated at mRNA level in cerebral cortex by social isolation. HDAC-2, which negatively regulates BDNF expression, was down-regulated at mRNA and protein level in cerebral cortex by social isolation. Furthermore, BDNF acts in concert with Limk-1, miRNA-132 and miRNA-134 for the regulation of structural and morphological plasticity. Social isolation resulted in up-regulation of Limk-1 mRNA and miRNA-132 expression in the cerebral cortex. MiRNA-134, which inhibits the translation of Limk-1, was decreased in cerebral cortex by social isolation. Taken together, our study suggests that social isolation mediated anxiety like behavior is associated with up-regulation of BDNF expression and concomitant increase in the expression of CBP, CREB-1, Limk-1 and miRNA-132, and decrease

  17. Brain Migration Revisited

    Science.gov (United States)

    Vinokur, Annie

    2006-01-01

    The "brain drain/brain gain" debate has been going on for the past 40 years, with irresolvable theoretical disputes and unenforceable policy recommendations that economists commonly ascribe to the lack of reliable empirical data. The recent report of the World Bank, "International migration, remittances and the brain drain", documents the…

  18. Complement mediated renal inflammation induced by donor brain death : role of renal C5a-C5aR interaction

    NARCIS (Netherlands)

    van Werkhoven, M. B.; Damman, J.; van Dijk, M. C. R. F.; Daha, M. R.; de Jong, I. J.; Leliveld, A.; Krikke, C.; Leuvenink, H. G.; van Goor, H.; van Son, W. J.; Olinga, P.; Hillebrands, J. -L.; Seelen, M. A. J.

    Kidneys retrieved from brain-dead donors have impaired allograft function after transplantation compared to kidneys from living donors. Donor brain death (BD) triggers inflammatory responses, including both systemic and local complement activation. The mechanism by which systemic activated

  19. Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics.

    Science.gov (United States)

    Kou, Xianjuan; Li, Jie; Liu, Xingran; Chang, Jingru; Zhao, Qingxia; Jia, Shaohui; Fan, Jingjing; Chen, Ning

    2017-06-01

    microRNAs (miRNAs) have been reported to be involved in many neurodegenerative diseases. To explore the regulatory role of miR-34a in aging-related diseases such as Alzheimer's disease (AD) during exercise intervention, we constructed a rat model with d-galactose (d-gal)-induced oxidative stress and cognitive impairment coupled with dysfunctional autophagy and abnormal mitochondrial dynamics, determined the mitigation of cognitive impairment of d-gal-induced aging rats during swimming intervention, and evaluated miR-34a-mediated functional status of autophagy and abnormal mitochondrial dynamics. Meanwhile, whether the upregulation of miR-34a can lead to dysfunctional autophagy and abnormal mitochondrial dynamics was confirmed in human SH-SY5Y cells with silenced miR-34a by the transfection of a miR-34a inhibitor. Results indicated that swimming intervention could significantly attenuate cognitive impairment, prevent the upregulation of miR-34a, mitigate the dysfunctional autophagy, and inhibit the increase of dynamin-related protein 1 (DRP1) in d-gal-induced aging model rats. In contrast, the miR-34a inhibitor in cell model not only attenuated D-gal-induced the impairment of autophagy but also decreased the expression of DRP1 and mitofusin 2 (MFN2). Therefore, swimming training can delay brain aging of d-gal-induced aging rats through attenuating the impairment of miR-34a-mediated autophagy and abnormal mitochondrial dynamics, and miR-34a could be the novel therapeutic target for aging-related diseases such as AD. NEW & NOTEWORTHY In the present study, we have found that the upregulation of miR-34a is the hallmark of aging or aging-related diseases, which can result in dysfunctional autophagy and abnormal mitochondrial dynamics. In contrast, swimming intervention can delay the aging process by rescuing the impaired functional status of autophagy and abnormal mitochondrial dynamics via the suppression of miR-34a. Copyright © 2017 the American Physiological Society.

  20. Differential regulation of collapsin response mediator protein 2 (CRMP2 phosphorylation by GSK3ß and CDK5 following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Sarah Marie Wilson

    2014-05-01

    Full Text Available Aberrant ion channel function has been heralded as a main underlying mechanism driving epilepsy and its symptoms. However, it has become increasingly clear that treatment strategies targeting voltage-gated sodium or calcium channels merely mask the symptoms of epilepsy without providing disease-modifying benefits. Ion channel function is likely only one important cog in a highly complex machine. Gross morphological changes, such as reactive sprouting and outgrowth, may also play a role in epileptogenesis. Mechanisms responsible for these changes are not well understood. Here we investigate the potential involvement of the neurite outgrowth-promoting molecule collapsin response mediator protein 2 (CRMP2. CRMP2 activity, in this respect, is regulated by phosphorylation state, where phosphorylation by a variety of kinases, including glycogen synthase kinase 3 β (GSK3β renders it inactive. Phosphorylation (inactivation of CRMP2 was decreased at two distinct phases following traumatic brain injury (TBI. While reduced CRMP2 phosphorylation during the early phase was attributed to the inactivation of GSK3β, the sustained decrease in CRMP2 phosphorylation in the late phase appeared to be independent of GSK3β activity. Instead, the reduction in GSK3β-phosphorylated CRMP2 was attributed to a loss of priming by cyclin-dependent kinase 5 (CDK5, which allows for subsequent phosphorylation by GSK3β. Based on the observation that the proportion of active CRMP2 is increased for up to 4 weeks following TBI, it was hypothesized that it may drive neurite outgrowth, and therefore, circuit reorganization during this time. Therefore, a novel small-molecule tool was used to target CRMP2 in an attempt to determine its importance in mossy fiber sprouting following TBI. In this report, we demonstrate novel differential regulation of CRMP2 phosphorylation by GSK3β and CDK5 following TBI.

  1. Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by β-hydroxybutyrate

    Directory of Open Access Journals (Sweden)

    Jingzhu Zhang

    2018-01-01

    expression was reduced (0.2-folds and microRNA-29a expression was up-regulated (1.7-folds in HDAC2-silenced cells, but respectively increased (1.3-folds and down-regulated (0.8-folds in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression.

  2. Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by β-hydroxybutyrate.

    Science.gov (United States)

    Zhang, Jingzhu; Li, Xinhui; Ren, Yahao; Zhao, Yue; Xing, Aiping; Jiang, Congmin; Chen, Yanqiu; An, Li

    2018-01-01

    reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression.

  3. Cultural mediation or brain drain?

    African Journals Online (AJOL)

    chrischisoni

    2014-06-11

    Jun 11, 2014 ... citizenship dates back to the first explorers and the establishment of the First .... investments in education because of higher returns abroad (Bein, Docquier, and .... They include Bangladesh, Brazil, Canada, China, Colombia, Dominican .... teachers, and scientists from West Africa are being employed in ...

  4. Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of {sup 11}C-labeled topotecan using small-animal positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Yamasaki, Tomoteru; Fujinaga, Masayuki; Kawamura, Kazunori; Hatori, Akiko; Yui, Joji [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Nengaki, Nobuki; Ogawa, Masanao; Yoshida, Yuichiro [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); SHI Accelerator Service, Ltd., Tokyo 141-8686 (Japan); Wakizaka, Hidekatsu [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Yanamoto, Kazuhiko [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871 (Japan); Fukumura, Toshimitsu [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Zhang Mingrong, E-mail: zhang@nirs.go.jp [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)

    2011-07-15

    Introduction: Topotecan (TPT) is a camptothecin derivative and is an anticancer drug working as a topoisomerase-I-specific inhibitor. But TPT cannot penetrate through the blood-brain barrier. In this study, we synthesized a new positron emission tomography (PET) probe, [{sup 11}C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [{sup 11}C]TPT using small-animal PET. Methods: [{sup 11}C]TPT was synthesized by the reaction of a desmethyl precursor with [{sup 11}C]CH{sub 3}I. In vitro study using [{sup 11}C]TPT was carried out in MES-SA and doxorubicin-resistant MES-SA/Dx5 cells in the presence or absence of elacridar, a specific inhibitor for Pgp and BCRP. The biodistribution of [{sup 11}C]TPT was determined using small-animal PET and the dissection method in mice. Results: The transport of [{sup 11}C]TPT to the extracellular side was determined in MES-SA/Dx5 cells exhibiting the expressions of Pgp and BCRP at high levels. This transport was inhibited by coincubation with elacridar. In Mdr1a/b{sup -/-}Bcrp1{sup -/-} mice, PET results indicated that the brain uptake of [{sup 11}C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [{sup 11}C]TPT in wild-type mice was increased by treatment with elacridar. The radioactivity in the brain of elacridar-treated mice was maintained at a certain level after the injection of [{sup 11}C]TPT, although the radioactivity in the blood decreased with time. Conclusions: We demonstrated the increase of brain penetration of [{sup 11}C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.

  5. Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia.

    Science.gov (United States)

    Sethy, Niroj Kumar; Singh, Manjulata; Kumar, Rajesh; Ilavazhagan, Govindasamy; Bhargava, Kalpana

    2011-03-01

    Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.

  6. PET-CT imaging with [18F]-gefitinib to measure Abcb1a/1b (P-gp) and Abcg2 (Bcrp1) mediated drug–drug interactions at the murine blood–brain barrier

    International Nuclear Information System (INIS)

    Vlaming, Maria L.H.; Läppchen, Tilman; Jansen, Harm T.; Kivits, Suzanne; Driel, Andy van; Steeg, Evita van de; Hoorn, José W. van der; Sio, Charles F.; Steinbach, Oliver C.; DeGroot, Jeroen

    2015-01-01

    Introduction: The efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) are expressed at the blood–brain barrier (BBB), and can limit the access of a wide range of drugs to the brain. In this study we developed a PET-CT imaging method for non-invasive, quantitative analysis of the effect of ABCB1 and ABCG2 on brain penetration of the anti-cancer drug gefitinib, and demonstrated the applicability of this method for identification and quantification of potential modulators of ABCB1 and ABCB2 using the dual inhibitor elacridar. Methods: In vitro cellular accumulation studies with [ 14 C]-gefitinib were conducted in LLC-PK1, MDCKII, and the corresponding ABCB1/Abcb1a and ABCG2/Abcg2 overexpressing cell lines. Subsequently, in vivo brain penetration of [ 18 F]-gefitinib was quantified by PET-CT imaging studies in wild-type, Abcg2 −/− , Abcb1a/1b −/− , and Abcb1a/1b;Abcg2 −/− mice. Results: In vitro studies showed that [ 14 C]-gefitinib is a substrate of the human ABCB1 and ABCG2 transporters. After i.v. administration of [ 18 F]-gefitinib (1 mg/kg), PET-CT imaging showed 2.3-fold increased brain levels of [ 18 F]-gefitinib in Abcb1a/1b;Abcg2 −/− mice, compared to wild-type. Levels in single knockout animals were not different from wild-type, showing that Abcb1a/1b and Abcg2 together limit access of [ 18 F]-gefitinib to the brain. Furthermore, enhanced brain accumulation of [ 18 F]-gefitinib after administration of the ABCB1 and ABCG2 inhibitor elacridar (10 mg/kg) could be quantified with PET-CT imaging. Conclusions: PET-CT imaging with [ 18 F]-gefitinib is a powerful tool to non-invasively assess potential ABCB1- and ABCG2-mediated drug–drug interactions (DDIs) in vivo. Advances in knowledge and implications for patient care: This minimally-invasive, [ 18 F]-based PET-CT imaging method shows the interplay of ABCB1 and ABCG2 at the BBB in vivo. The method may be applied in the future to assess ABCB1 and

  7. Corticotropin-releasing hormone-mediated metamorphosis in the neotenic axolotl Ambystoma mexicanum: synergistic involvement of thyroxine and corticoids on brain type II deiodinase.

    Science.gov (United States)

    Kühn, Eduard R; De Groef, Bert; Van der Geyten, Serge; Darras, Veerle M

    2005-08-01

    In the present study, morphological changes leading to complete metamorphosis have been induced in the neotenic axolotl Ambystoma mexicanum using a submetamorphic dose of T(4) together with an injection of corticotropin-releasing hormone (CRH). An injection of CRH alone is ineffective in this regard presumably due to a lack of thyrotropic stimulation. Using this low hormone profile for induction of metamorphosis, the deiodinating enzymes D2 and D3 known to be present in amphibians were measured in liver and brain 24h following an intraperitoneal injection. An injection of T(4) alone did not influence liver nor brain D2 and D3, but dexamethasone (DEX) or CRH alone or in combination with T(4) decreased liver D2 and D3. Brain D2 activity was slightly increased with a higher dose of DEX, though CRH did not have this effect. A profound synergistic effect occurred when T(4) and DEX or CRH were injected together, in the dose range leading to metamorphosis, increasing brain D2 activity more than fivefold. This synergistic effect was not found in the liver. It is concluded that brain T(3) availability may play an important role for the onset of metamorphosis in the neotenic axolotl.

  8. Trillium tschonoskii maxim saponin mitigates D-galactose-induced brain aging of rats through rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway.

    Science.gov (United States)

    Wang, Lingjie; Du, Junlong; Zhao, Fangyu; Chen, Zonghai; Chang, Jingru; Qin, Furong; Wang, Zili; Wang, Fengjie; Chen, Xianbing; Chen, Ning

    2018-02-01

    During the expansion of aging population, the study correlated with brain aging is one of the important research topics. Developing novel and effective strategies for delaying brain aging is highly desired. Brain aging is characteristics of impaired cognitive capacity due to dysfunctional autophagy regulated by Rheb-mTOR signal pathway in hippocampal tissues. In the present study, we have established a rat model with brain aging through subcutaneous injection of D-galactose (D-gal). Upon the intervention of Trillium tschonoskii Maxim (TTM) saponin, one of bioactive components from local natural herbs in China, the learning and memory capacity of D-gal-induced aging rats was evaluated through Morris water maze test, and the regulation of Rheb-mTOR signal pathway and functional status of autophagy in hippocampal tissues of D-gal-induced aging rats was explored by Western blot. TTM saponin revealed an obvious function to improve learning and memory capacity of D-gal-induced aging rats through up-regulating Rheb and down-regulating mTOR, thereby rescuing dysfunctional autophagy to execute anti-aging role. Meanwhile, this study confirmed the function of TTM saponin for preventing and treating brain aging, and provided a reference for the development and utilization of natural products in health promotion and aging-associated disease treatment. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: A survey in 66 neurotrauma centers participating in the CENTER-TBI study

    NARCIS (Netherlands)

    M.C. Cnossen (Maryse); Huijben, J.A. (Jilske A.); van der Jagt, M. (Mathieu); Volovici, V. (Victor); van Essen, T. (Thomas); S. Polinder (Suzanne); D. Nelson (David); Ercole, A. (Ari); Stocchetti, N. (Nino); Citerio, G. (Giuseppe); W.C. Peul (Wilco); A.I.R. Maas (Andrew I.R.); D.K. Menon (David ); E.W. Steyerberg (Ewout W.); Lingsma, H.F. (Hester F.); Adams, H. (Hadie); Alessandro, M. (Masala); J.E. Allanson (Judith); Amrein, K. (Krisztina); Andaluz, N. (Norberto); N. Andelic (Nada); Andrea, N. (Nanni); L. Andreassen (Lasse); Anke, A. (Audny); Antoni, A. (Anna); Ardon, H. (Hilko); Audibert, G. (Gérard); Auslands, K. (Kaspars); Azouvi, P. (Philippe); Baciu, C. (Camelia); Bacon, A. (Andrew); Badenes, R. (Rafael); Baglin, T. (Trevor); R.H.M.A. Bartels (Ronald); P. Barzo (P.); Bauerfeind, U. (Ursula); R. Beer (Ronny); Belda, F.J. (Francisco Javier); B.-M. Bellander (Bo-Michael); A. Belli (Antonio); Bellier, R. (Rémy); H. Benali (Habib); Benard, T. (Thierry); M. Berardino (Maurizio); L. Beretta (Luigi); Beynon, C. (Christopher); Bilotta, F. (Federico); H. Binder (Harald); Biqiri, E. (Erta); Blaabjerg, M. (Morten); Lund, S.B. (Stine Borgen); Bouzat, P. (Pierre); Bragge, P. (Peter); Brazinova, A. (Alexandra); F. Brehar (Felix); Brorsson, C. (Camilla); Buki, A. (Andras); M. Bullinger (Monika); Bucková, V. (Veronika); Calappi, E. (Emiliana); P. Cameron (Peter); Carbayo, L.G. (Lozano Guillermo); Carise, E. (Elsa); K.L.H. Carpenter (Keri L.H.); Castaño-León, A.M. (Ana M.); Causin, F. (Francesco); Chevallard, G. (Giorgio); A. Chieregato (Arturo); G. Citerio (Giuseppe); Cnossen, M. (Maryse); M. Coburn (Mark); J.P. Coles (Jonathan P.); Cooper, J.D. (Jamie D.); Correia, M. (Marta); A. Covic (Amra); N. Curry (Nicola); E. Czeiter (Endre); M. Czosnyka (Marek); Dahyot-Fizelier, C. (Claire); F. Damas (François); P. Damas (Pierre); H. Dawes (Helen); De Keyser, V. (Véronique); F.D. Corte (Francesco); B. Depreitere (Bart); Ding, S. (Shenghao); D.W.J. Dippel (Diederik); K. Dizdarevic (Kemal); Dulière, G.-L. (Guy-Loup); Dzeko, A. (Adelaida); G. Eapen (George); Engemann, H. (Heiko); A. Ercole (Ari); P. Esser (Patrick); Ezer, E. (Erzsébet); M. Fabricius (Martin); V.L. Feigin (V.); Feng, J. (Junfeng); Foks, K. (Kelly); F. Fossi (Francesca); Francony, G. (Gilles); J. Frantzén (Janek); Freo, U. (Ulderico); S.K. Frisvold (Shirin Kordasti); Furmanov, A. (Alex); Gagliardo, P. (Pablo); D. Galanaud (Damien); G. Gao (Guoyi); K. Geleijns (Karin); A. Ghuysen (Alexandre); Giraud, B. (Benoit); Glocker, B. (Ben); Gomez, P.A. (Pedro A.); Grossi, F. (Francesca); R.L. Gruen (Russell); Gupta, D. (Deepak); J.A. Haagsma (Juanita); E. Hadzic (Ermin); I. Haitsma (Iain); J.A. Hartings (Jed); R. Helbok (Raimund); E. Helseth (Eirik); Hertle, D. (Daniel); S. Hill (Sean); Hoedemaekers, A. (Astrid); S. Hoefer (Stefan); P.J. Hutchinson (Peter J.); Håberg, K.A. (Kristine Asta); B.C. Jacobs (Bart); Janciak, I. (Ivan); K. Janssens (Koen); Jiang, J.-Y. (Ji-Yao); Jones, K. (Kelly); Kalala, J.-P. (Jean-Pierre); Kamnitsas, K. (Konstantinos); Karan, M. (Mladen); Karau, J. (Jana); A. Katila (Ari); M. Kaukonen (Maija); Keeling, D. (David); Kerforne, T. (Thomas); N. Ketharanathan (Naomi); Kettunen, J. (Johannes); Kivisaari, R. (Riku); A.G. Kolias (Angelos G.); Kolumbán, B. (Bálint); E.J.O. Kompanje (Erwin); D. Kondziella (Daniel); L.-O. Koskinen (Lars-Owe); Kovács, N. (Noémi); F. Kalovits (Ferenc); A. Lagares (Alfonso); L. Lanyon (Linda); S. Laureys (Steven); Lauritzen, M. (Martin); F.E. Lecky (Fiona); C. Ledig (Christian); R. Lefering; V. Legrand (Valerie); Lei, J. (Jin); L. Levi (Leon); R. Lightfoot (Roger); H.F. Lingsma (Hester); D. Loeckx (Dirk); Lozano, A. (Angels); Luddington, R. (Roger); Luijten-Arts, C. (Chantal); Maas, A.I.R. (Andrew I.R.); MacDonald, S. (Stephen); MacFayden, C. (Charles); M. Maegele (Marc); M. Majdan (Marek); Major, S. (Sebastian); A. Manara (Alex); Manhes, P. (Pauline); G. Manley (Geoffrey); Martin, D. (Didier); C. Martino (Costanza); Maruenda, A. (Armando); H. Maréchal (Hugues); Mastelova, D. (Dagmara); Mattern, J. (Julia); McMahon, C. (Catherine); Melegh, B. (Béla); Menon, D. (David); T. Menovsky (Tomas); Morganti-Kossmann, C. (Cristina); Mulazzi, D. (Davide); Mutschler, M. (Manuel); H. Mühlan (Holger); Negru, A. (Ancuta); Nelson, D. (David); E. Neugebauer (Eddy); V.F. Newcombe (Virginia F.); Noirhomme, Q. (Quentin); Nyirádi, J. (József); M. Oddo (Mauro); A.W. Oldenbeuving; M. Oresic (Matej); Ortolano, F. (Fabrizio); A. Palotie (Aarno); P.M. Parizel; Patruno, A. (Adriana); J.-F. Payen (Jean-François); Perera, N. (Natascha); V. Perlbarg (Vincent); Persona, P. (Paolo); Peul, W. (Wilco); N. Pichon (Nicolas); Piilgaard, H. (Henning); A. Piippo (Anna); S.P. Floury (Sébastien Pili); M. Pirinen (Matti); H. Ples (Horia); Polinder, S. (Suzanne); Pomposo, I. (Inigo); M. Psota (Marek); P. Pullens (Pim); L. Puybasset (Louis); A. Ragauskas (Arminas); R. Raj (Rahul); Rambadagalla, M. (Malinka); Rehorcíková, V. (Veronika); J.K.J. Rhodes (Jonathan K.J.); S. Richardson (Sylvia); S. Ripatti (Samuli); S. Rocka (Saulius); Rodier, N. (Nicolas); Roe, C. (Cecilie); Roise, O. (Olav); C.M.A.A. Roks (Gerwin); Romegoux, P. (Pauline); J. Rosand (Jonathan); Rosenfeld, J. (Jeffrey); C. Rosenlund (Christina); G. Rosenthal (Guy); R. Rossaint (Rolf); S. Rossi (Sandra); Rostalski, T. (Tim); D. Rueckert (Daniel); de Ruiz, A.F. (Arcaute Felix); M. Rusnák (Martin); Sacchi, M. (Marco); Sahakian, B. (Barbara); J. Sahuquillo (Juan); O. Sakowitz (Oliver); Sala, F. (Francesca); Sanchez-Pena, P. (Paola); Sanchez-Porras, R. (Renan); Sandor, J. (Janos); Santos, E. (Edgar); N. Sasse (Nadine); Sasu, L. (Luminita); Savo, D. (Davide); I.B. Schipper (Inger); Schlößer, B. (Barbara); S. Schmidt (Silke); Schneider, A. (Annette); H. Schoechl (Herbert); G.G. Schoonman; Rico, F.S. (Frederik Schou); E. Schwendenwein (Elisabeth); Schöll, M. (Michael); Sir, O. (özcan); T. Skandsen (Toril); Smakman, L. (Lidwien); D. Smeets (Dominique); Smielewski, P. (Peter); Sorinola, A. (Abayomi); E. Stamatakis (Emmanuel); S. Stanworth (Simon); Stegemann, K. (Katrin); Steinbüchel, N. (Nicole); R. Stevens (Robert); W. Stewart (William); E.W. Steyerberg (Ewout); N. Stocchetti (Nino); Sundström, N. (Nina); Synnot, A. (Anneliese); J. Szabó (József); J. Söderberg (Jeannette); F.S. Taccone (Fabio); Tamás, V. (Viktória); Tanskanen, P. (Päivi); A. Tascu (Alexandru); Taylor, M.S. (Mark Steven); Te, A.B. (Ao Braden); O. Tenovuo (Olli); Teodorani, G. (Guido); A. Theadom (Alice); Thomas, M. (Matt); D. Tibboel (Dick); C.M. Tolias (Christos M.); Tshibanda, J.-F.L. (Jean-Flory Luaba); Tudora, C.M. (Cristina Maria); P. Vajkoczy (Peter); Valeinis, E. (Egils); Hecke, W.V. (Wim Van); Praag, D.V. (Dominique Van); Dirk, V.R. (Van Roost); Vlierberghe, E.V. (Eline Van); Vyvere, T.V. (Thijs vande); Vanhaudenhuyse, A. (Audrey); A. Vargiolu (Alessia); E. Vega (Emmanuel); J. Verheyden (Jan); Vespa, P.M. (Paul M.); A. Vik (Anne); R. Vilcinis (Rimantas); Vizzino, G. (Giacinta); C.L.A.M. Vleggeert-Lankamp (Carmen); V. Volovici (Victor); P. Vulekovic (Peter); Vámos, Z. (Zoltán); Wade, D. (Derick); Wang, K.K.W. (Kevin K.W.); Wang, L. (Lei); E.D. Wildschut (Enno); G. Williams (Guy); Willumsen, L. (Lisette); Wilson, A. (Adam); Wilson, L. (Lindsay); Winkler, M.K.L. (Maren K.L.); P. Ylén (Peter); Younsi, A. (Alexander); M. Zaaroor (Menashe); Zhang, Z. (Zhiqun); Zheng, Z. (Zelong); Zumbo, F. (Fabrizio); de Lange, S. (Stefanie); G.C.W. De Ruiter (Godard C.W.); den Boogert, H. (Hugo); van Dijck, J. (Jeroen); T.A. van Essen (T.); C.M. van Heugten (Caroline M.); M. van der Jagt (Mathieu); J. van der Naalt (Joukje)

    2017-01-01

    textabstractBackground: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP)

  10. The Appetite-Inducing Peptide, Ghrelin, Induces Intracellular Store-Mediated Rises in Calcium in Addiction and Arousal-Related Laterodorsal Tegmental Neurons in Mouse Brain Slices

    DEFF Research Database (Denmark)

    Hauberg, Katrine; Kohlmeier, Kristi Anne

    2015-01-01

    Ghrelin, a gut and brain peptide, has recently been shown to be involved in motivated behavior and regulation of the sleep and wakefulness cycle. The laterodorsal tegmental nucleus (LDT) is involved in appetitive behavior and control of the arousal state of an organism, and accordingly, behaviora...

  11. ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals

    DEFF Research Database (Denmark)

    Ordóñez-Gutiérrez, Lara; Posado-Fernández, Adrián; Ahmadvand, Davoud

    2017-01-01

    ) and THP-1 phagocytes (stimulating uptake) was confirmed in vitro. The multivalent immunoliposomes dramatically reduced circulating and brain levels of Aβ1-40, and particularly Aβ1-42, in "aged" (16 month-old), but not "adult" (10 month-old) APP/PS1 transgenic mice on repeated intraperitoneal...

  12. Does job strain mediate the effect of socioeconomic group on smoking behaviour? The impact of different health policies in Denmark and Sweden

    DEFF Research Database (Denmark)

    Andersen, Ingelise; Rasmussen, Niels Kr; Ostergren, P O

    2008-01-01

    AIMS: The aim was to compare the impact of socioeconomic groups (SEG) on the risk of being a daily smoker or quitter, and to investigate whether the potentially mediating effect of psychosocial working conditions was similar in the Danish and the Swedish populations. METHODS: The study populations....... The association between SEG, current smoking, quitting, and influence at work, job demand and jobstrain, respectively, was tested by means of logistic regression. RESULTS: The contextual determinants defined by country had a different effect on smoking prevalence among men and women and among age groups. Low...... and more socially skewed among the Swedes, but did not mediate the effect of SEG on smoking behaviour. CONCLUSIONS: The smoking prevalence was lower and the quit-rates higher among Swedes than Danes. Both countries had social differences in smoking that in absolute terms were rather similar...

  13. Interleukin 6-Mediated Endothelial Barrier Disturbances Can Be Attenuated by Blockade of the IL6 Receptor Expressed in Brain Microvascular Endothelial Cells.

    Science.gov (United States)

    Blecharz-Lang, Kinga G; Wagner, Josephin; Fries, Alexa; Nieminen-Kelhä, Melina; Rösner, Jörg; Schneider, Ulf C; Vajkoczy, Peter

    2018-02-10

    Compromised blood-brain barrier (BBB) by dysregulation of cellular junctions is a hallmark of many cerebrovascular disorders due to the pro-inflammatory cytokines action. Interleukin 6 (IL6) is implicated in inflammatory processes and in secondary brain injury after subarachnoid hemorrhage (SAH) but its role in the maintenance of cerebral endothelium still requires a precise elucidation. Although IL6 has been shown to exert pro-inflammatory action on brain microvascular endothelial cells (ECs), the expression of one of the IL6 receptors, the IL6R is controversially discussed. In attempt to reach more clarity in this issue, we present here an evident baseline expression of the IL6R in BBB endothelium in vivo and in an in vitro model of the BBB, the cEND cell line. A significantly increased expression of IL6R and its ligand was observed in BBB capillaries 2 days after experimental SAH in mice. In vitro, we saw IL6 administration resulting in an intracellular and extracellular elevation of IL6 protein, which was accompanied by a reduced expression of tight and adherens junctions, claudin-5, occludin, and vascular-endothelial (VE-) cadherin. By functional assays, we could demonstrate IL6-incubated brain ECs to lose their endothelial integrity that can be attenuated by inhibiting the IL6R. Blockade of the IL6R by a neutralizing antibody has reconstituted the intercellular junction expression to the control level and caused a restoration of the transendothelial electrical resistance of the cEND cell monolayer. Our findings add depth to the current understanding of the involvement of the endothelial IL6R in the loss of EC integrity implicating potential therapy options.

  14. Glutamatergic Receptor Activation in the Commisural Nucleus Tractus Solitarii (cNTS) Mediates Brain Glucose Retention (BGR) Response to Anoxic Carotid Chemoreceptor (CChr) Stimulation in Rats.

    Science.gov (United States)

    Cuéllar, R; Montero, S; Luquín, S; García-Estrada, J; Dobrovinskaya, O; Melnikov, V; Lemus, M; de Álvarez-Buylla, E Roces

    2015-01-01

    Glutamate, released from central terminals of glossopharyngeal nerve, is a major excitatory neurotransmitter of commissural nucleus tractus solitarii (cNTS) afferent terminals, and brain derived neurotrophic factor (BDNF) has been shown to attenuate glutamatergic AMPA currents in NTS neurons. To test the hypothesis that AMPA contributes to glucose regulation in vivo modulating the hyperglycemic reflex with brain glucose retention (BGR), we microinjected AMPA and NBQX (AMPA antagonist) into the cNTS before carotid chemoreceptor stimulation in anesthetized normal Wistar rats, while hyperglycemic reflex an brain glucose retention (BGR) were analyzed. To investigate the underlying mechanisms, GluR2/3 receptor and c-Fos protein expressions in cNTS neurons were determined. We showed that AMPA in the cNTS before CChr stimulation inhibited BGR observed in aCSF group. In contrast, NBQX in similar conditions, did not modify the effects on glucose variables observed in aCSF control group. These experiments suggest that glutamatergic pathways, via AMPA receptors, in the cNTS may play a role in glucose homeostasis.

  15. Taurine reverses sodium fluoride-mediated increase in inflammation, caspase-3 activity, and oxidative damage along the brain-pituitary-gonadal axis in male rats.

    Science.gov (United States)

    Adedara, Isaac A; Olabiyi, Bolanle F; Ojuade, TeminiJesu D; Idris, Umar F; Onibiyo, Esther M; Farombi, Ebenezer O

    2017-09-01

    Excessive exposure to fluoride is associated with male reproductive dysfunction in humans and animals. Taurine (2-aminoethane sulfonic acid) is a free intracellular β-amino acid with antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of taurine on fluoride-induced reproductive toxicity has not been reported. The present study investigated the influence of taurine on sodium fluoride (NaF)-induced functional changes along the brain-pituitary-gonadal axis in male rats. NaF was administered singly in drinking water at 15 mg·L -1 alone or orally co-administered by gavage with taurine at 100 and 200 mg·(kg body mass) -1 for 45 consecutive days. Results showed that taurine significantly prevented NaF-induced increase in oxidative stress indices as well as augmented antioxidant enzymes activities and glutathione level in the brain, testes, and epididymis of the treated rats. Moreover, taurine reversed NaF-induced elevation in inflammatory biomarkers and caspase-3 activity as well as histological damage in the brain, testes, and epididymis of the treated rats. The significant reversal of NaF-induced decreases in testosterone level and testicular activities of acid phosphatase, alkaline phosphatase, and lactate dehydrogenase by taurine was accompanied by enhancement of sperm functional characteristics in the treated rats. Taurine may be a possible chemopreventive candidate against reproductive dysfunction resulting from fluoride exposure.

  16. Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury.

    Science.gov (United States)

    Chen, Xiangrong; Chen, Chunnuan; Fan, Sining; Wu, Shukai; Yang, Fuxing; Fang, Zhongning; Fu, Huangde; Li, Yasong

    2018-04-20

    Microglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the

  17. Evaluation of Novel Polyunsaturated Fatty Acid Derived Lipid Mediators of Inflammation to Ameliorate the Deleterious Effects of Blast Overpressure on Eye and Brain Visual Processing Centers in Rats

    Science.gov (United States)

    2014-10-01

    acid ( DHA ; 22:6ω-3) Eicosapentaenoic acid (EPA; 20:5ω-3) Lipoxin A4 Resolvin E1 Protectin DX Resolvin D1 LOX LOX LOX Structures and Endogenous Source...1 AD_________________ Award Number: W81XWH-12-2-0082 TITLE: Evaluation of Novel Polyunsaturated Fatty Acid Derived Lipid...Evaluation of Novel Polyunsaturated Fatty Acid Derived Lipid Mediators 5a. CONTRACT NUMBER of Inflammation to Ameliorate the Deleterious Effects of

  18. Brain herniation

    Science.gov (United States)

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  19. Activation of AMP-activated protein kinase by kainic acid mediates brain-derived neurotrophic factor expression through a NF-kappaB dependent mechanism in C6 glioma cells

    International Nuclear Information System (INIS)

    Yoon, Hana; Oh, Young Taek; Lee, Jung Yeon; Choi, Ji Hyun; Lee, Ju Hie; Baik, Hyung Hwan; Kim, Sung Soo; Choe, Wonchae; Yoon, Kyung-Sik; Ha, Joohun; Kang, Insug

    2008-01-01

    AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis. Kainic acid (KA), a prototype excitotoxin is known to induce brain-derived neurotrophic factor (BDNF) in brain. In this study, we examined the role of AMPK in KA-induced BDNF expression in C6 glioma cells. We showed that KA and KA receptor agonist induced activation of AMPK and KA-induced AMPK activation was blocked by inhibition of Ca 2+ /calmodulin-dependent protein kinase kinase (CaMKK) β. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPKα1 blocked KA-induced BDNF mRNA and protein expression. Inhibition of AMPK blocked KA-induced phosphorylation of CaMKII and I kappaB kinase (IKK) in C6 cells. Finally, we showed that inhibition of AMPK reduced DNA binding and transcriptional activation of nuclear factor-kappaB (NF-κB) in KA-treated cells. These results suggest that AMPK mediates KA-induced BDNF expression by regulating NF-κB activation

  20. Blood Brain Barrier and Neuroinflammation Are Critical Targets of IGF-1-Mediated Neuroprotection in Stroke for Middle-Aged Female Rats

    Science.gov (United States)

    Bake, Shameena; Selvamani, Amutha; Cherry, Jessica; Sohrabji, Farida

    2014-01-01

    Ischemia-induced cerebral infarction is more severe in older animals as compared to younger animals, and is associated with reduced availability of insulin-like growth factor (IGF)-1. This study determined the effect of post-stroke IGF-1 treatment, and used microRNA profiling to identify mechanisms underlying IGF-1’s neuroprotective actions. Post-stroke ICV administration of IGF-1 to middle-aged female rats reduced infarct volume by 39% when measured 24h later. MicroRNA analyses of ischemic tissue collected at the early post-stroke phase (4h) indicated that 8 out of 168 disease-related miRNA were significantly downregulated by IGF-1. KEGG pathway analysis implicated these miRNA in PI3K-Akt signaling, cell adhesion/ECM receptor pathways and T-and B-cell signaling. Specific components of these pathways were subsequently analyzed in vehicle and IGF-1 treated middle-aged females. Phospho-Akt was reduced by ischemia at 4h, but elevated by IGF-1 treatment at 24h. IGF-1 induced Akt activation was preceded by a reduction of blood brain barrier permeability at 4h post-stroke and global suppression of cytokines including IL-6, IL-10 and TNF-α. A subset of these cytokines including IL-6 was also suppressed by IGF-1 at 24h post-stroke. These data are the first to show that the temporal and mechanistic components of post-stroke IGF-1 treatment in older animals, and that cellular components of the blood brain barrier may serve as critical targets of IGF-1 in the aging brain. PMID:24618563

  1. Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

    Science.gov (United States)

    Emmert, Kirsten; Kopel, Rotem; Sulzer, James; Brühl, Annette B; Berman, Brian D; Linden, David E J; Horovitz, Silvina G; Breimhorst, Markus; Caria, Andrea; Frank, Sabine; Johnston, Stephen; Long, Zhiying; Paret, Christian; Robineau, Fabien; Veit, Ralf; Bartsch, Andreas; Beckmann, Christian F; Van De Ville, Dimitri; Haller, Sven

    2016-01-01

    An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate

  2. Generation of brain tumours in mice by Cre-mediated recombination of neural progenitors in situ with the tamoxifen metabolite endoxifen.

    Science.gov (United States)

    Benedykcinska, Anna; Ferreira, Andreia; Lau, Joanne; Broni, Jessica; Richard-Loendt, Angela; Henriquez, Nico V; Brandner, Sebastian

    2016-02-01

    Targeted cell- or region-specific gene recombination is widely used in the functional analysis of genes implicated in development and disease. In the brain, targeted gene recombination has become a mainstream approach to study neurodegeneration or tumorigenesis. The use of the Cre-loxP system to study tumorigenesis in the adult central nervous system (CNS) can be limited, when the promoter (such as GFAP) is also transiently expressed during development, which can result in the recombination of progenies of different lineages. Engineering of transgenic mice expressing Cre recombinase fused to a mutant of the human oestrogen receptor (ER) allows the circumvention of transient developmental Cre expression by inducing recombination in the adult organism. The recombination of loxP sequences occurs only in the presence of tamoxifen. Systemic administration of tamoxifen can, however, exhibit toxicity and might also recombine unwanted cell populations if the promoter driving Cre expression is active at the time of tamoxifen administration. Here, we report that a single site-specific injection of an active derivative of tamoxifen successfully activates Cre recombinase and selectively recombines tumour suppressor genes in neural progenitor cells of the subventricular zone in mice, and we demonstrate its application in a model for the generation of intrinsic brain tumours. © 2016. Published by The Company of Biologists Ltd.

  3. ESCRT-mediated uptake and degradation of brain-targeted α-synuclein single chain antibody attenuates neuronal degeneration in vivo.

    Science.gov (United States)

    Spencer, Brian; Emadi, Sharareh; Desplats, Paula; Eleuteri, Simona; Michael, Sarah; Kosberg, Kori; Shen, Jay; Rockenstein, Edward; Patrick, Christina; Adame, Anthony; Gonzalez, Tania; Sierks, Michael; Masliah, Eliezer

    2014-10-01

    Parkinson's disease and dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein (α-syn). Recently, single-chain fragment variables (scFVs) have been developed against individual conformational species of α-syn. Unlike more traditional monoclonal antibodies, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated an scFV directed against oligomeric α-syn fused to the LDL receptor-binding domain from apolipoprotein B (apoB). The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the endosomal sorting complex required for transport (ESCRT) pathway, leading to lysosomal degradation of α-syn aggregates. Further analysis showed that the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of dementia with Lewy bodies/Parkinson's disease. Thus, the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/α-syn complexes for degradation through the ESCRT pathway, leading to improved therapeutic potential of immunotherapy.

  4. Generation of brain tumours in mice by Cre-mediated recombination of neural progenitors in situ with the tamoxifen metabolite endoxifen

    Directory of Open Access Journals (Sweden)

    Anna Benedykcinska

    2016-02-01

    Full Text Available Targeted cell- or region-specific gene recombination is widely used in the functional analysis of genes implicated in development and disease. In the brain, targeted gene recombination has become a mainstream approach to study neurodegeneration or tumorigenesis. The use of the Cre-loxP system to study tumorigenesis in the adult central nervous system (CNS can be limited, when the promoter (such as GFAP is also transiently expressed during development, which can result in the recombination of progenies of different lineages. Engineering of transgenic mice expressing Cre recombinase fused to a mutant of the human oestrogen receptor (ER allows the circumvention of transient developmental Cre expression by inducing recombination in the adult organism. The recombination of loxP sequences occurs only in the presence of tamoxifen. Systemic administration of tamoxifen can, however, exhibit toxicity and might also recombine unwanted cell populations if the promoter driving Cre expression is active at the time of tamoxifen administration. Here, we report that a single site-specific injection of an active derivative of tamoxifen successfully activates Cre recombinase and selectively recombines tumour suppressor genes in neural progenitor cells of the subventricular zone in mice, and we demonstrate its application in a model for the generation of intrinsic brain tumours.

  5. Involvement of serotonergic pathways in mediating the neuronal activity and genetic transcription of neuroendocrine corticotropin-releasing factor in the brain of systemically endotoxin-challenged rats

    Energy Technology Data Exchange (ETDEWEB)

    Laflamme, N.; Feuvrier, E.; Richard, D.; Rivest, S. [Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Laval University, 2705 boul. Laurier, Ste-Foy Quebec (Canada)

    1999-01-01

    The present study investigated the effect of serotonin depletion on the neuronal activity and transcription of corticotropin-releasing factor in the rat brain during the acute-phase response. Conscious male rats received an intraperitoneal (i.p.) injection with the immune activator lipopolysaccaride (25 {mu}g/100 g body wt) after being treated for three consecutive days with para-chlorophenylalanine (30 mg/100 g/day). This irreversible inhibitor of tryptophane-5-hydroxylase decreased hypothalamic serotonin levels by 96%. One, 3 and 6 h after a single i.p. injection of lipopolysaccharide or vehicle solution, rats were killed and their brains cut in 30-{mu}m coronal sections. Messenger RNAs encoding c-fos, nerve-growth factor inducible-B gene, corticotropin-releasing factor and the heteronuclear RNA encoding corticotropin-releasing factor primary transcript were assayed by in situ hybridization using {sup 35}S-labeled riboprobes, whereas Fos-immunoreactive nuclei were labeled by immunocytochemistry. Lipopolysaccharide induced a wide neuronal activation indicated by the expression of both immediate-early gene transcripts and Fos protein in numerous structures of the brain. The signal for both immediate-early gene transcripts was low to moderate 1 h after lipopolysaccharide administration, maximal at 3 h and decline at 6 h post-injection, whereas at that time, Fos-immunoreactive nuclei were still detected in most of the c-fos messenger RNA-positive structures. Interestingly, the strong and widespread induction of both immediate-early gene transcripts was almost totally inhibited by para-chlorophenylalanine treatment; in the hypothalamic paraventricular nucleus for example, c-fos messenger RNA signal and the number of Fos-immunoreactive positive cells were reduced by 80 and 48%, respectively, in serotonin-depleted rats treated with the bacterial endotoxin. This blunted neuronal response was also associated with an attenuated stimulation of neuroendocrine corticotropin

  6. Intercultural Mediation

    OpenAIRE

    Dragos Marian Radulescu; Denisa Mitrut

    2012-01-01

    The Intercultural Mediator facilitates exchanges between people of different socio-cultural backgrounds and acts as a bridge between immigrants and national and local associations, health organizations, services and offices in order to foster integration of every single individual. As the use mediation increases, mediators are more likely to be involved in cross-cultural mediation, but only the best mediators have the opportunity to mediate cross border business disputes or international poli...

  7. Early intervention with human albumin to reduce the tissue plasminogen activator-mediated blood-brain barrier permeability damaged by delayed reperfusion: an experimental study in rats

    International Nuclear Information System (INIS)

    Lu Haitao; Zhao Jungong; Li Minghua; Li Yongdong; Zhang Peilei

    2011-01-01

    Objective: To clarify whether early use of high-dose human albumin can reduce the permeability of blood-brain barrier (BBB) damaged by delayed thrombolysis or not, and, in tun, reduce the vasogenic brain edema. Methods: A total of 138 male SD rats weighing 320-380 grams were randomly divided into 4 groups: sham operation group (n=3), control group (n=45), albumin group (n=45) and albumin+rt-PA group (n=45). According to the reperfusion time after the onset of middle cerebral artery occlusion (MCAO), each group, except sham operation group, was divided into three subgroups of 2 h, 3 h and 4 h with 15 rats in each subgroup. Rats in albumin group and albumin+rt-PA group received an intravenous infusion of 20% human albumin (2.5 g/kg) 2 hours after the onset of MCAO, and rats in albumin+rt-PA group received an intravenous infusion of rt-PA (10 mg/kg) at all points of reperfusion time via the rat's femoral vein immediately after the reperfusion. All rats were sacrificed 24 hours after MCAO, the infarct volume of the brain was determined with TTC dye method, the leakage extent of BBB was quantitatively estimated by using Evans blue method, and the matrix metalloproteinase-9 (MMP-9) expression was assessed with immunohistochemistry technique. Results: Early intervention with the use of high-dose human albumin could significantly improve the neurological score at 24 h. In MCAO 3 h albumin group, MCAO 4 h albumin group and MCAO 3 h albumin+rt-PA group, neurological score was significantly better than that in the control group (P 0.05). The volume of the infarct tissue was also significantly smaller in all the treated groups with high-dose human albumin groups (P<0.05) when compared with the control group. The infarct volume of the MCAO 4 h in albumin group and albumin+rt-PA group was reduced by 23% and by 17.3%, respectively. Cerebral hemorrhage transformation occurred in two rats of MCAO 4 h control group, in one rat of MCAO 4 h albumin group and in one rat of MCAO 4 h

  8. Distinct prediction errors in mesostriatal circuits of the human brain mediate learning about the values of both states and actions: evidence from high-resolution fMRI.

    Science.gov (United States)

    Colas, Jaron T; Pauli, Wolfgang M; Larsen, Tobias; Tyszka, J Michael; O'Doherty, John P

    2017-10-01

    Prediction-error signals consistent with formal models of "reinforcement learning" (RL) have repeatedly been found within dopaminergic nuclei of the midbrain and dopaminoceptive areas of the striatum. However, the precise form of the RL algorithms implemented in the human brain is not yet well determined. Here, we created a novel paradigm optimized to dissociate the subtypes of reward-prediction errors that function as the key computational signatures of two distinct classes of RL models-namely, "actor/critic" models and action-value-learning models (e.g., the Q-learning model). The state-value-prediction error (SVPE), which is independent of actions, is a hallmark of the actor/critic architecture, whereas the action-value-prediction error (AVPE) is the distinguishing feature of action-value-learning algorithms. To test for the presence of these prediction-error signals in the brain, we scanned human participants with a high-resolution functional magnetic-resonance imaging (fMRI) protocol optimized to enable measurement of neural activity in the dopaminergic midbrain as well as the striatal areas to which it projects. In keeping with the actor/critic model, the SVPE signal was detected in the substantia nigra. The SVPE was also clearly present in both the ventral striatum and the dorsal striatum. However, alongside these purely state-value-based computations we also found evidence for AVPE signals throughout the striatum. These high-resolution fMRI findings suggest that model-free aspects of reward learning in humans can be explained algorithmically with RL in terms of an actor/critic mechanism operating in parallel with a system for more direct action-value learning.

  9. Proton-coupled organic cation antiporter-mediated uptake of apomorphine enantiomers in human brain capillary endothelial cell line hCMEC/D3.

    Science.gov (United States)

    Okura, Takashi; Higuchi, Kei; Kitamura, Atsushi; Deguchi, Yoshiharu

    2014-01-01

    R(-)-Apomorphine is a dopamine agonist used for rescue management of motor function impairment associated with levodopa therapy in Parkinson's disease patients. The aim of this study was to examine the role of proton-coupled organic cation antiporter in uptake of R(-)-apomorphine and its S-enantiomer in human brain, using human endothelial cell line hCMEC/D3 as a model. Uptake of R(-)- or S(+)-apomorphine into hCMEC/D3 cells was measured under various conditions to evaluate its time-, concentration-, energy- and ion-dependency. Inhibition by selected organic cations was also examined. Uptakes of both R(-)- and S(+)-apomorphine increased with time. The initial uptake velocities of R(-)- and S(+)-apomorphine were concentration-dependent, with similar Km and Vmax values. The cell-to-medium (C/M) ratio of R(-)-apomorphine was significantly reduced by pretreatment with sodium azide, but was not affected by replacement of extracellular sodium ion with N-methylglucamine or potassium. Intracellular alkalization markedly reduced the uptake, while intracellular acidification increased it, suggesting that the uptake is driven by an oppositely directed proton gradient. The C/M ratio was significantly decreased by amantadine, verapamil, pyrilamine and diphenhydramine (substrates or inhibitors of proton-coupled organic cation antiporter), while tetraethylammonium (substrate of organic cation transporters (OCTs)) and carnitine (substrate of carnitine/organic cation transporter 2; (OCTN2)) had no effect. R(-)-Apomorphine uptake was competitively inhibited by diphenhydramine. Our results indicate that R(-)-apomorphine transport in human blood-brain barrier (BBB) model cells is similar to S(+)-apomorphine uptake. The transport was dependent on an oppositely directed proton gradient, but was sodium- or membrane potential-independent. The transport characteristics were consistent with involvement of the previously reported proton-coupled organic cation antiporter.

  10. Development of the Young Brain

    Medline Plus

    Full Text Available ... brain involved in controlling our impulses, long range planning, judgment, decision making. Announcer: Imaging has shown by ... Institute of Mental Health Office of Science Policy, Planning, and Communications 6001 Executive Boulevard, Room 6200, MSC ...

  11. Development of the Young Brain

    Medline Plus

    Full Text Available ... have a huge impact on how the brain forms and adapts. Announcer: Through the work of Dr. ... National Institute of Mental Health Office of Science Policy, Planning, and Communications 6001 Executive Boulevard, Room 6200, ...

  12. New tricks by an old dogma: mechanisms of the Organizational/Activational Hypothesis of steroid-mediated sexual differentiation of brain and behavior.

    Science.gov (United States)

    McCarthy, Margaret M; Wright, Christopher L; Schwarz, Jaclyn M

    2009-05-01

    The hormonal regulation of sexual behavior has been the topic of study for over 50 years and yet controversies persist regarding the importance of early versus late events and the identity of the critical neural and cellular substrates. We have taken a mechanistic approach toward the masculinizing actions of the gonadal steroid estradiol, as a means to understand how organization of the neuroarchitechture during a perinatal sensitive period exerts enduring influences on adult behavior. We have identified important roles for prostaglandins, FAK and paxillin, PI3 kinase and glutamate, and determined that cell-to-cell signaling is a critical component of the early organizational events. We have further determined that the mechanisms mediating different components of sexual behavior are distinct and regionally specific. The multitude of mechanisms by which the steroid estradiol, exerts divergent effects on the developing nervous system provides for a multitude of phenotypes which can vary significantly both within and between the sexes.

  13. Company as mediator for sustainable development: work in the TRANSPETRO nearest community of Chacaras Douradinho for public policy of Uberlandia, MG-Brazil

    Energy Technology Data Exchange (ETDEWEB)

    Boloni, Leonardo [WBS Empreendimentos Ltda., Salvador, BA (Brazil); Vidal, Marlon; Castro, Newton Camelo de [PETROBRAS Transporte S.A. (TRANSPETRO), Rio de Janeiro, RJ (Brazil)

    2009-07-01

    In this paper we will present the experience of relationship between the team of keeping track of pro pipelines and TRANSPETRO and the Chacaras Douradinho community, particularly in this community approach to public bodies of the city of Uberlandia, MG, in view of the population's access to public policies available in the region. Through these links with public agencies and also with an association of residents, has been made, more intensively between 2006 and 2008, activities of environmental in nature Chacaras Douradinho, a community across the range of Pipeline Sao Paulo - Brazil - OSBRA situated in rural area of the city and still is considered by the local mayor as an irregular. This impossible to receive the various services offered by municipal authorities. Chacaras Douradinho residing in approximately 200 families, most low-income, who do not have documentation of their land, living in temporary work, family agriculture and the resources that they possess. The proposed work aligns with the concept of sustainability, based on the National Program of Social and Environmental Responsibility TRANSPETRO. (author)

  14. Ketogenic Diet Improves Brain Ischemic Tolerance and Inhibits NLRP3 Inflammasome Activation by Preventing Drp1-Mediated Mitochondrial Fission and Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Min Guo

    2018-03-01

    Full Text Available Background: Neuroprotective effects of ketogenic diets (KD have been reported in stroke models, and nucleotide-binding domain (NOD-like receptor protein 3 (NLRP3 inflammasome has also been implicated in the pathogenesis of stroke. This study aimed to investigate the effects of KD on NLRP3 inflammasome and explore the potential molecular mechanisms.Methods: In in vivo study, mice were fed with KD for 3 weeks and then subjected to middle cerebral artery occlusion/reperfusion (MCAO/R-injury. In in vitro study, SH-SY-5Y cells were treated with β-hydroxybutyrate (BHB followed by oxygen–glucose deprivation/reoxygenation (OGD/R. NLRP3 inflammasome activation and related regulatory mechanisms were evaluated.Results: Mice fed with KD had increased tolerance to MCAO/R. KD inhibited endoplasmic reticulum (ER stress and suppressed TXNIP/NLRP3 inflammasome activation in the brain. The in vitro study showed BHB (10 mM prevented the mitochondrial translocation of dynamin-related protein 1 (Drp1 to inhibit mitochondrial fission. Furthermore, BHB decreased reactive oxygen species (ROS generation, inhibited ROS-NLRP3 pathway in OGD/R-treated cells, and suppressed ER stress-induced NLRP3 inflammasome activation.Conclusions: KD may suppress ER stress and protect mitochondrial integrity by suppressing the mitochondrial translocation of Drp1 to inhibit NLRP3 inflammasome activation, thus exerting neuroprotective effects. Our findings provide evidence for the potential application of KD in the prevention of ischemic stroke.

  15. Dynamic functional brain connectivity for face perception

    NARCIS (Netherlands)

    Yang, Yuan; Qiu, Yihong; Schouten, Alfred C.

    2015-01-01

    Face perception is mediated by a distributed brain network comprised of the core system at occipito-temporal areas and the extended system at other relevant brain areas involving bilateral hemispheres. In this study we explored how the brain connectivity changes over the time for face-sensitive

  16. Brain Health Fitness: Beyond Retirement

    Science.gov (United States)

    Anand, Raksha; Chapman, Sandra B.; Rackley, Audette; Zientz, Jennifer

    2011-01-01

    The greatest accomplishment of the 20th century--the doubling of the human lifespan--has brought issues related to brain health to the forefront of public health policy. Given that our bodies are outlasting our minds, maximizing brain health is the scientific cause of this millennium. In this paper, we address three major issues related to…

  17. Grit and the brain: spontaneous activity of the dorsomedial prefrontal cortex mediates the relationship between the trait grit and academic performance

    Science.gov (United States)

    Zhou, Ming; Chen, Taolin; Yang, Xun; Chen, Guangxiang; Wang, Meiyun; Gong, Qiyong

    2017-01-01

    Abstract As a personality trait, grit involves the tendency to strive to achieve long-term goals with continual passion and perseverance and plays an extremely crucial role in personal achievement. However, the neural mechanisms of grit remain largely unknown. In this study, we aimed to explore the association between grit and the fractional amplitude of low-frequency fluctuations (fALFF) in 217 healthy adolescent students using resting-state functional magnetic resonance imaging (RS-fMRI). We found that an individual’s grit was negatively related to the regional fALFF in the right dorsomedial prefrontal cortex (DMPFC), which is involved in self-regulation, planning, goal setting and maintenance, and counterfactual thinking for reflecting on past failures. The results persisted even after the effects of general intelligence and the ‘big five’ personality traits were adjusted for. More importantly, the fALFF of the right DMPFC played a mediating role in the association between grit and academic performance. Overall, these findings reveal regional fALFF as a neural basis of grit and highlight the right DMPFC as a neural link between grit and academic performance. PMID:27672175

  18. Causal Mediation Analysis: Warning! Assumptions Ahead

    Science.gov (United States)

    Keele, Luke

    2015-01-01

    In policy evaluations, interest may focus on why a particular treatment works. One tool for understanding why treatments work is causal mediation analysis. In this essay, I focus on the assumptions needed to estimate mediation effects. I show that there is no "gold standard" method for the identification of causal mediation effects. In…

  19. The small-molecule kinase inhibitor D11 counteracts 17-AAG-mediated up-regulation of HSP70 in brain cancer cells.

    Science.gov (United States)

    Schaefer, Susanne; Svenstrup, Tina H; Guerra, Barbara

    2017-01-01

    Many types of cancer express high levels of heat shock proteins (HSPs) that are molecular chaperones regulating protein folding and stability ensuring protection of cells from potentially lethal stress. HSPs in cancer cells promote survival, growth and spreading even in situations of growth factors deprivation by associating with oncogenic proteins responsible for cell transformation. Hence, it is not surprising that the identification of potent inhibitors of HSPs, notably HSP90, has been the primary research focus, in recent years. Exposure of cancer cells to HSP90 inhibitors, including 17-AAG, has been shown to cause resistance to chemotherapeutic treatment mostly attributable to induction of the heat shock response and increased cellular levels of pro-survival chaperones. In this study, we show that treatment of glioblastoma cells with 17-AAG leads to HSP90 inhibition indicated by loss of stability of the EGFR client protein, and significant increase in HSP70 expression. Conversely, co-treatment with the small-molecule kinase inhibitor D11 leads to suppression of the heat shock response and inhibition of HSF1 transcriptional activity. Beside HSP70, Western blot and differential mRNA expression analysis reveal that combination treatment causes strong down-regulation of the small chaperone protein HSP27. Finally, we demonstrate that incubation of cells with both agents leads to enhanced cytotoxicity and significantly high levels of LC3-II suggesting autophagy induction. Taken together, results reported here support the notion that including D11 in future treatment regimens based on HSP90 inhibition can potentially overcome acquired resistance induced by the heat shock response in brain cancer cells.

  20. Oxidative damage mediated iNOS and UCP-2 upregulation in rat brain after sub-acute cyanide exposure: dose and time-dependent effects.

    Science.gov (United States)

    Bhattacharya, Rahul; Singh, Poonam; John, Jebin Jacob; Gujar, Niranjan L

    2018-04-03

    Cyanide-induced chemical hypoxia is responsible for pronounced oxidative damage in the central nervous system. The disruption of mitochondrial oxidative metabolism has been associated with upregulation of uncoupling proteins (UCPs). The present study addresses the dose- and time-dependent effect of sub-acute cyanide exposure on various non-enzymatic and enzymatic oxidative stress markers and their correlation with inducible-nitric oxide synthase (iNOS) and uncoupling protein-2 (UCP-2) expression. Animals received (oral) triple distilled water (vehicle control), 0.25 LD50 potassium cyanide (KCN) or 0.50 LD50 KCN daily for 21 d. Animals were sacrificed on 7, 14 and 21 d post-exposure to measure serum cyanide and nitrite, and brain malondialdehyde (MDA), reduced glutathione (GSH), glutathione disulfide (GSSG), cytochrome c oxidase (CCO), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CA) levels, together with iNOS and UCP-2 expression, and DNA damage. The study revealed that a dose- and time-dependent increase in cyanide concentration was accompanied by corresponding CCO inhibition and elevated MDA levels. Decrease in GSH levels was not followed by reciprocal change in GSSG levels. Diminution of SOD, GPx, GR and CA activity was congruent with elevated nitrite levels and upregulation of iNOS and UCP-2 expression, without any DNA damage. It was concluded that long-term cyanide exposure caused oxidative stress, accompanied by upregulation of iNOS. The upregulation of UCP-2 further sensitized the cells to cyanide and accentuated the oxidative stress, which was independent of DNA damage.

  1. Antiepileptic activity of total triterpenes isolated from Poria cocos is mediated by suppression of aspartic and glutamic acids in the brain.

    Science.gov (United States)

    Gao, Yanqiong; Yan, Hua; Jin, Ruirui; Lei, Peng

    2016-11-01

    Triterpenes from Poria cocos Wolf (Polyporaceae) have been used to treat various diseases in traditional Chinese medicine. However, the antiepileptic effects and mechanism are not fully understood. The objective of this study is to investigate the antiepileptic properties of total triterpenes (TTP) from the whole P. cocos. The ethanol extract TTP was identified by HPLC fingerprint analysis. Male ICR mice were gavaged (i.g.) with TTP (5, 20, 80 or 160 mg/kg) or reference drugs twice a day for 7 d. Antiepileptic activities of TTP were evaluated by maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizures in mice for 30 and 60 min, respectively. Locomotor activity and Rota-rod tests were performed for 60 min and 5 min, respectively. The levels of glutamic acid (Glu), aspartic acid (Asp), γ-aminobutyric acid (GABA) and glycine (Gly) in convulsive mice were estimated. The chronic epileptic model of Wistar rats was built to measure expressions of glutamate decarboxylase 65 (GAD65) and GABA A in rat brain after TTP treatment. The LC 50 of TTP (i.g.) was above 6 g/kg. TTP (5-160 mg/kg) protected mice against MES- and PTZ-induced convulsions at 65.0% and 62.5%, respectively, but have no effect on rota-rod treadmill; TTP (20-160 mg/kg) significantly reduced the locomotor activities, shortened the onset of pentobarbital sodium-induced sleep; TTP decreased Glu and Asp levels in convulsive mice, but increased the GAD65 and GABA A expressions in chronic epileptic rats at doses usage. TTP extracted from P. cocos possessed potential antiepileptic properties and is a candidate for further antiepileptic drug development.

  2. Melatonin disturbs SUMOylation mediated crosstalk between c-Myc and Nestin via MT1 activation and promotes the sensitivity of Paclitaxel in brain cancer stem cells.

    Science.gov (United States)

    Lee, Hyemin; Lee, Hyo-Jung; Jung, Ji Hoon; Shin, Eun Ah; Kim, Sung-Hoon

    2018-04-14

    Here the underlying antitumor mechanism of melatonin and its potency as a sensitizer of Paclitaxel was investigated in X02 cancer stem cells. Melatonin suppressed sphere formation and induced G2/M arrest in X02 cells expressing Nestin, CD133, CXCR4 and SOX-2 as biomarkers of stemness. Furthermore, melatonin reduced the expression of CDK2, CDK4, cyclin D1, cyclin E, and c-Myc and upregulated cyclin B1 in X02 cells. Notably, genes of c-Myc related mRNAs were differentially expressed in melatonin treated X02 cells by microarray analysis. Consistently, melatonin reduced the expression of c-Myc at mRNA and protein levels, which was blocked by MG132. Of note, overexpression of c-Myc increased the expression of Nestin, while overexpression of Nestin enhanced c-Myc through crosstalk despite different locations, nucleus and cytoplasm. Interestingly, melatonin attenuated small ubiquitin-related modifier-1 (SUMO-1) more than SUMO-2 or SUMO-3 and disturbed nuclear translocation of Nestin for direct binding to c-Myc by SUMOylation of SUMO-1 protein by immunofluorescence and immunoprecipitation. Also, melatonin reduced trimethylated histone H3K4me3 and H3K36me3 more than dimethylation in X02 cells by Western blotting and Chromatin immunoprecipitation assay. Notably, melatonin upregulated MT1, not MT2, in X02 cells and melatonin receptor inhibitor Luzindole blocked the ability of melatonin to decrease the expression of Nestin, p-c-Myc(S62) and c-Myc. Furthermore, melatonin promoted cytotoxicity, sub G1 accumulation and apoptotic body formation by Paclitaxcel in X02 cells. Taken together, these findings suggest that melatonin inhibits stemness via suppression of c-Myc, Nestin, and histone methylation via MT1 activation and promotes anticancer effect of Paclitaxcel in brain cancer stem cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  3. Brain Tumors

    Science.gov (United States)

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  4. Mediation Analysis with Multiple Mediators.

    Science.gov (United States)

    VanderWeele, T J; Vansteelandt, S

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators.

  5. Magnetic resonance and photoacoustic imaging of brain tumor mediated by mesenchymal stem cell labeled with multifunctional nanoparticle introduced via carotid artery injection

    Science.gov (United States)

    Qiao, Yang; Gumin, Joy; MacLellan, Christopher J.; Gao, Feng; Bouchard, Richard; Lang, Frederick F.; Stafford, R. Jason; Melancon, Marites P.

    2018-04-01

    Objective. To evaluate the feasibility of visualizing bone marrow-derived human mesenchymal stem cells (MSCs) labeled with a gold-coated magnetic resonance (MR)-active multifunctional nanoparticle and injected via the carotid artery for assessing the extent of MSC homing in glioma-bearing mice. Materials and methods. Nanoparticles containing superparamagnetic iron oxide coated with gold (SPIO@Au) with a diameter of ˜82 nm and maximum absorbance in the near infrared region were synthesized. Bone marrow-derived MSCs conjugated with green fluorescent protein (GFP) were successfully labeled with SPIO@Au at 4 μg ml-1 and injected via the internal carotid artery in six mice bearing orthotopic U87 tumors. Unlabeled MSCs were used as a control. The ability of SPIO@Au-loaded MSCs to be imaged using MR and photoacoustic (PA) imaging at t = 0 h, 2 h, 24 h, and 72 h was assessed using a 7 T Bruker Biospec experimental MR scanner and a Vevo LAZR PA imaging system with a 5 ns laser as the excitation source. Histological analysis of the brain tissue was performed 72 h after MSC injection using GFP fluorescence, Prussian blue staining, and hematoxylin-and-eosin staining. Results. MSCs labeled with SPIO@Au at 4 μg ml-1 did not exhibit cell death or any adverse effects on differentiation or migration. The PA signal in tumors injected with SPIO@Au-loaded MSCs was clearly more enhanced post-injection, as compared with the tumors injected with unlabeled MSCs at t = 72 h. Using the same mice, T2-weighted MR imaging results taken before injection and at t = 2 h, 24 h, and 72 h were consistent with the PA imaging results, showing significant hypointensity of the tumor in the presence of SPIO@Au-loaded MSCs. Histological analysis also showed co-localization of GFP fluorescence and iron, thereby confirming that SPIO@Au-labeled MSCs continue to carry their nanoparticle payloads even at 72 h after injection. Conclusions. Our results demonstrated the feasibility of tracking carotid artery

  6. Estimation of ellagic acid and/or repaglinide effects on insulin signaling, oxidative stress, and inflammatory mediators of liver, pancreas, adipose tissue, and brain in insulin resistant/type 2 diabetic rats.

    Science.gov (United States)

    Amin, Mohamed M; Arbid, Mahmoud S

    2017-02-01

    Even though ellagic acid has previously been valued in many models of cancer, so far its full mechanistic effect as a natural antiapoptotic agent in the prevention of type 2 diabetes complications has not been completely elucidated, which was the goal of this study. We fed albino rats a high-fat fructose diet (HFFD) for 2 months to induce insulin resistance/type 2 diabetes and then treated the rats with ellagic acid (10 mg/kg body weight, orally) and/or repaglinide (0.5 mg/kg body weight, orally) for 2 weeks. At the serum level, ellagic acid challenged the consequences of HFFD, significantly improving the glucose/insulin balance, liver enzymes, lipid profile, inflammatory cytokines, redox level, adipokines, ammonia, and manganese. At the tissue level (liver, pancreas, adipose tissue, and brain), ellagic acid significantly enhanced insulin signaling, autophosphorylation, adiponectin receptors, glucose transporters, inflammatory mediators, and apoptotic markers. Remarkably, combined treatment with both ellagic acid and repaglinide had a more pronounced effect than treatment with either alone. These outcomes give new insight into the promising molecular mechanisms by which ellagic acid modulates numerous factors induced in the progression of diabetes.

  7. Brain surgery

    Science.gov (United States)

    Craniotomy; Surgery - brain; Neurosurgery; Craniectomy; Stereotactic craniotomy; Stereotactic brain biopsy; Endoscopic craniotomy ... cut depends on where the problem in the brain is located. The surgeon creates a hole in ...

  8. Brain Malformations

    Science.gov (United States)

    Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

  9. Postnatal brain development

    DEFF Research Database (Denmark)

    Jernigan, Terry L; Baaré, William F C; Stiles, Joan

    2011-01-01

    After birth, there is striking biological and functional development of the brain's fiber tracts as well as remodeling of cortical and subcortical structures. Behavioral development in children involves a complex and dynamic set of genetically guided processes by which neural structures interact...... in children and adolescents, as well as studies that link these changes to behavioral differences. Finally, we discuss evidence for effects on the brain of several factors that may play a role in mediating these brain-behavior associations in children, including genetic variation, behavioral interventions...... constantly with the environment. This is a protracted process, beginning in the third week of gestation and continuing into early adulthood. Reviewed here are studies using structural imaging techniques, with a special focus on diffusion weighted imaging, describing age-related brain maturational changes...

  10. Postnatal brain development

    DEFF Research Database (Denmark)

    Jernigan, Terry L; Baaré, William F C; Stiles, Joan

    2011-01-01

    After birth, there is striking biological and functional development of the brain's fiber tracts as well as remodeling of cortical and subcortical structures. Behavioral development in children involves a complex and dynamic set of genetically guided processes by which neural structures interact...... constantly with the environment. This is a protracted process, beginning in the third week of gestation and continuing into early adulthood. Reviewed here are studies using structural imaging techniques, with a special focus on diffusion weighted imaging, describing age-related brain maturational changes...... in children and adolescents, as well as studies that link these changes to behavioral differences. Finally, we discuss evidence for effects on the brain of several factors that may play a role in mediating these brain-behavior associations in children, including genetic variation, behavioral interventions...

  11. Cannabinoids on the Brain

    Directory of Open Access Journals (Sweden)

    Andrew J. Irving

    2002-01-01

    Full Text Available Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.

  12. Immunopathogenesis of brain abscess

    Directory of Open Access Journals (Sweden)

    Kielian Tammy

    2004-08-01

    Full Text Available Abstract Brain abscess represents a significant medical problem despite recent advances made in detection and therapy. Due to the emergence of multi-drug resistant strains and the ubiquitous nature of bacteria, the occurrence of brain abscess is likely to persist. Our laboratory has developed a mouse experimental brain abscess model allowing for the identification of key mediators in the CNS anti-bacterial immune response through the use of cytokine and chemokine knockout mice. Studies of primary microglia and astrocytes from neonatal mice have revealed that S. aureus, one of the main etiologic agents of brain abscess in humans, is a potent stimulus for proinflammatory mediator production. Recent evidence from our laboratory indicates that Toll-like receptor 2 plays a pivotal role in the recognition of S. aureus and its cell wall product peptidoglycan by glia, although other receptors also participate in the recognition event. This review will summarize the consequences of S. aureus on CNS glial activation and the resultant neuroinflammatory response in the experimental brain abscess model.

  13. Mediation Analysis with Multiple Mediators

    OpenAIRE

    VanderWeele, T.J.; Vansteelandt, S.

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects throu...

  14. Blueberry Phenolics Reduce Gastrointestinal Infection of Patients with Cerebral Venous Thrombosis by Improving Depressant-Induced Autoimmune Disorder via miR-155-Mediated Brain-Derived Neurotrophic Factor

    Science.gov (United States)

    Xu, Ning; Meng, Hao; Liu, Tianyi; Feng, Yingli; Qi, Yuan; Zhang, Donghuan; Wang, Honglei

    2017-01-01

    Cerebral venous thrombosis (CVT) often causes human depression, whereas depression-induced low immunity makes the patients susceptible to gastrointestinal infection. Blueberry possesses antidepressant properties which may improve autoimmunity and reduce gastrointestinal infection. Brain-derived neurotrophic factor (BDNF) performs antidepressant function and can be regulated by miR-155, which may be affected by blueberry. To explore the possible molecular mechanism, blueberry compounds were analyzed by high-performance liquid chromatography. Activity of compounds was tested by using HT22 cells. The present study tested 124 patients with CVT-induced mild-to-moderate depressive symptoms (Center for Epidemiologic Studies—Depression Scale [CES-D] ≥16) and gastrointestinal infection. Patients were randomly assigned to blueberry extract group (BG, received 10 mg blueberry extract daily) and placebo group (PG, received 10 mg placebo daily). After 3 months, depression, gastrointestinal infection and lipid profiles were investigated. Serum miR-155 and BDNF were measured using real-time quantitative polymerase chain reaction and or Western Blot. Blueberry treatment improved depressive symptoms and lipid profiles, and also reduced gastrointestinal infection in the BG group (P blueberry extracts were the main phenolic acids with 0.18, 0.85, 0.26, 0.72, 0.66, 0.4,1, and 1.92 mg/g of gentisic acid, chlorogenic acid, [2]-epicatechin, p-coumaric acid, benzoic acid, p-anisic acid, and quercetin in blueberry extracts, respectively. Phenolics in blueberry are possible causal agents in improving antidepressant activity and reducing gastrointestinal infection. Administration of blueberry increased BDNF expression and miR-155. Blueberry cannot affect BDNF level when miR-155 is overexpressed or inhibited. Phenolics from blueberry reduced gastrointestinal infection of patients with CVT by improving antidepressant activity via upregulation of miR-155-mediated BDNF. PMID:29230173

  15. Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis.

    Science.gov (United States)

    Lu, Jun; Wu, Dong-mei; Zheng, Yuan-lin; Hu, Bin; Zhang, Zi-feng

    2010-05-01

    Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, protects brain function against oxidative stress induced by D-galactose (D-gal) (Sigma-Aldrich, St. Louis, MO, USA). Our data showed that PSPC enhanced open-field activity, decreased step-through latency, and improved spatial learning and memory ability in D-gal-treated old mice by decreasing advanced glycation end-products' (AGEs) formation and the AGE receptor (RAGE) expression, and by elevating Cu,Zn-superoxide dismutase (Cu,Zn-SOD) (Sigma-Aldrich) and catalase (CAT) expression and activity. Cleavage of caspase-3 and increased terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in D-gal-treated old mice were inhibited by PSPC, which might be attributed to its antioxidant property. PSPC also suppressed the activation of c-Jun NH(2)-terminal kinase (JNK) and the release of cytochrome c from mitochondria that counteracted the onset of neuronal apoptosis in D-gal-treated old mice. Furthermore, it was demonstrated that phosphoinositide 3-kinase (PI3K) activation was required for PSPC to promote the neuronal survival accompanied with phosphorylation and activation of Akt and p44/42 mitogen-activated protein kinase (MAPK) by using PI3K inhibitor LY294002 (Cell Signaling Technology, Inc., Beverly, MA, USA), implicating a neuronal survival mechanism. The present results suggest that neuronal survival promoted by PSPC may be a potentially effective method to enhance resistance of neurons to age-related disease.

  16. Sustainability Policy and Environmental Policy

    OpenAIRE

    John C. V. Pezzey

    2001-01-01

    A theoretical, representative agent economy with a depletable resource stock, polluting emissions and productive capital is used to contrast environmental policy, which internalises externalised environmental values, with sustainability policy, which achieves some form of intergenerational equity. The obvious environmental policy comprises an emissions tax and a resource stock subsidy, each equal to the respective external cost or benefit. Sustainability policy comprises an incentive affectin...

  17. Theories of the Family and Policy

    OpenAIRE

    Veronica Jacobsen; Lindy Fursman; John Bryant; Megan Claridge; Benedikte Jensen

    2004-01-01

    Policy interventions that affect or are mediated through the family typically assume a behavioural response. Policy analyses proceeding from different disciplinary bases may come to quite different conclusions about the effects of policies on families, depending how individuals within families behave. This paper identifies the implications of five theories of family and individual behaviour for the likely success of policy intervention. Anthropology documents not only the universality of the ...

  18. Complex Mediation

    DEFF Research Database (Denmark)

    Bødker, Susanne; Andersen, Peter Bøgh

    2005-01-01

    This article has its starting point in a large number of empirical findings regarding computer-mediated work. These empirical findings have challenged our understanding of the role of mediation in such work; on the one hand as an aspect of communication and cooperation at work and on the other hand...... as an aspect of human engagement with instruments of work. On the basis of previous work in activity-theoretical and semiotic human—computer interaction, we propose a model to encompass both of these aspects. In a dialogue with our empirical findings we move on to propose a number of types of mediation...... that have helped to enrich our understanding of mediated work and the design of computer mediation for such work....

  19. Brain Diseases

    Science.gov (United States)

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  20. Nordic Mediation - Comparing Denmark and Finland

    DEFF Research Database (Denmark)

    Lappi-Seppälä, Tapio; Storgaard, Anette

    2015-01-01

    The Nordic Countries have a long common history in criminal policy but a closer look also indicates individual Development. the introduction of Victim Offender Mediation is one example of Nordic diversity in details.......The Nordic Countries have a long common history in criminal policy but a closer look also indicates individual Development. the introduction of Victim Offender Mediation is one example of Nordic diversity in details....

  1. Privacy Policy

    Science.gov (United States)

    ... Home → NLM Privacy Policy URL of this page: https://medlineplus.gov/privacy.html NLM Privacy Policy To ... out of cookies in the most popular browsers, http://www.usa.gov/optout_instructions.shtml. Please note ...

  2. Brain Aneurysm

    Science.gov (United States)

    A brain aneurysm is an abnormal bulge or "ballooning" in the wall of an artery in the brain. They are sometimes called berry aneurysms because they ... often the size of a small berry. Most brain aneurysms produce no symptoms until they become large, ...

  3. Brain Development

    Science.gov (United States)

    ... Become a Member Home Early Development & Well-Being Brain Development A child’s brain undergoes an amazing period of development from birth ... neural connections each second. The development of the brain is influenced by many factors, including a child’s ...

  4. The policies

    International Nuclear Information System (INIS)

    Laruelle, Ph.; Snegaroff, Th.; Moreau, S.; Tellenne, C.; Brunel, S.

    2005-01-01

    Fourth chapter of the book on the geo-policy of the sustainable development, this chapter deal with the different and international policies concerned by the problem. The authors analyze the american energy attitude and policy, the economical equilibrium facing the environmental equilibrium for the european policy, the sanctified and sacrificed nature and the japanese attitude, India and China, the great fear of the 21 century and the sustainable development in Africa. (A.L.B.)

  5. Trade Policy

    OpenAIRE

    Murray Gibbs

    2007-01-01

    In an otherwise insightful and thoughtful article, Sebastian Pfotenhauer (Trade Policy Is Science Policy,” Issues, Fall 2013) might better have entitled his contribution “Trade Policy Needs to Be Reconciled with Science Policy.” The North American Free Trade Agreement (NAFTA) and the agreements administered by the World Trade Organization, particularly the General Agreement on Tariffs and Trade (GATT) and the Technical Barriers to Trade (TBT), were adopted to promote international trade and i...

  6. Left Brain. Right Brain. Whole Brain

    Science.gov (United States)

    Farmer, Lesley S. J.

    2004-01-01

    As the United States student population is becoming more diverse, library media specialists need to find ways to address these distinctive needs. However, some of these differences transcend culture, touching on variations in the brain itself. Most people have a dominant side of the brain, which can affect their personality and learning style.…

  7. Bidirectional apical-basal traffic of the cation-independent mannose-6-phosphate receptor in brain endothelial cells

    DEFF Research Database (Denmark)

    Siupka, Piotr; Hersom, Maria N. S.; Lykke-Hartmann, Karin

    2017-01-01

    Brain capillary endothelium mediates the exchange of nutrients between blood and brain parenchyma. This barrier function of the brain capillaries also limits passage of pharmaceuticals from blood to brain, which hinders treatment of several neurological disorders. Receptor-mediated transport has ...

  8. Brain Basics: Know Your Brain

    Science.gov (United States)

    ... however, the brain is beginning to relinquish its secrets. Scientists have learned more about the brain in ... through the activity of these lobes. At the top of each temporal lobe is an area responsible ...

  9. Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor (BDNF) tohuman umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) promotescrush-injured rat sciatic nerve regeneration.

    Science.gov (United States)

    Hei, Wei-Hong; Almansoori, Akram A; Sung, Mi-Ae; Ju, Kyung-Won; Seo, Nari; Lee, Sung-Ho; Kim, Bong-Ju; Kim, Soung-Min; Jahng, Jeong Won; He, Hong; Lee, Jong-Ho

    2017-03-16

    This study was designed toinvestigate the efficacy of adenovirus vector-mediated brain-derived neurotrophic factor (BDNF) ex vivo gene transfer to human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) in a rat sciatic nerve crush injury model. BDNF protein and mRNA expression after infection was checked through an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Male Sprague-Dawley rats (200-250g, 6 weeks old) were distributed into threegroups (n=20 each): the control group, UCB-MSC group, and BDNF-adenovirus infected UCB-MSC (BDNF-Ad+UCB-MSC) group. UCB-MSCs (1×10 6 cells/10μl/rat) or BDNF-Ad+UCB-MSCs (1×10 6 cells/10μl/rat)were transplantedinto the rats at the crush site immediately after sciatic nerve injury. Cell tracking was done with PKH26-labeled UCB-MSCs and BDNF-Ad+UCB-MSCs (1×10 6 cells/10μl/rat). The rats were monitored for 4 weeks post-surgery. Results showed that expression of BDNF at both the protein and mRNA levels was higher inthe BDNF-Ad+UCB-MSC group compared to theUCB-MSC group in vitro.Moreover, BDNF mRNA expression was higher in both UCB-MSC group and BDNF-Ad+ UCB-MSC group compared tothe control group, and BDNF mRNA expression in theBDNF-Ad+UCB-MSC group was higher than inboth other groups 5days after surgeryin vivo. Labeled neurons in the dorsal root ganglia (DRG), axon counts, axon density, and sciatic function index were significantly increased in the UCB-MSC and BDNF-Ad+ UCB-MSCgroupscompared to the controlgroup four weeksaftercell transplantation. Importantly,the BDNF-Ad+UCB-MSCgroup exhibited more peripheral nerve regeneration than the other two groups.Our results indicate thatboth UCB-MSCs and BDNF-Ad+UCB-MSCscan improve rat sciatic nerve regeneration, with BDNF-Ad+UCB-MSCsshowing a greater effectthan UCB-MSCs. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Brain glycogen

    DEFF Research Database (Denmark)

    Obel, Linea Lykke Frimodt; Müller, Margit S; Walls, Anne B

    2012-01-01

    Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia....... In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies-it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic...... activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms...

  11. Mediatized play

    DEFF Research Database (Denmark)

    Johansen, Stine Liv

    Children’s play must nowadays be understood as a mediatized field in society and culture. Media – understood in a very broad sense - holds severe explanatory power in describing and understanding the practice of play, since play happens both with, through and inspired by media of different sorts........ In this presentation the case of ‘playing soccer’ will be outlined through its different mediated manifestations, including soccer games and programs on TV, computer games, magazines, books, YouTube videos and soccer trading cards....

  12. Mediating Business

    DEFF Research Database (Denmark)

    "Mediating Business" is a study of the expansion of business journalism. Building on evidence from Denmark, Finland, Norway and Sweden, "Mediating Business" is a comparative and multidisciplinary study of one of the major transformations of the mass media and the realm of business - nationally...... and globally. The book explores the history of key innovations and innovators in the business press. It analyzes changes in the discourse of business journalism associated with the growth in business news and the development of new ways of framing business issues and events. Finally, it examines...... the organizational implications of the increased media visibility of business and, in particular, the development of corporate governance and media relations....

  13. ENERGY POLICY

    OpenAIRE

    Avrupa Topluluğu Enstitüsü, Marmara Üniversitesi

    2015-01-01

    John Mitchell considers EU policies on energy supply security; Tera Allas on energy security of supply in the UK: the way forward; Peter Odell assesses public/private partnerships on the UKCS; Olivier Appert provides an overview of French energy policy.

  14. Energy policy

    International Nuclear Information System (INIS)

    Forrester, J.W.

    1979-01-01

    The author places the energy problem in the context of world economy. The various obstacles encountered in the United States to spell out a viable national energy policy are cited. A certain number of practical proposals is given to lead to an 'effective policy' which would allow energy economy at the same time as energy development, that is, including nuclear energy [fr

  15. Brain imaging

    International Nuclear Information System (INIS)

    Mishkin, F.S.

    1978-01-01

    The techniques of brain imaging and results in perfusion studies and delayed images are outlined. An analysis of the advantages and disadvantages of the brain scan in a variety of common problems is discussed, especially as compared with other available procedures. Both nonneoplastic and neoplastic lesions are considered. (Auth/C.F.)

  16. Brain docosahexaenoic acid uptake and metabolism.

    Science.gov (United States)

    Lacombe, R J Scott; Chouinard-Watkins, Raphaël; Bazinet, Richard P

    2018-02-08

    Docosahexaenoic acid (DHA) is the most abundant n-3 polyunsaturated fatty acid in the brain where it serves to regulate several important processes and, in addition, serves as a precursor to bioactive mediators. Given that the capacity of the brain to synthesize DHA locally is appreciably low, the uptake of DHA from circulating lipid pools is essential to maintaining homeostatic levels. Although, several plasma pools have been proposed to supply the brain with DHA, recent evidence suggests non-esterified-DHA and lysophosphatidylcholine-DHA are the primary sources. The uptake of DHA into the brain appears to be regulated by a number of complementary pathways associated with the activation and metabolism of DHA, and may provide mechanisms for enrichment of DHA within the brain. Following entry into the brain, DHA is esterified into and recycled amongst membrane phospholipids contributing the distribution of DHA in brain phospholipids. During neurotransmission and following brain injury, DHA is released from membrane phospholipids and converted to bioactive mediators which regulate signaling pathways important to synaptogenesis, cell survival, and neuroinflammation, and may be relevant to treating neurological diseases. In the present review, we provide a comprehensive overview of brain DHA metabolism, encompassing many of the pathways and key enzymatic regulators governing brain DHA uptake and metabolism. In addition, we focus on the release of non-esterified DHA and subsequent production of bioactive mediators and the evidence of their proposed activity within the brain. We also provide a brief review of the evidence from post-mortem brain analyses investigating DHA levels in the context of neurological disease and mood disorder, highlighting the current disparities within the field. Copyright © 2017. Published by Elsevier Ltd.

  17. Rasio Utang Memediasi Pengaruh Kemampulabaan Dan Ukuran Aktiva Terhadap Kebijakan Dividen: Studi Empiris Pada Perusahaan Perkebunan Kelapa Sawit Yang Terdaftar Di Bursa Efek Indonesia [Debt Ratio to Mediate Effect of Profitability and Asset Size on Dividend Policy: An Empirical Study on Oil Palm Plantation Companies Listed with the Indonesia Stock Exchange

    Directory of Open Access Journals (Sweden)

    Rudolf Lumbantobing

    2017-06-01

    Full Text Available This research explores the influence of the debt policy, profitability, and size of asset toward company's dividend policy on oil palm plantation companies listed with the Indonesia Stock Exchange for the years 2011-2015. The secondary data used in this research were obtained directly from the company website and the Indonesia Stock Exchange (IDX. The data collection was conducted by direct observation upon the research object. The data were analyzed using path analysis and logistical regression model. The result showed that profitability has a significant and negative effect on the debt ratio. Size of asset does not have a significant and positive effect on the debt ratio. Profitability and size of assets have significant and positive effects on dividend policy, which proves that the larger profitability and the size of assets, the greater the probabilty of paying dividends. Debt ratio does not have a significant and positive effect on dividend policy. Debt ratio has a significant positively partial mediating effect toward the influence of profitability on dividend policy. Otherwise, debt ratio does not have a significant negatively mediating effect toward the positive effect of size of asset on dividend policy.  BAHASA INDONESIA ABSTRAK: Penelitian ini mengeksplorasi engaruh kebijakan utang, kemampulabaan dan ukuran aktiva terhadap kebijakan dividen perusahaan perkebunan kelapa sawit yang terdaftar di Bursa Efek Indonesia periode tahun 2011-2015. Data yang digunakan adalah data sekunder yang diperoleh secara langsung dari website perusahaan dan Bursa Efek Indonesia. Pengumpulan data dilakukan dengan observasi tidak langsung terhadap objek penelitian yaitu perusahaan kelapa sawit. Data dianalisis dengan menggunakan path analysis dan model regresi logistik. Temuan penelitian ini menunjukkan bukti bahwa kemampulabaan signifikan berpengaruh negatif terhadap rasio utang. Ukuran aktiva tidak signifikan berpengaruh positif terhadap rasio

  18. Data Policy

    Directory of Open Access Journals (Sweden)

    Mark A Parsons

    2013-07-01

    Full Text Available The first purpose of data policy should be to serve the objectives of the organization or project sponsoring the collection of the data. With research data, data policy should also serve the broader goals of advancing scientific and scholarly inquiry and society at large. This is especially true with government-funded data, which likely comprise the vast majority of research data. Data policy should address multiple issues, depending on the nature and objectives of the data. These issues include data access requirements, data preservation and stewardship requirements, standards and compliance mechanisms, data security issues, privacy and ethical concerns, and potentially even specific collection protocols and defined data flows. The specifics of different policies can vary dramatically, but all data policies need to address data access and preservation. Research data gain value with use and must therefore be accessible and preserved for future access. This article focuses on data access. While policy might address multiple issues, at a first level it must address where the data stand on what Lyon (2009 calls the continuum of openness. Making data as openly accessible as possible provides the greatest societal benefit, and a central purpose of data policy is to work toward ethically open data access. An open data regime not only maximizes the benefit of the data, it also simplifies most of the other issues around effective research data stewardship and infrastructure development.

  19. How Can Research Mediators Better Mediate?: The Importance of Inward-Looking Processes

    Science.gov (United States)

    Shaw, Jessica

    2018-01-01

    Science can provide empirically-informed strategies and resources to inform and improve policy and practice, though all too often science, policy, and practice operate independently from one another. Research mediators play a critical role by attempting to connect these different worlds. This practice paper presents lessons learned and…

  20. Enhancement of plasmid-mediated stable gene expression by ...

    African Journals Online (AJOL)

    ARL

    2012-06-12

    Jun 12, 2012 ... production and faithful translation and processing of proteins (Baldi et al., ..... deeper understanding of the interaction of cellular factors and regulatory DNA .... mediated transgene expression in the rat brain. Gene Ther., 7: ...

  1. Brain tumor - primary - adults

    Science.gov (United States)

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  2. Brain Stimulation Therapies

    Science.gov (United States)

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  3. Brain radiation - discharge

    Science.gov (United States)

    Radiation - brain - discharge; Cancer - brain radiation; Lymphoma - brain radiation; Leukemia - brain radiation ... Decadron) while you are getting radiation to the brain. It may make you hungrier, cause leg swelling ...

  4. Brain abscess

    Science.gov (United States)

    ... found. However, the most common source is a lung infection. Less often, a heart infection is the cause. The following raise your chance of developing a brain abscess: A weakened immune system (such as in people ...

  5. What will this do to me and my brain? Ethical issues in brain-to-brain interfacing

    Directory of Open Access Journals (Sweden)

    Elisabeth eHildt

    2015-02-01

    Full Text Available For several years now, brain-computer interfaces (BCIs in which brain signals are used to navigate a computer, a prostheses or a technical device, have been developed in various experimental contexts (Wolpaw & Wolpaw 2012; Grübler & Hildt 2014. Researchers have recently taken the next step and run experiments based on connections between two brains. These so-called brain-to-brain interfaces (abbreviation: BBIs or BTBIs involve not only a BCI component deriving information from a brain and sending it to a computer, but also a computer-brain interface (CBI component delivering information to another brain. What results is technology-mediated brain-to-brain communication (B2B communication, i.e. direct communication between two brains that does not involve any activity of the peripheral nervous system. In what follows, ethical issues that arise in neural interfacing will be discussed after a short introduction to recent BBI experiments. In this, the focus will be on the implications BBIs may have on the individual at the CBI side of the BBI, i.e. on the recipient.

  6. Brain imaging and brain function

    International Nuclear Information System (INIS)

    Sokoloff, L.

    1985-01-01

    This book is a survey of the applications of imaging studies of regional cerebral blood flow and metabolism to the investigation of neurological and psychiatric disorders. Contributors review imaging techniques and strategies for measuring regional cerebral blood flow and metabolism, for mapping functional neural systems, and for imaging normal brain functions. They then examine the applications of brain imaging techniques to the study of such neurological and psychiatric disorders as: cerebral ischemia; convulsive disorders; cerebral tumors; Huntington's disease; Alzheimer's disease; depression and other mood disorders. A state-of-the-art report on magnetic resonance imaging of the brain and central nervous system rounds out the book's coverage

  7. Mediating Empowerment

    DEFF Research Database (Denmark)

    Budeanu, Adriana

    from conflicting goals of conservation versus development plans for tourism. Mixed approaches that combine top-down governance models with bottom-up collaborative strategies and policy networks are considered able to provide resilient decision making systems able to cope with unexpected challenges......Tourism has a dualistic nature characterised on the one hand by a high resilience and constant growth and on the other hand by a short-term greed of “consuming” its own life support systems: nature, culture and communities (Snepenger, Snepenger, Dalbey, & Wessol, 2007). Both aspects are constantly...... spurred by the rapid changes in demand and the diversity of supply, and the intrinsic importance that tourism has gained in individual lifestyles and in national economies. In addition, the strong influence of globalization on the institutional, organizational and policy formulation (Hall, 2005...

  8. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairmen...

  9. Alcohol Control and Harm Reduction Policies in Lebanon | IDRC ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Findings will document the current national alcohol policy and identify the direct and indirect influences of policy-relevant factors and psychosocial mediators on alcohol consumption and purchasing. Researchers will also assess the potential impact of specific alcohol-control policy packages. The results should help to ...

  10. Policy Innovation in Innovation Policy

    DEFF Research Database (Denmark)

    Borras, Susana

    During the past two decades Europe has experienced important changes and transformations in the way in which governments approach the issue of science, technology and innovation, and their relation to economic growth and competitiveness. This has to do with the European Union level as well...... as with national and sub-national governments in Europe, all of them introducing interesting novelties in their innovation policy. These changes refer to different aspects of policy, mainly the content of policy initiatives towards science, technology and innovation; the instruments governments are using...... at the EU level, and mentions similar trends taking place at national and sub-national levels. The questions that guide the contents here are essentially three, namely, what are the main traits of innovation policies in Europe since the 1990s and how have the EU and different national governments approached...

  11. The Potential of Systems Thinking in Teacher Reform as Theorized for the Teaching Brain Framework

    Science.gov (United States)

    Rodriguez, Vanessa

    2013-01-01

    The teaching brain is a dynamic system that is in constant interaction with the learning brain. If we fail to explore the teaching brain we will continue to design educational reform policies that ignore the most important lens in the classroom: the teachers'. Master teachers recognize their perspective and leverage their teaching brains to embody…

  12. Automatic Evolution of Multimodal Behavior with Multi-Brain HyperNEAT

    DEFF Research Database (Denmark)

    Schrum, Jacob; Lehman, Joel; Risi, Sebastian

    2016-01-01

    indirect encoding. A previous multimodal approach called situational policy geometry assumes that multiple brains benefit from being embedded within an explicit geometric space. However, this paper introduces HyperNEAT extensions for evolving many brains without assuming geometric relationships between...

  13. Policy stories

    DEFF Research Database (Denmark)

    Ren, Carina Bregnholm; Rasmussen, Rasmus Kjærgaard

    This article uses Arctic Winter 2016 as an exploration site of values and futures in Greenland. By taking a valuation approach where the creation and interpretation of event values are seen as an ongoing and taxing accomplishment, we firstly expand the understanding of events beyond their actual...... present three central policy stories from the field. The stories tell of how the event was first interested, then activated and finally evaluated. Besides adding a new understanding to policy-driven events as a locus of value creation, we also argue that the AWG 2016 offer speculative bets for new...... planning and execution and of event outcomes beyond the narrow confines of bed nights and legacies. Second, we introduce policies as an entry point to unlock discussions and manifestations of value and futures which connect to AWG. In order to exemplify the workings of the AWG event in these domains, we...

  14. Brain SPECT

    International Nuclear Information System (INIS)

    Feistel, H.

    1991-01-01

    Brain SPECT investigations have gained broad acceptance since the introduction of the lipophilic tracer Tc-99m-HMPAO. Depending on equipment and objectives in different departments, the examinations can be divided into three groups: 1. Under normal conditions and standardised patient preparation the 'rest' SPECT can be performed in every department with a tomographic camera. In cerebrovascular disease there is a demand for determination of either the perfusion reserve in reversible ischemia or prognostic values in completed stroke. In cases of dementia, SPECT may yield useful results according to differential diagnosis. Central cerebral system involvement in immunologic disease may be estimated with higher sensitivity than in conventional brain imaging procedures. In psychiatric diseases there is only a relative indication for brain SPECT, since results during recent years have been contradictory and may be derived only in interventional manner. In brain tumor diagnostics SPECT with Tl-201 possibly permits grading. In inflammatory disease, especially in viral encephalitis, SPECT may be used to obtain early diagnosis. Normal pressure hydrocephalus can be distinguished from other forms of dementia and, consequently, the necessity for shunting surgery can be recognised. 2. In departments equipped for emergency cases an 'acute' SPECT can be performed in illnesses with rapid changing symptoms such as different forms of migraine, transient global amnesia, epileptic seizures (so-called 'ictal SPECT') or urgent forms like trauma. 3. In cooperation with several departments brain SPECT can be practised as an interventional procedure in clinical and in scientific studies. (orig./MG) [de

  15. Population policy.

    Science.gov (United States)

    1987-03-01

    Participants in the Seminar on Population Policies for Top-level Policy Makers and Program Managers, meeting in Thailand during January 1987, examined the challenges now facing them regarding the implementation of fertility regulation programs in their respective countries -- Bangladesh, China, India, Indonesia, Malaysia, Nepal, Pakistan, the Philippines, the Republic of Korea, and Thailand. This Seminar was organized to coincide with the completion of an Economic and Social Commission for Asia and the Pacific (ESCAP) study investigating the impact and efficiency of family planning programs in the region. Country studies were reviewed at the Seminar along with policy issues about the status of women, incentive and disincentive programs, and socioeconomic factors affecting fertility. In Bangladesh the government recognizes population growth as its top priority problem related to the socioeconomic development of the country and is working to promote a reorientation strategy from the previous clinic-oriented to a multidimensional family welfare program. China's family planning program seeks to postpone marraige, space the births of children between 3-5 years, and promote the 1-child family. Its goal is to reduce the rate of natural increase from 12/1000 in 1978 to 5/1000 by 1985 and 0 by 2000. India's 7th Five-Year-Plan (1986-90) calls for establishing a 2-child family norm by 2000. In Indonesia the government's population policy includes reducing the rate of population growth, achieving a redistribution of the population, adjusting economic factors, and creating prosperous families. The government of Indonesia reversed its policy to reduce the population growth rate in 1984 and announced its goal of achieving a population of 70 million by 2100 in order to support mass consumption industries. It has created an income tax deduction system favoring large families and maternity benefits for women who have up to 5 children as incentives. Nepal's official policy is to

  16. Policy Reader

    International Nuclear Information System (INIS)

    1985-09-01

    This policy reader comprises: Correspondence; Memorandum of Understanding between the US Department of Transportation and the US Department of Energy for the Transportation of Radioactive Materials under the Nuclear Waste Policy Act; Internal Guidelines for Interactions with Communities and Local Governments; Statement by Ben C. Rusche before the Committee on Interior and Insular Affairs, Subcommittee on Energy and the Environment, US House of Representatives, September 13, 1985; Speech presented by Ben C. Rusche before the ANS/CNS/AESJ/ENS Topical Meeting, Pasco, Washington, September 24, 1985 - ''Status of the United States' High-Level Nuclear Waste Disposal Program''; and ''DOE Seeks Comments on Nuclear Transportation Planning,'' DOE News, September 30, 1985

  17. Language Policy

    DEFF Research Database (Denmark)

    Lauridsen, Karen M.

    2008-01-01

    Like any other text, instructive texts function within a given cultural and situational setting and may only be available in one language. However, the end users may not be familiar with that language and therefore unable to read and understand the instructions. This article therefore argues...... that instructive texts should always be available in a language that is understood by the end users, and that a corporate communication policy which includes a language policy should ensure that this is in fact the case for all instructive texts....

  18. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairment...... specific for the serotonin 2A receptor (5-HT(2A)R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT(2A)Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered...... was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT(2A) and 5-HT(1A) mRNA expression but normal 5-HT(2C) content in these brain regions in BDNF(2L/2LCk-cre) mice. We investigated whether the reduction in frontal 5-HT(2A...

  19. Characterization of BASP1-mediated neurite outgrowth

    DEFF Research Database (Denmark)

    Korshunova, Irina; Caroni, Pico; Kolkova, Kateryna

    2008-01-01

    The brain acid-soluble protein BASP1 (CAP-23, NAP-22) belongs to the family of growth-associated proteins, which also includes GAP-43, a protein recently shown to regulate neural cell adhesion molecule (NCAM)-mediated neurite outgrowth. Here, the effects of BASP1 overexpression were investigated...

  20. CEP energy policy : Policy 917

    International Nuclear Information System (INIS)

    2002-10-01

    Some of the environmental challenges facing the world in the twenty-first century are energy and global warming. Vital human needs such as warmth, light and transportation require energy, which is also required in the production of goods. Absent from the debate concerning the energy industry and its efforts to stop climate change is the voice of energy workers. Previous policies from the Communications, Energy and Paperworkers Union of Canada (CEP) were replaced by this policy document. After providing a brief introduction, the document tackled global challenge: climate change. The following section dealt with global challenge: corporate rule. Canada's energy industries were examined from the workers' perspective, and the state of Canada's energy reserves was discussed. From national policies to national betrayal was the title of the following section of the document. Energy de-regulation and privatization was discussed, and an argument was made for a Canadian energy policy. The industrial policy was explored, as was the environment. A transition to sustainability was examined. refs

  1. Informed policies

    International Development Research Centre (IDRC) Digital Library (Canada)

    INTERNATIONAL DEVELOPMENT RESEARCH CENTRE. Informed ... more evidence-based policy on social ... Community involvement is key to the success of CBMS in reducing poverty. IDRC ... nationwide network of “telecentres” that ... and holidays for young people to use for ... National Conference on Youth led to the.

  2. Vaccination Policies

    NARCIS (Netherlands)

    Verweij, M.F.

    2013-01-01

    Vaccination involves priming the immune system with an antigenic agent that mimics a virus or bacterium, which results in immunity against the “real” microorganism. Collective vaccination policies have played an important role in the control of infectious disease worldwide. They can serve the

  3. Brain Fog

    Science.gov (United States)

    ... relationship with your doctor(s): • Always report changes in cognition/memory and mood (depression, anxiety). • Make sure your physician ... joint pain. • Exercise regularly. Adequate physical exercise enhances cognition/memory. • Train the Brain! “If you don’t use ...

  4. Robot brains

    NARCIS (Netherlands)

    Babuska, R.

    2011-01-01

    The brain hosts complex networks of neurons that are responsible for behavior in humans and animals that we generally call intelligent. I is not easy to give an exact definition of intelligence – for the purpose of this talk it will suffice to say that we refer to intelligence as a collection of

  5. Thailand and brain drain

    Directory of Open Access Journals (Sweden)

    Terry Commins

    2009-01-01

    Full Text Available Brain drain has been the subject of research since the 1960s. This research has been hampered by a lack of accurate data from both source and receiving countries on migration and on the losses and gains to developing economies of skilled migration. However, despite these handicaps, research has been able to clearly show that trends are changing and the effect this is having is usually quite different for individual source countries.Thailand, as a developing economy, could be regarded as a source country. Fortunately, Thailand has never ranked highly in terms of brain drain when compared to other states in Asia and while it may not be a significant problem it nonetheless needs to be monitored. Thailand is also somewhat unique in that the migration that has occurred has been almost equally split between secondary and tertiary educated Thais. Thailand also ranks low in terms of tertiary educated population who have migrated when compared to other countries in the region. Globalisation is having a profound effect on the migration of skilled workers. As trade becomes increasingly free, barriers to the movement of services or people are also freed. As the better educated are encouraged to think globally, so too will they be inclined to move globally into the world community.This paper examines Thailand’s position with respect to brain drain, some of the lessons we have learned and some of the steps that are being taken to minimise the impact of the loss of skilled workers, with a particular focus on science and technology. The conclusion is that brain drain should not be viewed as an entirely negative development and that the positive outcomes should be recognised, encouraged and incorporated into policy.

  6. Activity-Based Anorexia Reduces Body Weight without Inducing a Separate Food Intake Microstructure or Activity Phenotype in Female Rats—Mediation via an Activation of Distinct Brain Nuclei

    Science.gov (United States)

    Scharner, Sophie; Prinz, Philip; Goebel-Stengel, Miriam; Kobelt, Peter; Hofmann, Tobias; Rose, Matthias; Stengel, Andreas

    2016-01-01

    Anorexia nervosa (AN) is accompanied by severe somatic and psychosocial complications. However, the underlying pathogenesis is poorly understood, treatment is challenging and often hampered by high relapse. Therefore, more basic research is needed to better understand the disease. Since hyperactivity often plays a role in AN, we characterized an animal model to mimic AN using restricted feeding and hyperactivity. Female Sprague-Dawley rats were divided into four groups: no activity/ad libitum feeding (ad libitum, AL, n = 9), activity/ad libitum feeding (activity, AC, n = 9), no activity/restricted feeding (RF, n = 12) and activity/restricted feeding (activity-based anorexia, ABA, n = 11). During the first week all rats were fed ad libitum, ABA and AC had access to a running wheel for 24 h/day. From week two ABA and RF only had access to food from 9:00 to 10:30 a.m. Body weight was assessed daily, activity and food intake monitored electronically, brain activation assessed using Fos immunohistochemistry at the end of the experiment. While during the first week no body weight differences were observed (p > 0.05), after food restriction RF rats showed a body weight decrease: −13% vs. day eight (p 0.05). Similarly, the daily physical activity was not different between AC and ABA (p > 0.05). The investigation of Fos expression in the brain showed neuronal activation in several brain nuclei such as the supraoptic nucleus, arcuate nucleus, locus coeruleus and nucleus of the solitary tract of ABA compared to AL rats. In conclusion, ABA combining physical activity and restricted feeding likely represents a suited animal model for AN to study pathophysiological alterations and pharmacological treatment options. Nonetheless, cautious interpretation of the data is necessary since rats do not voluntarily reduce their body weight as observed in human AN. PMID:27826222

  7. Activity-based anorexia reduces body weight without inducing a separate food intake microstructure or activity phenotype in female rats – mediation via an activation of distinct brain nuclei

    Directory of Open Access Journals (Sweden)

    Sophie Scharner

    2016-10-01

    Full Text Available Anorexia nervosa (AN is accompanied by severe somatic and psychosocial complications. However, the underlying pathogenesis is poorly understood, treatment is challenging and often hampered by high relapse. Therefore, more basic research is needed to better understand the disease. Since hyperactivity often plays a role in AN, we characterized an animal model to mimic AN using restricted feeding and hyperactivity. Female Sprague-Dawley rats were divided into four groups: no activity/ad libitum feeding (ad libitum, AL, n=9, activity/ad libitum feeding (activity, AC, n=9, no activity/restricted feeding (RF, n=12 and activity/restricted feeding (activity-based anorexia, ABA, n=11. During the first week all rats were fed ad libitum, ABA and AC had access to a running wheel for 24h/d. From week two ABA and RF only had access to food from 9:00-10:30 am. Body weight was assessed daily, activity and food intake monitored electronically, brain activation assessed using Fos immunohistochemistry at the end of the experiment. While during the first week no body weight differences were observed (p>0.05, after food restriction RF rats showed a body weight decrease: -13% vs. day eight (p0.05. Similarly, the daily physical activity was not different between AC and ABA (p>0.05. The investigation of Fos expression in the brain showed neuronal activation in several brain nuclei such as the supraoptic nucleus, arcuate nucleus, locus coeruleus and nucleus of the solitary tract of ABA compared to AL rats. In conclusion, ABA combining physical activity and restricted feeding likely represents a suited animal model for AN to study pathophysiological alterations and pharmacological treatment options. Nonetheless, cautious interpretation of the data is necessary since rats do not voluntarily reduce their body weight as observed in human AN.

  8. Understanding Brain Tumors

    Science.gov (United States)

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  9. Brain tumor - children

    Science.gov (United States)

    ... children; Neuroglioma - children; Oligodendroglioma - children; Meningioma - children; Cancer - brain tumor (children) ... The cause of primary brain tumors is unknown. Primary brain tumors may ... (spread to nearby areas) Cancerous (malignant) Brain tumors ...

  10. Brain Tumors (For Parents)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Brain Tumors KidsHealth / For Parents / Brain Tumors What's in ... radiation therapy or chemotherapy, or both. Types of Brain Tumors There are many different types of brain ...

  11. Brain and Nervous System

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Brain and Nervous System KidsHealth / For Parents / Brain and ... healthy, and remove waste products. All About the Brain The brain is made up of three main ...

  12. Health Policy and Dementia.

    Science.gov (United States)

    Powell, Tia

    2018-02-01

    The anticipated number of persons with dementia continues to grow, and the US has insufficiently planned to provide and pay for care for this large population. A number of significant clinical trials aiming to prevent or cure dementia, including Alzheimer's disease, have not demonstrated success. Because of the lack of efficacious treatments, and the fact that brain changes associated with dementia may begin decades before symptoms, we can predict that efforts to cure or prevent dementia will not succeed in time for millions of people in the baby boomer generation. Because of the anticipated increase in people suffering with dementia in the coming years, US health policy must address major gaps in how to provide and pay for dementia care. Reliance on Medicaid and Medicare as currently structured will not sustain the necessary care, nor can families alone provide all necessary dementia care. Innovative forms of providing long-term care and paying for it are crucially needed.

  13. Energy policy

    International Nuclear Information System (INIS)

    1992-09-01

    Gasoline consumption by passenger cars and light trucks is a major source of air pollution. It also adds to the economy's dependence on petroleum and vulnerability to oil price shocks. Despite these environmental and other costs, called external cost, the price of gasoline, adjusted for inflation, has generally been declining since 1985, encouraging increased consumption. This paper reports that with these concerns in mind, the Chairman, Subcommittee on Environment, House Committee on Science, Space, and Technology, requested that GAO assess policy options for addressing the external costs of gasoline consumption. To do this, GAO identified six major policy options and evaluated whether they addressed several relevant objectives, including economic growth, environmental quality, equity, petroleum conservation, visibility of costs, energy security, traffic congestion, competitiveness, and administrative feasibility

  14. Non-invasive brain-to-brain interface (BBI: establishing functional links between two brains.

    Directory of Open Access Journals (Sweden)

    Seung-Schik Yoo

    Full Text Available Transcranial focused ultrasound (FUS is capable of modulating the neural activity of specific brain regions, with a potential role as a non-invasive computer-to-brain interface (CBI. In conjunction with the use of brain-to-computer interface (BCI techniques that translate brain function to generate computer commands, we investigated the feasibility of using the FUS-based CBI to non-invasively establish a functional link between the brains of different species (i.e. human and Sprague-Dawley rat, thus creating a brain-to-brain interface (BBI. The implementation was aimed to non-invasively translate the human volunteer's intention to stimulate a rat's brain motor area that is responsible for the tail movement. The volunteer initiated the intention by looking at a strobe light flicker on a computer display, and the degree of synchronization in the electroencephalographic steady-state-visual-evoked-potentials (SSVEP with respect to the strobe frequency was analyzed using a computer. Increased signal amplitude in the SSVEP, indicating the volunteer's intention, triggered the delivery of a burst-mode FUS (350 kHz ultrasound frequency, tone burst duration of 0.5 ms, pulse repetition frequency of 1 kHz, given for 300 msec duration to excite the motor area of an anesthetized rat transcranially. The successful excitation subsequently elicited the tail movement, which was detected by a motion sensor. The interface was achieved at 94.0±3.0% accuracy, with a time delay of 1.59±1.07 sec from the thought-initiation to the creation of the tail movement. Our results demonstrate the feasibility of a computer-mediated BBI that links central neural functions between two biological entities, which may confer unexplored opportunities in the study of neuroscience with potential implications for therapeutic applications.

  15. Internet Policy

    Science.gov (United States)

    Lehr, William H.; Pupillo, Lorenzo Maria

    The Internet is now widely regarded as essential infrastructure for our global economy and society. It is in our homes and businesses. We use it to communicate and socialize, for research, and as a platform for E-commerce. In the late 1990s, much was predicted about what the Internet has become at present; but now, we have actual experience living with the Internet as a critical component of our everyday lives. Although the Internet has already had profound effects, there is much we have yet to realize. The present volume represents a third installment in a collaborative effort to highlight the all-encompassing, multidisciplinary implications of the Internet for public policy. The first installment was conceived in 1998, when we initiated plans to organize an international conference among academic, industry, and government officials to discuss the growing policy agenda posed by the Internet. The conference was hosted by the European Commission in Brussels in 1999 and brought together a diverse mix of perspectives on what the pressing policy issues would be confronting the Internet. All of the concerns identified remain with us today, including how to address the Digital Divide, how to modify intellectual property laws to accommodate the new realities of the Internet, what to do about Internet governance and name-space management, and how to evolve broadcast and telecommunications regulatory frameworks for a converged world.

  16. Blood-brain barrier permeability and brain uptake mechanism of kainic Acid and dihydrokainic Acid

    DEFF Research Database (Denmark)

    Gynther, Mikko; Petsalo, Aleksanteri; Hansen, Steen Honoré

    2015-01-01

    tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion...... technique to determine the brain uptake mechanism and permeability across the BBB. To determine KA and DHK concentrations in the rat brain, simple and rapid sample preparation and liquid chromatography mass spectrometer methods were developed. According to our results the BBB permeability of KA and DHK...... is low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug...

  17. The Creative Brain.

    Science.gov (United States)

    Herrmann, Ned

    1982-01-01

    Outlines the differences between left-brain and right-brain functioning and between left-brain and right-brain dominant individuals, and concludes that creativity uses both halves of the brain. Discusses how both students and curriculum can become more "whole-brained." (Author/JM)

  18. What are lipoproteins doing in the brain?

    Science.gov (United States)

    Wang, Hong; Eckel, Robert H

    2014-01-01

    Lipoproteins in plasma transport lipids between tissues, however, only high-density lipoproteins (HDL) appear to traverse the blood-brain barrier (BBB); thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes, and are found on HDL. In the hippocampus and other brain regions, lipoproteins help to regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, acting through lipoprotein lipase (LPL) and the low-density lipoprotein (LDL) receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Glutamate Transporters in the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Helms, Hans Christian Cederberg; Nielsen, Carsten Uhd; Waagepetersen, Helle S

    2017-01-01

    concentration of L-glutamate causes excitotoxicity. A tight control of the brain interstitial fluid L-glutamate levels is therefore imperative, in order to maintain optimal neurotransmission and to avoid such excitotoxicity. The blood-brain barrier, i.e., the endothelial lining of the brain capillaries...... cells. The mechanisms underlying transendothelial L-glutamate transport are however still not well understood. The present chapter summarizes the current knowledge on blood-brain barrier L-glutamate transporters and the suggested pathways for the brain-to-blood L-glutamate efflux......., regulates the exchange of nutrients, gases, and metabolic waste products between plasma and brain interstitial fluid. It has been suggested that brain capillary endothelial cells could play an important role in L-glutamate homeostasis by mediating brain-to-blood L-glutamate efflux. Both in vitro and in vivo...

  20. mediation: R package for causal mediation analysis

    OpenAIRE

    Tingley, Dustin; Yamamoto, Teppei; Hirose, Kentaro; Keele, Luke; Imai, Kosuke

    2012-01-01

    In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting su...

  1. Brain imaging

    International Nuclear Information System (INIS)

    Greenfield, L.D.; Bennett, L.R.

    1976-01-01

    Imaging with radionuclides should be used in a complementary fashion with other neuroradiologic techniques. It is useful in the early detection and evaluation of intracranial neoplasm, cerebrovascular accident and abscess, and in postsurgical follow-up. Cisternography yields useful information about the functional status of cerebrospinal fluid pathways. Computerized axial tomography is a new technique of great promise that produced a cross-sectional image of the brain

  2. Brain imaging

    International Nuclear Information System (INIS)

    Bradshaw, J.R.

    1989-01-01

    This book presents a survey of the various imaging tools with examples of the different diseases shown best with each modality. It includes 100 case presentations covering the gamut of brain diseases. These examples are grouped according to the clinical presentation of the patient: headache, acute headache, sudden unilateral weakness, unilateral weakness of gradual onset, speech disorders, seizures, pituitary and parasellar lesions, sensory disorders, posterior fossa and cranial nerve disorders, dementia, and congenital lesions

  3. Mind Over Matter: The Brain's Response to Marijuana

    Science.gov (United States)

    ... Search Term(s): Teachers / Lesson Plan and Activity Finder / Mind Over Matter Series / Marijuana / The Brain's Response to ... Us Accessibility FOIA NIH Home Privacy Policy Site Map Contact Us Find NIDA for Teens on: Site ...

  4. POPULATION POLICY OR SOCIAL POLICY?

    Directory of Open Access Journals (Sweden)

    ANDREI STANOIU

    2011-04-01

    Full Text Available After 1989, the demographic situation of Romania population experienced a dramatic, very concerning and dangerous evolution trend. One of the first measures of the new political power was to abolish the very restrictive, anti-human and abusive legal regulation adopted in 1966 by the communist regime concerning abortion and the whole old demographic policy. As a result of this measure and of the worsening economic and social situation of the great majority of Romanian population, the birth rate declined sharply and, from 1992, the natural demographic growth rate became a negative one. The absolute number of Romanian population decreased more and more and, if nothing changes, in the next few decades it will be no bigger than 15 million people. At the same time, the process of demographic ageing of population will accentuate, generating serious problems from demographic and social-economic point of view, Taking into account the present demographic situation and, especially, the foreseen trend of evolution, it is more than clear that there should be taken some urgent, coherent and consistent measures in order to stop this dangerous demographic evolution, until it is not too late, and to avoid, as much as possible, a potential demographic disaster. The problem is: what kind of measures should be taken and what kind of policy should be adopted? Some social scientists believe that a new population policy should be adopted; some others believe that rather a social policy should be adopted. The purpose of my paper is to analyze this different opinions and to show that, behind the dispute on the terminology, should be taken consistent measures, at governmental level, in order to assure a substantial improvement of demographic situation, not only from a quantitative, but from a qualitative point of view as well, and to identify some of these kind of measures.

  5. Marijuana and cannabinoid regulation of brain reward circuits

    OpenAIRE

    Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

    2004-01-01

    The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Δ9-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation o...

  6. Micro dynamics in mediation

    OpenAIRE

    Boserup, Hans

    2014-01-01

    The author has identified a number of styles in mediation, which lead to different processes and different outcomes. Through discourse and conversation analysis he examines the micro dynamics in three of these, the postmodern styles: systemic, transformative and narrative mediation. The differences between the three mediation ideologies and practice is illustrated through role play scripts enacted in each style. Mediator and providers of mediation and trainers in mediation are encouraged to a...

  7. 12 CFR 269.9 - Mediation of negotiation impasses.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Mediation of negotiation impasses. 269.9 Section 269.9 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM POLICY ON LABOR RELATIONS FOR THE FEDERAL RESERVE BANKS § 269.9 Mediation of negotiation...

  8. The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated β-amyloid protein internalization in mouse brain.

    Science.gov (United States)

    Ma, Kai-Ge; Lv, Jia; Hu, Xiao-Dan; Shi, Li-Li; Chang, Ke-Wei; Chen, Xin-Lin; Qian, Yi-Hua; Yang, Wei-Na; Qu, Qiu-Min

    2016-07-01

    Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular β-amyloid protein (Aβ) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control Aβ internalization may provide new insight for regulating Aβ levels. In the present study, the regulation of Aβ internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that Aβ1-42 were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. Aβ1-42-LRP1 complex was formed during Aβ1-42 internalization, and the p38 MAPK signaling pathway was activated by Aβ1-42 via LRP1. Aβ1-42 and LRP1 were co- localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in Aβ1-42 internalization in mouse brain. The results of this investigation demonstrated that Aβ1-42 induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of Aβ1-42. These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of Aβ1-42 internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Legitimizing policies

    DEFF Research Database (Denmark)

    Jørgensen, Martin Bak

    2012-01-01

    The focus of this article is on representations of irregular migration in a Scandinavian context and how irregular migrants are constructed as a target group. A common feature in many (Western-)European states is the difficult attempt to navigate between an urge for control and respecting......, upholding and promoting humanitarian aspects of migration management. Legitimizing policies therefore become extremely important as governments have to appease national voters to remain in power and have to respect European regulations and international conventions. Doing so raises questions of social...

  10. Cannabis use disorders and brain morphology

    NARCIS (Netherlands)

    Lorenzetti, V.; Cousijn, J.; Preedy, V.R.

    2016-01-01

    Cannabis use disorders (CUDs) affect 13.1. million individuals worldwide and represent the most vulnerable portion of regular cannabis users. Neuroanatomical alterations in the brain may mediate the adverse outcomes of CUDs. We reviewed findings from 16 structural neuroimaging studies of gray matter

  11. OWNERSHIP POLICY

    Directory of Open Access Journals (Sweden)

    V. Branovitskiy

    2018-01-01

    Full Text Available The article examines the ownership policy in Ukraine. It makes a survey of the following: the current situation at state-run enterprises and their efficiency; the key criteria of the classification of state-run enterprises for the privatization for the period of 2017-2020. The article evaluates the institutional changes coming from a new law on the privatization of state-owned property in Ukraine. It reveals the stages of making the ownership policy as a state strategy. It describes the measures meant to raise efficiency in the area of the public property management. The article assesses the state of play of the stock market in Ukraine as a mechanism to attract money to the real economy. It recommends attracting foreign investment to the public sector of economy following the restructuring process via IPO or sale to a strategic investor (Private equity. It considers the positive aspects in the completion of active privatization and the scope of the main privatization risks.

  12. Social Science Research Findings and Educational Policy Dilemmas

    Directory of Open Access Journals (Sweden)

    Steven I. Miller

    2000-01-01

    Full Text Available The article attempts to raise several distinctions regarding the presumed relationship of social science research findings to social policy making. The distinctions are made using Glymour's critique of the Bell Curve. An argument is made that (1 social science models and research findings are largely irrelevant to the actual concerns of policy makers and (2 what is relevant, but overlooked by Glymour, is how ideological factors mediate the process. The forms that ideological mediation may take are indicated.

  13. Traumatic Brain Injuries during Development: Implications for Alcohol Abuse

    Directory of Open Access Journals (Sweden)

    Zachary M. Weil

    2017-07-01

    Full Text Available Traumatic brain injuries are strongly related to alcohol intoxication as by some estimates half or more of all brain injuries involve at least one intoxicated individual. Additionally, there is mounting evidence that traumatic brain injuries can themselves serve as independent risk factors for the development of alcohol use disorders, particularly when injury occurs during juvenile or adolescent development. Here, we will review the epidemiological and experimental evidence for this phenomenon and discuss potential psychosocial mediators including attenuation of negative affect and impaired decision making as well as neurochemical mediators including disruption in the glutamatergic, GABAergic, and dopaminergic signaling pathways and increases in inflammation.

  14. Brain Size, IQ, and Racial-Group Differences: Evidence from Musculoskeletal Traits.

    Science.gov (United States)

    Rushton, J. Philippe; Rushton, Elizabeth W.

    2003-01-01

    Correlated brain size differences with 37 musculoskeletal variables shown in evolutionary textbooks to change with brain size. Findings from a sample of more than 6,000 U.S. military personnel indicate that racial differences in brain size are securely established and are the most likely biological mediators of race differences in intelligence.…

  15. Policy Actors: Doing Policy Work in Schools

    Science.gov (United States)

    Ball, Stephen J.; Maguire, Meg; Braun, Annette; Hoskins, Kate

    2011-01-01

    This paper considers the "policy work" of teacher actors in schools. It focuses on the "problem of meaning" and offers a typology of roles and positions through which teachers engage with policy and with which policies get "enacted". It argues that "policy work" is made up of a set of complex and…

  16. Visual artistic creativity and the brain.

    Science.gov (United States)

    Heilman, Kenneth M; Acosta, Lealani Mae

    2013-01-01

    Creativity is the development of a new or novel understanding--insight that leads to the expression of orderly relationships (e.g., finding and revealing the thread that unites). Visual artistic creativity plays an important role in the quality of human lives, and the goal of this chapter is to describe some of the brain mechanisms that may be important in visual artistic creativity. The initial major means of learning how the brain mediates any activity is to understand the anatomy and physiology that may support these processes. A further understanding of specific cognitive activities and behaviors may be gained by studying patients who have diseases of the brain and how these diseases influence these functions. Physiological recording such as electroencephalography and brain imaging techniques such as PET and fMRI have also allowed us to gain a better understanding of the brain mechanisms important in visual creativity. In this chapter, we discuss anatomic and physiological studies, as well as neuropsychological studies of healthy artists and patients with neurological disease that have helped us gain some insight into the brain mechanisms that mediate artistic creativity. © 2013 Elsevier B.V. All rights reserved.

  17. Nuclear policy

    International Nuclear Information System (INIS)

    Ford, G.R.

    1976-01-01

    Then-President Gerald Ford outlines the potential benefits of nuclear power as opposed to the danger of proliferation. He points out that not all nations have the same interest or views toward nuclear energy; but also he says that if a choice must be made, nonproliferation objectives must take precedence over economic and energy benefits. It is pointed out that the management of nuclear energy can be only partial and temporary by technical measures, and that full management can result only if nations realistically face the task prepared to forego preconceived short-term advantages in favor of long-term gains. Coordination of the policies of all nations toward the common goal of nonproliferation is predicted to lead to success

  18. Understanding Traumatic Brain Injury: An Introduction

    Science.gov (United States)

    Trudel, Tina M.; Scherer, Marcia J.; Elias, Eileen

    2009-01-01

    This article is the first of a multi-part series on traumatic brain injury (TBI). Historically, TBI has received very limited national public policy attention and support. However since it has become the signature injury of the military conflicts in Iraq and Afghanistan, TBI has gained the attention of elected officials, military leaders,…

  19. Kebijakan Pemerintah Najib Tun Razak terhadap Fenomena Brain Drain dari Malaysia ke Singapura Tahun 2009-2013

    OpenAIRE

    Patmawati, Pipit; Rani, Faisyal

    2017-01-01

    Brain Drain is a Phenomenon the International migration of highly qualified persons, e.g. surgeons, physicians, scientists and engineers, from low income countries to more prosperous economies. Motive of migration brain drainer as the lack of better opportunities, upgrade of living conditions, goverment policies and better education system. This research aims to analyze the Malaysia's Brain Drainer to the Singapura since 2009-2013, analyse the policy Najib Tun Razak the phenomenon of brain dr...

  20. La mirada del otro en los dispositivos de formación de lenguas extranjeras. Isomorfismos de la política lingüística y la mediación. A look at the other devices in the Foreign Language Training: Isomorphisms of Language Policy and the Mediation

    Directory of Open Access Journals (Sweden)

    Teresa Yurén

    2006-10-01

    Full Text Available Se analiza el caso de las licenciaturas para formar enseñantes del francés en México a fin de mostrar en qué y cómo las formas de mirar al otro y ser mirado por el otro condicionan los tipos de mediación y el tratamiento de las distancias culturales, lo que a su vez repercute en la apropiación de la lengua extranjera, la configuración del ethos profesional y la adquisición de competencias para la autoformación. Se obtuvieron datos cualitativos mediante entrevistas, observaciones y acopio de documentos y se trabajó combinando análisis estructural, analítica de las representaciones, analítica de la identidad, genealogía y análisis político del discurso. Como enfoque epistémico se adoptó la reconstrucción del dispositivo de formación, privilegiando la dimensión ético-política. Después de analizar las representaciones de los profesores sobre su tarea y su actividad como mediadores, así como sus identificaciones socioculturales, se identificaron cinco tipos de mediación y cuatro formas de tratamiento de la alteridad: la alteridad conjurada, la alteridad confiscada, la apertura aculturante y la apertura polivalente. Se encontró que esas formas de mirar al otro están también presentes en el ámbito de la cooperación educativa y cultural entre los países involucrados, así como en las estrategias y políticas de uso y difusión de la lengua desplegadas en la historia de dichos países. Se concluye que sólo una mirada no confiscatoria y con apertura polivalente contribuye a la apropiación de la lengua meta, la conformación de un ethos profesional autónomo y la adquisición de disposiciones para la autoformación. "The look of the other in the devices of foreign languages formation. Isomorphisms of linguistic policy and mediation". The case of the bachelor degrees for French teachers in Mexico is analyzed in order to show how the ways of looking at the other and be looked by the other can impact the mediation types and

  1. Administration and Policy-Making in Education: The Contemporary Predicament.

    Science.gov (United States)

    Housego, Ian E.

    This paper is based on the assumption that the educational administrator is the mediator in policy development. The author sees the administrator as caught between two conflicting approaches to policy-making--one characterized as "rational" and the other as "political." In attempting to deal with this dilemma and with the dilemma of shrinking…

  2. Baby Brain Map

    Science.gov (United States)

    ... a Member Home Resources & Services Professional Resource Baby Brain Map Mar 17, 2016 The Brain Map was adapted in 2006 by ZERO TO ... supports Adobe Flash Player. To view the Baby Brain Map, please visit this page on a browser ...

  3. Pediatric Brain Tumor Foundation

    Science.gov (United States)

    ... navigate their brain tumor diagnosis. WATCH AND SHARE Brain tumors and their treatment can be deadly so ... Pediatric Central Nervous System Cancers Read more >> Pediatric Brain Tumor Foundation 302 Ridgefield Court, Asheville, NC 28806 ...

  4. That's Using Your Brain!

    Science.gov (United States)

    Visser, Dana R.

    1996-01-01

    Discusses new adult learning theories, including those of Roger Sperry (left brain/right brain), Paul McLean (triune brain), and Howard Gardner (multiple intelligences). Relates adult learning theory to training. (JOW)

  5. Role of the Blood-Brain Barrier in the Formation of Brain Metastases

    Directory of Open Access Journals (Sweden)

    István A. Krizbai

    2013-01-01

    Full Text Available The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB. The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting metastatic cells during extravasation and proliferation in the brain. The mechanisms of interaction of cancer cells and cerebral endothelial cells are largely uncharacterized. Here, we provide a comprehensive review on our current knowledge about the role of junctional and adhesion molecules, soluble factors, proteolytic enzymes and signaling pathways mediating the attachment of tumor cells to brain endothelial cells and the transendothelial migration of metastatic cells. Since brain metastases represent a great therapeutic challenge, it is indispensable to understand the mechanisms of the interaction of tumor cells with the BBB in order to find targets of prevention of brain metastasis formation.

  6. Policy options

    International Nuclear Information System (INIS)

    Miller, A.

    1990-01-01

    The obstacles to bringing about consumer response to environmental dangers are particularly challenging for global problems like ozone depletion and the greenhouse effect. In this situation, there is the danger of what is commonly termed the tragedy of the commons, the ecological destruction that can occur from uncontrolled use of shared resources like the atmosphere. There is probably no country for which reductions in global warming provide an adequate economic incentive to reduce greenhouse gas emissions unilaterally, even though such action could yield substantial global benefits. From any one country's viewpoint, the costs of controlling emissions may exceed the benefits since, without international agreement, reductions achieved by one nation may be offset by another. Therefore, even though the entire world may be better off as a result of efforts to lower emissions, new economic incentives are necessary to lead the market to a socially efficient outcome. This paper describes the range of domestic and international policies that could be adopted to reduce emissions of greenhouse gases, and also discusses the results of modeling analyses of government actions that could reduce or increase such emissions

  7. Conscious brain-to-brain communication in humans using non-invasive technologies.

    Science.gov (United States)

    Grau, Carles; Ginhoux, Romuald; Riera, Alejandro; Nguyen, Thanh Lam; Chauvat, Hubert; Berg, Michel; Amengual, Julià L; Pascual-Leone, Alvaro; Ruffini, Giulio

    2014-01-01

    Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI) has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI). These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B) communication between subjects (hyperinteraction). Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG) changes with a CBI inducing the conscious perception of phosphenes (light flashes) through neuronavigated, robotized transcranial magnetic stimulation (TMS), with special care taken to block sensory (tactile, visual or auditory) cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.

  8. Conscious brain-to-brain communication in humans using non-invasive technologies.

    Directory of Open Access Journals (Sweden)

    Carles Grau

    Full Text Available Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI. These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B communication between subjects (hyperinteraction. Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG changes with a CBI inducing the conscious perception of phosphenes (light flashes through neuronavigated, robotized transcranial magnetic stimulation (TMS, with special care taken to block sensory (tactile, visual or auditory cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.

  9. Brain SPECT in children

    International Nuclear Information System (INIS)

    Guyot, M.; Baulieu, J.L.

    1996-01-01

    Brain SPECT in child involves specific trends regarding the patient cooperation, irradiation, resolution and especially interpretation because of the rapid scintigraphic modifications related to the brain maturation. In a general nuclear medicine department, child brain SPECT represents about 2 % of the activity. The choice indications are the perfusion children: thallium and MIBI in brain tumours, pharmacological and neuropsychological interventions. In the future, brain dedicated detectors and new radiopharmaceuticals will promote the development of brain SPECT in children. (author)

  10. Management Matters. Selection Policies

    Science.gov (United States)

    Pappas, Marjorie L.

    2003-01-01

    One of the most important policy documents for a school library media center is the selection policy or the collection development policy. A well-developed selection policy provides a rationale for the selection decisions made by the school library media specialist. A selection policy represents the criteria against which a challenged book is…

  11. Research for health policy

    National Research Council Canada - National Science Library

    Bell, Erica

    2010-01-01

    ... Explicit, implicit, and pragmatic dimensions of policy-maker's needs and context 31 Constraints on policy-makers 32 Deciphering trade-offs 33 The policy-problem: deciphering uncertainty and the problem of innovation 34 A tool for deciphering policy problems 35 The different components of the policy problem 37 Recommended reading 38 Case studies in...

  12. Aquaporin-11 (AQP11 Expression in the Mouse Brain

    Directory of Open Access Journals (Sweden)

    Shin Koike

    2016-06-01

    Full Text Available Aquaporin-11 (AQP11 is an intracellular aquaporin expressed in various tissues, including brain tissues in mammals. While AQP11-deficient mice have developed fatal polycystic kidneys at one month old, the role of AQP11 in the brain was not well appreciated. In this study, we examined the AQP11 expression in the mouse brain and the brain phenotype of AQP11-deficient mice. AQP11 messenger ribonucleic acid (mRNA and protein were expressed in the brain, but much less than in the thymus and kidney. Immunostaining showed that AQP11 was localized at the epithelium of the choroid plexus and at the endothelium of the brain capillary, suggesting that AQP11 may be involved in water transport at the choroid plexus and blood-brain barrier (BBB in the brain. The expression of AQP4, another brain AQP expressed at the BBB, was decreased by half in AQP11-deficient mice, thereby suggesting the presence of the interaction between AQP11 and AQP4. The brain of AQP11-deficient mice, however, did not show any morphological abnormalities and the function of the BBB was intact. Our findings provide a novel insight into a water transport mechanism mediated by AQPs in the brain, which may lead to a new therapy for brain edema.

  13. Lithium-mediated protection against ethanol neurotoxicity

    Directory of Open Access Journals (Sweden)

    Jia Luo

    2010-06-01

    Full Text Available Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke–Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3 which has recently been identified as a mediator of ethanol neurotoxicity. Lithium’s neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms.

  14. Revisiting Einstein's brain in Brain Awareness Week.

    Science.gov (United States)

    Chen, Hao; Chen, Su; Zeng, Lidan; Zhou, Lin; Hou, Shengtao

    2014-10-01

    Albert Einstein's brain has long been an object of fascination to both neuroscience specialists and the general public. However, without records of advanced neuro-imaging of his brain, conclusions regarding Einstein's extraordinary cognitive capabilities can only be drawn based on the unique external features of his brain and through comparison of the external features with those of other human brain samples. The recent discovery of 14 previously unpublished photographs of Einstein's brain taken at unconventional angles by Dr. Thomas Stoltz Harvey, the pathologist, ignited a renewed frenzy about clues to explain Einstein's genius. Dr. Dean Falk and her colleagues, in their landmark paper published in Brain (2013; 136:1304-1327), described in such details about the unusual features of Einstein's brain, which shed new light on Einstein's intelligence. In this article, we ask what are the unique structures of his brain? What can we learn from this new information? Can we really explain his extraordinary cognitive capabilities based on these unique brain structures? We conclude that studying the brain of a remarkable person like Albert Einstein indeed provides us a better example to comprehensively appreciate the relationship between brain structures and advanced cognitive functions. However, caution must be exercised so as not to over-interpret his intelligence solely based on the understanding of the surface structures of his brain.

  15. The role of mediation in resolving workplace relationship conflict.

    Science.gov (United States)

    McKenzie, Donna Margaret

    2015-01-01

    Stress triggered by workplace-based interpersonal conflict can result in damaged relationships, loss of productivity, diminished job satisfaction and increasingly, workers' compensation claims for psychological injury. This paper examined the literature on the role and effectiveness of mediation, as the most common method of Alternative Dispute Resolution, in resolving workplace relationship conflict. Available evidence suggests that mediation is most effective when supported by organisational commitment to ADR strategies, policies and processes, and conducted by independent, experienced and qualified mediators. The United States Postal Service program REDRESS™ is described as an illustration of the successful use of mediation to resolve conflict in the workplace. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

    Science.gov (United States)

    Patel, Mayur M; Patel, Bhoomika M

    2017-02-01

    CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

  17. MRI of fetal acquired brain lesions

    International Nuclear Information System (INIS)

    Prayer, Daniela; Brugger, Peter C.; Kasprian, Gregor; Witzani, Linde; Helmer, Hanns; Dietrich, Wolfgang; Eppel, Wolfgang; Langer, Martin

    2006-01-01

    Acquired fetal brain damage is suspected in cases of destruction of previously normally formed tissue, the primary cause of which is hypoxia. Fetal brain damage may occur as a consequence of acute or chronic maternal diseases, with acute diseases causing impairment of oxygen delivery to the fetal brain, and chronic diseases interfering with normal, placental development. Infections, metabolic diseases, feto-fetal transfusion syndrome, toxic agents, mechanical traumatic events, iatrogenic accidents, and space-occupying lesions may also qualify as pathologic conditions that initiate intrauterine brain damage. MR manifestations of acute fetal brain injury (such as hemorrhage or acute ischemic lesions) can easily be recognized, as they are hardly different from postnatal lesions. The availability of diffusion-weighted sequences enhances the sensitivity in recognizing acute ischemic lesions. Recent hemorrhages are usually readily depicted on T2 (*) sequences, where they display hypointense signals. Chronic fetal brain injury may be characterized by nonspecific changes that must be attributable to the presence of an acquired cerebral pathology. The workup in suspected acquired fetal brain injury also includes the assessment of extra-CNS organs that may be affected by an underlying pathology. Finally, the placenta, as the organ that mediates oxygen delivery from the maternal circulation to the fetus, must be examined on MR images

  18. MRI of fetal acquired brain lesions

    Energy Technology Data Exchange (ETDEWEB)

    Prayer, Daniela [Department of Radiodiagnostics, Medical University of Vienna (Austria)]. E-mail: daniela.prayer@meduniwien.ac.at; Brugger, Peter C. [Center of Anatomy and Cell Biology, Medical University of Vienna (Austria); Kasprian, Gregor [Department of Radiodiagnostics, Medical University of Vienna (Austria); Witzani, Linde [Department of Radiodiagnostics, Medical University of Vienna (Austria); Helmer, Hanns [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria); Dietrich, Wolfgang [Department of Neurosurgery, Medical University of Vienna (Austria); Eppel, Wolfgang [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria); Langer, Martin [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria)

    2006-02-15

    Acquired fetal brain damage is suspected in cases of destruction of previously normally formed tissue, the primary cause of which is hypoxia. Fetal brain damage may occur as a consequence of acute or chronic maternal diseases, with acute diseases causing impairment of oxygen delivery to the fetal brain, and chronic diseases interfering with normal, placental development. Infections, metabolic diseases, feto-fetal transfusion syndrome, toxic agents, mechanical traumatic events, iatrogenic accidents, and space-occupying lesions may also qualify as pathologic conditions that initiate intrauterine brain damage. MR manifestations of acute fetal brain injury (such as hemorrhage or acute ischemic lesions) can easily be recognized, as they are hardly different from postnatal lesions. The availability of diffusion-weighted sequences enhances the sensitivity in recognizing acute ischemic lesions. Recent hemorrhages are usually readily depicted on T2 (*) sequences, where they display hypointense signals. Chronic fetal brain injury may be characterized by nonspecific changes that must be attributable to the presence of an acquired cerebral pathology. The workup in suspected acquired fetal brain injury also includes the assessment of extra-CNS organs that may be affected by an underlying pathology. Finally, the placenta, as the organ that mediates oxygen delivery from the maternal circulation to the fetus, must be examined on MR images.

  19. Left brain, right brain: facts and fantasies.

    Science.gov (United States)

    Corballis, Michael C

    2014-01-01

    Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the "norm" of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal.

  20. Mechanisms of action of brain insulin against neurodegenerative diseases.

    Science.gov (United States)

    Ramalingam, Mahesh; Kim, Sung-Jin

    2014-06-01

    Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.

  1. Nordic Mediation Reseach

    DEFF Research Database (Denmark)

    A presentation of 12 studies on mediation from researchers from Denmark, Finland, Norway and Sweden.......A presentation of 12 studies on mediation from researchers from Denmark, Finland, Norway and Sweden....

  2. Maternity Leave Policies

    Science.gov (United States)

    Strang, Lucy; Broeks, Miriam

    2017-01-01

    Abstract Over recent years many European Union countries have made changes to the design of the maternity leave provision. These policy developments reflect calls for greater gender equality in the workforce and more equal share of childcare responsibilities. However, while research shows that long period of leave can have negative effects on women's labour market attachment and career advancements, early return to work can be seen as a factor preventing exclusive breastfeeding, and therefore, potentially having negative health impacts for babies. Indeed, the World Health Organisation recommends exclusive breastfeeding up to 6 months of age to provide babies with the nutrition for healthy growth and brain development, protection from life-threatening ailments, obesity and non-communicable diseases such as asthma and diabetes. Therefore, labour market demands on women may be at odds with the health benefits for children gained by longer periods of maternity leave. The aim of this article is to examine the relationship between leave provision and health benefits for children. We examine maternity and parental leave provision across European countries and its potential impact on the breastfeeding of very young babies (up to 6-months of age). We also consider economic factors of potential extension of maternity leave provision to 6 months, such as costs to businesses, effects on the female labour market attachment, and wider consequences (benefits and costs) for individuals, families, employers and the wider society. PMID:28983432

  3. Bayesian Mediation Analysis

    OpenAIRE

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

    This article proposes Bayesian analysis of mediation effects. Compared to conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate prior information into the mediation analysis, thus potentially improving the efficiency of estimates. Second, under the Bayesian mediation analysis, inference is straightforward and exact, which makes it appealing for studies with small samples. Third, the Bayesian approach is conceptua...

  4. Policy Feedback System (PFS)

    Data.gov (United States)

    Social Security Administration — The Policy Feedback System (PFS) is a web application developed by the Office of Disability Policy Management Information (ODPMI) team that gathers empirical data...

  5. mediation: R Package for Causal Mediation Analysis

    Directory of Open Access Journals (Sweden)

    Dustin Tingley

    2014-09-01

    Full Text Available In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting such an analysis. The package is organized into two distinct approaches. Using the model-based approach, researchers can estimate causal mediation effects and conduct sensitivity analysis under the standard research design. Furthermore, the design-based approach provides several analysis tools that are applicable under different experimental designs. This approach requires weaker assumptions than the model-based approach. We also implement a statistical method for dealing with multiple (causally dependent mediators, which are often encountered in practice. Finally, the package also offers a methodology for assessing causal mediation in the presence of treatment noncompliance, a common problem in randomized trials.

  6. Bayesian Mediation Analysis

    Science.gov (United States)

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

    In this article, we propose Bayesian analysis of mediation effects. Compared with conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate prior information into the mediation analysis, thus potentially improving the efficiency of estimates. Second, under the Bayesian…

  7. Plumbing the brain drain.

    Science.gov (United States)

    Saravia, Nancy Gore; Miranda, Juan Francisco

    2004-08-01

    Opportunity is the driving force of migration. Unsatisfied demands for higher education and skills, which have been created by the knowledge-based global economy, have generated unprecedented opportunities in knowledge-intensive service industries. These multi-trillion dollar industries include information, communication, finance, business, education and health. The leading industrialized nations are also the focal points of knowledge-intensive service industries and as such constitute centres of research and development activity that proactively draw in talented individuals worldwide through selective immigration policies, employment opportunities and targeted recruitment. Higher education is another major conduit of talent from less-developed countries to the centres of the knowledge-based global economy. Together career and educational opportunities drive "brain drain and recirculation". The departure of a large proportion of the most competent and innovative individuals from developing nations slows the achievement of the critical mass needed to generate the enabling context in which knowledge creation occurs. To favourably modify the asymmetric movement and distribution of global talent, developing countries must implement bold and creative strategies that are backed by national policies to: provide world-class educational opportunities, construct knowledge-based research and development industries, and sustainably finance the required investment for these strategies. Brazil, China and India have moved in this direction, offering world-class education in areas crucial to national development, such as biotechnology and information technology, paralleled by investments in research and development. As a result, only a small proportion of the most highly educated individuals migrate from these countries, and research and development opportunities employ national talent and even attract immigrants.

  8. A classical regression framework for mediation analysis: fitting one model to estimate mediation effects.

    Science.gov (United States)

    Saunders, Christina T; Blume, Jeffrey D

    2017-10-26

    Mediation analysis explores the degree to which an exposure's effect on an outcome is diverted through a mediating variable. We describe a classical regression framework for conducting mediation analyses in which estimates of causal mediation effects and their variance are obtained from the fit of a single regression model. The vector of changes in exposure pathway coefficients, which we named the essential mediation components (EMCs), is used to estimate standard causal mediation effects. Because these effects are often simple functions of the EMCs, an analytical expression for their model-based variance follows directly. Given this formula, it is instructive to revisit the performance of routinely used variance approximations (e.g., delta method and resampling methods). Requiring the fit of only one model reduces the computation time required for complex mediation analyses and permits the use of a rich suite of regression tools that are not easily implemented on a system of three equations, as would be required in the Baron-Kenny framework. Using data from the BRAIN-ICU study, we provide examples to illustrate the advantages of this framework and compare it with the existing approaches. © The Author 2017. Published by Oxford University Press.

  9. General gauge mediation

    International Nuclear Information System (INIS)

    Meade, Patrick; Seiberg, Nathan; Shih, David

    2009-01-01

    We give a general definition of gauge mediated supersymmetry breaking which encompasses all the known gauge mediation models. In particular, it includes both models with messengers as well as direct mediation models. A formalism for computing the soft terms in the generic model is presented. Such a formalism is necessary in strongly-coupled direct mediation models where perturbation theory cannot be used. It allows us to identify features of the entire class of gauge mediation models and to distinguish them from specific signatures of various subclasses. (author)

  10. Impact of Hypoglycemia on Brain Metabolism During Diabetes.

    Science.gov (United States)

    Rehni, Ashish K; Dave, Kunjan R

    2018-04-10

    Diabetes is a metabolic disease afflicting millions of people worldwide. A substantial fraction of world's total healthcare expenditure is spent on treating diabetes. Hypoglycemia is a serious consequence of anti-diabetic drug therapy, because it induces metabolic alterations in the brain. Metabolic alterations are one of the central mechanisms mediating hypoglycemia-related functional changes in the brain. Acute, chronic, and/or recurrent hypoglycemia modulate multiple metabolic pathways, and exposure to hypoglycemia increases consumption of alternate respiratory substrates such as ketone bodies, glycogen, and monocarboxylates in the brain. The aim of this review is to discuss hypoglycemia-induced metabolic alterations in the brain in glucose counterregulation, uptake, utilization and metabolism, cellular respiration, amino acid and lipid metabolism, and the significance of other sources of energy. The present review summarizes information on hypoglycemia-induced metabolic changes in the brain of diabetic and non-diabetic subjects and the manner in which they may affect brain function.

  11. Bayesian dynamic mediation analysis.

    Science.gov (United States)

    Huang, Jing; Yuan, Ying

    2017-12-01

    Most existing methods for mediation analysis assume that mediation is a stationary, time-invariant process, which overlooks the inherently dynamic nature of many human psychological processes and behavioral activities. In this article, we consider mediation as a dynamic process that continuously changes over time. We propose Bayesian multilevel time-varying coefficient models to describe and estimate such dynamic mediation effects. By taking the nonparametric penalized spline approach, the proposed method is flexible and able to accommodate any shape of the relationship between time and mediation effects. Simulation studies show that the proposed method works well and faithfully reflects the true nature of the mediation process. By modeling mediation effect nonparametrically as a continuous function of time, our method provides a valuable tool to help researchers obtain a more complete understanding of the dynamic nature of the mediation process underlying psychological and behavioral phenomena. We also briefly discuss an alternative approach of using dynamic autoregressive mediation model to estimate the dynamic mediation effect. The computer code is provided to implement the proposed Bayesian dynamic mediation analysis. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  12. Artificial selection on relative brain size in the guppy reveals costs and benefits of evolving a larger brain.

    Science.gov (United States)

    Kotrschal, Alexander; Rogell, Björn; Bundsen, Andreas; Svensson, Beatrice; Zajitschek, Susanne; Brännström, Ioana; Immler, Simone; Maklakov, Alexei A; Kolm, Niclas

    2013-01-21

    The large variation in brain size that exists in the animal kingdom has been suggested to have evolved through the balance between selective advantages of greater cognitive ability and the prohibitively high energy demands of a larger brain (the "expensive-tissue hypothesis"). Despite over a century of research on the evolution of brain size, empirical support for the trade-off between cognitive ability and energetic costs is based exclusively on correlative evidence, and the theory remains controversial. Here we provide experimental evidence for costs and benefits of increased brain size. We used artificial selection for large and small brain size relative to body size in a live-bearing fish, the guppy (Poecilia reticulata), and found that relative brain size evolved rapidly in response to divergent selection in both sexes. Large-brained females outperformed small-brained females in a numerical learning assay designed to test cognitive ability. Moreover, large-brained lines, especially males, developed smaller guts, as predicted by the expensive-tissue hypothesis, and produced fewer offspring. We propose that the evolution of brain size is mediated by a functional trade-off between increased cognitive ability and reproductive performance and discuss the implications of these findings for vertebrate brain evolution. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Lighting up the brain's reward circuitry.

    Science.gov (United States)

    Lobo, Mary Kay

    2012-07-01

    The brain's reward circuit is critical for mediating natural reward behaviors including food, sex, and social interaction. Drugs of abuse take over this circuit and produce persistent molecular and cellular alterations in the brain regions and their neural circuitry that make up the reward pathway. Recent use of optogenetic technologies has provided novel insights into the functional and molecular role of the circuitry and cell subtypes within these circuits that constitute this pathway. This perspective will address the current and future use of light-activated proteins, including those involved in modulating neuronal activity, cellular signaling, and molecular properties in the neural circuitry mediating rewarding stimuli and maladaptive responses to drugs of abuse. © 2012 New York Academy of Sciences.

  14. A split microdrive for simultaneous multi-electrode recordings from two brain areas in awake small animals.

    NARCIS (Netherlands)

    Lansink, C.S.; Bakker, M.; Buster, W.; Lankelma, J.; van der Blom, R.; Westdorp, R.; Joosten, R.N.J.M.A.; Mc.Naughton, B.L.; Pennartz, C.M.A.

    2007-01-01

    Complex cognitive operations such as memory formation and decision-making are thought to be mediated not by single, isolated brain structures but by multiple, connected brain areas. To facilitate studies on the neural communication between connected brain structures, we developed a multi-electrode

  15. Consensus document on European brain research

    DEFF Research Database (Denmark)

    Di Luca, Monica; Baker, Mary; Corradetti, Renato

    2011-01-01

    Psychiatric and neurological diseases combined represent a considerable social and economic burden in Europe. A recent study conducted by the European Brain Council (EBC) quantified the 'cost and burden' of major brain diseases in Europe, amounting to €386bn per year. Considering that these costs...... version. Multinational and multidisciplinary teams have once again come together to express their views, not only on the current strengths in European research, but also on what needs to be done in priority, hoping that this update will inspire policy makers and stakeholders in directing funding...

  16. EU Industrial Policy

    DEFF Research Database (Denmark)

    Pellegrin, Julie; Giorgetti, Maria Letizia; Jensen, Camilla

    Following disregard in the 1980s, industrial policy has recently attracted policy attention at EU level. The objective of this study provided by Policy Department A at the request of the ITRE Committee, is to establish the state of the art of a coordinated and integrated EU industrial policy...

  17. Food policy an ethics

    DEFF Research Database (Denmark)

    Coff, Christian Eyde; Kemp, Peter

    2014-01-01

    This entry gives an overview of food policy and major ethical principles that in the last decades have been proposed and advocated for in debates on food policy. Food policies touch upon a vast area of interrelated policies (like health, transport, environment, poverty, animal welfare etc.) which...

  18. Education Policy Outlook: Austria

    Science.gov (United States)

    Figueroa, Diana Toledo; Golden, Gillian; Giovinazzo, Manon; Peterka, Judith; Ullmann, Marie

    2017-01-01

    This policy profile on education in Austria is part of the "Education Policy Outlook" series, which presents comparative analysis of education policies and reforms across OECD countries. Building on the OECD's substantial comparative and sectoral knowledge base, the series offers a comparative outlook on education policy by providing…

  19. Working for Policy

    NARCIS (Netherlands)

    Colebatch, H.K.; Hoppe, Robertus; Noordegraaf, Mirko

    2010-01-01

    Though democratic government calls for well-designed and implemented policy, there is surprisingly little expert guidance available for policy makers and politicians. Working for Policy fills that gap, addressing the nature of policy work and offering necessary guidance. The contributors bring

  20. Environmental policy in Japan

    Energy Technology Data Exchange (ETDEWEB)

    Tsuru, Shigeto; Weidner, H. (eds.)

    1989-01-01

    This book deals in English with the most important features of Japanese environmental policy in a number of individual articles by different authors. The various sections report on: 1. History and organization of environmental policy; 2. The role of non-governmental actors in environmental policy (large industries); 3. Special features of environmental policies and problems; 4. Classical pollution control areas: Regulations and effects; 5. Environmental problems in a broader perspective (nature conservation); 6. Policy areas with influence on environmental quality; 7. Environmental monitoring and reporting; 8. Japanese environmental policy in an international perspective (preventive policies, developing countries). (HSCH).

  1. Pharmaceutical policy and the lay public

    DEFF Research Database (Denmark)

    Traulsen, Janine Marie; Almarsdóttir, Anna Birna

    2005-01-01

    Almost every national and supranational health policy document accords high importance to the need to listen to and 'empower' patients. The relationship between pharmaceutical policy and the lay public is not direct but mediated by several actors, including health care workers, patient organisati......Almost every national and supranational health policy document accords high importance to the need to listen to and 'empower' patients. The relationship between pharmaceutical policy and the lay public is not direct but mediated by several actors, including health care workers, patient...... organisations, industry and, most recently, the media. Although the overall aim of health and pharmaceutical policy is to address the needs of all citizens, there are only a few, well organised groups who are actually consulted and involved in the policymaking process, often with the support of the industry....... The reasons for this lack of citizen involvement in health and pharmaceutical policymaking are many, for example: there is no consensus about what public involvement means; there is a predominance of special interest groups with narrow, specific agendas; not all decision makers welcome lay participation...

  2. Environmental policy performance revisited

    DEFF Research Database (Denmark)

    Daugbjerg, Carsten; Sønderskov, Kim Mannemar

    2012-01-01

    . On the basis of the typology, a hypothesis on their ability to expand green markets is generated and tested in a comparative analysis of the performance of organic food policies in Denmark, Sweden, the UK and the US, focusing on their impact on organic consumption. Our analysis demonstrates that cross......Studies of environmental policy performance tend to concentrate on the impact of particular policy institutions or of single policy instruments. However, environmental policies most often consist of a package of policy instruments. Further, these studies pay no or very little attention to policy...... instruments directed at the demand side of the market. Therefore this article develops a policy typology for government intervention aimed at creating green markets. The typology distinguishes between four types of policy based on the balance between the supply-side and demand-side policy instruments...

  3. Role of Brain Inflammation in Epileptogenesis

    OpenAIRE

    Choi, Jieun; Koh, Sookyong

    2008-01-01

    Inflammation is known to participate in the mediation of a growing number of acute and chronic neurological disorders. Even so, the involvement of inflammation in the pathogenesis of epilepsy and seizure-induced brain damage has only recently been appreciated. Inflammatory processes, including activation of microglia and astrocytes and production of proinflammatory cytokines and related molecules, have been described in human epilepsy patients as well as in experimental models of epilepsy. Fo...

  4. Brain Cancer—Patient Version

    Science.gov (United States)

    Brain cancer refers to growths of malignant cells in tissues of the brain. Tumors that start in the brain are called primary brain tumors. Tumors that spread to the brain are called metastatic brain tumors. Start here to find information on brain cancer treatment, research, and statistics.

  5. Neuroscience, brains, and computers

    Directory of Open Access Journals (Sweden)

    Giorno Maria Innocenti

    2013-07-01

    Full Text Available This paper addresses the role of the neurosciences in establishing what the brain is and how states of the brain relate to states of the mind. The brain is viewed as a computational deviceperforming operations on symbols. However, the brain is a special purpose computational devicedesigned by evolution and development for survival and reproduction, in close interaction with theenvironment. The hardware of the brain (its structure is very different from that of man-made computers.The computational style of the brain is also very different from traditional computers: the computationalalgorithms, instead of being sets of external instructions, are embedded in brain structure. Concerningthe relationships between brain and mind a number of questions lie ahead. One of them is why andhow, only the human brain grasped the notion of God, probably only at the evolutionary stage attainedby Homo sapiens.

  6. FROM BRAIN DRAIN TO BRAIN NETWORKING

    Directory of Open Access Journals (Sweden)

    Irina BONCEA

    2015-06-01

    Full Text Available Scientific networking is the most accessible way a country can turn the brain drain into brain gain. Diaspora’s members offer valuable information, advice or financial support from the destination country, without being necessary to return. This article aims to investigate Romania’s potential of turning brain drain into brain networking, using evidence from the medical sector. The main factors influencing the collaboration with the country of origin are investigated. The conclusions suggest that Romania could benefit from the diaspora option, through an active implication at institutional level and the implementation of a strategy in this area.

  7. Deconstructing domestic violence policy

    OpenAIRE

    Branney, PE

    2006-01-01

    The primary objectives of this thesis are to, circularly, deconstruct contemporary domestic violence policy while developing and evaluating methods for deconstructing policy. Policy is theorised as a discursive practice, which allows a variety of policies to be compared and critiqued by how they position the people they affect. These are known as subject positions, or subjectivities, and throughout this thesis I attempt to critique policy by examining the (re)construction of subjectivity. In ...

  8. Hormones and the blood-brain barrier.

    Science.gov (United States)

    Hampl, Richard; Bičíková, Marie; Sosvorová, Lucie

    2015-03-01

    Hormones exert many actions in the brain, and brain cells are also hormonally active. To reach their targets in brain structures, hormones must overcome the blood-brain barrier (BBB). The BBB is a unique device selecting desired/undesired molecules to reach or leave the brain, and it is composed of endothelial cells forming the brain vasculature. These cells differ from other endothelial cells in their almost impermeable tight junctions and in possessing several membrane structures such as receptors, transporters, and metabolically active molecules, ensuring their selection function. The main ways how compounds pass through the BBB are briefly outlined in this review. The main part concerns the transport of major classes of hormones: steroids, including neurosteroids, thyroid hormones, insulin, and other peptide hormones regulating energy homeostasis, growth hormone, and also various cytokines. Peptide transporters mediating the saturable transport of individual classes of hormones are reviewed. The last paragraph provides examples of how hormones affect the permeability and function of the BBB either at the level of tight junctions or by various transporters.

  9. Causal mediation analysis with multiple mediators.

    Science.gov (United States)

    Daniel, R M; De Stavola, B L; Cousens, S N; Vansteelandt, S

    2015-03-01

    In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed. © 2014 The Authors Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.

  10. An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting : The importance of selective blood–brain barrier uptake

    NARCIS (Netherlands)

    Bode, Gerard H.; Coué, G.M.J.P.C.; Freese, Christian; Pickl, Karin E.; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C.; Tziveleka, Leto Aikaterini; Sideratou, Zili; Engbersen, Johan F.J.; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J.G.; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M.; Kirkpatrick, C. James; Steinbusch, Harry W.M.; Frank, Hans Georg; Unger, Ronald E.; Martinez-Martinez, Pilar

    2017-01-01

    Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood–brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial

  11. Education Policy Mediation: Principals' Work with Mandated Literacy Assessment

    Science.gov (United States)

    Comber, Barbara; Cormack, Phil

    2011-01-01

    Mandated literacy assessment is now a ubiquitous practice in many western educational systems. While educational researchers, principals, teachers and education unions continue to offer vociferous resistance in some nations, in others it is now commonplace in the educational landscape and built into the rhythms of the school year. This paper is…

  12. Glial and neuronal control of brain blood flow

    DEFF Research Database (Denmark)

    Attwell, David; Buchan, Alastair M; Charpak, Serge

    2010-01-01

    Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...... recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts...

  13. [Brain oedema and acute liver failure].

    Science.gov (United States)

    Spahr, L

    2003-04-01

    Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

  14. Potassium channels in brain mitochondria.

    Science.gov (United States)

    Bednarczyk, Piotr

    2009-01-01

    Potassium channels are the most widely distributed class of ion channels. These channels are transmembrane proteins known to play important roles in both normal and pathophysiological functions in all cell types. Various potassium channels are recognised as potential therapeutic targets in the treatment of Parkinson's disease, Alzheimer's disease, brain/spinal cord ischaemia and sepsis. In addition to their importance as therapeutic targets, certain potassium channels are known for their beneficial roles in anaesthesia, cardioprotection and neuroprotection. Some types of potassium channels present in the plasma membrane of various cells have been found in the inner mitochondrial membrane as well. Potassium channels have been proposed to regulate mitochondrial membrane potential, respiration, matrix volume and Ca(+) ion homeostasis. It has been proposed that mitochondrial potassium channels mediate ischaemic preconditioning in various tissues. However, the specificity of a pharmacological agents and the mechanisms underlying their effects on ischaemic preconditioning remain controversial. The following potassium channels from various tissues have been identified in the inner mitochondrial membrane: ATP-regulated (mitoK(ATP)) channel, large conductance Ca(2+)-regulated (mitoBK(Ca)) channel, intermediate conductance Ca(2+)-regulated (mitoIK(Ca)) channel, voltage-gated (mitoKv1.3 type) channel, and twin-pore domain (mitoTASK-3) channel. It has been shown that increased potassium flux into brain mitochondria induced by either the mitoK(ATP) channel or mitoBK(Ca) channel affects the beneficial effects on neuronal cell survival under pathological conditions. Recently, differential distribution of mitoBK(Ca) channels has been observed in neuronal mitochondria. These findings may suggest a neuroprotective role for the mitoBK(Ca) channel in specific brain structures. This minireview summarises current data on brain mitochondrial potassium channels and the efforts to identify

  15. Nutrients, Microglia Aging, and Brain Aging

    Directory of Open Access Journals (Sweden)

    Zhou Wu

    2016-01-01

    Full Text Available As the life expectancy continues to increase, the cognitive decline associated with Alzheimer’s disease (AD becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

  16. Nutrients, Microglia Aging, and Brain Aging.

    Science.gov (United States)

    Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

    2016-01-01

    As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

  17. Flexible Mediation Analysis With Multiple Mediators.

    Science.gov (United States)

    Steen, Johan; Loeys, Tom; Moerkerke, Beatrijs; Vansteelandt, Stijn

    2017-07-15

    The advent of counterfactual-based mediation analysis has triggered enormous progress on how, and under what assumptions, one may disentangle path-specific effects upon combining arbitrary (possibly nonlinear) models for mediator and outcome. However, current developments have largely focused on single mediators because required identification assumptions prohibit simple extensions to settings with multiple mediators that may depend on one another. In this article, we propose a procedure for obtaining fine-grained decompositions that may still be recovered from observed data in such complex settings. We first show that existing analytical approaches target specific instances of a more general set of decompositions and may therefore fail to provide a comprehensive assessment of the processes that underpin cause-effect relationships between exposure and outcome. We then outline conditions for obtaining the remaining set of decompositions. Because the number of targeted decompositions increases rapidly with the number of mediators, we introduce natural effects models along with estimation methods that allow for flexible and parsimonious modeling. Our procedure can easily be implemented using off-the-shelf software and is illustrated using a reanalysis of the World Health Organization's Large Analysis and Review of European Housing and Health Status (WHO-LARES) study on the effect of mold exposure on mental health (2002-2003). © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    2003-01-01

    This study analyzes how a group of ‘mediators’ in a large, multinational company adapted a computer-mediated communication technology (a ‘virtual workspace’) to the organizational context (and vice versa) by modifying features of the technology, providing ongoing support for users, and promoting...... appropriate conventions of use. Our findings corroborate earlier research on technology-use mediation, which suggests that such mediators can exert considerable influence on how a particular technology will be established and used in an organization. However, this study also indicates that the process...... of technology-use mediation is more complex and indeterminate than earlier literature suggests. In particular, we want to draw attention to the fact that advanced computer-mediated communication technologies are equivocal and that technology-use mediation consequently requires ongoing sensemaking (Weick 1995)....

  19. The Schizosaccharomyces pombe Mediator

    DEFF Research Database (Denmark)

    Venturi, Michela

    , Schizosaccharomyces pombe and mammalian Mediator. In our study, we have taken the S. pombe Mediator into consideration and characterized genetically and biochemically two subunits already know in S. cerevisiae, Med9 and Med11, but still not identified in the S. pombe Mediator. Genetic analysis has shown that med9......In the past several years great attention has been dedicated to the characterization of the Mediator complex in a different range of model organisms. Mediator is a conserved co-activator complex involved in transcriptional regulation and it conveys signals from regulatory transcription factors...... to the basal transcription machinery. Mediator was initially isolated from Saccharomyces cerevisiae based on its ability to render a RNA polymerase II in vitro transcription system responsive to activators. Additionally, structural studies have revealed striking structural similarities between S. cerevisiae...

  20. Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model

    OpenAIRE

    Wagner, Sylvia; Zensi, Anja; Wien, Sascha L.; Tschickardt, Sabrina E.; Maier, Wladislaw; Vogel, Tikva; Worek, Franz; Pietrzik, Claus U.; Kreuter, Jörg; von Briesen, Hagen

    2012-01-01

    Background: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. Methodology/Principal Fi...

  1. Applied mediation analyses

    DEFF Research Database (Denmark)

    Lange, Theis; Hansen, Kim Wadt; Sørensen, Rikke

    2017-01-01

    In recent years, mediation analysis has emerged as a powerful tool to disentangle causal pathways from an exposure/treatment to clinically relevant outcomes. Mediation analysis has been applied in scientific fields as diverse as labour market relations and randomized clinical trials of heart...... disease treatments. In parallel to these applications, the underlying mathematical theory and computer tools have been refined. This combined review and tutorial will introduce the reader to modern mediation analysis including: the mathematical framework; required assumptions; and software implementation...

  2. Immunologically mediated oral diseases

    OpenAIRE

    Jimson, Sudha; Balachader, N.; Anita, N.; Babu, R.

    2015-01-01

    Immune mediated diseases of oral cavity are uncommon. The lesions may be self-limiting and undergo remission spontaneously. Among the immune mediated oral lesions the most important are lichen planus, pemphigus, erythema multiformi, epidermolysis bullosa, systemic lupus erythematosis. Cellular and humoral mediated immunity play a major role directed against epithelial and connective tissue in chronic and recurrent patterns. Confirmatory diagnosis can be made by biopsy, direct and indirect imm...

  3. Corporate Language Policies

    DEFF Research Database (Denmark)

    Sanden, Guro Refsum

    This paper offers a review of literature dealing with language policies in general and corporate language policies in particular. Based on a discussion of various definitions of these concepts within two research traditions, i.e. sociolinguistics and international management, a three......-level definition of corporate language policies is presented, emphasising that a corporate language policy is a context-specific policy about language use. The three-level definition is based on the argument that in order to acquire a complete understanding of what corporate language policies involve, one needs...... to consider three progressive questions; 1) what is a policy? 2) what is a language policy?, and ultimately, 3) what is a corporate language policy?...

  4. Corporate Language Policies

    DEFF Research Database (Denmark)

    Sanden, Guro Refsum

    2015-01-01

    This paper offers a review of literature dealing with language policies in general and corporate language policies in particular. Based on a discussion of various definitions of these concepts within two research traditions, i.e. sociolinguistics and international management, a three......-level definition of corporate language policies is presented, emphasising that a corporate language policy is a context-specific policy about language use. The three-level definition is based on the argument that in order to acquire a complete understanding of what corporate language policies involve, one needs...... to consider three progressive questions; 1) what is a policy? 2) what is a language policy?, and ultimately, 3) what is a corporate language policy?...

  5. Single Policy Study

    DEFF Research Database (Denmark)

    Kronsell, Annica; Manners, Ian James

    2015-01-01

    Single policy studies are the most common form of European Union (EU) research. Single policy studies are widely used to understand the role of the EU in a wide variety of sectors, together with their development over time, and often offer public policy prescriptions. This chapter discusses...... the relevance of single policy studies in EU research and give examples of how such research can be designed and carried out. The chapter reviews three examples of single policy studies using different methods based on EU environmental policy, the EU biofuels directive, and the EU Common Security and Defence...... Policy (CSDP). The examples are illustrative of how single policy studies can be designed to use different approaches in the analysis: multiple streams approach to policy-making; a comparative hypothesis testing; and feminist institutional theory....

  6. On the Evolution of the Mammalian Brain.

    Science.gov (United States)

    Torday, John S; Miller, William B

    2016-01-01

    Hobson and Friston have hypothesized that the brain must actively dissipate heat in order to process information (Hobson et al., 2014). This physiologic trait is functionally homologous with the first instantation of life formed by lipids suspended in water forming micelles- allowing the reduction in entropy (heat dissipation). This circumvents the Second Law of Thermodynamics permitting the transfer of information between living entities, enabling them to perpetually glean information from the environment, that is felt by many to correspond to evolution per se. The next evolutionary milestone was the advent of cholesterol, embedded in the cell membranes of primordial eukaryotes, facilitating metabolism, oxygenation and locomotion, the triadic basis for vertebrate evolution. Lipids were key to homeostatic regulation of calcium, forming calcium channels. Cell membrane cholesterol also fostered metazoan evolution by forming lipid rafts for receptor-mediated cell-cell signaling, the origin of the endocrine system. The eukaryotic cell membrane exapted to all complex physiologic traits, including the lung and brain, which are molecularly homologous through the function of neuregulin, mediating both lung development and myelinization of neurons. That cooption later exapted as endothermy during the water-land transition (Torday, 2015a), perhaps being the functional homolog for brain heat dissipation and conscious/mindful information processing. The skin and brain similarly share molecular homologies through the "skin-brain" hypothesis, giving insight to the cellular-molecular "arc" of consciousness from its unicellular origins to integrated physiology. This perspective on the evolution of the central nervous system clarifies self-organization, reconciling thermodynamic and informational definitions of the underlying biophysical mechanisms, thereby elucidating relations between the predictive capabilities of the brain and self-organizational processes.

  7. Implementing general gauge mediation

    International Nuclear Information System (INIS)

    Carpenter, Linda M.; Dine, Michael; Festuccia, Guido; Mason, John D.

    2009-01-01

    Recently there has been much progress in building models of gauge mediation, often with predictions different than those of minimal gauge mediation. Meade, Seiberg, and Shih have characterized the most general spectrum which can arise in gauge-mediated models. We discuss some of the challenges of building models of general gauge mediation, especially the problem of messenger parity and issues connected with R symmetry breaking and CP violation. We build a variety of viable, weakly coupled models which exhibit some or all of the possible low energy parameters.

  8. The endocannabinoid system in brain reward processes.

    Science.gov (United States)

    Solinas, M; Goldberg, S R; Piomelli, D

    2008-05-01

    Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

  9. Left brain, right brain: facts and fantasies.

    Directory of Open Access Journals (Sweden)

    Michael C Corballis

    2014-01-01

    Full Text Available Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the "norm" of right-handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal.

  10. Streamlining Policy Creation in Policy Frameworks

    NARCIS (Netherlands)

    M.A. Hills (Mark); N. Martí-Oliet; M. Palomino

    2012-01-01

    textabstract{\\it Policy frameworks} provide a technique for improving reuse in program analysis: the same language frontend, and a core analysis semantics, can be shared among multiple analysis policies for the same language, while analysis domains (such as units of measurement) can be shared among

  11. Biomechanics of the brain

    CERN Document Server

    Miller, Karol

    2011-01-01

    With contributions from scientists at major institutions, this book presents an introduction to brain anatomy for engineers and scientists. It provides, for the first time, a comprehensive resource in the field of brain biomechanics.

  12. Brain Basics: Understanding Sleep

    Science.gov (United States)

    ... You are here Home » Disorders » Patient & Caregiver Education Brain Basics: Understanding Sleep Anatomy of Sleep Sleep Stages ... t form or maintain the pathways in your brain that let you learn and create new memories, ...

  13. Aneurysm in the brain

    Science.gov (United States)

    ... gov/ency/article/001414.htm Aneurysm in the brain To use the sharing features on this page, ... aneurysm occurs in a blood vessel of the brain, it is called a cerebral, or intracranial, aneurysm. ...

  14. Brain injury - discharge

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000163.htm Brain injury - discharge To use the sharing features on ... know was in the hospital for a serious brain injury. At home, it will take time for ...

  15. Genetic Brain Disorders

    Science.gov (United States)

    A genetic brain disorder is caused by a variation or a mutation in a gene. A variation is a different form ... mutation is a change in a gene. Genetic brain disorders affect the development and function of the ...

  16. Childhood Brain Tumors

    Science.gov (United States)

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  17. Brain aneurysm repair

    Science.gov (United States)

    ... aneurysm repair; Dissecting aneurysm repair; Endovascular aneurysm repair - brain; Subarachnoid hemorrhage - aneurysm ... Your scalp, skull, and the coverings of the brain are opened. A metal clip is placed at ...

  18. Children's Brain Tumor Foundation

    Science.gov (United States)

    ... 2 Family Donate Volunteer Justin's Hope Fund Children’s Brain Tumor Foundation, A non-profit organization, was founded ... and the long term outlook for children with brain and spinal cord tumors through research, support, education, ...

  19. Brain aneurysm repair - discharge

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000123.htm Brain aneurysm repair - discharge To use the sharing features ... this page, please enable JavaScript. You had a brain aneurysm . An aneurysm is a weak area in ...

  20. Numbers and brains.

    Science.gov (United States)

    Gallistel, C R

    2017-12-01

    The representation of discrete and continuous quantities appears to be ancient and pervasive in animal brains. Because numbers are the natural carriers of these representations, we may discover that in brains, it's numbers all the way down.

  1. Protect Your Brain

    Centers for Disease Control (CDC) Podcasts

    At least three and a half million people in the U.S. sustained a traumatic brain injury (TBI), either with or without other injuries. This podcast discusses the importance of early diagnosis and treatment of brain injuries.

  2. Traumatic Brain Injury

    Science.gov (United States)

    ... brain injury Some traumatic brain injuries have lasting effects, and some do not. You may be left with disabilities. These can be physical, behavioral, communicative, and/or mental. Customized treatment helps you to have as full ...

  3. Right Brain Drawing.

    Science.gov (United States)

    Whalen, Adryce C.

    1985-01-01

    The author describes activities of a weekly enrichment class providing right-brain tasks to gifted elementary students. Activities, which centered on artistic creativity, were taken from "Drawing On the Right Side of the Brain" by B. Edwards. (CL)

  4. Innovation policies for tourism

    DEFF Research Database (Denmark)

    Hjalager, Anne-Mette

    2012-01-01

    The nature, extent, and implications of innovation in tourism are increasingly investigated in academic research, but the policies that affect these transformations in the industry and at tourism destinations are not equally well conceptualised theoretically or analysed empirically. The purpose...... of this article is, in an analysis of the literature, to interpret the rationale behind innovation policy, and to explain the persisting challenges related to acquisition of an informed foundation for policies based upon quantitative and qualitative inquiries. Observed in a historical perspective, innovation...... framework of policy instruments for innovation in tourism. New generations of policies instigate a mainstreaming of the innovation agenda in ways that proceed beyond the traditional policy concepts....

  5. Insulin and the Brain

    Directory of Open Access Journals (Sweden)

    Grosu Cristina

    2017-12-01

    Full Text Available The brain represents an important site for the action of insulin. Besides the traditionally known importance in glucoregulation, insulin has significant neurotrophic properties and influences the brain activity: insulin influences eating behavior, regulates the storage of energy and several aspects concerning memory and knowledge. Insulin resistance and hyperinsulinism could be associated with brain aging, vascular and metabolic pathologies. Elucidating the pathways and metabolism of brain insulin could have a major impact on future targeted therapies.

  6. Brain cancer spreads

    DEFF Research Database (Denmark)

    Perryman, Lara; Erler, Janine Terra

    2014-01-01

    The discovery that ~20% of patients with brain cancer have circulating tumor cells breaks the dogma that these cells are confined to the brain and has important clinical implications (Müller et al., this issue).......The discovery that ~20% of patients with brain cancer have circulating tumor cells breaks the dogma that these cells are confined to the brain and has important clinical implications (Müller et al., this issue)....

  7. Neuromythology of Einstein's brain.

    Science.gov (United States)

    Hines, Terence

    2014-07-01

    The idea that the brain of the great physicist Albert Einstein is different from "average" brains in both cellular structure and external shape is widespread. This belief is based on several studies examining Einstein's brain both histologically and morphologically. This paper reviews these studies and finds them wanting. Their results do not, in fact, provide support for the claim that the structure of Einstein's brain reflects his intellectual abilities. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Brain imaging and schizophrenia

    International Nuclear Information System (INIS)

    Martinot, J.L.; Dao-Castellana, M.H.

    1991-01-01

    Brain structures and brain function have been investigated by the new brain imaging techniques for more than ten years. In Psychiatry, these techniques could afford a new understanding of mental diseases. In schizophrenic patients, CAT scanner and RMI pointed out statistically significant ventricular enlargments which are presently considered as evidence for abnormalities in brain maturation. Functional imaging techniques reported metabolic dysfunctions in the cortical associative areas which are probably linked to the cognitive features of schizophrenics [fr

  9. Agricultural policy, food policy, and communicable disease policy.

    Science.gov (United States)

    Grant, Wyn

    2012-12-01

    Food and agricultural policy is an essential element of a communicable disease policy. The European Union has developed a more systematic and broadly based interest in questions of food safety and animal health and welfare linked to modernization of the Common Agricultural Policy, reflected in a new treaty obligation on animal welfare. Following the bovine spongiform encephalopathy crisis, moves were made to create a European competency, but implementation and enforcement resources reside with the member states. The European Animal Health Strategy is meant to lead to an EU animal health law, but this has already been constrained by fiscal austerity. The development of such a law may lead to a lowest common denominator formula that does little to enhance consumer protection or improve animal welfare. This is an inherent risk with top-down forms of Europeanization; more attention should be paid to lessons to be learned from bottom-up initiatives of the type used to counteract the bovine diarrhea virus. There will always be a tension among what is good policy for reducing the incidence of communicable disease, policy that is popular with EU citizens, and policy that is acceptable to member states.

  10. Transport of thyroxine across the blood-brain barrier is directed primarily from brain to blood in the mouse

    International Nuclear Information System (INIS)

    Banks, W.A.; Kastin, A.J.; Michals, E.A.

    1985-01-01

    The role of the blood-brain barrier (BBB) in the transport of thyroxine was examined in mice. Radioiodinated (hot thyroxine (hT 4 ) administered icv had a half-time disappearance from the brain of 30 min. This increased to 60 min (p 4 ). The Km for this inhibition of hT 4 transport out of the brain by cT 4 was 9.66 pmole/brain. Unlabeled 3,3',5 triiodothyronine (cT 3 ) was unable to inhibit transport of hT 4 out of the brain, although both cT 3 (p 4 (p 3 ) to a small degree. Entry of hT 4 into the brain after peripheral administration was negligible and was not affected by either cT 4 nor cT 3 . By contrast, the entry of hT 3 into the brain after peripheral administration was inhibited by cT 3 (p 4 (p < 0.01). The levels of the unlabeled thyroid hormones administered centrally in these studies did not affect bulk flow, as assessed by labeled red blood cells (/sup 99m/Tc-RBC), or the carrier mediated transport of iodide out of the brain. Likewise, the vascular space of the brain and body, as assessed by /sup 99m/Tc-RBC, was unchanged by the levels of peripherally administered unlabeled thyroid hormones. Therefore, the results of these studies are not due to generalized effects of thyroid hormones on BBB transport. The results indicate that in the mouse the major carrier-mediated system for thyroxine in the BBB transports thyroxine out of the brain, while the major system for triiodothyronine transports hormone into the brain. 14 references, 3 figures, 2 tables

  11. Brain atrophy during aging

    International Nuclear Information System (INIS)

    Matsuzawa, Taiju; Takeda, Shumpei; Hatazawa, Jun

    1985-01-01

    Age-related brain atrophy was investigated in thousands of persons with no neurologic disturbances using X-CT and NMR-CT and following results were obtained. Brain atrophy was minimal in 34 -- 35 years old in both sexes, increased exponentially to the increasing age after 34 -- 35 years, and probably resulted in dementia, such as vascular or multiinfarct dementia. Brain atrophy was significantly greater in men than in women at all ages. Brain volumes were maximal in 34 -- 35 years old in both sexes with minimal individual differences which increased proportionally to the increasing age. Remarkable individual differences in the extents of brain atrophy (20 -- 30 %) existed among aged subjects. Some aged subjects had little or no atrophy of their brains, as seen in young subjects, and others had markedly shrunken brains associated with senility. From these results there must be pathological factors promoting brain atrophy with a great individual difference. We have studied the relation of intelligence to brain volume, and have ascertained that progression of brain atrophy was closely related to loss of mental activities independently of their ages. Our longitudinal study has revealed that the most important factors promoting brain atrophy during aging was decrease in the cerebral blood flow. MNR-CT can easily detected small infarction (lacunae) and edematous lesions resulting from ischemia and hypertensive encephalopathy, while X-CT can not. Therefore NMR-CT is very useful for detection of subtle changes in the brain. (J.P.N.)

  12. Radiopharmaceuticals for brain - SPECT

    International Nuclear Information System (INIS)

    Moretti, J.L.

    1992-01-01

    Perfusion tracers for brain SPECT imaging suitable for regional cerebral blood flow measurement and regional cerebral blood volume determination, with respect to their ability to pass the blood-brain-barrier, are described. Problems related t the use of specific radiotracers to map receptors distribution in the brain are also discussed in this lecture. 9 figs, 6 tabs

  13. Brain Research and Learning.

    Science.gov (United States)

    Claycomb, Mary

    Current research on brain activity has many implications for educators. The triune brain concept and the left and right hemisphere concepts are among the many complex theories evolving from experimentation and observation. The triune brain concept suggests that the human forebrain has expanded while retaining three structurally unique formations…

  14. Primary lymphoma of the brain

    Science.gov (United States)

    Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

  15. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain.

    Science.gov (United States)

    McCarthy, Margaret M; Nugent, Bridget M; Lenz, Kathryn M

    2017-08-01

    The study of sex differences in the brain is a topic of neuroscientific study that has broad reaching implications for culture, society and biomedical science. Recent research in rodent models has led to dramatic shifts in our views of the mechanisms underlying the sexual differentiation of the brain. These include the surprising discoveries of a role for immune cells and inflammatory mediators in brain masculinization and a role for epigenetic suppression in brain feminization. How and to what degree these findings will translate to human brain development will be questions of central importance in future research in this field.

  16. IT Policy Archive

    Data.gov (United States)

    National Aeronautics and Space Administration — CIO defines IT processes and policies. The CIO defines the development processes, milestones, review gates, and the overall policies for all capital planning,...

  17. National Environmental Policy Act

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The National Environmental Policy Act (NEPA) was the first major environmental law in the United States and established national environmental policies for the...

  18. Nordic cultural policies

    DEFF Research Database (Denmark)

    Duelund, Peter

    2008-01-01

    A critical view on Nordic Cultural Policy 1961-2008 - Aims, measures, forms of organisation, state og national identity......A critical view on Nordic Cultural Policy 1961-2008 - Aims, measures, forms of organisation, state og national identity...

  19. Teaching Mediated Public Relations.

    Science.gov (United States)

    Kent, Michael L.

    2001-01-01

    Discusses approaches to teaching a mediated public relations course, emphasizing the World Wide Web. Outlines five course objectives, assignments and activities, evaluation, texts, and lecture topics. Argues that students mastering these course objectives will understand ethical issues relating to media use, using mediated technology in public…

  20. Fashion, Mediations & Method Assemblages

    DEFF Research Database (Denmark)

    Sommerlund, Julie; Jespersen, Astrid Pernille

    of handling multiple, fluid realities with multiple, fluid methods. Empirically, the paper works with mediation in fashion - that is efforts the active shaping of relations between producer and consumer through communication, marketing and PR. Fashion mediation is by no means simple, but organise complex...

  1. The Mediated Transparent Society

    DEFF Research Database (Denmark)

    Backer, Lise

    2001-01-01

    in the mediated transparent society. The paper concludes that, based on these analyses, the mediated panopticism working on the business segment is not an effective disciplinary apparatus, which can guarantee that business corporations are carrying out important ecological or ethical improvements....

  2. Laccase/Mediator Systems

    NARCIS (Netherlands)

    Hilgers, Roelant; Vincken, Jean Paul; Gruppen, Harry; Kabel, Mirjam A.

    2018-01-01

    Laccase-mediator systems (LMS) have been widely studied for their capacity to oxidize the nonphenolic subunits of lignin (70-90% of the polymer). The phenolic subunits (10-30% of the polymer), which can also be oxidized without mediators, have received considerably less attention. Consequently, it

  3. Why do policies change? Institutions, interests, ideas and networks in three cases of policy reform.

    Science.gov (United States)

    Shearer, Jessica C; Abelson, Julia; Kouyaté, Bocar; Lavis, John N; Walt, Gill

    2016-11-01

    Policy researchers have used various categories of variables to explain why policies change, including those related to institutions, interests and ideas. Recent research has paid growing attention to the role of policy networks-the actors involved in policy-making, their relationships with each other, and the structure formed by those relationships-in policy reform across settings and issues; however, this literature has largely ignored the theoretical integration of networks with other policy theories, including the '3Is' of institutions, interests and ideas. This article proposes a conceptual framework integrating these variables and tests it on three cases of policy change in Burkina Faso, addressing the need for theoretical integration with networks as well as the broader aim of theory-driven health policy analysis research in low- and middle-income countries. We use historical process tracing, a type of comparative case study, to interpret and compare documents and in-depth interview data within and between cases. We found that while network changes were indeed associated with policy reform, this relationship was mediated by one or more of institutions, interests and ideas. In a context of high donor dependency, new donor rules affected the composition and structure of actors in the networks, which enabled the entry and dissemination of new ideas and shifts in the overall balance of interest power ultimately leading to policy change. The case of strategic networking occurred in only one case, by civil society actors, suggesting that network change is rarely the spark that initiates the process towards policy change. This analysis highlights the important role of changes in institutions and ideas to drive policymaking, but hints that network change is a necessary intermediate step in these processes. © The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For

  4. Brain atrophy during aging

    International Nuclear Information System (INIS)

    Matsuzawa, Taiju; Yamada, Kenji; Yamada, Susumu; Ono, Shuichi; Takeda, Shunpei; Hatazawa, Jun; Ito, Masatoshi; Kubota, Kazuo

    1985-01-01

    Age-related brain atrophy was investigated in thousands of persons with no neurologic disturbances using X-CT and NMR-CT. Brain atrophy was minimal in 34-35 years old in both sexes, increased exponentially to the increasing age after 34-35 years, and probably resulted in dementia, such as vascular or multi-infarct dementia. Brain atrophy was significantly greater in men than in women at all ages. Brain volumes were maximal in 34-35 years old in both sexes with minimal individual differences which increased proportionally to the increasing age. Remarkable individual differences in the extent of brain atrophy (20 - 30 %) existed among aged subjects. Progression of brain atrophy was closely related to loss of mental activities independently of their ages. Our longitudinal study has revealed that the most important factors promoting brain atrophy during aging was the decrease in the cerebral blood flow. We have classified brain atrophy into sulcal and cisternal enlargement type (type I), ventricular enlargement type (type II) and mixed type (type III) according to the clinical study using NMR-CT. Brain atrophy of type I progresses significantly in almost all of the geriatric disorders. This type of brain atrophy progresses significantly in heavy smokers and drinkers. Therefore this type of brain atrophy might be caused by the decline in the blood flow in anterior and middle cerebral arteries. Brain atrophy of type II was caused by the disturbance of cerebrospinal fluid circulation after cerebral bleeding and subarachnoid bleeding. Brain atrophy of type III was seen in vascular dementia or multi-infarct dementia which was caused by loss of brain matter after multiple infarction, and was seen also in dementia of Alzheimer type in which degeneration of nerve cells results in brain atrophy. NMR-CT can easily detect small infarction (lacunae) and edematous lesions resulting from ischemia and hypertensive encephalopathy. (J.P.N.)

  5. Economics and obesity policy.

    Science.gov (United States)

    Lusk, J L

    2017-06-01

    This paper elucidates the challenges surrounding the economics of some popular obesity-related policy proposals. Solid economic justifications for anti-obesity policies are often lacking, and evidence suggests policies like fat and soda taxes or restrictions on food stamp spending are unlikely to substantively affect obesity prevalence. In short, many of the same factors that make obesity such a complicated and multifaceted issue extend to the economic analysis of public health policies.

  6. Innovation policies for tourism

    DEFF Research Database (Denmark)

    Hjalager, Anne-Mette

    2012-01-01

    The nature, extent, and implications of innovation in tourism are increasingly investigated in academic research, but the policies that affect these transformations in the industry and at tourism destinations are not equally well conceptualised theoretically or analysed empirically. The purpose...... framework of policy instruments for innovation in tourism. New generations of policies instigate a mainstreaming of the innovation agenda in ways that proceed beyond the traditional policy concepts....

  7. Hybrid Security Policies

    Directory of Open Access Journals (Sweden)

    Radu CONSTANTINESCU

    2006-01-01

    Full Text Available Policy is defined as the rules and regulations set by the organization. They are laid down by management in compliance with industry regulations, law and internal decisions. Policies are mandatory. Security policies rules how the information is protected against security vulnerabilities and they are the basis for security awareness, training and vital for security audits. Policies are focused on desired results. The means of achieving the goals are defined on controls, standards and procedures.

  8. Brain expression of the water channels Aquaporin-1 and -4 in mice with acute liver injury, hyperammonemia and brain edema

    DEFF Research Database (Denmark)

    Eefsen, Martin; Jelnes, Peter; Schmidt, Lars E

    2010-01-01

    Cerebral edema is a feared complication to acute liver failure (ALF), but the pathogenesis is still poorly understood. The water channels Aquaporin-1 (Aqp1) and -4 (Aqp4) has been associated with brain edema formation in several neuropathological conditions, indicating a possible role of Aqp1 and....../or Aqp4 in ALF mediated brain edema. We induced acute liver injury and hyperammonemia in mice, to evaluate brain edema formation and the parallel expression of Aqp1 and Aqp4 in ALF. Liver injury and hyperammonemia were induced by +D-galactosamine (GLN) plus lipopolysaccharide (LPS) intraperitoneally......(6266) (p edema in mice with ALF....

  9. The multitalented Mediator complex.

    Science.gov (United States)

    Carlsten, Jonas O P; Zhu, Xuefeng; Gustafsson, Claes M

    2013-11-01

    The Mediator complex is needed for regulated transcription of RNA polymerase II (Pol II)-dependent genes. Initially, Mediator was only seen as a protein bridge that conveyed regulatory information from enhancers to the promoter. Later studies have added many other functions to the Mediator repertoire. Indeed, recent findings show that Mediator influences nearly all stages of transcription and coordinates these events with concomitant changes in chromatin organization. We review the multitude of activities associated with Mediator and discuss how this complex coordinates transcription with other cellular events. We also discuss the inherent difficulties associated with in vivo characterization of a coactivator complex that can indirectly affect diverse cellular processes via changes in gene transcription. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Music, radio and mediatization

    DEFF Research Database (Denmark)

    Michelsen, Morten; Krogh, Mads

    2016-01-01

    of mediatization where media as such seem to be ascribed agency. Instead, we consider historical accounts of music–radio in order to address the complex nonlinearity of concrete processes of mediatization as they take place in the multiple meetings between a decentred notion of radio and musical life.......Mediatization has become a key concept for understanding the relations between media and other cultural and social fields. Contributing to the discussions related to the concept of mediatization, this article discusses how practices of radio and music(al life) influence each other. We follow Deacon......’s and Stanyer’s advice to supplement the concept of mediatization with ‘a series of additional concepts at lower levels of abstraction’ and suggest, in this respect, the notion of heterogeneous milieus of music–radio. Hereby, we turn away from the all-encompassing perspectives related to the concept...

  11. [Brain imaging in autism spectrum disorders. A review].

    Science.gov (United States)

    Dziobek, I; Köhne, S

    2011-05-01

    In the past two decades, an increasing number of functional and structural brain imaging studies has provided insights into the neurobiological basis of autism spectrum disorders (ASD). This article summarizes pertinent functional brain imaging studies addressing the neuronal underpinnings of ASD symptomatology (impairments in social interaction and communication, repetitive and restrictive behavior) and associated neuropsychological deficits (theory of mind, executive functions, central coherence), complemented by relevant structural imaging findings. The results of these studies show that although cognitive functions in ASD are generally mediated by the same brain regions as in typically developed individuals, the degree and especially the patterns of brain activation often differ. Therefore, a hypothesis of aberrant network connectivity has increasingly been favored over one of focal brain dysfunction.

  12. Glutamate Efflux at the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Cederberg-Helms, Hans Christian; Uhd-Nielsen, Carsten; Brodin, Birger

    2014-01-01

    is well known, however endothelial cells may also play an important role through mediating brain-to-blood L-glutamate efflux. Expression of excitatory amino acid transporters has been demonstrated in brain endothelial cells of bovine, human, murine, rat and porcine origin. These can account for high...... affinity concentrative uptake of L-glutamate from the brain interstitial fluid into the capillary endothelial cells. The mechanisms in between L-glutamate uptake in the endothelial cells and L-glutamate appearing in the blood are still unclear and may involve a luminal transporter for L......-glutamate, metabolism of L-glutamate and transport of metabolites or a combination of the two. However, both in vitro and in vivo studies have demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. This review summarizes the current knowledge on the brain-to-blood L-glutamate efflux...

  13. Instant BrainShark

    CERN Document Server

    Li, Daniel

    2013-01-01

    Filled with practical, step-by-step instructions and clear explanations for the most important and useful tasks. ""Instant BrainShark"" is a step-by-step guide to creating online presentations using BrainShark. The book covers digital marketing best practices alongside tips for sales conversions. The book is written in an easy-to-read style for anybody to easily pick up and get started with BrainShark.Instant BrainShark is for anyone who wants to use BrainShark to create presentations online and share them around the community. The book is also useful for developers who are looking to explore

  14. David Ferrier: brain drawings and brain maps.

    Science.gov (United States)

    Lazar, J Wayne

    2013-01-01

    This chapter has two emphases, one is about the men who influenced the visual representations that David Ferrier (1843-1928) used to illustrate his work on localization of brain functions during the years 1873-1875, namely, Alexander Ecker, John C. Galton, and Ernest Waterlow, and the other is about the nature of medical representations and of Ferrier's illustrations in particular. Medical illustrations are characterized either as pictures, line drawings, or brain maps. Ferrier's illustrations will be shown to be increasingly sophisticated brain maps that contrast with early nineteenth-century standards of medical illustrations, as exemplified by John Bell (1763-1829). © 2013 Elsevier B.V. All rights reserved.

  15. MACROPRUDENTIAL POLICY: CONCEPTUAL POSITIONS

    OpenAIRE

    Radu CUHAL; Ludmila STARIŢÎNA; Nicolae BASISTÎI

    2013-01-01

    The article explains the conceptual principles of macroprudential policy, its main objectives and instruments. The classification of macroprudential policy tools of the Committee on the Global Financial System is defined. The comparative characteristics of macro-prudential policy in the Western developed countries are also examined.

  16. Macroprudential policy: conceptual positions

    OpenAIRE

    Stariţîna Ludmila; Cuhal Radu

    2013-01-01

    The article explains the conceptual principles of macroprudential policy, its main objectives and instruments. The classification of macroprudential policy tools of the Committee on the Global Financial System is defined. The comparative characteristics of macro-prudential policy in the Western developed countries are also examined.

  17. Italian energy policy

    International Nuclear Information System (INIS)

    1988-01-01

    This document discusses problems associated with Italian energy policy; economic and industrial development as it relates to that policy is covered. Specific areas covered are: (1) the basis of Italy's new energy policy; (2) energy demand; (3) five objectives; (4) the electrical power system; (5) proposed action; and (6) energy resources

  18. Energy. Policy and Implementation

    International Nuclear Information System (INIS)

    Stroop, A.

    2006-01-01

    Why does the government have an energy policy? What form does it take? Who is involved in implementing that policy? These and similar questions are answered in the latest Energy Report. The Dutch Ministry of Economic Affairs (EZ) argues that the objectives are feasible as long as the energy policies are matched by suitable implementation measures [nl

  19. Quarterly fiscal policy

    NARCIS (Netherlands)

    Kendrick, D.A.; Amman, H.M.

    2014-01-01

    Monetary policy is altered once a month. Fiscal policy is altered once a year. As a potential improvement this article examines the use of feedback control rules for fiscal policy that is altered quarterly. Following the work of Blinder and Orszag, modifications are discussed in Congressional

  20. The glucocorticoid receptor in the limbic system of the human brain

    NARCIS (Netherlands)

    Wang, Qian

    2016-01-01

    Glucocorticoid hormones (GCs) are important mediators of the stress response in mammals including humans. GCs are released from the adrenal in response to stress and affect numerous processes in the body and brain. Their levels are controlled via negative feedback exerted by GC binding to brain

  1. Cobalt-55 positron emission tomography in traumatic brain injury : A pilot study

    NARCIS (Netherlands)

    Jansen, HML; vanderNaalt, J; vanZomeren, AH; Paans, AMJ; VeenmavanderDuin, L; Hew, JM; Pruim, J; Minderhoud, JM; Korf, J

    Traumatic brain injury is usually assessed with the Glasgow coma scale (GCS), CT, or MRI. After such injury, the injured brain tissue is characterised by calcium mediated neuronal damage and inflammation. Positron emission tomography with the isotope cobalt-55 (Go-PET) as a calcium tracer enables

  2. Learning Predictive Statistics: Strategies and Brain Mechanisms.

    Science.gov (United States)

    Wang, Rui; Shen, Yuan; Tino, Peter; Welchman, Andrew E; Kourtzi, Zoe

    2017-08-30

    When immersed in a new environment, we are challenged to decipher initially incomprehensible streams of sensory information. However, quite rapidly, the brain finds structure and meaning in these incoming signals, helping us to predict and prepare ourselves for future actions. This skill relies on extracting the statistics of event streams in the environment that contain regularities of variable complexity from simple repetitive patterns to complex probabilistic combinations. Here, we test the brain mechanisms that mediate our ability to adapt to the environment's statistics and predict upcoming events. By combining behavioral training and multisession fMRI in human participants (male and female), we track the corticostriatal mechanisms that mediate learning of temporal sequences as they change in structure complexity. We show that learning of predictive structures relates to individual decision strategy; that is, selecting the most probable outcome in a given context (maximizing) versus matching the exact sequence statistics. These strategies engage distinct human brain regions: maximizing engages dorsolateral prefrontal, cingulate, sensory-motor regions, and basal ganglia (dorsal caudate, putamen), whereas matching engages occipitotemporal regions (including the hippocampus) and basal ganglia (ventral caudate). Our findings provide evidence for distinct corticostriatal mechanisms that facilitate our ability to extract behaviorally relevant statistics to make predictions. SIGNIFICANCE STATEMENT Making predictions about future events relies on interpreting streams of information that may initially appear incomprehensible. Past work has studied how humans identify repetitive patterns and associative pairings. However, the natural environment contains regularities that vary in complexity from simple repetition to complex probabilistic combinations. Here, we combine behavior and multisession fMRI to track the brain mechanisms that mediate our ability to adapt to

  3. Strategies to improve drug delivery across the blood-brain barrier.

    Science.gov (United States)

    de Boer, Albertus G; Gaillard, Pieter J

    2007-01-01

    The blood-brain barrier (BBB), together with the blood-cerebrospinal-fluid barrier, protects and regulates the homeostasis of the brain. However, these barriers also limit the transport of small-molecule and, particularly, biopharmaceutical drugs such as proteins, genes and interference RNA to the brain, thereby limiting the treatment of many brain diseases. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. In this review, we discuss briefly the biology and physiology of the BBB as the most important barrier for drug transport to the brain and, in more detail, the possibilities for delivering large-molecule drugs, particularly genes, by receptor-mediated nonviral drug delivery to the (human) brain. In addition, the systemic and intracellular pharmacokinetics of nonviral gene delivery, together with targeted brain imaging, are reviewed briefly.

  4. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier.

    Science.gov (United States)

    Georgieva, Julia V; Hoekstra, Dick; Zuhorn, Inge S

    2014-11-17

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood-brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier-drug system ("Trojan horse complex") is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

  5. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier

    Directory of Open Access Journals (Sweden)

    Julia V. Georgieva

    2014-11-01

    Full Text Available The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood–brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier–drug system (“Trojan horse complex” is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

  6. Metal ion toxins and brain aquaporin-4 expression: an overview

    Directory of Open Access Journals (Sweden)

    Adriana eXimenes-Da-Silva

    2016-06-01

    Full Text Available Metal ions such as iron, zinc, and manganese are essential to metabolic functions, protein synthesis, neurotransmission, and antioxidant neuroprotective mechanisms. Conversely, non-essential metals such as mercury and lead are sources of human intoxication due to occupational activities or environmental contamination. Essential or non-essential metal accumulation in the central nervous system (CNS results in changes in blood-brain barrier (BBB permeability, as well as triggering microglia activation and astrocyte reactivity and changing water transport through the cells, which could result in brain swelling. Aquaporin-4 is the main water channel in the CNS, is expressed in astrocyte foot processes in brain capillaries and along the circumventricular epithelium in the ventricles, and has important physiological functions in maintaining brain osmotic homeostasis and supporting brain excitability through regulation of the extracellular space. Some evidence has pointed to a role of AQP4 during metal intoxication in the brain, where it may act in a dual form as a neuroprotector or a mediator of the development of oxidative stress in neurons and astrocytes, resulting in brain swelling and neuronal damage. This mini-review presents the way some metal ions affect changes in AQP4 expression in the CNS and discuss the ways in which water transport in brain cells can be involved in brain damage.

  7. Symbolic severance. Charlie or the broken circle of cultural mediation

    Directory of Open Access Journals (Sweden)

    Isabelle MATHIEU

    2015-07-01

    Full Text Available The cultural dimension of the attack on Charlie Hebdo raises questions about the meaning of the event in terms of public policies on art and culture. At issue particulary is the re-situation of those policies in their relationship with democratic achievement in the context of the French republican model. Analysis through the prism of cultural mediation, considered as a communication process designed ti produce a symbolic type of work, casts new light on the objectives and the ways and means of implementing such policies.

  8. Canada, China collaborate to encourage “brain flow” between the ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2016-04-28

    Apr 28, 2016 ... The "brain flow" between Canada and China involves the ... The impact of China's development model on worker migration; The effects of human ... To extend knowledge sharing and capacity building, workshops and policy ...

  9. Endothelial cell marker PAL-E reactivity in brain tumor, developing brain, and brain disease

    NARCIS (Netherlands)

    Leenstra, S.; Troost, D.; Das, P. K.; Claessen, N.; Becker, A. E.; Bosch, D. A.

    1993-01-01

    The endothelial cell marker PAL-E is not reactive to vessels in the normal brain. The present study concerns the PAL-E reactivity in brain tumors in contrast to normal brain and nonneoplastic brain disease. A total of 122 specimens were examined: brain tumors (n = 94), nonneoplastic brain disease (n

  10. Mapping brain function to brain anatomy

    International Nuclear Information System (INIS)

    Valentino, D.J.; Huang, H.K.; Mazziotta, J.C.

    1988-01-01

    In Imaging the human brain, MRI is commonly used to reveal anatomical structure, while PET is used to reveal tissue function. This paper presents a protocol for correlating data between these two imaging modalities; this correlation can provide in vivo regional measurements of brain function which are essential to our understanding of the human brain. The authors propose a general protocol to standardize the acquisition and analysis of functional image data. First, MR and PET images are collected to form three-dimensional volumes of structural and functional image data. Second, these volumes of image data are corrected for distortions inherent in each imaging modality. Third, the image volumes are correlated to provide correctly aligned structural and functional images. The functional images are then mapped onto the structural images in both two-dimensional and three-dimensional representations. Finally, morphometric techniques can be used to provide statistical measures of the structure and function of the human brain

  11. Brain imaging during seizure: ictal brain SPECT

    International Nuclear Information System (INIS)

    Kottamasu, Sambasiva Rao

    1997-01-01

    The role of single photon computed tomography (SPECT) in presurgical localization of medically intractable complex partial epilepsy (CPE) in children is reviewed. 99m Technetium neurolite, a newer lipophylic agent with a high first pass brain extraction and little or no redistribution is injected during a seizure, while the child is monitored with a video recording and continuous EEG and SPECT imaging is performed in the next 1-3 hours with the images representing regional cerebral profusion at the time of injection. On SPECT studies performed with radiopharmaceutical injected during a seizure, ictal focus is generally hypervascular. Other findings on ictal brain SPECT include hypoperfusion of adjacent cerebral cortex and white matter, hyperperfusion of contralateral motor cortex, hyperperfusion of ipsilateral basal ganglia and thalamus, brain stem and contralateral cerebellum. Ictal brain SPECT is non-invasive, cost effective and highly sensitive for localization of epileptic focus in patients with intractable CPE. (author)

  12. Economic and Policy Review: Editorial Policies

    African Journals Online (AJOL)

    The NESG Economic and Policy Review (EPR) is a quarterly publication of the ... of government and the Nigerian economy in the short, medium and long terms. ... must be of impeccable quality and must conform to world class standard.

  13. Designing collaborative policy innovation

    DEFF Research Database (Denmark)

    Agger, Annika; Sørensen, Eva

    2014-01-01

    Recent approaches to enhancing public innovation suffer from two shortcomings: They overemphasize competition as a driver of innovation and overlook the fact that public sector innovation involves policy innovation as well as service innovation. Drawing on governance research and innovation theory......, the chapter investigates the extent to which and how collaboration between politicians and relevant stakeholders can spur the formulation, implementation and diffusion of new innovative policies. A case study of a process of collaborative policy innovation in a Danish municipality shows that collaborative...... policy arenas do contribute to policy innovation but also that the degree to which they do so depends on the institutional design of these arenas....

  14. EUROPEAN MARITIME TRANSPORT POLICY

    Directory of Open Access Journals (Sweden)

    Jerzy Kujawa

    2014-03-01

    Full Text Available The article describes the common EU policy on maritime transport, which comprises almost 80% of the volume of external trade of the Union and about 40% of internal transport needs. The first part of the paper presents the origins of the common maritime transport policy and the difficulties encountered during its initial formation. Subsequently, the evolution of the concepts of the policy and its current shape is discussed. The final, substantial part of the article describes the main aims and directions of the EU maritime transport policy and includes an evaluation of the effects of the policy.

  15. Cyber security policy guidebook

    CERN Document Server

    Bayuk, nifer L; Rohmeyer, l; Sachs, cus; Schmidt, frey; Weiss, eph

    2012-01-01

    This book is a taxonomy and thesaurus of current cybersecurity policy issues, including a thorough description of each issue and a corresponding list of pros and cons with respect to identified stances on each issue. It documents policy alternatives for the sake of clarity with respect to policy alone, and dives into organizational implementation issues. Without using technical jargon, the book emphasizes the importance of critical and analytical thinking when making policy decisions.  It also equips the reader with descriptions of the impact of specific policy ch

  16. Energy policy and foreign policy in Italy

    International Nuclear Information System (INIS)

    Venanzi, F.

    2001-01-01

    Energy policy in Italy is principally a matter of foreign policy. As a result, extensive programmes for the exploration, development, transport and marketing of oil and natural gas have to be planned and carried out together with the producing countries. In this effort, the country shall need the support of its national energy companies. That is why ENI's controlling interest as well as its mission had better be on Italian hands [it

  17. Structural and Functional Plasticity in the Maternal Brain Circuitry

    Science.gov (United States)

    Pereira, Mariana

    2016-01-01

    Parenting recruits a distributed network of brain structures (and neuromodulators) that coordinates caregiving responses attuned to the young's affect, needs, and developmental stage. Many of these structures and connections undergo significant structural and functional plasticity, mediated by the interplay between maternal hormones and social…

  18. The Role of Brain-Reactive Autoantibodies in Brain Pathology and Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Simone Mader

    2017-09-01

    Full Text Available Antibodies to different brain proteins have been recently found to be associated with an increasing number of different autoimmune diseases. They need to penetrate the blood–brain barrier (BBB in order to bind antigens within the central nervous system (CNS. They can target either neuronal or non-neuronal antigen and result in damage either by themselves or in synergy with other inflammatory mediators. Antibodies can lead to acute brain pathology, which may be reversible; alternatively, they may trigger irreversible damage that persists even though the antibodies are no longer present. In this review, we will describe two different autoimmune conditions and the role of their antibodies in causing brain pathology. In systemic lupus erythematosus (SLE, patients can have double stranded DNA antibodies that cross react with the neuronal N-methyl-d-aspartate receptor (NMDAR, which have been recently linked to neurocognitive dysfunction. In neuromyelitis optica (NMO, antibodies to astrocytic aquaporin-4 (AQP4 are diagnostic of disease. There is emerging evidence that pathogenic T cells also play an important role for the disease pathogenesis in NMO since they infiltrate in the CNS. In order to enable appropriate and less invasive treatment for antibody-mediated diseases, we need to understand the mechanisms of antibody-mediated pathology, the acute and chronic effects of antibody exposure, if the antibodies are produced intrathecally or systemically, their target antigen, and what triggers their production. Emerging data also show that in utero exposure to some brain-reactive antibodies, such as those found in SLE, can cause neurodevelopmental impairment since they can penetrate the embryonic BBB. If the antibody exposure occurs at a critical time of development, this can result in irreversible damage of the offspring that persists throughout adulthood.

  19. On the evolution of the mammalian brain

    Directory of Open Access Journals (Sweden)

    John Steven Torday

    2016-04-01

    Full Text Available Hobson and Friston have hypothesized that the brain must actively dissipate heat in order to process information (Virtual reality and consciousness inference in dreaming. Front Psychol. 2014 Oct 9;5:1133.. This physiologic trait is functionally homologous with the first instantation of life formed by lipids suspended in water forming micelles- allowing the reduction in entropy (heat dissipation, circumventing the Second Law of Thermodynamics permitting the transfer of information between living entities, enabling them to perpetually glean information from the environment (= evolution. The next evolutionary milestone was the advent of cholesterol, embedded in the cell membranes of primordial eukaryotes, facilitating metabolism, oxygenation and locomotion, the triadic basis for vertebrate evolution. Lipids were key to homeostatic regulation of calcium, forming calcium channels. Cell membrane cholesterol also fostered metazoan evolution by forming lipid rafts for receptor-mediated cell-cell signaling, the origin of the endocrine system. The eukaryotic cell membrane exapted to all complex physiologic traits, including the lung and brain, which are molecularly homologous through the function of neuregulin, mediating both lung development and myelinization of neurons. That cooption later exapted as endothermy during the water-land transition (Torday JS. A Central Theory of Biology. Med Hypotheses. 2015 Jul;85(1:49-57, perhaps being the functional homolog for brain heat dissipation and consciousness/mind. The skin and brain similarly share molecular homologies through the ‘skin-brain’ hypothesis, giving insight to the cellular-molecular ‘arc’ of consciousness from its unicellular origins to integrated physiology. This perspective on the evolution of the central nervous system clarifies self-organization, reconciling thermodynamic and informational definitions of the underlying biophysical mechanisms, thereby elucidating relations between the

  20. Interleukin-1 and acute brain injury

    Directory of Open Access Journals (Sweden)

    Katie N Murray

    2015-02-01

    Full Text Available Inflammation is the key host-defense response to infection and injury, yet also a major contributor to a diverse range of diseases, both peripheral and central in origin. Brain injury as a result of stroke or trauma is a leading cause of death and disability worldwide, yet there are no effective treatments, resulting in enormous social and economic costs. Increasing evidence, both preclinical and clinical, highlights inflammation as an important factor in stroke, both in determining outcome and as a contributor to risk. A number of inflammatory mediators have been proposed as key targets for intervention to reduce the burden of stroke, several reaching clinical trial, but as yet yielding no success. Many factors could explain these failures, including the lack of robust preclinical evidence and poorly designed clinical trials, in addition to the complex nature of the clinical condition. Lack of consideration in preclinical studies of associated co-morbidities prevalent in the clinical stroke population is now seen as an important omission in previous work. These co-morbidities (atherosclerosis, hypertension, diabetes, infection have a strong inflammatory component, supporting the need for greater understanding of how inflammation contributes to acute brain injury. Interleukin (IL-1 is the prototypical pro-inflammatory cytokine, first identified many years ago as the endogenous pyrogen. Research over the last 20 years or so reveals that IL-1 is an important mediator of neuronal injury and blocking the actions of IL-1 is beneficial in a number of experimental models of brain damage. Mechanisms underlying the actions of IL-1 in brain injury remain unclear, though increasing evidence indicates the cerebrovasculature as a key target. Recent literature supporting this and other aspects of how IL-1 and systemic inflammation in general contribute to acute brain injury are discussed in this review.