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Sample records for bloodbrain partitioning straightforward

  1. Water-solvent partition coefficients and Delta Log P values as predictors for blood-brain distribution; application of the Akaike information criterion.

    PubMed

    Abraham, Michael H; Acree, William E; Leo, Albert J; Hoekman, David; Cavanaugh, Joseph E

    2010-05-01

    It is shown that log P values for water-alkane or water-cyclohexane partitions, and the corresponding Delta log P values when used as descriptors for blood-brain distribution, as log BB, yield equations with very poor correlation coefficients but very good standard deviations, S from 0.25 to 0.33 log units. Using quite large data sets, we have verified that similar S-values apply to predictions of log BB. A suggested model, based on log P for water-dodecane and water-hexadecane partition coefficients, has 109 data points and a fitted S = 0.254 log units. It is essential to include in the model an indicator variable for volatile compounds, and an indicator variable for drugs that contain the carboxylic group. A similar equation based on water-chloroform partition coefficients has 83 data points and a fitted S = 0.287 log units. We can find no causal connection between these log P values and log BB in terms of correlation or in terms of chemical similarity, but conclude that the log P descriptor will yield excellent predictions of log BB provided that predictions are within the chemical space of the compounds used to set up the model. We also show that model based on log P(octanol) and an Abraham descriptor provides a simple and easy method of predicting log BB with an error of no more than 0.31 log units. We have used the Akaike information criterion to investigate the most economic models for log BB.

  2. DETERMINATION OF IN VITRO AND IN SILICO INDEXES FOR THE MODELLING OF BLOOD-BRAIN BARRIER PARTITIONING OF DRUGS VIA MICELLAR AND IMMOBILIZED ARTIFICIAL MEMBRANE LIQUID CHROMATOGRAPHY.

    PubMed

    Russo, Giacomo; Grumetto, Lucia; Szucs, Roman; Barbato, Francesco; Lynen, Frederic

    2017-04-11

    In the present work, 79 structurally unrelated analytes were taken into account and their chromatographic retention coefficients, measured by Immobilized Artificial Membrane Liquid Chromatography (IAM-LC), and by Micellar Liquid Chromatography (MLC) employing sodium dodecyl sulfate (SDS) as surfactant, were determined. Such indexes were subsequently used for the development of Blood-Brain Barrier passage-predictive statistical models using partial least square (PLS) regression along with topological and physico-chemical parameters, calculated in silico. Highly significant relationships were observed either using IAM (r2 (n-1) = 0.78) or MLC (r2 (n-1) = 0.83) derived indexes along with in silico descriptors. This hybrid approach proved fast and effective in the development of highly predictive BBB passage oriented models and, therefore, it can be of interest for pharmaceutical industries as a high-throughput BBB penetration oriented screening method. Finally, it offered interesting insights into the molecular mechanism actually involved in the BBB permeation of drugs.

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

    PubMed

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

    2015-09-01

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

  4. Partition search

    SciTech Connect

    Ginsberg, M.L.

    1996-12-31

    We introduce a new form of game search called partition search that incorporates dependency analysis, allowing substantial reductions in the portion of the tree that needs to be expanded. Both theoretical results and experimental data are presented. For the game of bridge, partition search provides approximately as much of an improvement over existing methods as {alpha}-{beta} pruning provides over minimax.

  5. Partition Equilibrium

    NASA Astrophysics Data System (ADS)

    Feldman, Michal; Tennenholtz, Moshe

    We introduce partition equilibrium and study its existence in resource selection games (RSG). In partition equilibrium the agents are partitioned into coalitions, and only deviations by the prescribed coalitions are considered. This is in difference to the classical concept of strong equilibrium according to which any subset of the agents may deviate. In resource selection games, each agent selects a resource from a set of resources, and its payoff is an increasing (or non-decreasing) function of the number of agents selecting its resource. While it has been shown that strong equilibrium exists in resource selection games, these games do not possess super-strong equilibrium, in which a fruitful deviation benefits at least one deviator without hurting any other deviator, even in the case of two identical resources with increasing cost functions. Similarly, strong equilibrium does not exist for that restricted two identical resources setting when the game is played repeatedly. We prove that for any given partition there exists a super-strong equilibrium for resource selection games of identical resources with increasing cost functions; we also show similar existence results for a variety of other classes of resource selection games. For the case of repeated games we identify partitions that guarantee the existence of strong equilibrium. Together, our work introduces a natural concept, which turns out to lead to positive and applicable results in one of the basic domains studied in the literature.

  6. "Lego" chemistry for the straightforward synthesis of dendrimers.

    PubMed

    Maraval, Valérie; Pyzowski, Jaroslaw; Caminade, Anne-Marie; Majoral, Jean-Pierre

    2003-07-25

    A new straightforward method of synthesis of dendrimers, using two branched monomers (CA(2) and DB(2)), is described. Each generation is obtained in a single quantitative step, with only N(2) or H(2)O as byproducts; generation 4 is obtained in only four steps. The end groups are alternatively phosphines and hydrazines; their versatile reactivity is illustrated by the reaction of generation 4 with a branched CD(5) monomer, which increases the number of end groups in a single step from 48 to 250.

  7. Blood-brain barrier delivery.

    PubMed

    Pardridge, William M

    2007-01-01

    Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the blood-brain barrier (BBB). Essentially 100% of large-molecule drugs and >98% of small-molecule drugs do not cross the BBB. The BBB can be traversed because there are multiple endogenous transporters within this barrier. Therefore, brain drug development programs of the future need to be re-configured so that drugs are formulated to enable transport into the brain via endogenous BBB transporters.

  8. Revisiting the seemingly straightforward hydrogen cyanide/hydrogen isocyanide isomerisation

    NASA Astrophysics Data System (ADS)

    Gutiérrez-Oliva, Soledad; Díaz, Silvia; Toro-Labbé, Alejandro; Lane, Pat; Murray, Jane S.; Politzer, Peter

    2014-02-01

    Both HCN and HNC are prominent in the interstellar medium and may have significant roles in prebiotic chemistry. Considerable attention has, therefore, been accorded to the HCN ↔ CNH isomerisation, sometimes viewed as a prototypical unimolecular process. However, detailed analysis of the potential energy of the HCN/CNH system along its intrinsic reaction coordinate, in terms of the first and second derivatives of the energy, shows that this is not a straightforward proton transfer. It appears to involve two distinct transition regions, one in which the C-H bond breaks and the other in which the N-H forms. Between these regions is a transitory state, with all vibrational frequencies being real, in which the hydrogen is situated above the C-N bond and not directly associated with either the carbon or the nitrogen. In this state, the vibrational modes of the hydrogen are, respectively, approximately parallel and perpendicular to the C-N bond.

  9. A Straightforward Method to Determine Equilibrium Constants from Spectrophotometric Data

    NASA Astrophysics Data System (ADS)

    Keszei, E.; Takács, M. G.; Vizkeleti, B.

    2000-07-01

    Spectrophotometry provides reliable information on the equilibrium concentration in chemically reacting mixtures. However, the widely used traditional linearized models to determine the equilibrium constant from spectrophotometric data do not provide optimal information and unnecessarily complicate data evaluation for students. In this paper we show an easy and straightforward inference method, which makes use only of Beer's Law and an elementary mathematical treatment of the problem. Though the resulting parameter estimation is nonlinear with respect to the equilibrium constant, the commercial availability of many nonlinear parameter estimation software packages eliminates the need for the student to bother with either mathematical or numerical details. Adding a suitable spectral shape function to the model describing equilibrium further facilitates the use of the proposed method and makes it an easy task to determine the components' spectra from equilibrium measurements. Three practical examples are treated in detail in the online version. They illustrate how the method works at different complexity levels and are easy to install in undergraduate physical chemistry labs.

  10. Assessing blood-brain barrier function using in vitro assays.

    PubMed

    Bressler, Joseph; Clark, Katherine; O'Driscoll, Cliona

    2013-01-01

    The impermeability of the blood-brain barrier (BBB) is due to a number of properties including tight junctions on adjoining endothelial cells, absence of pinocytic vesicles, and expression of multidrug transporters. Although the permeability of many chemicals can be predicted by their polarity, or oil/water partition coefficient, many lipophilic chemicals are not permeable because of multidrug transporters at the luminal and abluminal membranes. In contrast, many nutrients, which are usually polar, cross the BBB more readily than predicted by their oil/water partition coefficients due to the expression of specific nutrient transporters. In vitro models are being developed because rodent models are of low input and relatively expensive. Isolated brain microvessels and cell culture models each offers certain advantages and disadvantages. Isolated brain microvessels are useful in measuring multidrug drug transporters and tight junction integrity, whereas cell culture models allow the investigator to measure directional transport and can be genetically manipulated. In this chapter, we describe how to isolate large batches of brain microvessels from freshly slaughtered cows. The different steps in the isolation procedure include density gradient centrifugations and filtering. Purity is determined microscopically and by marker enzymes. Permeability is assessed by measuring the uptake of fluorescein-labeled dextran in an assay that has been optimized to have a large dynamic range and low inter-day variability. We also describe how to evaluate transendothelial cell electrical resistance and paracellular transport in cell culture models.

  11. ABC transporters and the blood-brain barrier.

    PubMed

    Begley, David J

    2004-01-01

    The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier to the free diffusion of many polar solutes into the brain. Many metabolites that are polar have their brain entry facilitated by specific inwardly-directed transport mechanisms. In general the more lipid soluble a molecule or drug is, the more readily it will tend to partition into brain tissue. However, a very significant number of lipid soluble molecules, among them many useful therapeutic drugs have lower brain permeability than would be predicted from a determination of their lipid solubility. These molecules are substrates for the ABC efflux transporters which are present in the BBB and BCSB and the activity of these transporters very efficiently removes the drug from the CNS, thus limiting brain uptake. P-glycoprotein (Pgp) was the first of these ABC transporters to be described, followed by the multidrug resistance-associated proteins (MRP) and more recently breast cancer resistance protein (BCRP). All are expressed in the BBB and BCSFB and combine to reduce the brain penetration of many drugs. This phenomenon of "multidrug resistance" is a major hurdle when it comes to the delivery of therapeutics to the brain, not to mention the problem of cancer chemotherapy in general. Therefore, the development of strategies for bypassing the influence of these ABC transporters and for the design of effective drugs that are not substrates and the development of inhibitors for the ABC transporters becomes a high imperative for the pharmaceutical industry.

  12. Dissecting gene expression at the blood-brain barrier

    PubMed Central

    Huntley, Melanie A.; Bien-Ly, Nga; Daneman, Richard; Watts, Ryan J.

    2014-01-01

    The availability of genome-wide expression data for the blood-brain barrier is an invaluable resource that has recently enabled the discovery of several genes and pathways involved in the development and maintenance of the blood-brain barrier, particularly in rodent models. The broad distribution of published data sets represents a viable starting point for the molecular dissection of the blood-brain barrier and will further direct the discovery of novel mechanisms of blood-brain barrier formation and function. Technical advances in purifying brain endothelial cells, the key cell that forms the critical barrier, have allowed for greater specificity in gene expression comparisons with other central nervous system cell types, and more systematic characterizations of the molecular composition of the blood-brain barrier. Nevertheless, our understanding of how the blood-brain barrier changes during aging and disease is underrepresented. Blood-brain barrier data sets from a wider range of experimental paradigms and species, including invertebrates and primates, would be invaluable for investigating the function and evolution of the blood-brain barrier. Newer technologies in gene expression profiling, such as RNA-sequencing, now allow for finer resolution of transcriptomic changes, including isoform specificity and RNA-editing. As our field continues to utilize more advanced expression profiling in its ongoing efforts to elucidate the blood-brain barrier, including in disease and drug delivery, we will continue to see rapid advances in our understanding of the molecular mediators of barrier biology. We predict that the recently published data sets, combined with forthcoming genomic and proteomic blood-brain barrier data sets, will continue to fuel the molecular genetic revolution of blood-brain barrier biology. PMID:25414634

  13. Plasmid Partition Mechanisms.

    PubMed

    Baxter, Jamie C; Funnell, Barbara E

    2014-12-01

    The stable maintenance of low-copy-number plasmids in bacteria is actively driven by partition mechanisms that are responsible for the positioning of plasmids inside the cell. Partition systems are ubiquitous in the microbial world and are encoded by many bacterial chromosomes as well as plasmids. These systems, although different in sequence and mechanism, typically consist of two proteins and a DNA partition site, or prokaryotic centromere, on the plasmid or chromosome. One protein binds site-specifically to the centromere to form a partition complex, and the other protein uses the energy of nucleotide binding and hydrolysis to transport the plasmid, via interactions with this partition complex inside the cell. For plasmids, this minimal cassette is sufficient to direct proper segregation in bacterial cells. There has been significant progress in the last several years in our understanding of partition mechanisms. Two general areas that have developed are (i) the structural biology of partition proteins and their interactions with DNA and (ii) the action and dynamics of the partition ATPases that drive the process. In addition, systems that use tubulin-like GTPases to partition plasmids have recently been identified. In this chapter, we concentrate on these recent developments and the molecular details of plasmid partition mechanisms.

  14. Blood-brain barrier and energy balance.

    PubMed

    Banks, William A

    2006-08-01

    The blood-brain barrier (BBB) plays a critical role in the transduction of signals between the central nervous system and peripheral tissues. It does so through several mechanisms, including the direct transport of peptides and regulatory proteins such as insulin and leptin. Another mechanism that may be important is the secretion by brain endothelial cells of substances that affect feeding, such as proinflammatory cytokines and NO. We have recently shown that the BBB is capable of receiving an input from one side and secreting a substance into the other. Additionally, BBB secretions can be modulated by substances that affect feeding, such as adiponectin and lipopolysaccharide.

  15. The blood-brain barrier in psychoneuroimmunology.

    PubMed

    Banks, William A

    2009-05-01

    The term ''psychoneuroimmunology'' connotes separate compartments that interact. The blood-brain barrier (BBB) is both the dividing line, physical and physiologic, between the immune system and the central nervous system (CNS) and the locale for interaction. The BBB restricts unregulated mixing of immune substances in the blood with those in the CNS, directly transports neuroimmune-active substances between the blood and CNS, and itself secretes neuroimmune substances. These normal functions of the BBB can be altered by neuroimmune events. As such, the BBB is an important conduit in the communication between the immune system and the CNS.

  16. Permeability of the blood-brain barrier to a rhenacarborane.

    PubMed

    Hawkins, Patrick M; Jelliss, Paul A; Nonaka, Naoko; Shi, Xiaoming; Banks, William A

    2009-05-01

    The treatment of brain malignancies with boron neutron capture therapy depends on their ability to cross the blood-brain barrier (BBB). An especially promising class of boron-containing compounds is the rhenacarboranes that, if able to cross the BBB, could act as delivery vehicles as well as a source of boron. Here, we examined the ability of the 3-NO-3,3-kappa(2)-(2,2'-N(2)C(10)H(6)(Me)[(CH(2))(7)(131)I]-4,4')-closo-3,1,2-ReC(2)B(9)H(11) (rhenacarborane) labeled with iodine-131 to be taken up into the bloodstream after subcutaneous administration and to cross the BBB. The (131)I-rhenacarborane was quickly absorbed from the injection site and reached a steady state in arterial serum of 2.59%/ml of the administered dose. Between 73 and 95% of the radioactivity in serum 6 h after administration represented intact (131)I-rhenacarborane. Its octanol/buffer partition coefficient was 1.74, showing it to be lipophilic. Tissue/serum ratios for brain, lung, and liver showed classic patterns for a lipid-soluble substance with high levels immediately achieved and rapid redistribution. For brain, a steady state of approximately 0.107% of the administered dose/gram-brain was rapidly reached, and 71% of the radioactivity in brain 6 h after subcutaneous administration represented intact (131)I-rhenacarborane. Steady-state values were 1.53 and 0.89% of the injected dose per gram for lung and liver, respectively. (131)I-Rhenacarborane was quickly effluxed from brain by a nonsaturable system after its injection into the lateral ventricle of the brain. In conclusion, these results show that a rhenacarborane was enzymatically resistant and able to cross the BBB by transmembrane diffusion and accumulate in brain in substantial amounts. This supports their use as therapeutic agents for targeting the central nervous system.

  17. When Is Straightforwardness a Liability in Negotiations? The Role of Integrative Potential and Structural Power

    ERIC Educational Resources Information Center

    DeRue, D. Scott; Conlon, Donald E.; Moon, Henry; Willaby, Harold W.

    2009-01-01

    Negotiations present individuals with a paradox. On the one hand, individuals are expected via social norms and formal regulations to be honest and straightforward in their negotiations. On the other hand, individuals who mislead their negotiation counterpart are often rewarded with more favorable settlements. The authors investigate this paradox…

  18. Monitoring Human Development Goals: A Straightforward (Bayesian) Methodology for Cross-National Indices

    ERIC Educational Resources Information Center

    Abayomi, Kobi; Pizarro, Gonzalo

    2013-01-01

    We offer a straightforward framework for measurement of progress, across many dimensions, using cross-national social indices, which we classify as linear combinations of multivariate country level data onto a univariate score. We suggest a Bayesian approach which yields probabilistic (confidence type) intervals for the point estimates of country…

  19. AIDS and the blood-brain barrier

    PubMed Central

    Ivey, Nathan S.; MacLean, Andrew G.; Lackner, Andrew A.

    2009-01-01

    The blood-brain barrier (BBB) plays a critical role in normal physiology of the central nervous system by regulating what reaches the brain from the periphery. The BBB also plays a major role in neurologic disease including neuropathologic sequelae associated with infection by human immunodeficiency virus (HIV) in humans and the closely related simian immunodeficiency virus (SIV) in macaques. In this review, we provide an overview of the function, structure and components of the BBB, followed by a more detailed discussion of the subcellular structures and regulation of the tight junction. We then discuss the ways in which HIV/SIV affects the BBB, largely through infection of monocytes/macrophages, and how infected macrophages crossing the BBB ultimately results in breakdown of the barrier. PMID:19306229

  20. Blood-brain barrier permeability imaging using perfusion computed tomography

    PubMed Central

    Avsenik, Jernej; Bisdas, Sotirios; Popovic, Katarina Surlan

    2015-01-01

    Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases. Conclusions. Blood-brain barrier permeability can be evaluated in vivo by perfusion computed tomography - an efficient diagnostic method that involves the sequential acquisition of tomographic images during the intravenous administration of iodinated contrast material. The major clinical applications of perfusion computed tomography are in acute stroke and in brain tumor imaging. PMID:26029020

  1. Netrin 1 regulates blood-brain barrier function and neuroinflammation.

    PubMed

    Podjaski, Cornelia; Alvarez, Jorge I; Bourbonniere, Lyne; Larouche, Sandra; Terouz, Simone; Bin, Jenea M; Lécuyer, Marc-André; Saint-Laurent, Olivia; Larochelle, Catherine; Darlington, Peter J; Arbour, Nathalie; Antel, Jack P; Kennedy, Timothy E; Prat, Alexandre

    2015-06-01

    Blood-brain barrier function is driven by the influence of astrocyte-secreted factors. During neuroinflammatory responses the blood-brain barrier is compromised resulting in central nervous system damage and exacerbated pathology. Here, we identified endothelial netrin 1 induction as a vascular response to astrocyte-derived sonic hedgehog that promotes autocrine barrier properties during homeostasis and increases with inflammation. Netrin 1 supports blood-brain barrier integrity by upregulating endothelial junctional protein expression, while netrin 1 knockout mice display disorganized tight junction protein expression and barrier breakdown. Upon inflammatory conditions, blood-brain barrier endothelial cells significantly upregulated netrin 1 levels in vitro and in situ, which prevented junctional breach and endothelial cell activation. Finally, netrin 1 treatment during experimental autoimmune encephalomyelitis significantly reduced blood-brain barrier disruption and decreased clinical and pathological indices of disease severity. Our results demonstrate that netrin 1 is an important regulator of blood-brain barrier maintenance that protects the central nervous system against inflammatory conditions such as multiple sclerosis and experimental autoimmune encephalomyelitis.

  2. Controlling ferrofluid permeability across the blood-brain barrier model

    NASA Astrophysics Data System (ADS)

    Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J.

    2014-02-01

    In the present study, an in vitro blood-brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood-brain barrier model was completed by examining the permeability of FITC-Dextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood-brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood-brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood-brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood-brain barrier (e.g. CPB).

  3. The blood-brain barrier: an engineering perspective

    PubMed Central

    Wong, Andrew D.; Ye, Mao; Levy, Amanda F.; Rothstein, Jeffrey D.; Bergles, Dwight E.; Searson, Peter C.

    2013-01-01

    It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore, advances in our understanding of the structure and function of the blood-brain barrier are key to developing effective treatments for a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases. PMID:24009582

  4. Design and straightforward synthesis of novel galloyl phytosterols with excellent antioxidant activity.

    PubMed

    Fu, Yuanqing; Zhang, Yan; Hu, Huiying; Chen, Ying; Wang, Rong; Li, Duo; Liu, Songbai

    2014-11-15

    Novel galloyl phytosterols were rationally designed by incorporation of gallic acid into phytosterols through straightforward esterification. The esterification was successfully achieved by coupling of gallic acid and phytosterols through a mild chemical Steglich esterification reaction that is more straightforward than the enzymatic method. The identity of the newly synthesized galloyl phytosterols was confirmed by NMR, HPLC-MS and IR spectroscopies. Further evaluation of the novel galloyl phytosterols with radical scavenging, ferrous ion chelating, and Rancimat methods revealed its excellent antioxidant activities that are comparable to the most potent fat-soluble antioxidants. This novel antioxidant offers an intriguing solution for naturally derived antioxidants and will have great potential application as antioxidant in food industry. The methods developed in this study will be valuable for development of other phenolic phytosterols.

  5. More reasons to be straightforward: findings and norms for two scales relevant to social anxiety.

    PubMed

    Rodebaugh, Thomas L; Heimberg, Richard G; Brown, Patrick J; Fernandez, Katya C; Blanco, Carlos; Schneier, Franklin R; Liebowitz, Michael R

    2011-06-01

    The validity of both the Social Interaction Anxiety Scale and Brief Fear of Negative Evaluation scale has been well-supported, yet the scales have a small number of reverse-scored items that may detract from the validity of their total scores. The current study investigates two characteristics of participants that may be associated with compromised validity of these items: higher age and lower levels of education. In community and clinical samples, the validity of each scale's reverse-scored items was moderated by age, years of education, or both. The straightforward items did not show this pattern. To encourage the use of the straightforward items of these scales, we provide normative data from the same samples as well as two large student samples. We contend that although response bias can be a substantial problem, the reverse-scored questions of these scales do not solve that problem and instead decrease overall validity.

  6. Quantitative comparison between the straight-forward and anatomical insertion technique for pedicle screw placement

    NASA Astrophysics Data System (ADS)

    Knez, Dejan; Mohar, Janez; Likar, Boštjan; Pernuš, Franjo; Vrtovec, Tomaž

    2016-03-01

    Spinal deformity correction with vertebral fixation is nowadays the preferred surgical treatment, where pedicle screws are inserted through pedicles into corresponding vertebral bodies and afterwards connected with rods. In clinical practice, the straight-forward and anatomical insertion technique are currently being used for pedicle screw placement surgery. However, it is difficult to quantitatively compare both techniques and determine which technique is more adequate for each planned pedicle screw before surgery (i.e. preoperatively). In this paper, we therefore describe a framework for quantitative comparison between the straight-forward and anatomical insertion technique for pedicle screw placement surgery by evaluating the screw fastening strength. Quantitative comparisons were performed on computed tomography images of 11 patients with 74 manually planned pedicle screws, who underwent the vertebral fixation procedure. The first quantitative comparison was performed between the straight-forward and anatomical pedicle screw insertion technique, which resulted in a relatively high agreement with mean absolute difference of 0.0mm in screw diameter, 2.9mm in screw length, 1.2mm in pedicle crossing point and 6.5° in screw inclinations. The second quantitative comparison was performed between the best resulting pedicle screw insertion technique and manually obtained pedicle screw plans, which again resulted in a relatively high agreement with mean absolute difference of 0.5mm in screw diameter, 4.7mm in screw length, 2.4mm in pedicle crossing point and 6.0° in screw inclinations. Both the straight-forward and anatomical insertion technique proved approximately equal in terms of the screw fastening strength.

  7. Peptides and the blood-brain barrier.

    PubMed

    Banks, William A

    2015-10-01

    The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational molecules, informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiological changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaption goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system.

  8. Prolactin and blood-brain barrier permeability.

    PubMed

    Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Hamilton, W Ryan; Ramirez-Lee, Manuel A; Ali, Syed F; Gonzalez, Carmen

    2013-11-01

    The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins.

  9. Hormones and the blood-brain barrier.

    PubMed

    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.

  10. Partitioning Breaks Communities

    NASA Astrophysics Data System (ADS)

    Reid, Fergal; McDaid, Aaron; Hurley, Neil

    Considering a clique as a conservative definition of community structure, we examine how graph partitioning algorithms interact with cliques. Many popular community-finding algorithms partition the entire graph into non-overlapping communities. We show that on a wide range of empirical networks, from different domains, significant numbers of cliques are split across the separate partitions produced by these algorithms. We then examine the largest connected component of the subgraph formed by retaining only edges in cliques, and apply partitioning strategies that explicitly minimise the number of cliques split. We further examine several modern overlapping community finding algorithms, in terms of the interaction between cliques and the communities they find, and in terms of the global overlap of the sets of communities they find. We conclude that, due to the connectedness of many networks, any community finding algorithm that produces partitions must fail to find at least some significant structures. Moreover, contrary to traditional intuition, in some empirical networks, strong ties and cliques frequently do cross community boundaries; much community structure is fundamentally overlapping and unpartitionable in nature.

  11. Iron Partitioning in Ferropericlase

    NASA Astrophysics Data System (ADS)

    Braithwaite, J. W. H.; Stixrude, L. P.; Pinilla, C.; Holmstrom, E.

    2015-12-01

    Ferropericlase, (Mg,Fe)O, is the second most abundant mineral in the Earth's lower mantle. Whether iron favours the liquid or solid phase of (Mg,Fe)O has important implications for the Earth's mantle, both chemically and dynamically. As iron is much heavier than magnesium, the partitioning of iron between liquid and solid will lead to a contrast in densities. This difference in density will lead one phase to be more buoyant than the other and would help, in part, to explain how the mantle crystallised from the magma ocean of the Hadean eon to its current state. The partitioning of iron between the two phases is characterized by partition coefficients. Using ab-initio methods, thermodynamic integration and adiabatic switching these coefficients have been determined. Results are presented for pressures encompassing the region between the upper mantle and the core-mantle boundary (10-140GPa).

  12. FNAS phase partitions

    NASA Technical Reports Server (NTRS)

    Vanalstine, James M.

    1993-01-01

    Project NAS8-36955 D.O. #100 initially involved the following tasks: (1) evaluation of various coatings' ability to control wall wetting and surface zeta potential expression; (2) testing various methods to mix and control the demixing of phase systems; and (3) videomicroscopic investigation of cell partition. Three complementary areas were identified for modification and extension of the original contract. They were: (1) identification of new supports for column cell partition; (2) electrokinetic detection of protein adsorption; and (3) emulsion studies related to bioseparations.

  13. A straightforward ninhydrin-based method for collagenase activity and inhibitor screening of collagenase using spectrophotometry.

    PubMed

    Zhang, Yanfang; Fu, Yun; Zhou, Sufeng; Kang, Lixia; Li, Changzheng

    2013-06-01

    Currently protease assay kits, requiring substrate that is either radiolabeled or fluorescence labeled and specialized instruments, are all expensive. A simple, reliable assay of protease activity and its inhibitor screening for general laboratory is rare. Here we demonstrated a straightforward ninhydrin-based method for assay of collagenase activity and its inhibitor screening using spectrophotometry. In the method, without multistep sample treatments and substrate labeling, the hydrolytic products were directly traced by ninhydrin. The method is expected to be suitable for not only the assay of collagenase activity but also the others matrix metalloproteinases activities, and can be used for kinetic study.

  14. Human blood-brain barrier insulin receptor.

    PubMed

    Pardridge, W M; Eisenberg, J; Yang, J

    1985-06-01

    A new model system for characterizing the human brain capillary, which makes up the blood-brain barrier (BBB) in vivo, is described in these studies and is applied initially to the investigation of the human BBB insulin receptor. Autopsy brains were obtained from the pathologist between 22-36 h postmortem and were used to isolate human brain microvessels which appeared intact on both light and phase microscopy. The microvessels were positive for human factor 8 and for a BBB-specific enzyme marker, gamma-glutamyl transpeptidase. The microvessels avidly bound insulin with a high-affinity dissociation constant, KD = 1.2 +/- 0.5 nM. The human brain microvessels internalized insulin based on acid-wash assay, and 75% of insulin was internalized at 37 degrees C. The microvessels transported insulin to the medium at 37 degrees C with a t1/2 = approximately 70 min. Little of the 125I-insulin was metabolized by the microvessels under these conditions based on the elution profile of the medium extract over a Sephadex G-50 column. Plasma membranes were obtained from the human brain microvessels and these membranes were enriched in membrane markers such as gamma-glutamyl transpeptidase or alkaline phosphatase. The plasma membranes bound 125I-insulin with and ED50 = 10 ng/ml, which was identical to the 50% binding point in intact microvessels. The human BBB plasma membranes were solubilized in Triton X-100 and were adsorbed to a wheat germ agglutinin Sepharose affinity column, indicating the BBB insulin receptor is a glycoprotein. Affinity cross-linking of insulin to the plasma membranes revealed a 127K protein that specifically binds insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery.

    PubMed

    Banks, William A

    2016-04-01

    One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood-brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

  16. Straightforward production of encoded microbeads by Flow Focusing: potential applications for biomolecule detection.

    PubMed

    Gañán-Calvo, A M; Martín-Banderas, L; González-Prieto, R; Rodríguez-Gil, A; Berdún-Alvarez, T; Cebolla, A; Chávez, S; Flores-Mosquera, M

    2006-10-31

    Fluorescently encoded polymeric microparticles are acquiring great importance in the development of simultaneous multianalyte screening assays. We have developed a very versatile and straightforward method for the production of dye-labeled microparticles with a very reproducible size distribution and freely-chosen and discernible fluorescent properties. Our method combines Flow Focusing technology with a solvent evaporation/extraction procedure in a single step, yielding spherical, non-aggregate and non-porous particles. We have designed a multi-coloured bead array which includes the possibility of modifying the surface properties of the microparticles, which offer excellent properties for covalent attachment of biomolecules such as peptides, oligonucleotides, proteins, etc. We also show the potential of the fluorescently labeled microspheres for the detection of biomolecule (peptides and oligonucelotides) interactions using flow cytometry.

  17. A simple and straightforward expression for curling probe electron density diagnosis in reactive plasmas

    NASA Astrophysics Data System (ADS)

    Arshadi, Ali; Brinkmann, Ralf Peter; Hotta, Masaya; Nakamura, Keiji

    2017-04-01

    Active plasma resonance spectroscopy (APRS) refers to the family of plasma diagnostic methods which utilize the ability of plasmas to resonate at frequencies close to the plasma frequency. APRS operates by exciting the plasma with a weak RF signal by means of a small electric probe. The response of the plasma is recorded by a network analyzer (NA). A mathematical model is applied to derive characteristics like the electron density and the electron temperature. The curling probe is a promising realization of APRS. The curling probe is well-qualified for the local measurement of the electron density in reactive plasmas. This spiral probe resonates in plasma at a larger density dependent frequency than the plasma frequency. This manuscript represents a simple and straightforward expression relating this resonance frequency to the electron density of the plasma. A good agreement is observed between the proposed expression and the results obtained from previous studies and numerical simulations.

  18. Straightforward and robust synthesis of monodisperse surface-functionalized gold nanoclusters

    PubMed Central

    Varela-Aramburu, Silvia; Wirth, Richard; Lai, Chian-Hui; Orts-Gil, Guillermo

    2016-01-01

    Summary Gold nanoclusters are small (1–3 nm) nanoparticles with a high surface area that are useful for biomedical studies and drug delivery. The synthesis of small, surface-functionalized gold nanoclusters is greatly dependent on the reaction conditions. Here, we describe a straightforward, efficient and robust room temperature one-pot synthesis of 2 nm gold nanoclusters using thioglucose as a reducing and stabilizing agent, which was discovered by serendipity. The resultant monodisperse gold nanoclusters are more stable than those generated using some other common methods. The carboxylic acid contained in the stabilizing agent on the cluster surface serves as anchor for nanocluster functionalization. Alternatively, the addition of thiols serves to functionalize the nanoclusters. The resulting non-cytotoxic nanoclusters are taken up by cells and constitute a tuneable platform for biomedical applications including drug delivery. PMID:27826501

  19. The blood-brain barrier and methamphetamine: open sesame?

    PubMed Central

    Turowski, Patric; Kenny, Bridget-Ann

    2015-01-01

    The chemical and electrical microenvironment of neurons within the central nervous system is protected and segregated from the circulation by the vascular blood–brain barrier. This barrier operates on the level of endothelial cells and includes regulatory crosstalk with neighboring pericytes, astrocytes, and neurons. Within this neurovascular unit, the endothelial cells form a formidable, highly regulated barrier through the presence of inter-endothelial tight junctions, the absence of fenestrations, and the almost complete absence of fluid-phase transcytosis. The potent psychostimulant drug methamphetamine transiently opens the vascular blood–brain barrier through either or both the modulation of inter-endothelial junctions and the induction of fluid-phase transcytosis. Direct action of methamphetamine on the vascular endothelium induces acute opening of the blood-brain barrier. In addition, striatal effects of methamphetamine and resultant neuroinflammatory signaling can indirectly lead to chronic dysfunction of the blood-brain barrier. Breakdown of the blood-brain barrier may exacerbate the neuronal damage that occurs during methamphetamine abuse. However, this process also constitutes a rare example of agonist-induced breakdown of the blood-brain barrier and the adjunctive use of methamphetamine may present an opportunity to enhance delivery of chemotherapeutic agents to the underlying neural tissue. PMID:25999807

  20. Extraction of quasi-straightforward-propagating photons from diffused light transmitting through a scattering medium by polarization modulation

    NASA Astrophysics Data System (ADS)

    Horinaka, Hiromichi; Hashimoto, Koji; Wada, Kenji; Cho, Yoshio; Osawa, Masahiko

    1995-07-01

    The utilization of light polarization is proposed to extract quasi-straightforward-propagating photons from diffused light transmitting through a scattering medium under continuously operating conditions. Removal of a floor level normally appearing on the dynamic range over which the extraction capability is maintained is demonstrated. By use of pulse-based observations this cw scheme of extraction of quasi-straightforward-propagating photons is directly shown to be equivalent to the use of a temporal gate in the pulse-based operation.

  1. Investigation of straightforward impedance eduction in the presence of shear flow

    NASA Astrophysics Data System (ADS)

    Jing, Xiaodong; Peng, Sen; Wang, Lixun; Sun, Xiaofeng

    2015-01-01

    A straightforward impedance eduction method is proposed which combines Prony's method with the Pridmore-Brown equation to obtain the impedance of acoustic liners in the presence of shear flow. Particular attention is paid to the reported inconsistency problems associated with the boundary layer effect in the development of impedance eduction techniques. A kind of flow-insensitive acoustic liner is considered which is placed in a rectangular flow duct containing predominant grazing incidence mode. Three slip or no-slip flow profiles are examined, which are the parabola, the one-seventh power law and the uniform core flow with linear boundary layer. A shear-flow FEM model is also set up to simulate the duct acoustic field. The present impedance eduction method has been tested and validated using both the simulated and the published measured data. It is shown that, despite of their distinct boundary layers, the selected flow profiles lead to essentially the same impedance results. And also, for the impedance eduction the strict consideration of no-slip shear flow is very consistent with the use of the Ingard-Myers' boundary condition with the uniform flow assumption over the test conditions. Although not susceptible to the exact shape of flow profile, the impedance eduction critically depends on the determination of the cross-sectional average Mach number. The usual practice of approximately representing the duct flow with the midspan profile results in a slight overestimation of the average Mach number in the two-dimensional acoustic models, and thus can considerably affect the accuracy of the impedance eduction. To solve this problem, the average flow profile is introduced to account for the actual three-dimensional flow non-uniformity in the rectangular duct. It is further found that the effective Mach number, corresponding to a slightly modified average flow profile, can be used to achieve a considerable collapse of the impedance spectra educed at different Mach

  2. A simple, straightforward correlative live-cell-imaging-structured-illumination-microscopy approach for studying organelle dynamics.

    PubMed

    Sherman, Shachar; Nachmias, Dikla; Elia, Natalie

    2015-09-01

    Most cellular organelles are highly dynamic and continuously undergo membrane fission and fusion to mediate their function. Documenting organelle dynamics under physiological conditions, therefore, requires high temporal resolution of the recording system. Concurrently, these structures are relatively small and determining their substructural organization is often impossible using conventional microscopy. Structured Illumination Microscopy (SIM) is a super resolution technique providing a two-fold increase in resolution. Importantly, SIM is versatile because it allows the use of any fluorescent dye or protein and, hence, is highly applicable for cell biology. However, similar to other SR techniques, the applicability of SIM to high-speed live cell imaging is limited. Here we present an easy, straightforward methodology for coupling of high-speed live cell recordings, using spinning disk (SD) microscopy, with SIM. Using this simple methodology, we are able to track individual mitochondrial membrane fission and fusion events in real time and to determine the network connectivity and substructural organization of the membrane at high resolution. Applying this methodology to other cellular organelles such as, ER, golgi, and cilia will no doubt contribute to our understanding of membrane dynamics in cells.

  3. Straightforward approach to graft bioactive polysaccharides onto polyurethane surfaces using an ionic liquid

    NASA Astrophysics Data System (ADS)

    Bigot, Sandra; Louarn, Guy; Kébir, Nasreddine; Burel, Fabrice

    2014-09-01

    Surface properties directly affect the performance of a material in a biological environment. In this study, the goal was to develop a simple procedure allowing the grafting of antibacterial polysaccharides onto biomedical grade polyurethanes (e.g. Tecothane®). Thus, a straightforward chemical pathway involving an isothiocyanate-alcohol reaction in an ionic liquid (IL) was developed. PU isothiocyanted surfaces (PU-NCS) were first prepared by reacting p-phenylene diisothiocyanate with the surface urethane groups. Then, unmodified bioactive seaweed polysaccharides were directly grafted onto the surface, in mild conditions. The selected IL, i.e. 1-ethyl-3-methyl imidazolium phosphate, was of particular interest since this liquid worked as solvent for p-phenylene diisothiocyanate and the polysaccharides and as catalyst for the grafting reactions. Successful grafting of the different polysaccharides was attested by changes in the surface functional groups, using X-ray photoelectron spectroscopy (XPS). Atomic force microscopy (AFM) showed that polysaccharide grafting, slightly increased the surface roughness from 1.9 to more than 7 nm. Contact angle with water decreased from 88° (for native PU) to around 75° after polysaccharide grafting, attesting a more hydrophilic surface. This procedure would be transposed to the grafting onto PU surfaces of any macromolecule of interest bearing hydroxyl, thiol or amine groups.

  4. Chemical amplification based on fluid partitioning

    DOEpatents

    Anderson, Brian L.; Colston, Jr., Billy W.; Elkin, Chris

    2006-05-09

    A system for nucleic acid amplification of a sample comprises partitioning the sample into partitioned sections and performing PCR on the partitioned sections of the sample. Another embodiment of the invention provides a system for nucleic acid amplification and detection of a sample comprising partitioning the sample into partitioned sections, performing PCR on the partitioned sections of the sample, and detecting and analyzing the partitioned sections of the sample.

  5. Adrenomedullin and the blood-brain barrier.

    PubMed

    Kastin, A J; Akerstrom, V; Hackler, L; Pan, W

    2001-01-01

    Adrenomedullin (ADM) is present both in the periphery and brain. In addition to its peripheral effects, this peptide can exert central effects such as decreasing food ingestion. We used multiple-time regression analysis to determine that labeled ADM can cross from blood to brain with an apparent influx constant (K(I)) of 5.83 +/- 1.44 x 10(-4) ml/g-min, much faster than that of albumin, the vascular control. HPLC showed that almost all of the injected 125I-ADM in the brain was intact, and capillary depletion showed that it could reach the parenchyma of the brain. However, more 125I-ADM was reversibly associated with the brain vasculature than we have seen with any other peptide tested by these methods. After intracerebroventricular injection, 125I-ADM exited the brain with the bulk reabsorption of cerebrospinal fluid at an efflux rate comparable to that of albumin. Although there was no blood-to-brain saturation, in situ brain perfusion of 125I-ADM in blood-free physiological buffer showed self-inhibition by excess unlabeled ADM. This, along with evidence of the lack of protein binding shown by capillary zone electrophoresis, indicated competition for the binding site of ADM at the BBB. The low lipophilicity of ADM determined by the octanol/buffer partition coefficient was also consistent with the prominent reversible association of ADM with the vasculature of the BBB. This suggests a function for ADM at the cerebral blood vessels, such as altering cerebral blood flow and perfusion, without disruption of the BBB.

  6. Partitioning the Quaternary

    NASA Astrophysics Data System (ADS)

    Gibbard, Philip L.; Lewin, John

    2016-11-01

    We review the historical purposes and procedures for stratigraphical division and naming within the Quaternary, and summarize the current requirements for formal partitioning through the International Commission on Stratigraphy (ICS). A raft of new data and evidence has impacted traditional approaches: quasi-continuous records from ocean sediments and ice cores, new numerical dating techniques, and alternative macro-models, such as those provided through Sequence Stratigraphy and Earth-System Science. The practical usefulness of division remains, but there is now greater appreciation of complex Quaternary detail and the modelling of time continua, the latter also extending into the future. There are problems both of commission (what is done, but could be done better) and of omission (what gets left out) in partitioning the Quaternary. These include the challenge set by the use of unconformities as stage boundaries, how to deal with multiphase records in ocean and terrestrial sediments, what happened at the 'Early-Mid- (Middle) Pleistocene Transition', dealing with trends that cross phase boundaries, and the current controversial focus on how to subdivide the Holocene and formally define an 'Anthropocene'.

  7. Mathematical modelling of blood-brain barrier failure and edema

    NASA Astrophysics Data System (ADS)

    Waters, Sarah; Lang, Georgina; Vella, Dominic; Goriely, Alain

    2015-11-01

    Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic edema. Although the initial injury may be localised, the resulting edema causes mechanical damage and compression of the vasculature beyond the original injury site. We employ a biphasic mixture model to investigate the consequences of blood-brain barrier permeability changes within a region of brain tissue and the onset of vasogenic edema. We find that such localised changes can indeed result in brain tissue swelling and that the type of damage that results (stress damage or strain damage) depends on the ability of the brain to clear edema fluid.

  8. Folate nutrition and blood-brain barrier dysfunction.

    PubMed

    Stover, Patrick J; Durga, Jane; Field, Martha S

    2017-04-01

    Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.

  9. Straightforward inference of ancestry and admixture proportions through ancestry-informative insertion deletion multiplexing.

    PubMed

    Pereira, Rui; Phillips, Christopher; Pinto, Nádia; Santos, Carla; dos Santos, Sidney Emanuel Batista; Amorim, António; Carracedo, Ángel; Gusmão, Leonor

    2012-01-01

    Ancestry-informative markers (AIMs) show high allele frequency divergence between different ancestral or geographically distant populations. These genetic markers are especially useful in inferring the likely ancestral origin of an individual or estimating the apportionment of ancestry components in admixed individuals or populations. The study of AIMs is of great interest in clinical genetics research, particularly to detect and correct for population substructure effects in case-control association studies, but also in population and forensic genetics studies. This work presents a set of 46 ancestry-informative insertion deletion polymorphisms selected to efficiently measure population admixture proportions of four different origins (African, European, East Asian and Native American). All markers are analyzed in short fragments (under 230 basepairs) through a single PCR followed by capillary electrophoresis (CE) allowing a very simple one tube PCR-to-CE approach. HGDP-CEPH diversity panel samples from the four groups, together with Oceanians, were genotyped to evaluate the efficiency of the assay in clustering populations from different continental origins and to establish reference databases. In addition, other populations from diverse geographic origins were tested using the HGDP-CEPH samples as reference data. The results revealed that the AIM-INDEL set developed is highly efficient at inferring the ancestry of individuals and provides good estimates of ancestry proportions at the population level. In conclusion, we have optimized the multiplexed genotyping of 46 AIM-INDELs in a simple and informative assay, enabling a more straightforward alternative to the commonly available AIM-SNP typing methods dependent on complex, multi-step protocols or implementation of large-scale genotyping technologies.

  10. Maternal antibodies and developing blood-brain barrier.

    PubMed

    Kowal, Czeslawa; Athanassiou, Andrew; Chen, Huiyi; Diamond, Betty

    2015-12-01

    We briefly review the protective role of maternal antibodies during fetal development and at early postnatal stages. We describe antibody delivery to fetuses, particularly in the context of the developing blood-brain barrier (BBB), and present the essential concepts regarding the adult BBB, together with existing information on the prenatal developing BBB. We focus on maternal antibody transfer to the developing brain and the consequences of the presence of pathogenic antibodies at early stages of brain development on subsequent brain dysfunction.

  11. Regulation of ABC Transporters at the Blood-Brain Barrier

    PubMed Central

    Miller, David S.

    2015-01-01

    ATP Binding Cassette (ABC) transporters at the blood-brain barrier function as ATP-driven xenobiotic efflux pumps and limit delivery of small molecule drugs to the brain. Here I review recent progress in understanding the regulation of the expression and transport activity of these transporters and comment on how this new information might aid in improving drug delivery to the brain. PMID:25670036

  12. Blood-brain barrier: an impediment to neuropharmaceuticals.

    PubMed

    Henderson, J T; Piquette-Miller, M

    2015-04-01

    The blood-brain barrier (BBB) serves as a highly selective barrier separating the central nervous system from the systemic circulation. Although contributing to neurological health, the BBB restricts the ability of drugs to reach their site of action and thus presents a major challenge to the treatment of neurological disorders. Advances in our understanding of the complexity of the BBB have fostered development of novel pharmacometric models and drug delivery strategies to better predict and improve therapeutic access.

  13. Establishment and Dysfunction of the Blood-Brain Barrier

    PubMed Central

    Zhao, Zhen; Nelson, Amy R.; Betsholtz, Christer; Zlokovic, Berislav V.

    2015-01-01

    Structural and functional brain connectivity, synaptic activity and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit and intact blood-brain barrier (BBB) functions. Here, we examine the mechanisms regulating the formation and maintenance of the BBB and functions of BBB-associated cell types. Furthermore, we discuss the growing evidence associating BBB breakdown with the pathogenesis of inherited monogenic neurological disorders and complex multifactorial diseases including Alzheimer’s disease. PMID:26590417

  14. Partition Density Functional Theory

    NASA Astrophysics Data System (ADS)

    Wasserman, Adam

    2012-02-01

    Partition Density Functional Theory (PDFT) is a formally exact method for obtaining molecular properties from self-consistent calculations on isolated fragments [1,2]. For a given choice of fragmentation, PDFT outputs the (in principle exact) molecular energy and density, as well as fragment densities that sum to the correct molecular density. I describe our progress understanding the behavior of the fragment energies as a function of fragment occupations, derivative discontinuities, practical implementation, and applications of PDFT to small molecules. I also discuss implications for ground-state Density Functional Theory, such as the promise of PDFT to circumvent the delocalization error of approximate density functionals. [4pt] [1] M.H. Cohen and A. Wasserman, J. Phys. Chem. A, 111, 2229(2007).[0pt] [2] P. Elliott, K. Burke, M.H. Cohen, and A. Wasserman, Phys. Rev. A 82, 024501 (2010).

  15. Partitioning: splitting fact from fiction.

    PubMed

    Pike, Brian

    2012-05-01

    Many larger hospitals are sprawling complexes with endless corridors and rooms of varying purpose. While cleanliness and infection control are, understandably, leading considerations in any hospital building, fire safety also plays a crucial role. Here Brian Pike MBE, technical consultant at partitioning system designer and manufacturer, Komfort Workspace, looks at how current fire guidelines impact on the use of partitioning systems in hospital premises.

  16. Brain Distribution of Cediranib Is Limited by Active Efflux at the Blood-Brain Barrier

    PubMed Central

    Wang, Tianli; Agarwal, Sagar

    2012-01-01

    Cediranib is an orally active tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor family. Because of its potent antiangiogenic and antitumor activities, cediranib has been evaluated for therapy in glioma, a primary brain tumor. This study investigated the influence of two important efflux transporters at the blood-brain barrier, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), on the delivery of cediranib to the central nervous system. In vitro studies indicated that cediranib is a dual substrate for both P-gp and Bcrp. It is noteworthy that in spite of the in vitro data the in vivo mouse disposition studies conclusively showed that P-gp was the dominant transporter restricting the brain distribution of cediranib. The brain-to-plasma partitioning (AUCbrain/AUCplasma, where AUC is area under the curve) and the steady-state brain-to-plasma concentration ratio of cediranib were approximately 20-fold higher in Mdr1a/b(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice compared with wild-type and Bcrp1(−/−) mice. Moreover, there was no significant difference in brain distribution of cediranib between wild-type and Bcrp1(−/−) mice and between Mdr1a/b(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice. These results show that, unlike other tyrosine kinase inhibitors that are dual substrates for P-gp and Bcrp, Bcrp does not restrict the distribution of cediranib across the blood-brain barrier. We also show that inhibition of P-gp using specific or nonspecific inhibitors resulted in significantly enhanced delivery of cediranib to the brain. Concurrent administration of cediranib with chemical modulators of efflux transporters can be used as a strategy to enhance delivery and thus efficacy of cediranib in the brain. These findings are clinically relevant to the efficacy of cediranib chemotherapy in glioma. PMID:22323823

  17. Measurement of phosphorothioate oligodeoxynucleotide antisense transport across the blood-brain barrier.

    PubMed

    Banks, William A

    2011-01-01

    Phosphorothioate oligodeoxynucleotides (PODNs) can act as antisense molecules, knocking down proteins. Many PODNs have the unusual characteristic of being transported across the blood-brain barrier by a saturable system. This means that PODNs injected intravenously can accumulate in the central nervous system in quantities sufficient to knock down proteins in brain and the blood-brain barrier. A critical step in the development of PODNs that can be administered peripherally and knockdown proteins in the central nervous system is to determine the relation to the blood-brain barrier, specifically, does the PODN cross the blood-brain barrier and, if so, how fast and to what degree.

  18. An Efficient and Straightforward Method for Radiolabeling of Nanoparticles with {sup 64}Cu via Click Chemistry

    SciTech Connect

    Lee, Dong-Eun; Kim, Kwangmeyung; Park, Sang Hyun

    2015-07-01

    Recently, nanoparticles have received a great deal of interest in diagnosis and therapy applications. Since nanoparticles possess intrinsic features that are often required for a drug delivery system and diagnosis, they have potential to be used as platforms for integrating imaging and therapeutic functions, simultaneously. Intrinsic issues that are associated with theranostic nanoparticles, particularly in cancer treatment, include an efficient and straightforward radiolabeling method for understanding the in vivo biodistribution of nanoparticles to reach the tumor region, and monitoring therapeutic responses. Herein, we investigated a facile and highly efficient strategy to prepare radiolabeled nanoparticles with {sup 64}Cu via a strain-promoted azide, i.e., an alkyne cycloaddition strategy, which is often referred to as click chemistry. First, the azide (N3) group, which allows for the preparation of radiolabeled nanoparticles by copper-free click chemistry, was incorporated into glycol chitosan nanoparticles (CNPs). Second, the strained cyclooctyne derivative, dibenzyl cyclooctyne (DBCO) conjugated with a 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA) chelator, was synthesized for preparing the pre-radiolabeled alkyne complex with {sup 64}Cu radionuclide. Following incubation with the {sup 64}Cu-radiolabeled DBCO complex (DBCO-PEG4-Lys-DOTA-{sup 64}Cu with high specific activity, 18.5 GBq/μ mol), the azide-functionalized CNPs were radiolabeled successfully with {sup 64}Cu, with a high radiolabeling efficiency and a high radiolabeling yield (>98%). Importantly, the radiolabeling of CNPs by copper-free click chemistry was accomplished within 30 min, with great efficiency in aqueous conditions. After {sup 64}Cu-CNPs were intravenously administered to tumor-bearing mice, the real time, in vivo biodistribution and tumor-targeting ability of {sup 64}Cu-CNPs were quantitatively evaluated by micro-PET images of tumor-bearing mice. These results

  19. A straightforward three-component synthesis of alpha-amino esters containing a phenylalanine or a phenylglycine scaffold.

    PubMed

    Haurena, Caroline; Le Gall, Erwan; Sengmany, Stéphane; Martens, Thierry; Troupel, Michel

    2010-04-16

    A range of alpha-amino esters has been synthesized in good to high yields using a straightforward three-component reaction among preformed or in situ generated aromatic or benzylic organozinc reagents, primary or secondary amines, and ethyl glyoxylate. The procedure, which is characterized by its simplicity, allows the concise synthesis of esters bearing a phenylglycine or a phenylalanine scaffold.

  20. Prediction of partition coefficients of organic compounds between SPME/PDMS and aqueous solution.

    PubMed

    Chao, Keh-Ping; Lu, Yu-Ting; Yang, Hsiu-Wen

    2014-02-14

    Polydimethylsiloxane (PDMS) is commonly used as the coated polymer in the solid phase microextraction (SPME) technique. In this study, the partition coefficients of organic compounds between SPME/PDMS and the aqueous solution were compiled from the literature sources. The correlation analysis for partition coefficients was conducted to interpret the effect of their physicochemical properties and descriptors on the partitioning process. The PDMS-water partition coefficients were significantly correlated to the polarizability of organic compounds (r = 0.977, p < 0.05). An empirical model, consisting of the polarizability, the molecular connectivity index, and an indicator variable, was developed to appropriately predict the partition coefficients of 61 organic compounds for the training set. The predictive ability of the empirical model was demonstrated by using it on a test set of 26 chemicals not included in the training set. The empirical model, applying the straightforward calculated molecular descriptors, for estimating the PDMS-water partition coefficient will contribute to the practical applications of the SPME technique.

  1. Communicating Science: A Necessary Journey that is Neither Straightforward or Unobstructed

    NASA Astrophysics Data System (ADS)

    Socci, A.

    2008-12-01

    language to conjure up a desired mental 'frame' or perception (i.e., death tax vs. estate tax; enhanced interrogation techniques vs. torture). We have also come to learn that people do not necessarily make decisions borne out of economic self-interest. Consequently, communication would appear to be a more involved and less-than-straightforward process than perhaps many had assumed, particularly those vested in the culture of science. The circumstances described above suggest the following ways of effectively protecting and communicating science in the media and the general public: 1. Broader understanding and adoption of journalistic objectivity as a process for testing and validating information/facts. 2. Journalism's survival requires a new model based on service, not on achieving ever-higher profits secured by emptying newsrooms and with it, the capacity to gather and test information. 3. Encourage specialized training in addition to journalism. 4. Consider alternative career pathways in communication. 5. Unlike news, informing demands knowledge and scholarship which are inconsistent with tight news deadlines and 24/7 news cycles. 6. Institutions of science have a critical but largely unfulfilled role to play in fostering communication as a necessary element of an advanced degree in science. 7. Communication has long and deep research roots especially in the fields of psychology, linguistics, sociology and journalism; any training in communication should include cross-offerings among these disciplines. 8. It is often said that one gets the kind of [governance, media, communication, politics etc..] that one deserve. If so, then perhaps it is time to deserve better.

  2. Partitioning ecosystems for sustainability.

    PubMed

    Murray, Martyn G

    2016-03-01

    Decline in the abundance of renewable natural resources (RNRs) coupled with increasing demands of an expanding human population will greatly intensify competition for Earth's natural resources during this century, yet curiously, analytical approaches to the management of productive ecosystems (ecological theory of wildlife harvesting, tragedy of the commons, green economics, and bioeconomics) give only peripheral attention to the driving influence of competition on resource exploitation. Here, I apply resource competition theory (RCT) to the exploitation of RNRs and derive four general policies in support of their sustainable and equitable use: (1) regulate resource extraction technology to avoid damage to the resource base; (2) increase efficiency of resource use and reduce waste at every step in the resource supply chain and distribution network; (3) partition ecosystems with the harvesting niche as the basic organizing principle for sustainable management of natural resources by multiple users; and (4) increase negative feedback between consumer and resource to bring about long-term sustainable use. A simple policy framework demonstrates how RCT integrates with other elements of sustainability science to better manage productive ecosystems. Several problem areas of RNR management are discussed in the light of RCT, including tragedy of the commons, overharvesting, resource collapse, bycatch, single species quotas, and simplification of ecosystems.

  3. Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier

    SciTech Connect

    Pardridge, W.M.; Triguero, D.; Yang, J.; Cancilla, P.A. )

    1990-05-01

    Drug and solute transport through in vitro and in vivo models of the blood-brain barrier (BBB) were compared to provide a measure of how well the in vitro model predicted BBB permeability found in vivo. The in vitro model employed bovine brain capillary endothelial cells in either primary tissue culture or as a continuous line grown on Transwells and placed in side-by-side diffusion chambers. The in vivo model of BBB transport utilized an internal carotid artery perfusion/capillary depletion method in anesthetized rats. BBB permeability in vivo and in vitro was measured for 15 radiolabeled drugs and for L-(3H)dopa, D-(14C)glucose and (3H)albumin. (3H)- or (14C)sucrose was used in vivo as a blood volume reference. Lipid solubility of each drug was measured based on the 1-octanol/Ringer's partition coefficient. The morphology of the endothelial cell in primary tissue culture was spindle-shaped and the morphology of the endothelial cell in continuous culture was cuboid-shaped. The cuboidal morphology demonstrated a 2-fold greater resistance to solute transport and was used for the majority of the in vitro studies. Drug and solute permeability coefficients (Pe) ranged from 3.9 X 10(-3) to 2.5 X 10(-1) cm/min in vitro and from 1.0 X 10(-5) to 2.1 X 10(-2) cm/min in vivo. The In of the permeability.surface area product in vitro correlated with the In partition coefficient (r = 0.62, P less than .0125) and the In permeability.surface area product in vivo correlated with the In partition coefficient (r = 0.84, P less than .0005).

  4. Mad Tea Party Cyclic Partitions

    ERIC Educational Resources Information Center

    Bekes, Robert; Pedersen, Jean; Shao, Bin

    2012-01-01

    Martin Gardner's "The Annotated Alice," and Robin Wilson's "Lewis Carroll in Numberland" led the authors to put this article in a fantasy setting. Alice, the March Hare, the Hatter, and the Dormouse describe a straightforward, elementary algorithm for counting the number of ways to fit "n" identical objects into "k" cups arranged in a circle. The…

  5. Striatal blood-brain barrier permeability in Parkinson's disease.

    PubMed

    Gray, Madison T; Woulfe, John M

    2015-05-01

    In vivo studies have shown that blood-brain barrier (BBB) dysfunction is involved in the course of Parkinson's disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde trans-synaptic hypothesis of PD spread.

  6. Anatomy and physiology of the blood-brain barrier.

    PubMed

    Serlin, Yonatan; Shelef, Ilan; Knyazer, Boris; Friedman, Alon

    2015-02-01

    Essential requisite for the preservation of normal brain activity is to maintain a narrow and stable homeostatic control in the neuronal environment of the CNS. Blood flow alterations and altered vessel permeability are considered key determinants in the pathophysiology of brain injuries. We will review the present-day literature on the anatomy, development and physiological mechanisms of the blood-brain barrier, a distinctive and tightly regulated interface between the CNS and the peripheral circulation, playing a crucial role in the maintenance of the strict environment required for normal brain function.

  7. Anatomy and Physiology of the Blood-Brain Barrier

    PubMed Central

    Serlin, Yonatan; Shelef, Ilan; Knyazer, Boris; Friedman, Alon

    2015-01-01

    Essential requisite for the preservation of normal brain activity is to maintain a narrow and stable homeostatic control in the neuronal environment of the CNS. Blood flow alterations and altered vessel permeability are considered key determinants in the pathophysiology of brain injuries. We will review the present-day literature on the anatomy, development and physiological mechanisms of the blood-brain barrier, a distinctive and tightly regulated interface between the CNS and the peripheral circulation, playing a crucial role in the maintenance of the strict environment required for normal brain function. PMID:25681530

  8. Synthesis and alkylation activity of a nitrogen mustard agent to penetrate the blood-brain barrier.

    PubMed

    Bartzatt, Ronald L

    2004-01-01

    Nitrogen mustard agents are widely used for the clinical treatment of cancers. A nitrogen mustard (N-mustard) agent was synthesized utilizing nicotinic acid as the carrier of the alkylating substituent (-OCH2CH2N(CH2CH2Cl)2) that forms an ester group (R-C(O)-OR) on a heterocyclic ring. The N-mustard agent is a solid at room temperature and is stable for more than 6 weeks when stored at -10 degrees C. To determine the kinetics of alkylation activity a nucleophilic primary amine compound (4-chloroaniline) was placed in aqueous solution with the mustard agent at physiological pH 7.4 (pH of blood) and 37 degrees C. The alkylation reaction was found to be second-order with rate equation: rate = k2[N-mustard][Nu], where Nu = nucleophile and k2 = 0.0415 L/(mol x min). Pharmacological descriptors calculated showed values indicating a strong potential of penetrating the blood-brain barrier. The partition coefficient (Log P) of the mustard agent is 1.95 compared with 0.58 for nicotinic acid. Values of descriptors such as dipole, polar surface area, Log BB, molar refractivity, parachor, and violations of Rule of 5 were found to be 5.057 Debye, 42.44 A2, 0.662, 72.7 cm3, 607.7 cm3, and 0.0 for the N-mustard agent. Value of polar surface area for the mustard agent (42.44 A2) predicts that >90% of any amount present in the intestinal tract will be absorbed.

  9. Selective Tsuji-Trost type C-allylation of hydrazones: a straightforward entry into 4,5-dihydropyrazoles.

    PubMed

    El Mamouni, El Hachemia; Cattoen, Martin; Cordier, Marie; Cossy, Janine; Arseniyadis, Stellios; Ilitki, Hocine; El Kaïm, Laurent

    2016-12-13

    The 4,5-dihydropyrazole motif has drawn considerable attention over the years as it was shown to exhibit a plethora of biological and pharmacological properties, including anticancer, antibacterial, antifungal, antiviral, and anti-inflammatory properties. As such, it has been the target of a number of methods and drug discovery programs. We report here a straightforward and highly selective approach featuring a key palladium-catalysed Tsuji-Trost type C-allylation and subsequent intramolecular 1,4-addition of hydrazones.

  10. Harnessing the Electrophilicity of Keteniminium Ions: A Simple and Straightforward Entry to Tetrahydropyridines and Piperidines from Ynamides

    PubMed Central

    Lecomte, Morgan

    2016-01-01

    Abstract An efficient, modular and straightforward entry to tetrahydropyridines and piperidines is reported. This reaction is based on a formal intramolecular hydroalkylation of readily available, properly substituted ynamides which, upon simple activation under acidic conditions, generate highly reactive activated keteniminium ions whose reactivity can be finely controlled to induce a remarkably efficient [1,5]‐hydride shift from unactivated C−H bonds and trigger a cationic cyclization which is complete within minutes. PMID:26934474

  11. A four-component reaction involving in situ generated organometallic reagents: straightforward access to β-amino esters.

    PubMed

    Le Gall, Erwan; Léonel, Eric

    2013-04-22

    Four in one: A straightforward synthesis of β(2,3)-amino esters is described through a new zinc-mediated, cobalt-catalyzed four-component reaction between organic bromides, alkyl acrylates, amines, and aldehydes (see scheme). Synthesis involves a Mannich-related conjugate addition/aza-aldol domino sequence, allowing the formation of three single bonds in one step. A reaction mechanism, emphasizing the crucial role of zinc salts, is described.

  12. Blood-brain interfaces and bilirubin-induced neurological diseases.

    PubMed

    Ghersi-Egea, J F; Gazzin, S; Strazielle, N

    2009-01-01

    The endothelium of the brain microvessels and the choroid plexus epithelium form highly specialized cellular barriers referred to as blood-brain interfaces through which molecular exchanges take place between the blood and the neuropil or the cerebrospinal fluid, respectively. Within the brain, the ependyma and the pia-glia limitans modulate exchanges between the neuropil and the cerebrospinal fluid. All these interfaces are key elements of neuroprotection and fulfill trophic functions; both properties are critical to harmonious brain development and maturation. By analogy to hepatic bilirubin detoxification pathways, we review the transport and metabolic mechanisms which in all these interfaces may participate in the regulation of bilirubin cerebral bioavailability in physiologic conditions, both in adult and in developing brain. We specifically address the role of ABC and OATP transporters, glutathione-S-transferases, and the potential involvement of glucuronoconjugation and oxidative metabolic pathways. Regulatory mechanisms are explored which are involved in the induction of these pathways and represent potential pharmacological targets to prevent bilirubin accumulation into the brain. We then review the possible alteration of the neuroprotective and trophic barrier functions in the course of bilirubin-induced neurological dysfunctions resulting from hyperbilirubinemia. Finally, we highlight the role of the blood-brain and blood-CSF barriers in regulating the brain biodisposition of candidate drugs for the treatment or prevention of bilirubin-induced brain injury.

  13. Penetration of the blood-brain barrier by the antiviral drug (E)-5-(2-iodovinyl)-2'-deoxyuridine in a rat model of herpes encephalitis.

    PubMed

    Klapper, P E; Cleator, G M; Bruce, J M; Longson, M

    1988-07-01

    The blood-brain barrier penetration of a radiohalogenated (125I) derivative of the antiviral drug (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU) was investigated in a rat model of herpes encephalitis. CNS delivery was assessed by external gamma camera scintigraphic imaging in vivo, a technique which may have general application in evaluating brain specific delivery of drugs, and by autoradiography of cryostat sections of rat brain. Radiohalogenated IVDU was found to be almost totally excluded from the CNS. These findings may be explained in terms of the poor lipid solubility of IVDU (in vitro oil/aqueous salt solution partition coefficient 0.012). Since IVDU appears in CSF after carotid artery administration, our results stress the necessity, in the design of compounds for the treatment of CNS infections, of distinguishing blood-brain, blood-CSF, and CSF-brain drug barriers. The significance of our data both in relation to the development of neuro-radiological diagnosis and antiviral chemotherapy of CNS infection is discussed.

  14. The blood-brain barrier after stroke: Structural studies and the role of transcytotic vesicles.

    PubMed

    Haley, Michael J; Lawrence, Catherine B

    2017-02-01

    Blood-brain barrier breakdown worsens ischaemic damage, but it is unclear how molecules breach the blood-brain barrier in vivo. Using the obese ob/ob mouse as a model of enhanced blood-brain barrier breakdown, we investigated how stroke-induced structural changes to the microvasculature related to blood-brain barrier permeability. Ob/ob mice underwent middle cerebral artery occlusion, followed by 4 or 24 h reperfusion. Blood-brain barrier integrity was assessed using IgG and horseradish peroxidase staining, and blood-brain barrier structure by two-dimensional and three-dimensional electron microscopy. At 4 and 24 h post-stroke, ob/ob mice had increased ischaemic damage and blood-brain barrier breakdown compared to ob/- controls, and vessels from both genotypes showed astrocyte end-foot swelling and increased endothelial vesicles. Ob/ob mice had significantly more endothelial vesicles at 4 h in the striatum, where blood-brain barrier breakdown was most severe. Both stroke and genotype had no effect on tight junction structure visualised by electron microscopy, or protein expression in isolated microvessels. Astrocyte swelling severity did not correlate with tissue outcome, being unaffected by genotype or reperfusion times. However, the rare instances of vessel lumen collapse were always associated with severe astrocyte swelling in two-dimensional and three-dimensional electron microscopy. Endothelial vesicles were therefore the best spatial and temporal indicators of blood-brain barrier breakdown after cerebral ischaemia.

  15. Temporal Partitioning on Multicore Platform

    NASA Astrophysics Data System (ADS)

    Mahmud Pathan, Ristat; Hashi, Feysal; Stenstrom, Per; Green, Lars-Goran; Hult, Torbjorn; Sandin, Patrik

    2014-08-01

    This paper addresses the problem of ensuring temporal partitioning according to the ARINC-653 standard for integrating multiple applications on the same multicore platform. To employ temporal partitioning, we propose the design and analysis of a hierarchical scheduling framework (HSF) for multicore platform. In HSF, each application has a server task, which is mapped to one of the physical cores of the multicore platform. The HSF framework is based on scheduling at two-levels: (i) a system-level scheduler for each core schedules the server tasks that are mapped to that core, and (ii) a task- level scheduler for each application schedules the tasks of the application. This paper presents the design and analysis of this two-level HSF that can be used to ensure temporal partitioning and meeting all the deadlines of each application tasks. The effectiveness of our technique is demonstrated using real-world space applications provided by RUAG Space Sweden AB.

  16. A straightforward strategy toward large BN-embedded π-systems: synthesis, structure, and optoelectronic properties of extended BN heterosuperbenzenes.

    PubMed

    Wang, Xiao-Ye; Zhuang, Fang-Dong; Wang, Rui-Bo; Wang, Xin-Chang; Cao, Xiao-Yu; Wang, Jie-Yu; Pei, Jian

    2014-03-12

    A straightforward strategy has been used to construct large BN-embedded π-systems simply from azaacenes. BN heterosuperbenzene derivatives, the largest BN heteroaromatics to date, have been synthesized in three steps. The molecules exhibit curved π-surfaces, showing two different conformations which are self-organized into a sandwich structure and further packed into a π-stacking column. The assembled microribbons exhibit good charge transport properties and photoconductivity, representing an important step toward the optoelectronic applications of BN-embedded aromatics.

  17. Optical imaging to map blood-brain barrier leakage

    NASA Astrophysics Data System (ADS)

    Jaffer, Hayder; Adjei, Isaac M.; Labhasetwar, Vinod

    2013-11-01

    Vascular leakage in the brain is a major complication associated with brain injuries and certain pathological conditions due to disruption of the blood-brain barrier (BBB). We have developed an optical imaging method, based on excitation and emission spectra of Evans Blue dye, that is >1000-fold more sensitive than conventional ultraviolet spectrophotometry. We used a rat thromboembolic stroke model to validate the usefulness of our method for vascular leakage. Optical imaging data show that vascular leakage varies in different areas of the post-stroke brain and that administering tissue plasminogen activator causes further leakage. The new method is quantitative, simple to use, requires no tissue processing, and can map the degree of vascular leakage in different brain locations. The high sensitivity of our method could potentially provide new opportunities to study BBB leakage in different pathological conditions and to test the efficacy of various therapeutic strategies to protect the BBB.

  18. Extracellular vesicles of the blood-brain barrier

    PubMed Central

    András, Ibolya E; Toborek, Michal

    2016-01-01

    Extracellular vesicles (ECV), like exosomes, gained recently a lot of attention as potentially playing a significant role in neurodegenerative diseases, particularly in Aβ pathology. While there are a lot of reports on ECV/exosomes derived from a variety of cell types, there is limited information on ECV/exosomes originated from brain microvascular endothelial cells forming the blood-brain barrier (BBB). In this review, we summarize the literature data on brain endothelial ECV/exosomes and present our own data on BBB-derived ECV and their possible involvement in the brain's Aβ pathology. We propose that ECV/exosome release from brain endothelial cells associated with Aβ affects different cells of the neurovascular unit and may be an important contributor to the Aβ deposition in the central nervous system. PMID:27141419

  19. Models for predicting blood-brain barrier permeation.

    PubMed

    Nielsen, Peter Aadal; Andersson, Olga; Hansen, Steen Honoré; Simonsen, Klaus Bæk; Andersson, Gunnar

    2011-06-01

    The endothelial blood-brain barrier (BBB) ensures an optimal environment for proper neural function in vertebrates; however, it also creates a major obstacle for the medical treatment of brain diseases. Despite significant progress in the development of various in vitro and in silico models for predicting BBB permeation, many challenges remain and, so far, no model is able to meet the early drug discovery demands of the industry for reliability and time and cost efficiency. Recently, it was found that the grasshopper (Locusta migratoria) brain barrier has similar functionality as the vertebrate BBB. The insect model can thus be used as a surrogate for the vertebrate BBB as it meets the demands required during the drug discovery phase.

  20. The molecular constituents of the blood-brain barrier

    PubMed Central

    Chow, Brian Wai; Gu, Chenghua

    2015-01-01

    The blood-brain barrier (BBB) maintains the optimal microenvironment in the central nervous system (CNS) for proper brain function. The BBB is comprised of specialized CNS endothelial cells with fundamental molecular properties essential for the function and integrity of the BBB. The restrictive nature of the BBB hinders delivery of therapeutics for many neurological disorders. In addition, recent evidence shows that BBB dysfunction can precede or hasten the progression of several neurological diseases. Despite the physiological significance of the BBB in health and disease, major discoveries of the molecular regulators of BBB formation and function have only occurred recently. This review will highlight recent findings describing the molecular determinants and core cellular pathways that confer BBB properties upon CNS endothelial cells. PMID:26442694

  1. How Cryptococcus interacts with the blood-brain barrier.

    PubMed

    Tseng, Hsiang-Kuang; Huang, Tseng-Yu; Wu, Alice Ying-Jung; Chen, Hsin-Hong; Liu, Chang-Pan; Jong, Ambrose

    2015-01-01

    Cryptococcus demonstrates predilection for invasion of the brain, but the mechanism by which Cryptococcus crosses the blood-brain barrier (BBB) to cause brain invasion is largely unknown. In order for Cryptococcus to cross the BBB, there must be a way to either cross human brain microvascular endothelial cells, which are the main constitute of the BBB, or go in between tight junctions. Recent evidence of human brain microvascular endothelial cell responses to transcellular brain invasions includes membrane rearrangements, intracellular signaling pathways and cytoskeletal activations. Several Cryptococcal genes related to the traversal of BBB have been identified, including CPS1, ITR1a, ITR3c, PLB1, MPR1, FNX1 and RUB1. In addition, Cryptococcus neoformans-derived microvesicles may contribute to cryptococcal brain invasion. Paracellularly, Cryptococcus may traverse across BBB using either routes utilizing plasmin, ammonia or macrophages in a Trojan horse mechanism.

  2. Blood-brain barrier tight junction permeability and ischemic stroke.

    PubMed

    Sandoval, Karin E; Witt, Ken A

    2008-11-01

    The blood-brain barrier (BBB) is formed by the endothelial cells of cerebral microvessels, providing a dynamic interface between the peripheral circulation and the central nervous system. The tight junctions (TJs) between the endothelial cells serve to restrict blood-borne substances from entering the brain. Under ischemic stroke conditions decreased BBB TJ integrity results in increased paracellular permeability, directly contributing to cerebral vasogenic edema, hemorrhagic transformation, and increased mortality. This loss of TJ integrity occurs in a phasic manner, which is contingent on several interdependent mechanisms (ionic dysregulation, inflammation, oxidative and nitrosative stress, enzymatic activity, and angiogenesis). Understanding the inter-relation of these mechanisms is critical for the development of new therapies. This review focuses on those aspects of ischemic stroke impacting BBB TJ integrity and the principle regulatory pathways, respective to the phases of paracellular permeability.

  3. Circumventing the Blood-Brain Barrier with Autonomic Ganglion Transplants

    NASA Astrophysics Data System (ADS)

    Rosenstein, Jeffrey M.; Brightman, Milton W.

    1983-08-01

    Superior cervical ganglia, whose vessels are fenestrated and permeable to protein tracers such as horseradish peroxidase, were transplanted to undamaged surfaces in the fourth ventricle of rat pup brains. Horseradish peroxidase, infused systemically into the host, was exuded from the graft's vessels into the graft's extracellular stroma within 1 minute. At later times the glycoprotein reached the extracellular clefts of adjacent brain tissue, the vessels of which appeared to retain their impermeability. The blood-brain barrier to horseradish peroxide was thus bypassed where the extracellular compartments of graft and brain became confluent. The graft of autonomic ganglia can serve as a portal through which peptides, hormones, and immunoglobulins may likewise enter the brain.

  4. Generalised partition functions: inferences on phase space distributions

    NASA Astrophysics Data System (ADS)

    Treumann, Rudolf A.; Baumjohann, Wolfgang

    2016-06-01

    It is demonstrated that the statistical mechanical partition function can be used to construct various different forms of phase space distributions. This indicates that its structure is not restricted to the Gibbs-Boltzmann factor prescription which is based on counting statistics. With the widely used replacement of the Boltzmann factor by a generalised Lorentzian (also known as the q-deformed exponential function, where κ = 1/|q - 1|, with κ, q ∈ R) both the kappa-Bose and kappa-Fermi partition functions are obtained in quite a straightforward way, from which the conventional Bose and Fermi distributions follow for κ → ∞. For κ ≠ ∞ these are subject to the restrictions that they can be used only at temperatures far from zero. They thus, as shown earlier, have little value for quantum physics. This is reasonable, because physical κ systems imply strong correlations which are absent at zero temperature where apart from stochastics all dynamical interactions are frozen. In the classical large temperature limit one obtains physically reasonable κ distributions which depend on energy respectively momentum as well as on chemical potential. Looking for other functional dependencies, we examine Bessel functions whether they can be used for obtaining valid distributions. Again and for the same reason, no Fermi and Bose distributions exist in the low temperature limit. However, a classical Bessel-Boltzmann distribution can be constructed which is a Bessel-modified Lorentzian distribution. Whether it makes any physical sense remains an open question. This is not investigated here. The choice of Bessel functions is motivated solely by their convergence properties and not by reference to any physical demands. This result suggests that the Gibbs-Boltzmann partition function is fundamental not only to Gibbs-Boltzmann but also to a large class of generalised Lorentzian distributions as well as to the corresponding nonextensive statistical mechanics.

  5. Understanding Partitive Division of Fractions.

    ERIC Educational Resources Information Center

    Ott, Jack M.; And Others

    1991-01-01

    Concrete experience should be a first step in the development of new abstract concepts and their symbolization. Presents concrete activities based on Hyde and Nelson's work with egg cartons and Steiner's work with money to develop students' understanding of partitive division when using fractions. (MDH)

  6. METAL PARTITIONING IN COMBUSTION PROCESSES

    EPA Science Inventory

    This article summarizes ongoing research efforts at the National Risk Management Research Laboratory of the U.S. Environmental Protection Agency examining [high temperature] metal behavior within combustion environments. The partitioning of non-volatile (Cr and Ni), semi-volatil...

  7. Brief version of the Fear of Negative Evaluation Scale - Straightforward Items (BFNE-S): psychometric properties in a Spanish population.

    PubMed

    Pitarch, María José Gallego

    2010-11-01

    The aim of this study was to examine the psychometric properties of the Brief version of the Fear of Negative Evaluation Scale - Straightforward Items (BFNE-S) in a non-clinical Spanish population. Rodebaugh et al. (2004) recommend the use of this scale composed of 8 straightforwardly-worded items, instead of the 12-item version of the BFNE. The sample consisted of 542 undergraduate students, 71.3% of whom were women and 28.7% were men; the mean age was 21.71 (4.78) years. Exploratory factor analysis produced one factor which accounted for 51.28% of variance. The internal consistency of the scale was alpha = .89. The BFNE-S correlated with the Social Avoidance and Distress Scale (r = .44), the Personal Report of Confidence as Speaker Modified (r = .44), the Public Speaking Self-Efficacy Questionnaire (r = -.38) and both subscales of the Self-Statements during Public Speaking (SSPS-P r = -.22; SSPS-N r = .53). ANOVAs revealed significant differences in the BFNE-S amongst a non-clinical population, persons suffering from specific social phobia, non-generalized social phobia and generalized social phobia.

  8. Effects of partitioning and scheduling sparse matrix factorization on communication and load balance

    NASA Technical Reports Server (NTRS)

    Venugopal, Sesh; Naik, Vijay K.

    1991-01-01

    A block based, automatic partitioning and scheduling methodology is presented for sparse matrix factorization on distributed memory systems. Using experimental results, this technique is analyzed for communication and load imbalance overhead. To study the performance effects, these overheads were compared with those obtained from a straightforward 'wrap mapped' column assignment scheme. All experimental results were obtained using test sparse matrices from the Harwell-Boeing data set. The results show that there is a communication and load balance tradeoff. The block based method results in lower communication cost whereas the wrap mapped scheme gives better load balance.

  9. The Drosophila blood-brain barrier as interface between neurons and hemolymph.

    PubMed

    Schirmeier, Stefanie; Klämbt, Christian

    2015-11-01

    The blood-brain barrier is an evolutionary ancient structure that provides direct support and protection of the nervous system. In all systems, it establishes a tight diffusion barrier that hinders uncontrolled paracellular diffusion into the nervous system. In invertebrates, the blood-brain barrier separates the nervous system from the hemolymph. Thus, the barrier-forming cells need to actively import ions and nutrients into the nervous system. In addition, metabolic or environmental signals from the external world have to be transmitted across the barrier into the nervous system. The first blood-brain barrier that formed during evolution was most likely based on glial cells. Invertebrates as well as primitive vertebrates still have a purely glial-based blood-brain barrier. Here we review the development and function of the barrier forming glial cells at the example of Drosophila.

  10. Quantitative analysis of nanoparticle transport through in vitro blood-brain barrier models

    PubMed Central

    Åberg, Christoffer

    2016-01-01

    ABSTRACT Nanoparticle transport through the blood-brain barrier has received much attention of late, both from the point of view of nano-enabled drug delivery, as well as due to concerns about unintended exposure of nanomaterials to humans and other organisms. In vitro models play a lead role in efforts to understand the extent of transport through the blood-brain barrier, but unique features of the nanoscale challenge their direct adaptation. Here we highlight some of the differences compared to molecular species when utilizing in vitro blood-brain barrier models for nanoparticle studies. Issues that may arise with transwell systems are discussed, together with some potential alternative methodologies. We also briefly review the biomolecular corona concept and its importance for how nanoparticles interact with the blood-brain barrier. We end with considering future directions, including indirect effects and application of shear and fluidics-technologies. PMID:27141425

  11. Targeting the brain--surmounting or bypassing the blood-brain barrier.

    PubMed

    Potschka, Heidrun

    2010-01-01

    The constituents of the blood-brain barrier, including its efflux transporter system, can efficiently limit brain penetration of potential CNS therapeutics. Effective extrusion from the brain by transporters is a frequent reason for the pharmaceutical industry to exclude novel compounds from further development for CNS therapeutics. Moreover, high transporter expression levels that are present in individual patients or may be generally associated with the pathophysiology seem to be a major cause of therapeutic failure in a variety of CNS diseases including brain tumors, epilepsy, brain HIV infection, and psychiatric disorders. Increasing knowledge of the structure and function of the blood-brain barrier creates a basis for the development of strategies which aim to enhance brain uptake of beneficial pharmaceutical compounds. The different strategies discussed in this review aim to modulate blood-brain barrier function or to bypass constituents of the blood-brain barrier.

  12. Some trees with partition dimension three

    NASA Astrophysics Data System (ADS)

    Fredlina, Ketut Queena; Baskoro, Edy Tri

    2016-02-01

    The concept of partition dimension of a graph was introduced by Chartrand, E. Salehi and P. Zhang (1998) [2]. Let G(V, E) be a connected graph. For S ⊆ V (G) and v ∈ V (G), define the distance d(v, S) from v to S is min{d(v, x)|x ∈ S}. Let Π be an ordered partition of V (G) and Π = {S1, S2, ..., Sk }. The representation r(v|Π) of vertex v with respect to Π is (d(v, S1), d(v, S2), ..., d(v, Sk)). If the representations of all vertices are distinct, then the partition Π is called a resolving partition of G. The partition dimension of G is the minimum k such that G has a resolving partition with k partition classes. In this paper, we characterize some classes of trees with partition dimension three, namely olive trees, weeds, and centipedes.

  13. Pharmacologic manipulation of lysosomal enzyme transport across the blood-brain barrier.

    PubMed

    Urayama, Akihiko; Grubb, Jeffrey H; Sly, William S; Banks, William A

    2016-03-01

    The adult blood-brain barrier, unlike the neonatal blood-brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, enzyme transport can be re-induced with alpha-adrenergics. Here, we examined agents that are known to alter the blood-brain barrier transport of large molecules or to induce lysosomal enzyme transport across the blood-brain barrier ((±)epinephrine, insulin, retinoic acid, and lipopolysaccharide) in 2-week-old and adult mice. In 2-week-old adolescent mice, all these pharmacologic agents increased brain and heart uptake of phosphorylated human β-glucuronidase. In 8-week-old adult mice, manipulations with (±)epinephrine, insulin, and retinoic acid were significantly effective on uptake by brain and heart. The increased uptake of phosphorylated human β-glucuronidase was inhibited by mannose 6-phosphate for the agents (±)epinephrine and retinoic acid and by L-NG-nitroarginine methyl ester for the agent lipopolysaccharide in neonatal and adult mice. An in situ brain perfusion study revealed that retinoic acid directly modulated the transport of phosphorylated human β-glucuronidase across the blood-brain barrier. The present study indicates that there are multiple opportunities to at least transiently induce phosphorylated human β-glucuronidase transport at the adult blood-brain barrier.

  14. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood-brain barrier.

    PubMed

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood-brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood-brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood-brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood-brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood-brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood-brain barrier, and deserve further investigation for a wide range of applications.

  15. Immortalized endothelial cell lines for in vitro blood-brain barrier models: A systematic review.

    PubMed

    Rahman, Nurul Adhwa; Rasil, Alifah Nur'ain Haji Mat; Meyding-Lamade, Uta; Craemer, Eva Maria; Diah, Suwarni; Tuah, Ani Afiqah; Muharram, Siti Hanna

    2016-07-01

    Endothelial cells play the most important role in construction of the blood-brain barrier. Many studies have opted to use commercially available, easily transfected or immortalized endothelial cell lines as in vitro blood-brain barrier models. Numerous endothelial cell lines are available, but we do not currently have strong evidence for which cell lines are optimal for establishment of such models. This review aimed to investigate the application of immortalized endothelial cell lines as in vitro blood-brain barrier models. The databases used for this review were PubMed, OVID MEDLINE, ProQuest, ScienceDirect, and SpringerLink. A narrative systematic review was conducted and identified 155 studies. As a result, 36 immortalized endothelial cell lines of human, mouse, rat, porcine and bovine origins were found for the establishment of in vitro blood-brain barrier and brain endothelium models. This review provides a summary of immortalized endothelial cell lines as a guideline for future studies and improvements in the establishment of in vitro blood-brain barrier models. It is important to establish a good and reproducible model that has the potential for multiple applications, in particular a model of such a complex compartment such as the blood-brain barrier.

  16. Synthesis of Functional Fluorescent BODIPY‐based Dyes through Electrophilic Aromatic Substitution: Straightforward Approach towards Customized Fluorescent Probes

    PubMed Central

    Schoenmakers, Daniël C.; Veranič, Peter; Muševič, Igor

    2016-01-01

    Abstract Fluorescent materials are widely used in biological and material applications as probes for imaging or sensing; however, their customization is usually complicated without the support of an organic chemistry laboratory. Here, we present a straightforward method for the customization of BODIPY cores, which are among the most commonly used fluorescent probes. The method is based on the formation of a new C−C bond through Friedel–Crafts electrophilic aromatic substitution carried out at room temperature. The method presented can be used to obtain completely customized fluorescent materials in one or two steps from commercially available compounds. Examples of the preparation of fluorescent materials for cell staining and functionalization of silica colloids are also presented. PMID:27777837

  17. 7-endo radical cyclizations catalyzed by titanocene(III). Straightforward synthesis of terpenoids with seven-membered carbocycles.

    PubMed

    Justicia, José; Oller-López, Juan L; Campaña, Araceli G; Oltra, J Enrique; Cuerva, Juan M; Buñuel, Elena; Cárdenas, Diego J

    2005-10-26

    We describe a novel procedure for the straightforward synthesis of seven-membered carbocycles via free-radical chemistry, based on titanocene(III)-catalyzed 7-endo-dig and 7-endo-trig cyclizations. This procedure has proved to be useful for the chemical preparation of terpenoids with different skeletons containing cycloheptane rings, including the first total syntheses of dauca-4(11),8-diene (2), barekoxide (3), authentic laukarlaol (81), and a valparane diterpenoid (72), as well as a substantially improved synthesis of karahanaenone (1). We also provide theoretical and experimental evidence in support of a plausible mechanism, which may rationalize the preference for the unusual 7-endo cyclization mode shown by radicals with substitution patterns characteristic of the linalyl, nerolidyl, and geranyl linalyl systems. In light of these chemical findings, we discuss the potential involvement of radical cyclizations in the biosynthesis of some terpenoids containing seven-membered carbocycles.

  18. Straightforward and rapid determination of sulfadoxine and sulfamethoxazole in capillary blood on sampling paper with liquid chromatography and UV detection.

    PubMed

    Lindkvist, J; Malm, M; Bergqvist, Y

    2009-04-01

    A method for the determination of sulfadoxine and sulfamethoxazole in capillary blood on sampling paper has been developed and validated. The method is straightforward with minimal sample preparation, and is suitable for rural settings. Separation of sulfadoxine, sulfamethoxazole and internal standard was performed using a Purospher STAR RP-18 endcapped LC column (150x4.6mm) with a mobile phase consisting of acetonitrile:sodium acetate buffer pH 5.2, I=0.1 (1:2, v/v). For sulfadoxine, the within-day precision was 5.3% at 15micromol/l and 3.7% at 600micromol/l, while for sulfamethoxazole it was 5.7% at 15micromol/l and 3.8% at 600micromol/l. The lower limit of quantification was determined to 5micromol/l and precision was 5.5% and 5.0% for sulfadoxine and sulfamethoxazole, respectively.

  19. Synthesis of 45S5 Bioglass® via a straightforward organic, nitrate-free sol-gel process.

    PubMed

    Rezabeigi, Ehsan; Wood-Adams, Paula M; Drew, Robin A L

    2014-07-01

    More than four decades after the discovery of 45S5 Bioglass® as the first bioactive material, this composition is still one of the most promising materials in the tissue engineering field. Sol-gel-derived bioactive glasses generally possess improved properties over other bioactive glasses, because of their highly porous microstructure and unique surface chemistry which accelerate hydroxyapatite formation. In the current study, a new combination of precursors with lactic acid as the hydrolysis catalyst have been employed to design an organic, nitrate-free sol-gel procedure for synthesizing of 45S5 Bioglass®. This straightforward route is able to produce fully amorphous submicron particles of this glass with an appropriately high specific surface area on the order of ten times higher than that of the melt-derived glasses. These characteristics are expected to lead to rapid hydroxyapatite formation and consequently more efficient bone bonding.

  20. Fatty Acid-Binding Protein 5 Facilitates the Blood-Brain Barrier Transport of Docosahexaenoic Acid.

    PubMed

    Pan, Yijun; Scanlon, Martin J; Owada, Yuji; Yamamoto, Yui; Porter, Christopher J H; Nicolazzo, Joseph A

    2015-12-07

    The brain has a limited ability to synthesize the essential polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) from its omega-3 fatty acid precursors. Therefore, to maintain brain concentrations of this PUFA at physiological levels, plasma-derived DHA must be transported across the blood-brain barrier (BBB). While DHA is able to partition into the luminal membrane of brain endothelial cells, its low aqueous solubility likely limits its cytosolic transfer to the abluminal membrane, necessitating the requirement of an intracellular carrier protein to facilitate trafficking of this PUFA across the BBB. As the intracellular carrier protein fatty acid-binding protein 5 (FABP5) is expressed at the human BBB, the current study assessed the putative role of FABP5 in the brain endothelial cell uptake and BBB transport of DHA in vitro and in vivo, respectively. hFAPB5 was recombinantly expressed and purified from Escherichia coli C41(DE3) cells and the binding affinity of DHA to hFABP5 assessed using isothermal titration calorimetry. The impact of FABP5 siRNA on uptake of (14)C-DHA into immortalized human brain microvascular endothelial (hCMEC/D3) cells was assessed. An in situ transcardiac perfusion method was optimized in C57BL/6 mice and subsequently used to compare the BBB influx rate (Kin) of (14)C-DHA between FABP5-deficient (FABP5(-/-)) and wild-type (FABP5(+/+)) C57BL/6 mice. DHA bound to hFABP5 with an equilibrium dissociation constant of 155 ± 8 nM (mean ± SEM). FABP5 siRNA transfection decreased hCMEC/D3 mRNA and protein expression of FABP5 by 53.2 ± 5.5% and 44.8 ± 13.7%, respectively, which was associated with a 14.1 ± 2.7% reduction in (14)C-DHA cellular uptake. By using optimized conditions for the in situ transcardiac perfusion (a 1 min preperfusion (10 mL/min) followed by perfusion of (14)C-DHA (1 min)), the Kin of (14)C-DHA was 0.04 ± 0.01 mL/g/s. Relative to FABP5(+/+) mice, the Kin of (14)C-DHA decreased 36.7 ± 12.4% in FABP5(-/-) mice

  1. Partitioning sparse rectangular matrices for parallel processing

    SciTech Connect

    Kolda, T.G.

    1998-05-01

    The authors are interested in partitioning sparse rectangular matrices for parallel processing. The partitioning problem has been well-studied in the square symmetric case, but the rectangular problem has received very little attention. They will formalize the rectangular matrix partitioning problem and discuss several methods for solving it. They will extend the spectral partitioning method for symmetric matrices to the rectangular case and compare this method to three new methods -- the alternating partitioning method and two hybrid methods. The hybrid methods will be shown to be best.

  2. Effects of Adrenal Cortical Steroids and Osmotic Blood-Brain Barrier Opening on Methotrexate Delivery to Gliomas in the Rodent: The Factor of the Blood-Brain Barrier

    NASA Astrophysics Data System (ADS)

    Neuwelt, Edward A.; Barnett, Peggy A.; Bigner, Darrell D.; Frenkel, Eugene P.

    1982-07-01

    The effect of adrenal cortical steroids and osmotic blood-brain barrier modification on methotrexate delivery to normal and glioma-bearing rats was studied. In animals with the avian sarcoma virus-induced glioma, osmotic blood-brain barrier modification resulted in significantly increased delivery of methotrexate to the tumor-bearing hemisphere (including the tumor, the brain around the tumor, and the brain distant to the tumor), compared to the nonmodified hemisphere or to control animals. The administration of adrenal steroids, followed by intracarotid methotrexate, resulted in slightly decreased chemotherapeutic agent (methotrexate) delivery to the tumor, the brain around the tumor, and the brain distant to the tumor. When adrenal steroids were given prior to barrier modification and methotrexate therapy, the level of methotrexate was significantly less in the tumor. These studies provide evidence that the blood-brain barrier exists in tumors and is a factor in drug delivery to tumors. Steroid administration greatly interferes with the enhancement of drug delivery to tumors that can be achieved with osmotic blood-brain barrier modification.

  3. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

    PubMed

    Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M; Mariani, John N; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S; John, Gareth R

    2015-06-01

    In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an

  4. Real-time monitoring of human blood-brain barrier disruption

    PubMed Central

    Kiviniemi, Vesa; Korhonen, Vesa; Kortelainen, Jukka; Rytky, Seppo; Keinänen, Tuija; Tuovinen, Timo; Isokangas, Matti; Sonkajärvi, Eila; Siniluoto, Topi; Nikkinen, Juha; Alahuhta, Seppo; Tervonen, Osmo; Turpeenniemi-Hujanen, Taina; Myllylä, Teemu; Kuittinen, Outi; Voipio, Juha

    2017-01-01

    Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography (DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 μV followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for blood-brain barrier disruption augmented drug delivery. PMID:28319185

  5. Real-time monitoring of human blood-brain barrier disruption.

    PubMed

    Kiviniemi, Vesa; Korhonen, Vesa; Kortelainen, Jukka; Rytky, Seppo; Keinänen, Tuija; Tuovinen, Timo; Isokangas, Matti; Sonkajärvi, Eila; Siniluoto, Topi; Nikkinen, Juha; Alahuhta, Seppo; Tervonen, Osmo; Turpeenniemi-Hujanen, Taina; Myllylä, Teemu; Kuittinen, Outi; Voipio, Juha

    2017-01-01

    Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography (DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 μV followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for blood-brain barrier disruption augmented drug delivery.

  6. Tau Proteins Cross the Blood-Brain Barrier.

    PubMed

    Banks, William A; Kovac, Andrej; Majerova, Petra; Bullock, Kristin M; Shi, Min; Zhang, Jing

    2017-01-01

    Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease.

  7. Characteristics of compounds that cross the blood-brain barrier.

    PubMed

    Banks, William A

    2009-06-12

    Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.

  8. Middle cerebral artery thrombosis: acute blood-brain barrier consequences

    SciTech Connect

    Dietrich, W.D.; Prado, R.; Watson, B.D.; Nakayama, H.

    1988-07-01

    The effect of middle cerebral artery (MCA) thrombosis on the integrity of the blood-brain barrier (BBB) was studied in rats using horseradish peroxidase (HRP). Endothelial injury with subsequent platelet thrombosis was produced by means of a rose bengal-sensitized photochemical reaction, facilitated by irradiating the right proximal MCA segment with the focused beam of an argon laser. At 15 minutes following thrombosis formation, diffuse leakage of HRP was observed bilaterally within cortical and subcortical brain areas. Peroxidase extravasation was most dense within the territory of the occluded artery including neocortical areas and dorso-lateral striatum. Contralaterally, a similar distribution was observed but with less intense HRP leakage. Ultrastructural studies demonstrated an increase in permeability to HRP within arterioles, venules and capillaries. At these sites, the vascular endothelium contained HRP-filled pinocytotic vesicles and tubular profiles. Although less intense, bilateral HRP leakage was also observed following MCA stenosis or femoral artery occlusion. Endothelial-platelet interactions at the site of vascular injury may be responsible for releasing substances or neurohumoral factors which contribute to the acute opening of the BBB.

  9. Novel oximes as blood-brain barrier penetrating cholinesterase reactivators.

    PubMed

    Garcia, Gregory E; Campbell, Amy J; Olson, John; Moorad-Doctor, Deborah; Morthole, Venee I

    2010-09-06

    The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood-brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar-oxime conjugates were utilized. These 'sugar-oximes' would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar-oximes, as well as six novel sugar-oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar-oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar-oxime 8b had low toxicity with a LD(50) of 1,590 mg/kg from a single IM dose in the guinea pig and >2,000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar-oximes can be effective reactivators and suggest that high treatment doses may be possible.

  10. Barrier mechanisms in the Drosophila blood-brain barrier

    PubMed Central

    Hindle, Samantha J.; Bainton, Roland J.

    2014-01-01

    The invertebrate blood-brain barrier (BBB) field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through G-protein coupled receptor signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate BBB has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many BBB mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the BBB can govern whole animal physiologies. This includes novel functions of BBB gap junctions in orchestrating synchronized neuroblast proliferation, and of BBB secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate BBB anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study. PMID:25565944

  11. Transport characteristics of tramadol in the blood-brain barrier.

    PubMed

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

    2014-10-01

    Tramadol is a centrally acting analgesic whose action is mediated by both agonistic activity at opioid receptors and inhibitory activity on neuronal reuptake of monoamines. The purpose of this study was to characterize the blood-brain barrier (BBB) transport of tramadol by means of microdialysis studies in rat brain and in vitro studies with human immortalized brain capillary endothelial cells (hCMEC/D3). The Kp,uu,brain value of tramadol determined by rat brain microdialysis was greater than unity, indicating that tramadol is actively taken up into the brain across the BBB. Tramadol was transported into hCMEC/D3 cells in a concentration-dependent manner. The uptake was inhibited by type II cations (pyrilamine, verapamil, etc.), but not by substrates of organic cation transporter OCTs or OCTN2. It was also inhibited by a metabolic inhibitor but was independent of extracellular sodium or membrane potential. The uptake was altered by changes of extracellular pH, and by ammonium chloride-induced intracellular acidification, suggesting that transport of tramadol is driven by an oppositely directed proton gradient. Thus, our in vitro and in vivo results suggest that tramadol is actively transported, at least in part, from blood to the brain across the BBB by proton-coupled organic cation antiporter.

  12. Role of the blood-brain barrier in multiple sclerosis.

    PubMed

    Ortiz, Genaro Gabriel; Pacheco-Moisés, Fermín Paul; Macías-Islas, Miguel Ángel; Flores-Alvarado, Luis Javier; Mireles-Ramírez, Mario A; González-Renovato, Erika Daniela; Hernández-Navarro, Vanessa Elizabeth; Sánchez-López, Angélica Lizeth; Alatorre-Jiménez, Moisés Alejandro

    2014-11-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with demyelination and axonal loss eventually leading to neurodegeneration. MS exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB). The BBB is a complex organization of cerebral endothelial cells, pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. In pathological conditions, lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Cytotoxic factors including pro-inflammatory cytokines, proteases, and reactive oxygen and nitrogen species accumulate and may contribute to myelin destruction. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in MS brains and parallel the release of inflammatory cytokines. In this review we establish the importance of the role of the BBB in MS. Improvements in our understanding of molecular mechanism of BBB functioning in physiological and pathological conditions could lead to improvement in the quality of life of MS patients.

  13. [The blood-brain barrier and neurodegenerative lysosomal storage diseases].

    PubMed

    Urayama, Akihiko

    2013-02-01

    Enzyme replacement therapy has been a very effective treatment for several lysosomal storage diseases. However, correcting central nervous system (CNS) storage has been challenging due to the presence of the blood-brain barrier (BBB), which hampers the entry of circulating lysosomal enzymes into the brain. In our previous studies, we discovered that luminally expressed cation-independent mannose 6-phosphate (M6P) receptor is a universal transporter for lysosomal enzymes that contain M6P moieties on the enzyme molecule. This receptor-mediated transport of lysosomal enzymes showed developmental down-regulation that resulted in a failure of delivery of lysosomal enzymes across the BBB in the adult brain. Conceptually, if one can re-induce M6P receptor-mediated transport of lysosomal enzymes in adult BBB, this could provide a novel brain targeting approach for treating abnormal storage in the CNS, regardless of the age of subjects. We found that systemic adrenergic stimuli restored functional transport of β-glucuronidase across the adult BBB. The concept of manipulating BBB transport activity by endogenous characteristics has also been demonstrated by another group who showed effective treatment in a Pompe disease model animal in vivo. It is intriguing that lysosomal enzymes utilize multiple mechanisms for their transport across the BBB. This review explores pharmacological manipulations for the delivery of lysosomal enzymes into the CNS, and the mechanisms of their transport across the BBB, based on existing evidence from studies of β-glucuronidase, sulfamidase, acid α-glucosidase, and arylsulfatase A.

  14. Sleep restriction impairs blood-brain barrier function.

    PubMed

    He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J; Wang, Yuping; Pan, Weihong

    2014-10-29

    The blood-brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice.

  15. Plant population growth and competition in a light gradient: a mathematical model of canopy partitioning.

    PubMed

    Vance, Richard R; Nevai, Andrew L

    2007-03-21

    Can a difference in the heights at which plants place their leaves, a pattern we call canopy partitioning, make it possible for two competing plant species to coexist? To find out, we examine a model of clonal plants living in a nonseasonal environment that relates the dynamical behavior and competitive abilities of plant populations to the structural and functional features of the plants that form them. This examination emphasizes whole plant performance in the vertical light gradient caused by self-shading. This first of three related papers formulates a prototype single species Canopy Structure Model from biological first principles and shows how all plant properties work together to determine population persistence and equilibrium abundance. Population persistence is favored, and equilibrium abundance is increased, by high irradiance, high maximum photosynthesis rate, rapid saturation of the photosynthetic response to increased irradiance, low tissue respiration rate, small amounts of stem and root tissue necessary to support the needs of leaves, and low density of leaf, stem, and root tissues. In particular, equilibrium abundance decreases as mean leaf height increases because of the increased cost of manufacturing and maintaining stem tissue. All conclusions arise from this formulation by straightforward analysis. The argument concludes by stating this formulation's straightforward extension, called a Canopy Partitioning Model, to two competing species.

  16. Ischemia-reperfusion impairs blood-brain barrier function and alters tight junction protein expression in the ovine fetus.

    PubMed

    Chen, X; Threlkeld, S W; Cummings, E E; Juan, I; Makeyev, O; Besio, W G; Gaitanis, J; Banks, W A; Sadowska, G B; Stonestreet, B S

    2012-12-13

    The blood-brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood-brain barrier. Hypoxic-ischemic damage to the blood-brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood-brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood-brain barrier function in the fetus. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K(i)) and tight junction proteins by Western immunoblot in fetal sheep at 127 days of gestation without ischemia, and 4, 24, or 48 h after ischemia. The largest increase in K(i) (P<0.05) was 4 h after ischemia. Occludin and claudin-5 expressions decreased at 4 h, but returned toward control levels 24 and 48 h after ischemia. Zonula occludens-1 and -2 decreased after ischemia. Inverse correlations between K(i) and tight junction proteins suggest that the decreases in tight junction proteins contribute to impaired blood-brain barrier function after ischemia. We conclude that impaired blood-brain barrier function is an important component of hypoxic-ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (K(i)) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4 h after ischemia and blood-brain barrier function improves early after injury because the blood-brain barrier is less permeable 24 and 48 than 4 h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood-brain barrier permeability after ischemia.

  17. The protective influence of the locus ceruleus on the blood-brain barrier

    SciTech Connect

    Harik, S.I.; McGunigal, T. Jr.

    1984-06-01

    The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines.

  18. Review: Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases.

    PubMed

    Stolp, H B; Dziegielewska, K M

    2009-04-01

    The causes of most neurological disorders are not fully understood. Inflammation and blood-brain barrier dysfunction appear to play major roles in the pathology of these diseases. Inflammatory insults that occur during brain development may have widespread effects later in life for a spectrum of neurological disorders. In this review, a new hypothesis suggesting a mechanistic link between inflammation and blood-brain barrier function (integrity), which is universally important in both neurodevelopmental and neurodegenerative diseases, is proposed. The role of inflammation and the blood-brain barrier will be discussed in cerebral palsy, schizophrenia, Parkinson's disease, Alzheimer's disease and multiple sclerosis, conditions where both inflammation and blood-brain barrier dysfunction occur either during initiation and/or progression of the disease. We suggest that breakdown of normal blood-brain barrier function resulting in a short-lasting influx of blood-born molecules, in particular plasma proteins, may cause local damage, such as reduction of brain white matter observed in some newborn babies, but may also be the mechanism behind some neurodegenerative diseases related to underlying brain damage and long-term changes in barrier properties.

  19. The Drosophila blood-brain barrier: development and function of a glial endothelium

    PubMed Central

    Limmer, Stefanie; Weiler, Astrid; Volkenhoff, Anne; Babatz, Felix; Klämbt, Christian

    2014-01-01

    The efficacy of neuronal function requires a well-balanced extracellular ion homeostasis and a steady supply with nutrients and metabolites. Therefore, all organisms equipped with a complex nervous system developed a so-called blood-brain barrier, protecting it from an uncontrolled entry of solutes, metabolites or pathogens. In higher vertebrates, this diffusion barrier is established by polarized endothelial cells that form extensive tight junctions, whereas in lower vertebrates and invertebrates the blood-brain barrier is exclusively formed by glial cells. Here, we review the development and function of the glial blood-brain barrier of Drosophila melanogaster. In the Drosophila nervous system, at least seven morphologically distinct glial cell classes can be distinguished. Two of these glial classes form the blood-brain barrier. Perineurial glial cells participate in nutrient uptake and establish a first diffusion barrier. The subperineurial glial (SPG) cells form septate junctions, which block paracellular diffusion and thus seal the nervous system from the hemolymph. We summarize the molecular basis of septate junction formation and address the different transport systems expressed by the blood-brain barrier forming glial cells. PMID:25452710

  20. Laser system with partitioned prism

    SciTech Connect

    Nettleton, J. E.; Barr, D. N.

    1985-03-26

    An array of optical frequency-sensitive elements such as diffraction gratings or interference filters are arranged in a row, and the optical path of the laser cavity can be directed to include one of these elements. A partitioned optical prism consisting of a triangular portion and one or more paralleogramatic portions are used to direct the path. Between the portions are piezoelectric elements which, when energized, expand to provide an air gap between the portions and to allow total reflection of an optical ray at the surface of the prism next to the gap.

  1. On some trees having partition dimension four

    NASA Astrophysics Data System (ADS)

    Ida Bagus Kade Puja Arimbawa, K.; Baskoro, Edy Tri

    2016-02-01

    In 1998, G. Chartrand, E. Salehi and P. Zhang introduced the notion of partition dimension of a graph. Since then, the study of this graph parameter has received much attention. A number of results have been obtained to know the values of partition dimensions of various classes of graphs. However, for some particular classes of graphs, finding of their partition dimensions is still not completely solved, for instances a class of general tree. In this paper, we study the properties of trees having partition dimension 4. In particular, we show that, for olive trees O(n), its partition dimension is equal to 4 if and only if 8 ≤ n ≤ 17. We also characterize all centipede trees having partition dimension 4.

  2. Straightforward measurement of individual (1)J(CH) and (2)J(HH) in diastereotopic CH(2) groups.

    PubMed

    Saurí, Josep; Castañar, Laura; Nolis, Pau; Virgili, Albert; Parella, Teodor

    2014-05-01

    The C-H(A) cross-peak corresponding to a diastereotopic CHAHB methylene spin system exhibits a characteristic 1:0:1 multiplet pattern along the indirect dimension of a ω1-coupled HSQC spectrum. It is shown here that the use of the initial (13)C Boltzmann polarization instead of the regular INEPT-based (1)H Boltzmann polarization makes visible the central lines of this multiplet pattern. A spin-state-selective method is proposed for the efficient measurement of both (1)J(CHA) and (1)J(CHB) along the indirect dimension of a 2D spectrum as well as to the magnitude and the sign of the geminal (2)J(HAHB) coupling constant from the straightforward analysis of a single four-component E.COSY cross-peak. Additionally, the extraction of (1)J(CH) values for CH and CH3 multiplicities can be also performed from the same spectrum. The success of the method is also illustrated for the determination of residual dipolar (1)D(CH) and (2)D(HH) coupling constants in a small molecule weakly aligned in a PMMA swollen gel.

  3. A straightforward method of analysis for direct quantum dynamics: application to the photochemistry of a model cyanine.

    PubMed

    Allan, Charlotte S M; Lasorne, Benjamin; Worth, Graham A; Robb, Michael A

    2010-08-26

    We present a new way of analyzing direct quantum dynamics simulations based on a Mulliken-type population analysis. This provides a straightforward interpretation of the wavepacket in much the same way as semiclassical trajectories are usually analyzed. The result can be seen as a coupled set of quantum trajectories. We apply this to the study of the photochemistry of a 12-atom model cyanine to explore possibilities for intelligent optimal control. The work presented here builds on previous semiclassical dynamics simulations [ Hunt , P. A. ; Robb , M. A. J. Am. Chem. Soc. 2005 , 127 , 5720 ]. Those calculations suggested that, by controlling the distribution of momentum components in the initial wavepacket, it should be possible to drive the system to a specific region of the conical intersection seam and ultimately control the product distribution. This was confirmed experimentally by optimal control methods [ Dietzek , B. ; Bruggemann , B. ; Pascher , T. ; Yartsev , A. J. Am. Chem. Soc. 2007 , 129 , 13014 ]. This paper aims to demonstrate this in a quantum dynamics context and give further insight into the conditions required for control. Our results show that directly addressing the trans-cis torsional modes is not efficient. Instead, one needs to decrease the momentum in the skeletal deformation coordinates to prompt radiationless decay near the minimum conical intersection at large twist angles.

  4. Displaying multimedia environmental partitioning by triangular diagrams

    SciTech Connect

    Lee, S.C.; Mackay, D.

    1995-11-01

    It is suggested that equilateral triangular diagrams are a useful method of depicting the equilibrium partitioning of organic chemicals among the three primary environmental media of the atmosphere, the hydrosphere, and the organosphere (natural organic matter and biotic lipids and waxes). The technique is useful for grouping chemicals into classes according to their partitioning tendencies, for depicting the incremental effects of substituents such as alkyl groups and chlorine, and for showing how partitioning changes in response to changes in temperature.

  5. Chemical amplification based on fluid partitioning in an immiscible liquid

    DOEpatents

    Anderson, Brian L.; Colston, Bill W.; Elkin, Christopher J.

    2010-09-28

    A system for nucleic acid amplification of a sample comprises partitioning the sample into partitioned sections and performing PCR on the partitioned sections of the sample. Another embodiment of the invention provides a system for nucleic acid amplification and detection of a sample comprising partitioning the sample into partitioned sections, performing PCR on the partitioned sections of the sample, and detecting and analyzing the partitioned sections of the sample.

  6. The stringy instanton partition function

    NASA Astrophysics Data System (ADS)

    Bonelli, Giulio; Sciarappa, Antonio; Tanzini, Alessandro; Vasko, Petr

    2014-01-01

    We perform an exact computation of the gauged linear sigma model associated to a D1-D5 brane system on a resolved A 1 singularity. This is accomplished via supersymmetric localization on the blown-up two-sphere. We show that in the blow-down limit the partition function reduces to the Nekrasov partition function evaluating the equivariant volume of the instanton moduli space. For finite radius we obtain a tower of world-sheet instanton corrections, that we identify with the equivariant Gromov-Witten invariants of the ADHM moduli space. We show that these corrections can be encoded in a deformation of the Seiberg-Witten prepotential. From the mathematical viewpoint, the D1-D5 system under study displays a twofold nature: the D1-branes viewpoint captures the equivariant quantum cohomology of the ADHM instanton moduli space in the Givental formalism, and the D5-branes viewpoint is related to higher rank equivariant Donaldson-Thomas invariants of.

  7. Ultrasound-Induced Blood-Brain Barrier Opening

    PubMed Central

    Konofagou, Elisa E.; Tung, Yao-Sheng; Choi, James; Deffieux, Thomas; Baseri, Babak; Vlachos, Fotios

    2014-01-01

    Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions. PMID:22201586

  8. Blood-brain barrier as a regulatory interface.

    PubMed

    Banks, William A

    2010-01-01

    The blood-brain barrier (BBB) is an important component of the communication network that connects the central nervous system and peripheral tissues in the control of feeding-related behaviors. Specifically, the BBB acts as an interface that restricts and regulates the exchange of substances between the CNS and blood. Many of the eating-related peptides and regulatory proteins produced by peripheral tissues and with receptors in the brain have been found to cross the BBB. The consequences of BBB permeability to these substances can be viewed from various perspectives. Here, we briefly consider five views relating the BBB and eating. A view of physiologic integration emphasizes the BBB as a conduit that controls a humoral-dependent signaling between the CNS and peripheral tissues. A view of regulation emphasizes that the transporters for many of the eating-related hormones are themselves regulated by physiologic events. This means that blood-to-brain signaling across the BBB is state-dependent and adaptable to the needs of the organism. A view of pathologic dysfunction shows how dysregulation of BBB transporters can result in disease. Resistance to leptin caused by its decreased transport across the BBB in obesity is an example. An evolutionary view emphasizes how the role of the BBB in eating may have evolved and how adaptations to one set of eating conditions can result in maladaptations under other conditions. Finally, the implications of these views for drug development targeted at obesity or anorexia is explored. Overall, these views show the BBB is an integral part of the physiology of eating.

  9. The blood-brain barrier as a cause of obesity.

    PubMed

    Banks, William A

    2008-01-01

    The dramatic increase in the number of obese and overweight persons has spurred interest in control of appetite, body weight, and adiposity. Leptin is the humoral component of a negative feedback loop between adipose tissue and brain. Leptin is secreted from fat in proportion to the degree of adiposity, is transported across the blood-brain barrier (BBB), and acts in the brain to decrease appetite and increase thermogenesis, actions that ultimately decrease adiposity. However, leptin fails as an adipostat because leptin resistance arises in obesity. The BBB transporter is the first part of the feedback loop to fail, producing the so called "peripheral resistance" to leptin. In this sense, obesity is a disease of the BBB. Failure of leptin as an adipostat raises the question of what its primary role is as does its effects on reproduction, bone, immunity, breathing, cognition, and neurogenesis. Kinetics analysis shows that the BBB transporter performs most efficiently at low serum levels of leptin, suggesting that the feedback loop evolved to operate at lower leptin levels than those seen in ideal body weight. We suggest that low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on functions other than feeding, such as reproduction and the immune system. This feedback loop is short-circuited when an animal enters starvation. Hallmarks of starvation include decreased secretion of leptin by adipose tissue and hypertriglyceridemia. Triglycerides inhibit the transport of leptin across the BBB, thus attenuating the leptin signal across the BBB and providing a mechanism for peripheral leptin resistance. Triglycerides are elevated in both starvation and obesity. We postulate that hypertriglyceridemia evolved as a starvation signal to the brain that acts in part to inhibit the transport of the leptin across the BBB. The hypertriglyceridemia of obesity invokes this aspect of the starvation response, inducing leptin resistance at the

  10. Blood-Brain Barrier Changes in High Altitude.

    PubMed

    Lafuente, José V; Bermudez, Garazi; Camargo-Arce, Lorena; Bulnes, Susana

    2016-01-01

    Cerebral syndromes related to high-altitude exposure are becoming more frequent as the number of trips to high altitudes has increased in the last decade. The commonest symptom is headache, followed by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be fatal. The pathophysiology of these syndromes is not fully understood. The classical "tight-fit hypothesis" posits that there are some anatomical variations that would obstruct the sinovenous outflow and worsen vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain microhemorrhages seen in autopsies. However, recent magnetic resonance imaging studies have demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction in water balance at the cellular level. Currently, the "red-ox theory" supports trigemino-vascular system activation by free radicals formed after hypoxia and the consequent oxidative stress cascades. Apart from trigemino-vascular system activation, free radicals can also provoke membrane destabilisation mediated by lipid peroxidation, inflammation, and local hypoxia inducible factor-1α and vascular endothelial growth factor activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides alterations in endothelial cells such as increased pinocytotic vesicles and disassembly of interendothelial tight junction proteins, capillary permeability may also increase with subsequent swelling of astrocyte end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood, recent evidence proposes a multifactorial entity, with brain swelling and compromise of the BBB considered to play an important role. A fuller comprehension of these processes is crucial to reduce and prevent BBB alterations during high-altitude exposure.

  11. Blood-brain barrier impairment in MPS III patients

    PubMed Central

    2013-01-01

    Background Mucopolysaccharidosis type III (MPS III) is an autosomal recessive disorder caused by deficiency of a specific enzyme leading to heparan sulfate (HS) accumulation within cells and to eventual progressive cerebral and systemic organ abnormalities. Different enzyme deficiencies comprise the MPS III subcategories (A, B, C, D). Since neuropathological manifestations are common to all MPS III types, determining blood-brain barrier (BBB) condition may be critical to understand potential additional disease mechanisms. Methods We investigated BBB integrity in various brain structures of post-mortem tissues from an eleven year old Caucasian female with MPS III A and from a twenty four year old Caucasian female with MPS III D. Control tissues were obtained post-mortem from three Caucasians without neurological deficits: a twelve year old male, a twenty four year old female, and a twenty seven year old female. BBB capillary ultrastructure (electron microscopy) and capillary functional integrity (IgG leakage, tight junction proteins, and lysosomal accumulation within endothelium) were examined. Results Compromised BBB integrity was found in both MPS III cases. Major study findings were: (1) capillary endothelial and pericyte cell damage; (2) mucopolysaccharide bodies in a majority of endothelial cells and pericytes rupturing cell membranes; (3) severe extracellular edema; (4) IgG microvascular leakage and reductions of occludin and claudin-5 with variations between MPS III types; (5) extensive lysosomal accumulation in capillary endothelium. Conclusions These new findings of BBB structural and functional impairment, although from only two cases, MPS III A and III D, may have implications for disease pathogenesis and should be considered in treatment development for MPS III. PMID:24225396

  12. Hydrophilic solute transport across the rat blood-brain barrier

    SciTech Connect

    Lucchesi, K.J.

    1987-01-01

    Brain capillary permeability-surface area products (PS) of hydrophilic solutes ranging in size from 180 to 5,500 Daltons were measured in rats according to the method of Ohno, Pettigrew and Rapoport. The distribution volume of 70 KD dextran at 10 minutes after i.v. injection was also measured to determine the residual volume of blood in brain tissue at the time of sacrifice. Small test solutes were injected in pairs in order to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. This issue was examined in rats whose blood-brain barrier (BBB) was presumed to be intact (untreated) and in rats that received intracarotid infusions to open the BBB (isosmotic salt (ISS) and hyperosmolar arabinose). Ohno PS values of {sup 3}H-inulin and {sup 14}C-L-glucose in untreated rats were found to decrease as the labelling time was lengthened. This was evidence that a rapidly equilibrating compartment exists between blood and brain that renders the Ohno two-compartment model inadequate for computing true transfer rate constants. When the data were reanalyzed using a multi-compartment graphical analysis, solutes with different molecular radii were found to enter the brain at approximately equal rates. Furthermore, unidirectional transport is likely to be initiated by solute adsorption to a glycocalyx coat on the luminal surface of brain capillary endothelium. Apparently, more inulin than L-glucose was adsorbed, which may account for its slightly faster transfer across the BBB. After rats were treated with intracarotid infusions of ISS or hyperosmolar arabinose, solute PS values were significantly increased, but the ratio of PS for each of the solute pairs approached that of their free-diffusion coefficients.

  13. Ultrasound-induced blood-brain barrier opening.

    PubMed

    Konofagou, Elisa E; Tung, Yao-Sheng; Choi, James; Deffieux, Thomas; Baseri, Babak; Vlachos, Fotios

    2012-06-01

    Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.

  14. Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier.

    PubMed

    Wynendaele, Evelien; Verbeke, Frederick; Stalmans, Sofie; Gevaert, Bert; Janssens, Yorick; Van De Wiele, Christophe; Peremans, Kathelijne; Burvenich, Christian; De Spiegeleer, Bart

    2015-01-01

    Bacteria communicate with each other by the use of signaling molecules, a process called 'quorum sensing'. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (Kin = 20.87 μl/(g×min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (Kin = 2.68 μl/(g×min)) and very low (Kin = 0.18 μl/(g×min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP-2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis.

  15. Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview.

    PubMed

    Prasad, Shikha; Sajja, Ravi K; Naik, Pooja; Cucullo, Luca

    2014-06-01

    A host of diabetes-related insults to the central nervous system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. These host of neurological disorders encompass hemodynamic impairments (e.g., stroke), vascular dementia, cognitive deficits (mild to moderate), as well as a number of neurochemical, electrophysiological and behavioral alterations. The underlying causes of diabetes-induced CNS complications are multifactorial and are relatively little understood although it is now evident that blood-brain barrier (BBB) damage plays a significant role in diabetes-dependent CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g., glucose, insulin, choline, amino acids, etc.), integrity (tight junction disruption), and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aβ) from the blood into the brain across the BBB thus, establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD, also referred to as "type 3 diabetes"). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large, heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia in vivo has led to controversial results especially with regard to the effects of diabetes on BBB. In this article, we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia.

  16. Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier

    PubMed Central

    Wynendaele, Evelien; Verbeke, Frederick; Stalmans, Sofie; Gevaert, Bert; Janssens, Yorick; Van De Wiele, Christophe; Peremans, Kathelijne; Burvenich, Christian; De Spiegeleer, Bart

    2015-01-01

    Bacteria communicate with each other by the use of signaling molecules, a process called ‘quorum sensing’. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (Kin = 20.87 μl/(g×min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (Kin = 2.68 μl/(g×min)) and very low (Kin = 0.18 μl/(g×min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP-2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis. PMID:26536593

  17. Methamphetamine effects on blood-brain barrier structure and function

    PubMed Central

    Northrop, Nicole A.; Yamamoto, Bryan K.

    2015-01-01

    Methamphetamine (Meth) is a widely abuse psychostimulant. Traditionally, studies have focused on the neurotoxic effects of Meth on monoaminergic neurotransmitter terminals. Recently, both in vitro and in vivo studies have investigated the effects of Meth on the BBB and found that Meth produces a decrease in BBB structural proteins and an increase in BBB permeability to various molecules. Moreover, preclinical studies are validated by clinical studies in which human Meth users have increased concentrations of toxins in the brain. Therefore, this review will focus on the structural and functional disruption of the BBB caused by Meth and the mechanisms that contribute to Meth-induced BBB disruption. The review will reveal that the mechanisms by which Meth damages dopamine and serotonin terminals are similar to the mechanisms by which the blood-brain barrier (BBB) is damaged. Furthermore, this review will cover the factors that are known to potentiate the effects of Meth (McCann et al., 1998) on the BBB, such as stress and HIV, both of which are co-morbid conditions associated with Meth abuse. Overall, the goal of this review is to demonstrate that the scope of damage produced by Meth goes beyond damage to monoaminergic neurotransmitter systems to include BBB disruption as well as provide a rationale for investigating therapeutics to treat Meth-induced BBB disruption. Since a breach of the BBB can have a multitude of consequences, therapies directed toward the treatment of BBB disruption may help to ameliorate the long-term neurodegeneration and cognitive deficits produced by Meth and possibly even Meth addiction. PMID:25788874

  18. Noninvasive Blood-Brain Barrier Opening in Live Mice

    NASA Astrophysics Data System (ADS)

    Choi, James J.; Pernot, Mathieu; Small, Scott; Konofagou, Elisa E.

    2006-05-01

    Most therapeutic agents cannot be delivered to the brain because of brain's natural defense: the Blood-Brain Barrier (BBB). It has recently been shown that Focused Ultrasound (FUS) can produce reversible and localized BBB opening in the brain when applied in the presence of ultrasound contrast agents post-craniotomy in rabbits [1]. However, a major limitation of ultrasound in the brain is the strong phase aberration and attenuation of the skull bone, and, as a result, no study of trans-cranial ultrasound-targeted drug treatment in the brain in vivo has been reported as of yet. In this study, the feasibility of BBB opening in the hippocampus of wildtype mice using FUS through the intact skull and skin was investigated. In order to investigate the effect of the skull, simulations of ultrasound wave propagation (1.5 MHz) through the skull using μCT data, and needle hydrophone measurements through an ex-vivo skull were made. The pressure field showed minimal attenuation (18% of the pressure amplitude) and a well-focused pattern through the left and right halves of the parietal bone. In experiments in vivo, the brains of four mice were sonicated through intact skull and skin. Ultrasound sonications (burst length: 20 ms; duty cycle: 20%; acoustic pressure range: 2.0 to 2.7 MPa) was applied 5 times for 30 s per shot with a 30 s delay between shots. Prior to sonication, ultrasound contrast agents (Optison; 10 μL) were injected intravenously. Contrast material enhanced high resolution MR Imaging (9.4 Tesla) was able to distinguish opening of large vessels in the region of the hippocampus. These results demonstrate the feasibility of locally opening the BBB in the mouse hippocampus using focused ultrasound through intact skull and skin. Future investigations will deal with optimization and reproducibility of the technique as well as application on Alzheimer's-model mice.

  19. Automatic analysis of D-partition

    NASA Astrophysics Data System (ADS)

    Bogaevskaya, V. G.

    2017-01-01

    The paper is dedicated to automatization of D-partition analysis. D-partition is one of the most common methods for determination of solution stability in systems with time-delayed feedback control and its dependency on values of control parameters. A transition from analytical form of D-partition to plain graph has been investigated. An algorithm of graph faces determination and calculation of count of characteristic equation roots with positive real part for appropriate area of D-partition has been developed. The algorithm keeps an information about analytical formulas for edges of faces. It allows to make further analytical research based on the results of computer analysis.

  20. Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge

    PubMed Central

    Busquets, Maria Antònia; Espargaró, Alba; Sabaté, Raimon; Estelrich, Joan

    2015-01-01

    The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain.

  1. Anti-IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus.

    PubMed

    Zhang, Jiyong; Sadowska, Grazyna B; Chen, Xiaodi; Park, Seon Yeong; Kim, Jeong-Eun; Bodge, Courtney A; Cummings, Erin; Lim, Yow-Pin; Makeyev, Oleksandr; Besio, Walter G; Gaitanis, John; Banks, William A; Stonestreet, Barbara S

    2015-05-01

    Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti-IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti-IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti-IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.

  2. Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery.

    PubMed

    Patching, Simon G

    2017-03-01

    Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.

  3. Enhanced cell affinity of chitosan membranes mediated by superficial cross-linking: a straightforward method attainable by standard laboratory procedures.

    PubMed

    Rodríguez-Velázquez, Eustolia; Silva, Maite; Taboada, Pablo; Mano, João F; Suárez-Quintanilla, David; Alatorre-Meda, Manuel

    2014-01-13

    It is well accepted that the surface modification of biomaterials can improve their biocompatibility. In this context, techniques like ion etching, plasma-mediated chemical functionalization, electrospinning, and contact microprinting have successfully been employed to promote the cell adhesion and proliferation of chitosan (CH) substrates. However, they prove to be time-consuming, highly dependent on environmental conditions, and/or limited to the use of expensive materials and sophisticated instruments not accessible to standard laboratories, hindering to a high extent their straightforward application. Filling this gap, this paper proposes the superficial cross-linking of CH as a much simpler and accessible means to modify its superficial properties in order to enhance its cellular affinity. CH membranes were prepared by solvent casting followed by a cross-linking step mediated by the chemical vapor deposition (CVD) of glutaraldehyde (GA). The membranes were characterized against non- and solution cross-linked membranes in terms of their mechanical/surface properties and biological performance. Among others, the CVD membranes proved (i) to be more mechanically stable against cell culture and sterilization than membranes cross-linked in solution and (ii) to prompt the adherence and sustained proliferation of healthy cells to levels even superior to commercial tissue culture plates (TCPs). Accordingly, the CVD cross-linking approach was demonstrated to be a simple and cost-effective alternative to the aforementioned conventional methods. Interestingly, this concept can also be applied to other biomaterials as long as GA (or other volatile components alike) can be employed as a cross-linker, making possible the cross-linking reaction at mild experimental conditions, neither requiring sophisticated lab implements nor using any potentially harmful procedure.

  4. Facile and straightforward synthesis of superparamagnetic reduced graphene oxide-Fe3O4 hybrid composite by a solvothermal reaction.

    PubMed

    Liu, Yue-Wen; Guan, Meng-Xue; Feng, Lan; Deng, Shun-Liu; Bao, Jian-Feng; Xie, Su-Yuan; Chen, Zhong; Huang, Rong-Bin; Zheng, Lan-Sun

    2013-01-18

    A superparamagnetic reduced graphene oxide-Fe(3)O(4) hybrid composite (rGO-Fe(3)O(4)) was prepared via a facile and straightforward method through the solvothermal reaction of iron (III) acetylacetonate (Fe(acac)(3)) and graphene oxide (GO) in ethylenediamine (EDA) and water. By this method, chemical reduction of GO as well as the formation of Fe(3)O(4) nanoparticles (NPs) can be achieved in one step. The Fe(3)O(4) NPs are firmly deposited on the surfaces of rGO, avoiding their reassembly to graphite. The rGO sheets prevent the agglomeration of Fe(3)O(4) NPs and enable a uniform dispersion of these metal oxide particles. The size distribution and coverage density of Fe(3)O(4) NPs deposited on rGO can be controlled by varying the initial mass ratio of GO and iron precursor, Fe(acac)(3). With an initial mass ratio of GO and Fe(acac)(3) of 5:5, the surfaces of rGO sheets are densely covered by spherical Fe(3)O(4) NPs with an average size of 19.9 nm. The magnetic-functionalized rGO hybrid exhibits a good magnetic property and the specific saturation magnetization (M(s)) is 13.2 emu g(-1). The adsorption test of methylene blue from aqueous solution demonstrates the potential application of this rGO-Fe(3)O(4) hybrid composite in removing organic dyes from polluted water.

  5. Different mechanisms influencing permeation of PDGF-AA and PDGF-BB across the blood-brain barrier.

    PubMed

    Kastin, Abba J; Akerstrom, Victoria; Hackler, Laszlo; Pan, Weihong

    2003-10-01

    Platelet-derived growth factor (PDGF) exerts neurotrophic and neuromodulatory effects on the CNS. To determine the permeability of the blood-brain barrier (BBB) to PDGF, we examined the blood-to-brain influx of radioactively labeled PDGF isoforms (PDGF-AA and PDGF-BB) by multiple-time regression analysis after intravenous (i.v.) injection and by in-situ perfusion, and also determined the physicochemical characteristics which affect their permeation across the BBB, including lipophilicity (measured by octanol:buffer partition coefficient), hydrogen bonding (measured by differences in octanol : buffer and isooctane : buffer partition coefficients), serum protein binding (measured by capillary electrophoresis), and stability of PDGF in blood 10 min after i.v. injection (measured by HPLC). After i.v. bolus injection, neither 125I-PDGF-AA nor 125I-PDGF-BB crossed the BBB, their influx rates being similar to that of the vascular marker 99mTc-albumin. 125I-PDGF-AA degraded significantly faster in blood than 125I-PDGF-BB. PDGF-BB, however, was completely bound to a large protein in serum whereas PDGF-AA showed no binding. Thus, degradation might explain the poor blood-to-brain influx of PDGF-AA, whereas protein binding could explain the poor influx of circulating PDGF-BB. Despite their lack of permeation in the intact mouse, both 125I-PDGF-AA and 125I-PDGF-BB entered the brain by perfusion in blood-free buffer, and the significantly faster rate of 125I-PDGF-AA than 125I-PDGF-BB may be explained by the lower hydrogen bonding potential of 125I-PDGF-AA. Thus, the lack of significant distribution of PDGF from blood to brain is not because of the intrinsic barrier function of the BBB but probably because of degradation and protein binding. Information from these studies could be useful in the design of analogues for delivery of PDGF as a therapeutic agent.

  6. Ionic partitioning and stomatal regulation

    PubMed Central

    Sanoubar, Rabab; Orsini, Francesco; Gianquinto, Giorgio Prosdocimi

    2013-01-01

    Vegetable grafting is commonly claimed to improve crop’s tolerance to biotic and abiotic stresses, including salinity. Although the use of inter-specific graftings is relatively common, whether the improved salt tolerance should be attributed to the genotypic background rather than the grafting per se is a matter of discussion among scientists. It is clear that most of published research has to date overlooked the issue, with the mutual presence of self-grafted and non-grafted controls resulting to be quite rare within experimental evidences. It was recently demonstrated that the genotype of the rootstock and grafting per se are responsible respectively for the differential ion accumulation and partitioning as well as to the stomatal adaptation to the stress. The present paper contributes to the ongoing discussion with further data on the differences associated to salinity response in a range of grafted melon combinations. PMID:24309549

  7. Assimilate partitioning during reproductive growth

    SciTech Connect

    Finazzo, S.F.; Davenport, T.L.

    1987-04-01

    Leaves having various phyllotactic relationships to fruitlets were labeled for 1 hour with 10/sub r/Ci of /sup 14/CO/sub 2/. Fruitlets were also labeled. Fruitlets did fix /sup 14/CO/sub 2/. Translocation of radioactivity from the peel into the fruit occurred slowly and to a limited extent. No evidence of translocation out of the fruitlets was observed. Assimilate partitioning in avocado was strongly influenced by phyllotaxy. If a fruit and the labeled leaf had the same phyllotaxy then greater than 95% of the radiolabel was present in this fruit. When the fruit did not have the same phyllotaxy as the labeled leaf, the radiolabel distribution was skewed with 70% of the label going to a single adjacent position. Avocado fruitlets exhibit uniform labeling throughout a particular tissue. In avocado, assimilates preferentially move from leaves to fruits with the same phyllotaxy.

  8. MULTIVARIATE KERNEL PARTITION PROCESS MIXTURES

    PubMed Central

    Dunson, David B.

    2013-01-01

    Mixtures provide a useful approach for relaxing parametric assumptions. Discrete mixture models induce clusters, typically with the same cluster allocation for each parameter in multivariate cases. As a more flexible approach that facilitates sparse nonparametric modeling of multivariate random effects distributions, this article proposes a kernel partition process (KPP) in which the cluster allocation varies for different parameters. The KPP is shown to be the driving measure for a multivariate ordered Chinese restaurant process that induces a highly-flexible dependence structure in local clustering. This structure allows the relative locations of the random effects to inform the clustering process, with spatially-proximal random effects likely to be assigned the same cluster index. An exact block Gibbs sampler is developed for posterior computation, avoiding truncation of the infinite measure. The methods are applied to hormone curve data, and a dependent KPP is proposed for classification from functional predictors. PMID:24478563

  9. HPAM: Hirshfeld partitioned atomic multipoles

    NASA Astrophysics Data System (ADS)

    Elking, Dennis M.; Perera, Lalith; Pedersen, Lee G.

    2012-02-01

    An implementation of the Hirshfeld (HD) and Hirshfeld-Iterated (HD-I) atomic charge density partitioning schemes is described. Atomic charges and atomic multipoles are calculated from the HD and HD-I atomic charge densities for arbitrary atomic multipole rank l on molecules of arbitrary shape and size. The HD and HD-I atomic charges/multipoles are tested by comparing molecular multipole moments and the electrostatic potential (ESP) surrounding a molecule with their reference ab initio values. In general, the HD-I atomic charges/multipoles are found to better reproduce ab initio electrostatic properties over HD atomic charges/multipoles. A systematic increase in precision for reproducing ab initio electrostatic properties is demonstrated by increasing the atomic multipole rank from l=0 (atomic charges) to l=4 (atomic hexadecapoles). Both HD and HD-I atomic multipoles up to rank l are shown to exactly reproduce ab initio molecular multipole moments of rank L for L⩽l. In addition, molecular dipole moments calculated by HD, HD-I, and ChelpG atomic charges only ( l=0) are compared with reference ab initio values. Significant errors in reproducing ab initio molecular dipole moments are found if only HD or HD-I atomic charges used. Program summaryProgram title: HPAM Catalogue identifier: AEKP_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKP_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License v2 No. of lines in distributed program, including test data, etc.: 500 809 No. of bytes in distributed program, including test data, etc.: 13 424 494 Distribution format: tar.gz Programming language: C Computer: Any Operating system: Linux RAM: Typically, a few hundred megabytes Classification: 16.13 External routines: The program requires 'formatted checkpoint' files obtained from the Gaussian 03 or Gaussian 09 quantum chemistry program. Nature of problem: An ab initio

  10. [On the partition of acupuncture academic schools].

    PubMed

    Yang, Pengyan; Luo, Xi; Xia, Youbing

    2016-05-01

    Nowadays extensive attention has been paid on the research of acupuncture academic schools, however, a widely accepted method of partition of acupuncture academic schools is still in need. In this paper, the methods of partition of acupuncture academic schools in the history have been arranged, and three typical methods of"partition of five schools" "partition of eighteen schools" and "two-stage based partition" are summarized. After adeep analysis on the disadvantages and advantages of these three methods, a new method of partition of acupuncture academic schools that is called "three-stage based partition" is proposed. In this method, after the overall acupuncture academic schools are divided into an ancient stage, a modern stage and a contemporary stage, each schoolis divided into its sub-school category. It is believed that this method of partition can remedy the weaknesses ofcurrent methods, but also explore a new model of inheritance and development under a different aspect through thedifferentiation and interaction of acupuncture academic schools at three stages.

  11. Continuous Graph Partitioning for Camera Network Surveillance

    DTIC Science & Technology

    2012-07-23

    Symmetric Gossip partitioning algorithm The distributed algorithm presented in this section assumes a symmetric gossip -type communication protocol . In... gossip communication. We prove convergence of all these algorithms, and we analyze their performance in a simulation study. 2 Continuous Partitions of...section assumes an asymmetric broadcast communication protocol . In particular, at each iteration only one camera updates its state by using local

  12. Building Ecology and Partition Design. Technical Bulletin.

    ERIC Educational Resources Information Center

    Maryland State Dept. of Education, Baltimore.

    This bulletin is intended as a resource for school system facility planners and architects who design schools. Ways in which decision makers can incorporate environmental concerns in the design of school buildings are detailed. Focus is on the design of interior partition systems. Partition systems in schools serve several purposes; they define…

  13. Graph Partitioning Models for Parallel Computing

    SciTech Connect

    Hendrickson, B.; Kolda, T.G.

    1999-03-02

    Calculations can naturally be described as graphs in which vertices represent computation and edges reflect data dependencies. By partitioning the vertices of a graph, the calculation can be divided among processors of a parallel computer. However, the standard methodology for graph partitioning minimizes the wrong metric and lacks expressibility. We survey several recently proposed alternatives and discuss their relative merits.

  14. The use of biopartitioning micellar chromatography and immobilized artificial membrane column for in silico and in vitro determination of blood-brain barrier penetration of phenols.

    PubMed

    Stępnik, Katarzyna E; Malinowska, Irena

    2013-04-19

    Biopartitioning Micellar Chromatography (BMC) is a mode of micellar liquid chromatography that uses C18 stationary phases and micellar mobile phases of Brij35 under adequate experimental conditions and can be useful to mimic human drug absorption, blood-brain barrier distribution or partitioning processes in biological systems. BMC system can be useful in constructing good predictive models because the characteristics of the BMC system are similar to biological barriers and extracellular fluids. Immobilized Artificial Membrane (IAM) chromatography uses stationary phase which consists of a monolayer of phosphatidylcholine covalently immobilized on an inert silica support. IAM columns are thought to mimic very closely a membrane bilayer and are used in a HPLC system with a physiological buffer as eluent. In this paper the usefulness of BMC and IAM system for in silico and in vitro determination of blood-brain barrier (BBB) penetration of phenols has been demonstrated. The most important pharmacokinetic parameters of brain have been obtained for the determination of BBB penetration, i.e. BBB permeability - surface area product (PS), usually given as a logPS, brain/plasma equilibration rate (log(PS×fu,brain)) and fraction unbound in plasma (Fu). Moreover, the relationships between retention of eighteen phenols and different parameters of molecular size, lipophilicity and BBB penetration were studied. Extrapolated to pure water values of the logarithms of retention factors (logkw) have been compared with the corresponding octanol-water partition coefficient (logPo-w) values of the solutes. In addition, different physicochemical parameters from Foley's equation for BMC system have been collated with the chromatographic data. The Linear Solvation Energy Relationship (LSER) using Abraham model for the describing of phenols penetration across BBB has been used. Four equations were developed as a multiple linear regression using retention data from IAM and BMC system (QRAR

  15. Purification of biomaterials by phase partitioning

    NASA Technical Reports Server (NTRS)

    Harris, J. M.

    1984-01-01

    A technique which is particularly suited to microgravity environments and which is potentially more powerful than electrophoresis is phase partitioning. Phase partitioning is purification by partitioning between the two immiscible aqueous layers formed by solution of the polymers poly(ethylene glycol) and dextran in water. This technique proved to be very useful for separations in one-g but is limited for cells because the cells are more dense than the phase solutions thus tend to sediment to the bottom of the container before reaching equilibrium with the preferred phase. There are three phases to work in this area: synthesis of new polymers for affinity phase partitioning; development of automated apparatus for ground-based separations; and design of apparatus for performing simple phase partitioning space experiments, including examination of mechanisms for separating phases in the absence of gravity.

  16. Cell partition in two phase polymer systems

    NASA Technical Reports Server (NTRS)

    Brooks, D. E.

    1979-01-01

    Aqueous phase-separated polymer solutions can be used as support media for the partition of biological macromolecules, organelles and cells. Cell separations using the technique have proven to be extremely sensitive to cell surface properties but application of the systems are limited to cells or aggregates which do not significantly while the phases are settling. Partition in zero g in principle removes this limitation but an external driving force must be applied to induce the phases to separate since their density difference disappears. We have recently shown that an applied electric field can supply the necessary driving force. We are proposing to utilize the NASA FES to study field-driven phase separation and cell partition on the ground and in zero g to help define the separation/partition process, with the ultimate goal being to develop partition as a zero g cell separation technique.

  17. Parallel hypergraph partitioning for scientific computing.

    SciTech Connect

    Heaphy, Robert; Devine, Karen Dragon; Catalyurek, Umit; Bisseling, Robert; Hendrickson, Bruce Alan; Boman, Erik Gunnar

    2005-07-01

    Graph partitioning is often used for load balancing in parallel computing, but it is known that hypergraph partitioning has several advantages. First, hypergraphs more accurately model communication volume, and second, they are more expressive and can better represent nonsymmetric problems. Hypergraph partitioning is particularly suited to parallel sparse matrix-vector multiplication, a common kernel in scientific computing. We present a parallel software package for hypergraph (and sparse matrix) partitioning developed at Sandia National Labs. The algorithm is a variation on multilevel partitioning. Our parallel implementation is novel in that it uses a two-dimensional data distribution among processors. We present empirical results that show our parallel implementation achieves good speedup on several large problems (up to 33 million nonzeros) with up to 64 processors on a Linux cluster.

  18. Efficient multiple-way graph partitioning algorithms

    SciTech Connect

    Dasdan, A.; Aykanat, C.

    1995-12-01

    Graph partitioning deals with evenly dividing a graph into two or more parts such that the total weight of edges interconnecting these parts, i.e., cutsize, is minimized. Graph partitioning has important applications in VLSI layout, mapping, and sparse Gaussian elimination. Since graph partitioning problem is NP-hard, we should resort to polynomial-time algorithms to obtain a good solution, or hopefully a near-optimal solution. Kernighan-Lin (KL) propsoed a 2-way partitioning algorithms. Fiduccia-Mattheyses (FM) introduced a faster version of KL algorithm. Sanchis (FMS) generalized FM algorithm to a multiple-way partitioning algorithm. Simulated Annealing (SA) is one of the most successful approaches that are not KL-based.

  19. Recovery of small bioparticles by interfacial partitioning.

    PubMed

    Jauregi, P; Hoeben, M A; van der Lans, R G J M; Kwant, G; van der Wielen, L A M

    2002-05-20

    In this article, a qualitative study of the recovery of small bioparticles by interfacial partitioning in liquid-liquid biphasic systems is presented. A range of crystallised biomolecules with varying polarities have been chosen such as glycine, phenylglycine and ampicillin. Liquid-liquid biphasic systems in a range of polarity differences were selected such as an aqueous two-phase system (ATPS), water-butanol and water-hexanol. The results indicate that interfacial partitioning of crystals occurs even when their density exceeds that of the individual liquid phases. Yet, not all crystals partition to the same extent to the interface to form a stable and thick interphase layer. This indicates some degree of selectivity. From the analysis of these results in relation to the physicochemical properties of the crystals and the liquid phases, a hypothetical mechanism for the interfacial partitioning is deduced. Overall these results support the potential of interfacial partitioning as a large scale separation technology.

  20. Penetrating the Blood-Brain Barrier: Promise of Novel Nanoplatforms and Delivery Vehicles.

    PubMed

    Ali, Iqbal Unnisa; Chen, Xiaoyuan

    2015-10-27

    Multifunctional nanoplatforms combining versatile therapeutic modalities with a variety of imaging options have the potential to diagnose, monitor, and treat brain diseases. The promise of nanotechnology can only be realized by the simultaneous development of innovative brain-targeting delivery vehicles capable of penetrating the blood-brain barrier without compromising its structural integrity.

  1. Inflammatory events at blood-brain barrier in neuroinflammatory and neurodegenerative disorders: implications for clinical disease.

    PubMed

    de Vries, Helga E; Kooij, Gijs; Frenkel, Dan; Georgopoulos, Spiros; Monsonego, Alon; Janigro, Damir

    2012-11-01

    Proper function of the neurovasculature is required for optimal brain function and preventing neuroinflammation and neurodegeneration. Within this review, we discuss alterations of the function of the blood-brain barrier in neurologic disorders such as multiple sclerosis, epilepsy, and Alzheimer's disease and address potential underlying mechanisms.

  2. A method to determine the ability of drugs to diffuse through the blood-brain barrier.

    PubMed Central

    Seelig, A; Gottschlich, R; Devant, R M

    1994-01-01

    A method has been devised for predicting the ability of drugs to cross the blood-brain barrier. The criteria depend on the amphiphilic properties of a drug as reflected in its surface activity. The assessment was made with various drugs that either penetrate or do not penetrate the blood-brain barrier. The surface activity of these drugs was quantified by their Gibbs adsorption isotherms in terms of three parameters: (i) the onset of surface activity, (ii) the critical micelle concentration, and (iii) the surface area requirement of the drug at the air/water interface. A calibration diagram is proposed in which the critical micelle concentration is plotted against the concentration required for the onset of surface activity. Three different regions are easily distinguished in this diagram: a region of very hydrophobic drugs which fail to enter the central nervous system because they remain adsorbed to the membrane, a central area of less hydrophobic drugs which can cross the blood-brain barrier, and a region of relatively hydrophilic drugs which do not cross the blood-brain barrier unless applied at high concentrations. This diagram can be used to predict reliably the central nervous system permeability of an unknown compound from a simple measurement of its Gibbs adsorption isotherm. PMID:8278409

  3. Qualitative prediction of blood-brain barrier permeability on a large and refined dataset

    NASA Astrophysics Data System (ADS)

    Muehlbacher, Markus; Spitzer, Gudrun M.; Liedl, Klaus R.; Kornhuber, Johannes

    2011-12-01

    The prediction of blood-brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood-brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation between calculated and experimental cross-sectional area (r = 0.898, n = 32). Based on these results, we examined a correlation of the calculated cross-sectional area with blood-brain barrier penetration given by logBB values. We combined various literature data sets to form a large-scale logBB dataset with 362 experimental logBB values. Quantitative models were calculated using bootstrap validated multiple linear regression. Qualitative models were built by a bootstrapped random forest algorithm. Both methods found similar descriptors such as polar surface area, pKa, log P, charges and number of positive ionisable groups to be predictive for logBB. In contrast to our initial assumption, we were not able to obtain models with the cross-sectional area chosen as relevant parameter for both approaches. Comparing those two different techniques, qualitative random forest models are better suited for blood-brain barrier permeability prediction, especially when reducing the number of descriptors and using a large dataset. A random forest prediction system (ntrees = 5) based on only four descriptors yields a validated accuracy of 88%.

  4. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers.

    PubMed

    Rempe, Ralf G; Hartz, Anika Ms; Bauer, Björn

    2016-09-01

    Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

  5. Blood-Brain Barrier Permeability and Monocyte Infiltration in Experimental Allergic Encephalomyelitis

    ERIC Educational Resources Information Center

    Floris, S.; Blezer, E. L. A.; Schreibelt, G.; Dopp, E.; van der Pol, S. M. A.; Schadee-Eestermans, I. L.; Nicolay, K.; Dijkstra, C. D.; de Vries, H. E.

    2004-01-01

    Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive…

  6. Establishment of the straightforward electro-transformation system for Phytophthora infestans and its comparison with the improved PEG/CaCl₂ transformation.

    PubMed

    Dong, Lei; Zhu, Xiangyuan; Cui, Haichen; Ojika, Makoto; Wang, Ruigang; Liu, Huirong

    2015-05-01

    Phytophthora infestans is the most devastating pathogen of potato. For the biology study of P. infestans at the molecular level, one of the difficulties is the technique for the genetic transformation. In this study, the straightforward electro-transformation system was established for P. infestans with a green fluorescent protein expression vector and compared with the improved PEG/CaCl2 mediated protoplast transformation system. The results showed that the straightforward electro-transformation could work in P. infestans and 32 positive transformants were obtained per about 1.10×10(6) zoospores. The transformants per μg of vector DNA were 1.08. The transformation efficiency of the straightforward electro-transformation was approximately 2 times higher than that of the improved PEG/CaCl2 mediated protoplast transformation (17 positive transformants per about 1.05×10(6) protoplasts, 0.58 transformants per μg of vector DNA) according to the reported procedures. Furthermore, compared with the improved PEG/CaCl2 transformation, the straightforward electroporation is simpler and requires less starting materials and operating time from collecting material to obtaining the resistant transformants. Our work will lay a foundation for the biology study of P. infestans in the future.

  7. Acid extrusion via blood-brain barrier causes brain alkalosis and seizures after neonatal asphyxia.

    PubMed

    Helmy, Mohamed M; Ruusuvuori, Eva; Watkins, Paul V; Voipio, Juha; Kanold, Patrick O; Kaila, Kai

    2012-11-01

    Birth asphyxia is often associated with a high seizure burden that is predictive of poor neurodevelopmental outcome. The mechanisms underlying birth asphyxia seizures are unknown. Using an animal model of birth asphyxia based on 6-day-old rat pups, we have recently shown that the seizure burden is linked to an increase in brain extracellular pH that consists of the recovery from the asphyxia-induced acidosis, and of a subsequent plateau level well above normal extracellular pH. In the present study, two-photon imaging of intracellular pH in neocortical neurons in vivo showed that pH changes also underwent a biphasic acid-alkaline response, resulting in an alkaline plateau level. The mean alkaline overshoot was strongly suppressed by a graded restoration of normocapnia after asphyxia. The parallel post-asphyxia increase in extra- and intracellular pH levels indicated a net loss of acid equivalents from brain tissue that was not attributable to a disruption of the blood-brain barrier, as demonstrated by a lack of increased sodium fluorescein extravasation into the brain, and by the electrophysiological characteristics of the blood-brain barrier. Indeed, electrode recordings of pH in the brain and trunk demonstrated a net efflux of acid equivalents from the brain across the blood-brain barrier, which was abolished by the Na/H exchange inhibitor, N-methyl-isobutyl amiloride. Pharmacological inhibition of Na/H exchange also suppressed the seizure activity associated with the brain-specific alkalosis. Our findings show that the post-asphyxia seizures are attributable to an enhanced Na/H exchange-dependent net extrusion of acid equivalents across the blood-brain barrier and to consequent brain alkalosis. These results suggest targeting of blood-brain barrier-mediated pH regulation as a novel approach in the prevention and therapy of neonatal seizures.

  8. Partitioned Bayesian analyses, partition choice, and the phylogenetic relationships of scincid lizards.

    PubMed

    Brandley, Matthew C; Schmitz, Andreas; Reeder, Tod W

    2005-06-01

    Partitioned Bayesian analyses of approximately 2.2 kb of nucleotide sequence data (mtDNA) were used to elucidate phylogenetic relationships among 30 scincid lizard genera. Few partitioned Bayesian analyses exist in the literature, resulting in a lack of methods to determine the appropriate number of and identity of partitions. Thus, a criterion, based on the Bayes factor, for selecting among competing partitioning strategies is proposed and tested. Improvements in both mean -lnL and estimated posterior probabilities were observed when specific models and parameter estimates were assumed for partitions of the total data set. This result is expected given that the 95% credible intervals of model parameter estimates for numerous partitions do not overlap and it reveals that different data partitions may evolve quite differently. We further demonstrate that how one partitions the data (by gene, codon position, etc.) is shown to be a greater concern than simply the overall number of partitions. Using the criterion of the 2 ln Bayes factor > 10, the phylogenetic analysis employing the largest number of partitions was decisively better than all other strategies. Strategies that partitioned the ND1 gene by codon position performed better than other partition strategies, regardless of the overall number of partitions. Scincidae, Acontinae, Lygosominae, east Asian and North American "Eumeces" + Neoseps; North African Eumeces, Scincus, and Scincopus, and a large group primarily from sub-Saharan Africa, Madagascar, and neighboring islands are monophyletic. Feylinia, a limbless group of previously uncertain relationships, is nested within a "scincine" clade from sub-Saharan Africa. We reject the hypothesis that the nearly limbless dibamids are derived from within the Scincidae, but cannot reject the hypothesis that they represent the sister taxon to skinks. Amphiglossus, Chalcides, the acontines Acontias and Typhlosaurus, and Scincinae are paraphyletic. The globally widespread

  9. REE Partitioning in Lunar Minerals

    NASA Technical Reports Server (NTRS)

    Rapp, J. F.; Lapen, T. J.; Draper, D. S.

    2015-01-01

    Rare earth elements (REE) are an extremely useful tool in modeling lunar magmatic processes. Here we present the first experimentally derived plagioclase/melt partition coefficients in lunar compositions covering the entire suite of REE. Positive europium anomalies are ubiquitous in the plagioclase-rich rocks of the lunar highlands, and complementary negative Eu anomalies are found in most lunar basalts. These features are taken as evidence of a large-scale differentiation event, with crystallization of a global-scale lunar magma ocean (LMO) resulting in a plagioclase flotation crust and a mafic lunar interior from which mare basalts were subsequently derived. However, the extent of the Eu anomaly in lunar rocks is variable. Fagan and Neal [1] reported highly anorthitic plagioclase grains in lunar impact melt rock 60635,19 that displayed negative Eu anomalies as well as the more usual positive anomalies. Indeed some grains in the sample are reported to display both positive and negative anomalies. Judging from cathodoluminescence images, these anomalies do not appear to be associated with crystal overgrowths or zones.

  10. Spectral partitioning in diffraction tomography

    SciTech Connect

    Lehman, S K; Chambers, D H; Candy, J V

    1999-06-14

    The scattering mechanism of diffraction tomography is described by the integral form of the Helmholtz equation. The goal of diffraction tomography is to invert this equation in order to reconstruct the object function from the measured scattered fields. During the forward propagation process, the spatial spectrum of the object under investigation is ''smeared,'' by a convolution in the spectral domain, across the propagating and evanescent regions of the received field. Hence, care must be taken in performing the reconstruction, as the object's spectral information has been moved into regions where it may be considered to be noise rather than useful information. This will reduce the quality and resolution of the reconstruction. We show haw the object's spectrum can be partitioned into resolvable and non-resolvable parts based upon the cutoff between the propagating and evanescent fields. Operating under the Born approximation, we develop a beam-forming on transmit approach to direct the energy into either the propagating or evanescent parts of the spectrum. In this manner, we may individually interrogate the propagating and evanescent regions of the object spectrum.

  11. Partitioning of regular computation on multiprocessor systems

    NASA Technical Reports Server (NTRS)

    Lee, Fung Fung

    1988-01-01

    Problem partitioning of regular computation over two dimensional meshes on multiprocessor systems is examined. The regular computation model considered involves repetitive evaluation of values at each mesh point with local communication. The computational workload and the communication pattern are the same at each mesh point. The regular computation model arises in numerical solutions of partial differential equations and simulations of cellular automata. Given a communication pattern, a systematic way to generate a family of partitions is presented. The influence of various partitioning schemes on performance is compared on the basis of computation to communication ratio.

  12. Partitioning of regular computation on multiprocessor systems

    NASA Technical Reports Server (NTRS)

    Lee, Fung F.

    1990-01-01

    Problem partitioning of regular computation over two dimensional meshes on multiprocessor systems is examined. The regular computation model considered involves repetitive evaluation of values at each mesh point with local communication. The computational workload and the communication pattern are the same at each mesh point. The regular computation model arises in numerical solutions of partial differential equations and simulations of cellular automata. Given a communication pattern, a systematic way to generate a family of partitions is presented. The influence of various partitioning schemes on performance is compared on the basis of computation to communication ratio.

  13. Partitioning of regular computation on multiprocessor systems

    SciTech Connect

    Lee, F. . Computer Systems Lab.)

    1990-07-01

    Problem partitioning of regular computation over two-dimensional meshes on multiprocessor systems is examined. The regular computation model considered involves repetitive evaluation of values at each mesh point with local communication. The computational workload and the communication pattern are the same at each mesh point. The regular computation model arises in numerical solutions of partial differential equations and simulations of cellular automata. Given a communication pattern, a systematic way to generate a family of partitions is presented. The influence of various partitioning schemes on performance is compared on the basis of computation to communication ratio.

  14. Merging Groups to Maximize Object Partition Comparison.

    ERIC Educational Resources Information Center

    Klastorin, T. D.

    1980-01-01

    The problem of objectively comparing two independently determined partitions of N objects or variables is discussed. A similarity measure based on the simple matching coefficient is defined and related to previously suggested measures. (Author/JKS)

  15. Cell Partition in Two Polymer Aqueous Phases

    NASA Technical Reports Server (NTRS)

    Harris, J. M.

    1985-01-01

    Partition of biological cells in two phase aqueous polymer systems is recognized as a powerful separation technique which is limited by gravity. The synthesis of new, selective polymer ligand conjugates to be used in affinity partition separations is of interest. The two most commonly used polymers in two phase partitioning are dextran and polyethylene glycol. A thorough review of the chemistry of these polymers was begun, particularly in the area of protein attachment. Preliminary studies indicate the importance in affinity partitioning of minimizing gravity induced randomizing forces in the phase separation process. The PEG-protein conjugates that were prepared appear to be ideally suited for achieving high quality purifications in a microgravity environment. An interesting spin-off of this synthetic work was the observation of catalytic activity for certain of our polymer derivatives.

  16. Synthesis on evaporation partitioning using stable isotopes

    NASA Astrophysics Data System (ADS)

    Coenders-Gerrits, Miriam; Bogaard, Thom; Wenninger, Jochen; Jonson Sutanto, Samuel

    2015-04-01

    Partitioning of evaporation into productive (transpiration) and non-productive evaporation (interception, soil evaporation) is of highest importance for water management practices, irrigation scheme design, and climate modeling. Despite this urge, the magnitude of the ratio of transpiration over total evaporation is still under debate and poorly understood due to measuring difficulties. However, with the current development in isotope measuring devices, new opportunities arise to untangle the partitioning of evaporation. In this paper we synthesize the opportunities and limitations using stable water isotopes in evaporation partitioning. We will analyze a set of field as well as laboratory studies to demonstrate the different evaporation components for various climate and vegetation conditions using stable isotopes 18O/16O and 2H/1H. Experimental data on evaporation partitioning of crops, grass, shrubs and trees are presented and we will discuss the specific experimental set-ups and data collection methods. The paper will be a synthesis of these studies.

  17. Reducing variance in batch partitioning measurements

    SciTech Connect

    Mariner, Paul E.

    2010-08-11

    The partitioning experiment is commonly performed with little or no attention to reducing measurement variance. Batch test procedures such as those used to measure K{sub d} values (e.g., ASTM D 4646 and EPA402 -R-99-004A) do not explain how to evaluate measurement uncertainty nor how to minimize measurement variance. In fact, ASTM D 4646 prescribes a sorbent:water ratio that prevents variance minimization. Consequently, the variance of a set of partitioning measurements can be extreme and even absurd. Such data sets, which are commonplace, hamper probabilistic modeling efforts. An error-savvy design requires adjustment of the solution:sorbent ratio so that approximately half of the sorbate partitions to the sorbent. Results of Monte Carlo simulations indicate that this simple step can markedly improve the precision and statistical characterization of partitioning uncertainty.

  18. Connections between groundwater flow and transpiration partitioning

    NASA Astrophysics Data System (ADS)

    Maxwell, Reed M.; Condon, Laura E.

    2016-07-01

    Understanding freshwater fluxes at continental scales will help us better predict hydrologic response and manage our terrestrial water resources. The partitioning of evapotranspiration into bare soil evaporation and plant transpiration remains a key uncertainty in the terrestrial water balance. We used integrated hydrologic simulations that couple vegetation and land-energy processes with surface and subsurface hydrology to study transpiration partitioning at the continental scale. Both latent heat flux and partitioning are connected to water table depth, and including lateral groundwater flow in the model increases transpiration partitioning from 47 ± 13 to 62 ± 12%. This suggests that lateral groundwater flow, which is generally simplified or excluded in Earth system models, may provide a missing link for reconciling observations and global models of terrestrial water fluxes.

  19. Connections between groundwater flow and transpiration partitioning.

    PubMed

    Maxwell, Reed M; Condon, Laura E

    2016-07-22

    Understanding freshwater fluxes at continental scales will help us better predict hydrologic response and manage our terrestrial water resources. The partitioning of evapotranspiration into bare soil evaporation and plant transpiration remains a key uncertainty in the terrestrial water balance. We used integrated hydrologic simulations that couple vegetation and land-energy processes with surface and subsurface hydrology to study transpiration partitioning at the continental scale. Both latent heat flux and partitioning are connected to water table depth, and including lateral groundwater flow in the model increases transpiration partitioning from 47 ± 13 to 62 ± 12%. This suggests that lateral groundwater flow, which is generally simplified or excluded in Earth system models, may provide a missing link for reconciling observations and global models of terrestrial water fluxes.

  20. Transport of active flavonoids, based on cytotoxicity and lipophilicity: an evaluation using the blood-brain barrier cell and Caco-2 cell models.

    PubMed

    Yang, Yuya; Bai, Lu; Li, Xiaorong; Xiong, Jie; Xu, Pinxiang; Guo, Chenyang; Xue, Ming

    2014-04-01

    This in vitro study aims to evaluate and compare transmembrane transport of eight cardio-cerebrovascular protection flavonoids including puerarin, rutin, hesperidin, quercetin, genistein, kaempferol, apigenin and isoliquiritigenin via the rat blood-brain barrier cell and Caco-2 cell monolayer models, based on the data of cytotoxicity and lipophilicity. The cytotoxicity of the flavonoids to rat brain microvessel endothelial cell was determined by the MTT assay. The apparent permeability coefficients (Papp) of the flavonoids were calculated from the unilateral transport assays in Transwell system with simultaneous determination using a high performance liquid chromatography. The results showed that the cytotoxicity and oil-water partition coefficient of the flavonoids modified by the number and position of the glycoside and hydroxyl group were the key determinant for the transmembrane transport. The Papp values of the flavonoids reduced adversely when the numbers of glycoside and hydroxyl groups of the flavonoids increased accordingly. The tested flavonoids exhibited time-dependent Papp values in these models. The efflux mechanism related with P-glycoprotein also existed with the polar flavonoids; verapamil could enhance the permeation of rutin and quercetin via inhibition of P-glycoprotein. We propose that genistein and isoliquiritigenin with the permeation priority in vitro Caco-2 and BBB cell model could be better as the drug candidates for cardio-cerebral vascular protection. These findings provided important information for establishing the transport relationship for the flavonoid compounds and evaluating the potential oral bioavailability and brain distribution of the flavonoids.

  1. Confounding parameters in preclinical assessment of blood-brain barrier permeation: an overview with emphasis on species differences and effect of disease states.

    PubMed

    Deo, Anand K; Theil, Frank-Peter; Nicolas, Jean-Marie

    2013-05-06

    Drug delivery across the brain-blood interfaces is a complex process involving physicochemical drug properties, transporters, enzymes, and barrier dysfunction in diseased conditions. Intact blood-brain barrier (BBB) limits the entry of potentially harmful compounds into the brain but may also reduce the CNS permeability of therapeutic agents. BBB permeability is typically assessed by measuring brain-to-plasma ratio in rodents (referred to as B/P ratio, BB, or Kp, often calculated as logBB), an approach that suffers significant limitations as discussed in the present review. Kp is not a permeability measurement but a partition coefficient mainly driven by the relative binding to plasma and brain tissue components including lipids, phospholipids, and proteins. Compounds with high Kp are often lipophilic with low free fraction available to mediate CNS activities. Efforts should be more concentrated on measuring pharmacologically relevant free drug concentrations at the target site. Using healthy rodents to predict brain penetration in patients might be biased due to species differences in BBB-related parameters such as transporter expression and functional activities. In addition, pathophysiological conditions such as aging, multiple sclerosis, and Alzheimer's and Parkinson's diseases have been described to affect BBB permeability, with barrier leakage and altered transporter activity. The impact of these species differences and disease states on drug delivery to the brain is largely overlooked. More data are needed to better understand their clinical implication in order to design more appropriate screening strategies and ultimately better mitigate the risk for failure in late stage development.

  2. Deriving the Hirshfeld partitioning using distance metrics

    SciTech Connect

    Heidar-Zadeh, Farnaz; Ayers, Paul W.; Bultinck, Patrick

    2014-09-07

    The atoms in molecules associated with the Hirshfeld partitioning minimize the generalized Hellinger-Bhattacharya distance to the reference pro-atom densities. Moreover, the reference pro-atoms can be chosen by minimizing the distance between the pro-molecule density and the true molecular density. This provides an alternative to both the heuristic “stockholder” and the mathematical information-theoretic interpretations of the Hirshfeld partitioning. These results extend to any member of the family of f-divergences.

  3. PDMS free-flow electrophoresis chips with integrated partitioning bars for bubble segregation.

    PubMed

    Köhler, Stefan; Weilbeer, Claudia; Howitz, Steffen; Becker, Holger; Beushausen, Volker; Belder, Detlev

    2011-01-21

    In this work, a microfluidic free-flow electrophoresis device with a novel approach for preventing gas bubbles from entering the separation area is presented. This is achieved by integrating partitioning bars to reduce the channel depth between electrode channels and separation chamber in order to obtain electrical contact and simultaneously prevent bubbles from entering the separation area. The three-layer sandwich chip features a reusable carrier plate with integrated ports for fluidic connection combined with a softlithographically cast microfluidic PDMS layer and a sealing glass slide. This design allows for a straightforward and rapid chip prototyping process. The performance of the device is demonstrated by free-flow zone electrophoretic separations of fluorescent dye mixtures as well as by the separation of labeled amines and amino acids with separation voltages up to 297 V.

  4. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis.

    PubMed

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle J; Frederiksen, Jette L; Larsson, Henrik B W

    2015-09-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of

  5. Dualities and Curved Space Partition Functions of Supersymmetric Theories

    NASA Astrophysics Data System (ADS)

    Agarwal, Prarit

    In this dissertation we discuss some conjectured dualities in supersymmetric field theories and provide non-trivial checks for these conjectures. A quick review of supersymmetry and related topics is provided in chapter 1. In chapter 2, we develop a method to identify the so called BPS states in the Hilbert space of a supersymmetric field theory (that preserves at least two real supercharges) on a generic curved space. As an application we obtain the superconformal index (SCI) of 4d theories. The large N SCI of quiver gauge theories has been previously noticed to factorize over the set of extremal BPS mesonic operators. In chapter 3, we reformulate this factorization in terms of the zigzag paths in the dimer model associated to the quiver and extend the factorization theorem of the index to include theories obtained from D-branes probing orbifold singularities. In chapter 4, we consider the dualities in two classes of 3 dimensional theories. The first class consist of dualities of certain necklace type Chern-Simons (CS) quiver gauge theories. A non trivial check of these dualities is provided by matching their squashed sphere partition functions. The second class consists of theories whose duals are described by a collection of free fields. In such cases, due to mixing between the superconformal R-symmetry and accidental symmetries, the matching of electric and magnetic partition functions is not straightforward. We provide a prescription to rectify this mismatch. In chapter 5, we consider some the N = 1 4d theories with orthogonal and symplectic gauge groups, arising from N = 1 preserving reduction of 6d theories on a Riemann surface. This construction allows us to dual descriptions of 4d theories. Some of the dual frames have no known Lagrangian description. We check the dualities by computing the anomaly coefficients and the superconformal indices. We also give a prescription to write the index of the theory obtained by reduction of 6d theories on a three

  6. Influence of 50 Hz frequency sinusoidal magnetic field on the blood-brain barrier permeability of diabetic rats.

    PubMed

    Oztaş, Baria; Kalkan, Tunaya; Tuncel, Handan

    2004-07-01

    The combined effects of diabetes and a 50 Hz, 5 mT RMS flux density sinusoidal magnetic field for 8 h a day, for 21 consecutive days on the permeation of Evans-blue dye through the blood-brain barrier were studied in male Wistar albino rats. Our results suggest that magnetic field has no effect on the blood-brain barrier permeability in normoglycemic animals, but that diabetic rats are vulnerable to magnetic fields.

  7. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

    PubMed Central

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  8. Certificate Revocation Using Fine Grained Certificate Space Partitioning

    NASA Astrophysics Data System (ADS)

    Goyal, Vipul

    A new certificate revocation system is presented. The basic idea is to divide the certificate space into several partitions, the number of partitions being dependent on the PKI environment. Each partition contains the status of a set of certificates. A partition may either expire or be renewed at the end of a time slot. This is done efficiently using hash chains.

  9. Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice.

    PubMed Central

    Zhang, R. D.; Price, J. E.; Fujimaki, T.; Bucana, C. D.; Fidler, I. J.

    1992-01-01

    This study clarified whether and when the blood-brain barrier in experimental brain metastases is impaired by using hydrosoluble sodium fluorescein (MW 376) as a blood-brain barrier function indicator. Cells from eight human tumor lines (four melanomas, two breast carcinomas, one colon carcinoma, and one renal carcinoma) were inoculated into the internal carotid artery of nude mice. Brain metastases at different stages of development were sampled and the permeability of the blood-brain barrier around the metastases determined. Histologic examination showed two patterns of tumor growth. In the first, tumor cells formed isolated, well-defined nodules in the parenchyma of the brain. In lesions smaller than 0.2 mm2, the blood-brain barrier was intact. In the second, small diffuse nests of tumor cells were distributed throughout the brain parenchyma. The blood-brain barrier was intact until the small tumor cell colonies coalesced to form large tumor masses. These results suggest that the permeability of the blood-brain barrier varies among different experimental brain metastases and that its function is related to the growth pattern and size of the lesions. Images Figure 1 Figure 5 Figure 6 PMID:1443046

  10. Interleukin-34 restores blood-brain barrier integrity by upregulating tight junction proteins in endothelial cells.

    PubMed

    Jin, Shijie; Sonobe, Yoshifumi; Kawanokuchi, Jun; Horiuchi, Hiroshi; Cheng, Yi; Wang, Yue; Mizuno, Tetsuya; Takeuchi, Hideyuki; Suzumura, Akio

    2014-01-01

    Interleukin-34 (IL-34) is a newly discovered cytokine as an additional ligand for colony stimulating factor-1 receptor (CSF1R), and its functions are expected to overlap with colony stimulating factor-1/macrophage-colony stimulating factor. We have previously shown that the IL-34 is primarily produced by neurons in the central nervous system (CNS) and induces proliferation and neuroprotective properties of microglia which express CSF1R. However, the functions of IL-34 in the CNS are still elucidative. Here we show that CNS capillary endothelial cells also express CSF1R. IL-34 protected blood-brain barrier integrity by restored expression levels of tight junction proteins, which were downregulated by pro-inflammatory cytokines. The novel function of IL-34 on the blood-brain barrier may give us a clue for new therapeutic strategies in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease.

  11. Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

    PubMed Central

    Bertrand, Luc; Dygert, Levi; Toborek, Michal

    2016-01-01

    The introduction of antiretroviral drugs (ARVd) changed the prognosis of HIV infection from a deadly disease to a chronic disease. However, even with undetectable viral loads, patients still develop a wide range of pathologies, including cerebrovascular complications and stroke. It is hypothesized that toxic side effects of ARVd may contribute to these effects. To address this notion, we evaluated the impact of several non-nucleoside reverse transcriptase inhibitors (NNRTI; Efavirenz, Etravirine, Rilpivirine and Nevirapine) on the integrity of the blood-brain barrier, and their impact on severity of stroke. Among studied drugs, Efavirenz, but not other NNRTIs, altered claudin-5 expression, increased endothelial permeability, and disrupted the blood-brain barrier integrity. Importantly, Efavirenz exposure increased the severity of stroke in a model of middle cerebral artery occlusion in mice. Taken together, these results indicate that selected ARVd can exacerbate HIV-associated cerebrovascular pathology. Therefore, careful consideration should be taken when choosing an anti-retroviral therapy regimen. PMID:28008980

  12. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells.

    PubMed

    Lippmann, Ethan S; Azarin, Samira M; Kay, Jennifer E; Nessler, Randy A; Wilson, Hannah K; Al-Ahmad, Abraham; Palecek, Sean P; Shusta, Eric V

    2012-08-01

    The blood-brain barrier (BBB) is crucial to the health of the brain and is often compromised in neurological disease. Moreover, because of its barrier properties, this endothelial interface restricts uptake of neurotherapeutics. Thus, a renewable source of human BBB endothelium could spur brain research and pharmaceutical development. Here we show that endothelial cells derived from human pluripotent stem cells (hPSCs) acquire BBB properties when co-differentiated with neural cells that provide relevant cues, including those involved in Wnt/β-catenin signaling. The resulting endothelial cells have many BBB attributes, including well-organized tight junctions, appropriate expression of nutrient transporters and polarized efflux transporter activity. Notably, they respond to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance (1,450 ± 140 Ω cm2), and they possess molecular permeability that correlates well with in vivo rodent blood-brain transfer coefficients.

  13. Morphologic Effect of Dimethyl Sulfoxide on the Blood-Brain Barrier

    NASA Astrophysics Data System (ADS)

    Broadwell, Richard D.; Salcman, Michael; Kaplan, Richard S.

    1982-07-01

    Dimethyl sulfoxide (DMSO) opens the blood-brain barrier of mice to the enzymatic tracer horseradish peroxidase. A single injection of horseradish peroxidase in 10 to 15 percent DMSO into the tail vein along with 10 to 15 percent DMSO delivered intraperitoneally allowed horseradish peroxidase to fill the extracellular clefts throughout the brain within 2 hours. In the absence of DMSO, peroxidase failed to enter brain parenchyma except through the circumventricular organs. Opening of the blood-brain barrier by DMSO is reversible. Dimethyl sulfoxide stimulated the pinocytosis of horseradish peroxidase by the cerebral endothelium; the peroxidase was then directed to lysosomal dense bodies for degradation. Vesicular transport of horseradish peroxidase from the luminal to the abluminal wall of the endothelial cell was not observed. Dimethyl sulfoxide did not alter the morphology of endothelial cells or brain parenchyma.

  14. Atomistic modeling of the structural components of the blood-brain barrier

    NASA Astrophysics Data System (ADS)

    Glukhova, O. E.; Grishina, O. A.; Slepchenkov, M. M.

    2015-03-01

    Blood-brain barrier, which is a barrage system between the brain and blood vessels, plays a key role in the "isolation" of the brain of unnecessary information, and reduce the "noise" in the interneuron communication. It is known that the barrier function of the BBB strictly depends on the initial state of the organism and changes significantly with age and, especially in developing the "vascular accidents". Disclosure mechanisms of regulation of the barrier function will develop new ways to deliver neurotrophic drugs to the brain in the newborn. The aim of this work is the construction of atomistic models of structural components of the blood-brain barrier to reveal the mechanisms of regulation of the barrier function.

  15. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    PubMed

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.

  16. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

    PubMed Central

    Sarin, Hemant; Kanevsky, Ariel S; Wu, Haitao; Brimacombe, Kyle R; Fung, Steve H; Sousa, Alioscka A; Auh, Sungyoung; Wilson, Colin M; Sharma, Kamal; Aronova, Maria A; Leapman, Richard D; Griffiths, Gary L; Hall, Matthew D

    2008-01-01

    Background Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells. Methods Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging. Results We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells. Conclusion The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives. PMID:19094226

  17. Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

    NASA Astrophysics Data System (ADS)

    Rosenstein, Jeffrey M.

    1987-02-01

    In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

  18. Influence of antioxidants on blood-brain barrier permeability during adrenaline-induced hypertension.

    PubMed

    Oztaş, B; Erkin, E; Dural, E; Isbir, T

    2000-11-01

    We have examined the effect of antioxidants (vitamin E, and selenium) on the blood-brain barrier permeability during adreneline-induced acute hypertension in the female rats. The rats supplemented with nontoxic doses of sodium selenite in drinking water for three months or vitamin E was given intraperitoneally before adrenaline-induced acute hypertension. Evans-blue was used as a blood-brain barrier tracer. Mean values for Evans-blue dye were found to be 0.28 +/- 0.04 microg/g tissue in control animals and 1.0 +/- 0.2 microg tissue after adrenaline-induced acute hypertension (p < .01). Rats pretreated with selenium or vitamin E also showed macroscopic leakage of Evans-blue albumin after adrenaline injection i.e., there was no significant difference in protein extravasation between untreated and treated animals (p > .5). The mean value for Evans-blue dye was found to be 1.0 +/- 0.2 microg/g tissue in acute hypertension group, 0.9 +/- 0.2 microg/g tissue in selenium pretreated animals and 1.0 +/- 0.2 micrg/g tissue vitamin E injected animals after acute hypertension. The results show that antioxidants did not influence the blood-brain barrier breakdown during adrenaline-induced acute hypertension.

  19. Hypomyelination, memory impairment, and blood-brain barrier permeability in a model of sleep apnea.

    PubMed

    Kim, Lenise Jihe; Martinez, Denis; Fiori, Cintia Zappe; Baronio, Diego; Kretzmann, Nélson Alexandre; Barros, Helena Maria Tannhauser

    2015-02-09

    We investigated the effect of intermittent hypoxia, mimicking sleep apnea, on axonal integrity, blood-brain barrier permeability, and cognitive function of mice. Forty-seven C57BL mice were exposed to intermittent or sham hypoxia, alternating 30s of progressive hypoxia and 30s of reoxigenation, during 8h/day. The axonal integrity in cerebellum was evaluated by transmission electron microscopy. Short- and long-term memories were assessed by novel object recognition test. The levels of endothelin-1 were measured by ELISA. Blood-brain barrier permeability was quantified by Evans Blue dye. After 14 days, animals exposed to intermittent hypoxia showed hypomyelination in cerebellum white matter and higher serum levels of endothelin-1. The short and long-term memories in novel object recognition test was impaired in the group exposed to intermittent hypoxia as compared to controls. Blood-brain barrier permeability was similar between the groups. These results indicated that hypomyelination and impairment of short- and long-term working memories occurred in C57BL mice after 14 days of intermittent hypoxia mimicking sleep apnea.

  20. Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters.

    PubMed Central

    Agus, D B; Gambhir, S S; Pardridge, W M; Spielholz, C; Baselga, J; Vera, J C; Golde, D W

    1997-01-01

    Vitamin C concentrations in the brain exceed those in blood by 10-fold. In both tissues, the vitamin is present primarily in the reduced form, ascorbic acid. We identified the chemical form of vitamin C that readily crosses the blood-brain barrier, and the mechanism of this process. Ascorbic acid was not able to cross the blood-brain barrier in our studies. In contrast, the oxidized form of vitamin C, dehydroascorbic acid (oxidized ascorbic acid), readily entered the brain and was retained in the brain tissue in the form of ascorbic acid. Transport of dehydroascorbic acid into the brain was inhibited by d-glucose, but not by l-glucose. The facilitative glucose transporter, GLUT1, is expressed on endothelial cells at the blood-brain barrier, and is responsible for glucose entry into the brain. This study provides evidence showing that GLUT1 also transports dehydroascorbic acid into the brain. The findings define the transport of dehydroascorbic acid by GLUT1 as a mechanism by which the brain acquires vitamin C, and point to the oxidation of ascorbic acid as a potentially important regulatory step in accumulation of the vitamin by the brain. These results have implications for increasing antioxidant potential in the central nervous system. PMID:9389750

  1. Blood--brain barrier sodium/potassium pump: modulation by central noradrenergic innervation.

    PubMed

    Harik, S I

    1986-06-01

    The active transport of Na+ and K+ across the blood--brain barrier by the membrane-bound enzyme Na+/K+-activated ATPase of brain microvessel endothelial cells has a major role in the maintenance of brain water and electrolyte homeostasis. To test whether the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus contributes to the regulation of Na+/K+-ATPase activity of the blood--brain barrier, specific [3H]ouabain-binding studies were performed on cerebral microvessels and crude cortical membranes obtained from Wistar rats with unilateral 6-hydroxydopamine lesion of the nucleus locus ceruleus. Such lesion depleted norepinephrine by about 90% in the ipsilateral cerebral cortex without affecting the contralateral cortex. [3H]Ouabain binding to membranes of cerebral cortex and the cerebral microvessels was specific and saturable. The maximal ouabain-binding capacity in microvessels of the ipsilateral, norepinephrine-depleted, cerebral cortex was reduced by about 40%, without change in the affinity of binding. [3H]Ouabain binding to crude membrane fractions of the cerebral cortex was not significantly affected by locus ceruleus lesion. The results suggest that Na+/K+-ATPase activity of cerebral microvessels, and the consequent transport of Na+ and K+ across the blood--brain barrier, is modulated by noradrenergic innervation from the locus ceruleus.

  2. Screening of pesticides for environmental partitioning tendency.

    PubMed

    Gramatica, Paola; Di Guardo, Antonio

    2002-06-01

    The partitioning tendency of chemicals, in this study pesticides in particular, into different environmental compartments depends mainly on the concurrent relevance of the physico-chemical properties of the chemical itself. To rank the pesticides according to their distribution tendencies in the different environmental compartments we propose a multivariate approach: the combination, by principal component analysis, of those physico-chemical properties like organic carbon partition coefficient (Koc), n-octanol/water partition coefficient (Kow), water solubility (Sw), vapour pressure and Henry's law constant (H) that are more relevant to the determination of environmental partitioning. The resultant macrovariables, the PC1 and PC2 scores here named leaching index (LIN) and volatality index (VIN), are proposed as preliminary environmental partitioning indexes in different media. These two indexes are modeled by theoretical molecular descriptors with satisfactory predictive power. Such an approach allows a rapid pre-determination and screening of the environmental distribution of pesticides starting only from the molecular structure of the pesticide, without any a priori knowledge of the physico-chemical properties.

  3. A biologically motivated partitioning of mortality.

    PubMed

    Carnes, B A; Olshansky, S J

    1997-01-01

    For over a century, actuaries and biologists working independently of each other have presented arguments for why total mortality needs to be partitioned into biologically meaningful subcomponents. These mortality partitions tended to overlook genetic diseases that are inherited because the partitions were motivated by a paradigm focused on aging. In this article, we combine and extend the concepts from these disciplines to develop a conceptual partitioning of total mortality into extrinsic and intrinsic causes of death. An extrinsic death is either caused or initiated by something that orginates outside the body of an individual, while an intrinsic death is either caused or initiated by processes that originate within the body. It is argued that extrinsic mortality has been a driving force in determining why we die when we do from intrinsic causes of death. This biologically motivated partitioning of mortality provides a useful perspective for researchers interested in comparative mortality analyses, the consequences of population aging, limits to human life expectancy, the progress made by the biomedical sciences against lethal diseases, and demographic models that predict the life expectancy of future populations.

  4. Octanol/air partitioning of polychlorinated biphenyls

    SciTech Connect

    Komp, P.; McLachlan, M.S.

    1997-12-01

    The partitioning of 16 polychlorinated biphenyls (PCBs) between air and 1-octanol was investigated using a fugacity meter. The measurements were conducted over an environmentally relevant temperature range (10--43 C). For a given congener the measured 1-octanol/air partition coefficient K{sub OA} was exponentially proportional to the reciprocal temperature. The enthalpy of phase change (octanol to air) {Delta}H{sub OA} ranged from 71 to 93 kJ/mol. Up to log K{sub OA} values of 9.37 (corresponding to 2,2{prime},3,4{prime},5{prime},6-hexachlorobiphenyl), the enthalpy of phase change was similar to the enthalpy of vaporization of the subcooled liquid PCB. For the less volatile congeners (log K{sub OA} > 9.37), the enthalpies of vaporization exceeded the enthalpies of phase change, the difference increasing with increasing log K{sub OA}. Solubilities of the PCBs in 1-octanol were calculated from the data, and the results were in excellent agreement with octanol solubilities calculated using the OCTASOL fragment method. A very good correlation between the measured octanol/air partition coefficients and values calculated from octanol/water and air/water partition coefficients was obtained. This yielded a method to estimate reliably the octanol/air partitioning of all PCB congeners.

  5. Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship with CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

    PubMed Central

    Chau, Tran Thi Hong; Fisher, Martin; Nelson, Mark; Winston, Alan; Else, Laura; Carr, Daniel F.; Taylor, Steven; Ustianowski, Andrew; Back, David; Pirmohamed, Munir; Solomon, Tom; Farrar, Jeremy; Törok, M. Estée; Khoo, Saye

    2016-01-01

    Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitro and in vivo data. The effect of the CYP2B6 c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitro toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitro toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6 genotype, particularly in those

  6. The EPRL intertwiners and corrected partition function

    NASA Astrophysics Data System (ADS)

    Kamiński, Wojciech; Kisielowski, Marcin; Lewandowski, Jerzy

    2010-08-01

    Do the SU(2) intertwiners parametrize the space of the Engle, Pereira, Rovelli, Livine (EPRL) solutions to the simplicity constraint? What is the complete form of the partition function written in terms of this parametrization? We prove that the EPRL map is injective in the general n-valent vertex case for the Barbero-Immirzi parameter less than 1. We find, however, that the EPRL map is not isometric. In the consequence, a partition function can be defined either using the EPRL intertwiners Hilbert product or the SU(2) intertwiners Hilbert product. We use the EPRL one and derive a new, complete formula for the partition function. Next, we view it in terms of the SU(2) intertwiners. The result, however, goes beyond the SU(2) spin-foam models' framework and the original EPRL proposal.

  7. New parallel SOR method by domain partitioning

    SciTech Connect

    Xie, D.; Adams, L.

    1999-07-01

    In this paper the authors propose and analyze a new parallel SOR method, the PSOR method, formulated by using domain partitioning and interprocessor data communication techniques. They prove that the PSOR method has the same asymptotic rate of convergence as the Red/Black (R/B) SOR method for the five-point stencil on both strip and block partitions, and as the four-color (R/B/G/O) SOR method for the nine-point stencil on strip partitions. They also demonstrate the parallel performance of the PSOR method on four different MIMD multiprocessors (a KSR1, an Intel Delta, a Paragon, and an IBM SP2). Finally, they compare the parallel performance of PSOR, R/B SOR, and R/B/G/O SOR. Numerical results on the Paragon indicate that PSOR is more efficient than R/B SOR and R/B/G/O SOR in both computation and interprocessor data communication.

  8. Factorization of the bosonic partition function

    NASA Astrophysics Data System (ADS)

    Alsharafat, Ayed; Chair, Noureddine

    2017-04-01

    The factorization formula in the non-interacting quantum field theories that relates the fermionic partition function to the bosonic partition function considered recently by Chair (2013) [3] is obtained for the harmonic oscillator using the path integral formulation. By using the latter, the fermionic partition function turns out to be the ratio of two determinants of the same operator (∂τ + ω), whose eigenmodes being both periodic on the imaginary time intervals [ 0 , 2 β ], [ 0 , β ]. The natural generalization of the factorization formula when β →2m β is derived, such a factorization implies that the bosonic oscillator at temperature β can be seen as a non-interacting mixture of a bosonic oscillator at temperature 2m β and m-fermionic oscillators at different temperatures 2 m - k β, k = 1 , 2 , … , m. As a consequence, a general relationship between the bosonic and fermionic thermal zeta functions is deduced.

  9. Parallel algorithms for dynamically partitioning unstructured grids

    SciTech Connect

    Diniz, P.; Plimpton, S.; Hendrickson, B.; Leland, R.

    1994-10-01

    Grid partitioning is the method of choice for decomposing a wide variety of computational problems into naturally parallel pieces. In problems where computational load on the grid or the grid itself changes as the simulation progresses, the ability to repartition dynamically and in parallel is attractive for achieving higher performance. We describe three algorithms suitable for parallel dynamic load-balancing which attempt to partition unstructured grids so that computational load is balanced and communication is minimized. The execution time of algorithms and the quality of the partitions they generate are compared to results from serial partitioners for two large grids. The integration of the algorithms into a parallel particle simulation is also briefly discussed.

  10. Partitioning SAT Instances for Distributed Solving

    NASA Astrophysics Data System (ADS)

    Hyvärinen, Antti E. J.; Junttila, Tommi; Niemelä, Ilkka

    In this paper we study the problem of solving hard propositional satisfiability problem (SAT) instances in a computing grid or cloud, where run times and communication between parallel running computations are limited.We study analytically an approach where the instance is partitioned iteratively into a tree of subproblems and each node in the tree is solved in parallel.We present new methods for constructing partitions which combine clause learning and lookahead. The methods are incorporated into the iterative approach and its performance is demonstrated with an extensive comparison against the best sequential solvers in the SAT competition 2009 as well as against two efficient parallel solvers.

  11. Chiral partition functions of quantum Hall droplets

    SciTech Connect

    Cappelli, Andrea Viola, Giovanni; Zemba, Guillermo R.

    2010-02-15

    Chiral partition functions of conformal field theory describe the edge excitations of isolated Hall droplets. They are characterized by an index specifying the quasiparticle sector and transform among themselves by a finite-dimensional representation of the modular group. The partition functions are derived and used to describe electron transitions leading to Coulomb blockade conductance peaks. We find the peak patterns for Abelian hierarchical states and non-Abelian Read-Rezayi states, and compare them. Experimental observation of these features can check the qualitative properties of the conformal field theory description, such as the decomposition of the Hilbert space into sectors, involving charged and neutral parts, and the fusion rules.

  12. Cochlear implant in incomplete partition type I.

    PubMed

    Berrettini, S; Forli, F; De Vito, A; Bruschini, L; Quaranta, N

    2013-02-01

    In this investigation, we report on 4 patients affected by incomplete partition type I submitted to cochlear implant at our institutions. Preoperative, surgical, mapping and follow-up issues as well as results in cases with this complex malformation are described. The cases reported in the present study confirm that cochlear implantation in patients with incomplete partition type I may be challenging for cochlear implant teams. The results are variable, but in many cases satisfactory, and are mainly related to the surgical placement of the electrode and residual neural nerve fibres. Moreover, in some cases the association of cochlear nerve abnormalities and other disabilities may significantly affect results.

  13. Partitioning and lipophilicity in quantitative structure-activity relationships.

    PubMed Central

    Dearden, J C

    1985-01-01

    The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available. PMID:3905374

  14. Equivalence of partition properties and determinacy

    PubMed Central

    Kechris, Alexander S.; Woodin, W. Hugh

    1983-01-01

    It is shown that, within L(ℝ), the smallest inner model of set theory containing the reals, the axiom of determinacy is equivalent to the existence of arbitrarily large cardinals below Θ with the strong partition property κ → (κ)κ. PMID:16593299

  15. Mapping Pesticide Partition Coefficients By Electromagnetic Induction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A potential method for reducing pesticide leaching is to base application rates on the leaching potential of a specific chemical and soil combination. However, leaching is determined in part by the partitioning of the chemical between the soil and soil solution, which varies across a field. Standard...

  16. Solute partitioning and filtration by extracellular matrices

    PubMed Central

    Hofmann, Christina L.; Ferrell, Nicholas; Schnell, Lisa; Dubnisheva, Anna; Zydney, Andrew L.; Yurchenco, Peter D.; Roy, Shuvo

    2009-01-01

    The physiology of glomerular filtration remains mechanistically obscure despite its importance in disease. The correspondence between proteinuria and foot process effacement suggests podocytes as the locus of the filtration barrier. If so, retained macromolecules ought to accumulate at the filtration barrier, an effect called concentration polarization. Literature data indicate macromolecule concentrations decrease from subendothelial to subepithelial glomerular basement membrane (GBM), as would be expected if the GBM were itself the filter. The objective of this study was to obtain insights into the possible role of the GBM in protein retention by performing fundamental experimental and theoretical studies on the properties of three model gels. Solute partitioning and filtration through thin gels of a commercially available laminin-rich extracellular matrix, Matrigel, were measured using a polydisperse polysaccharide tracer molecule, Ficoll 70. Solute partitioning into laminin gels and lens basement membrane (LBM) were measured using Ficoll 70. A novel model of a laminin gel was numerically simulated, as well as a mixed structure-random-fiber model for LBM. Experimental partitioning was predicted by numerical simulations. Sieving coefficients through thin gels of Matrigel were size dependent and strongly flux dependent. The observed flux dependence arose from compression of the gel in response to the applied pressure. Gel compression may alter solute partitioning into extracellular matrix at physiologic pressures present in the glomerular capillary. This suggests a physical mechanism coupling podocyte structure to permeability characteristics of the GBM. PMID:19587146

  17. A review of approaches for evapotranspiration partitioning

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Partitioning of evapotranspiration (ET) into evaporation from the soil surface (E) and transpiration (T) is challenging but important in order to assess biomass production and the allocation of increasingly scarce water resources. Generally T is the desired component with the water being used to enh...

  18. A Partition Formula for Fibonacci Numbers

    NASA Astrophysics Data System (ADS)

    Fahr, Philipp; Ringerl, Claus Michael

    2008-02-01

    We present a partition formula for the even index Fibonacci numbers. The formula is motivated by the appearance of these Fibonacci numbers in the representation theory of the socalled 3-Kronecker quiver, i.e., the oriented graph with two vertices and three arrows in the same direction.

  19. 25 CFR 152.33 - Partition.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER ISSUANCE OF PATENTS IN FEE, CERTIFICATES OF COMPETENCY, REMOVAL OF RESTRICTIONS, AND SALE OF CERTAIN INDIAN LANDS Partitions in Kind of Inherited Allotments § 152..., regardless of their competency, patents in fee to be issued to the competent heirs for their shares and...

  20. 25 CFR 152.33 - Partition.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER ISSUANCE OF PATENTS IN FEE, CERTIFICATES OF COMPETENCY, REMOVAL OF RESTRICTIONS, AND SALE OF CERTAIN INDIAN LANDS Partitions in Kind of Inherited Allotments § 152..., regardless of their competency, patents in fee to be issued to the competent heirs for their shares and...

  1. 25 CFR 152.33 - Partition.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER ISSUANCE OF PATENTS IN FEE, CERTIFICATES OF COMPETENCY, REMOVAL OF RESTRICTIONS, AND SALE OF CERTAIN INDIAN LANDS Partitions in Kind of Inherited Allotments § 152..., regardless of their competency, patents in fee to be issued to the competent heirs for their shares and...

  2. 25 CFR 152.33 - Partition.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER ISSUANCE OF PATENTS IN FEE, CERTIFICATES OF COMPETENCY, REMOVAL OF RESTRICTIONS, AND SALE OF CERTAIN INDIAN LANDS Partitions in Kind of Inherited Allotments § 152..., regardless of their competency, patents in fee to be issued to the competent heirs for their shares and...

  3. 25 CFR 152.33 - Partition.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER ISSUANCE OF PATENTS IN FEE, CERTIFICATES OF COMPETENCY, REMOVAL OF RESTRICTIONS, AND SALE OF CERTAIN INDIAN LANDS Partitions in Kind of Inherited Allotments § 152..., regardless of their competency, patents in fee to be issued to the competent heirs for their shares and...

  4. Set Partitions and the Multiplication Principle

    ERIC Educational Resources Information Center

    Lockwood, Elise; Caughman, John S., IV

    2016-01-01

    To further understand student thinking in the context of combinatorial enumeration, we examine student work on a problem involving set partitions. In this context, we note some key features of the multiplication principle that were often not attended to by students. We also share a productive way of thinking that emerged for several students who…

  5. Zr partitioning and kinetics and mechanism

    NASA Technical Reports Server (NTRS)

    Taylor, L. A.

    1973-01-01

    The results of investigations concerning the cooling histories of lunar rocks are reported. Publications resulting from this research are listed. Studies discussed include the partitioning of Zr between FeTi03 and Fe2Ti04 in the presence of Fe + Zr02, and ulvospinel reduction.

  6. Application of partition technology to particle electrophoresis

    NASA Technical Reports Server (NTRS)

    Van Alstine, James M.; Harris, J. Milton; Karr, Laurel J.; Bamberger, Stephan; Matsos, Helen C.; Snyder, Robert S.

    1989-01-01

    The effects of polymer-ligand concentration on particle electrophoretic mobility and partition in aqueous polymer two-phase systems are investigated. Polymer coating chemistry and affinity ligand synthesis, purification, and analysis are conducted. It is observed that poly (ethylene glycol)-ligands are effective for controlling particle electrophoretic mobility.

  7. Agent based modeling of the effects of potential treatments over the blood-brain barrier in multiple sclerosis.

    PubMed

    Pennisi, Marzio; Russo, Giulia; Motta, Santo; Pappalardo, Francesco

    2015-12-01

    Multiple sclerosis is a disease of the central nervous system that involves the destruction of the insulating sheath of axons, causing severe disabilities. Since the etiology of the disease is not yet fully understood, the use of novel techniques that may help to understand the disease, to suggest potential therapies and to test the effects of candidate treatments is highly advisable. To this end we developed an agent based model that demonstrated its ability to reproduce the typical oscillatory behavior observed in the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis. The model has then been used to test the potential beneficial effects of vitamin D over the disease. Many scientific studies underlined the importance of the blood-brain barrier and of the mechanisms that influence its permeability on the development of the disease. In the present paper we further extend our previously developed model with a mechanism that mimics the blood-brain barrier behavior. The goal of our work is to suggest the best strategies to follow for developing new potential treatments that intervene in the blood-brain barrier. Results suggest that the best treatments should potentially prevent the opening of the blood-brain barrier, as treatments that help in recovering the blood-brain barrier functionality could be less effective.

  8. Isotope fractionation of benzene during partitioning - Revisited.

    PubMed

    Kopinke, F-D; Georgi, A; Imfeld, G; Richnow, H-H

    2017-02-01

    Isotope fractionation between benzene-D0 and benzene-D6 caused by multi-step partitioning of the benzenes between water and two organic solvents, n-octane and 1-octanol, as well as between water and the gas phase, was measured. The obtained fractionation factors αH = KH/KD are αH = 1.080 ± 0.015 and αH = 1.074 ± 0.015 for extraction into n-octane and 1-octanol, respectively, and αH = 1.049 ± 0.010 for evaporation from aqueous solution. The comparison of solvent- and gas-phase partitioning reveals that about 2/3 of the driving force of fractionation is due to different interactions in the aqueous phase, whereas 1/3 is due to different interactions in the organic phase. The heavy benzene isotopologue behaves more 'hydrophilically' and the light one more 'hydrophobically'. This synergistic alignment gives rise to relatively large fractionation effects in partitioning between water and non-polar organic matter. In contrast to a previous study, there is no indication of strong fractionation by specific interactions between benzene and octanol. Partitioning under non-equilibrium conditions yields smaller apparent fractionation effects due to opposite trends of thermodynamic and kinetic fractionation parameters, i.e. partition and diffusion coefficients of the isotopologues. This may have consequences which should be taken into account when considering isotope fractionation due to sorption in environmental compartments.

  9. Open software tools for eddy covariance flux partitioning

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Agro-ecosystem management and assessment will benefit greatly from the development of reliable techniques for partitioning evapotranspiration (ET) into evaporation (E) and transpiration (T). Among other activities, flux partitioning can aid in evaluating consumptive vs. non-consumptive agricultural...

  10. Neutralizing anti-interleukin-1β antibodies modulate fetal blood-brain barrier function after ischemia.

    PubMed

    Chen, Xiaodi; Sadowska, Grazyna B; Zhang, Jiyong; Kim, Jeong-Eun; Cummings, Erin E; Bodge, Courtney A; Lim, Yow-Pin; Makeyev, Oleksandr; Besio, Walter G; Gaitanis, John; Threlkeld, Steven W; Banks, William A; Stonestreet, Barbara S

    2015-01-01

    We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1β monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1β protein. This antibody also neutralizes the effects of interleukin-1β protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1β monoclonal antibody attenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 min of carotid occlusion and 24h of reperfusion. Groups were sham operated placebo-control- (n=5), ischemia-placebo- (n=6), ischemia-anti-IL-1β antibody- (n=7), and sham-control antibody- (n=2) treated animals. Systemic infusions of placebo (0.154M NaCl) or anti-interleukin-1β monoclonal antibody (5.1±0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4h after ischemia. Concentrations of interleukin-1β protein and anti-interleukin-1β monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with α-aminoisobutyric acid in multiple brain regions. Interleukin-1β protein was also measured in parietal cerebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1β protein increased (P<0.001) after ischemia-reperfusion. After anti-interleukin-1β monoclonal antibody infusions, plasma anti-interleukin-1β monoclonal antibody was elevated (P<0.001), brain anti-interleukin-1β monoclonal antibody levels were higher (P<0

  11. Using Reward/Utility Based Impact Scores in Partitioning

    DTIC Science & Technology

    2014-05-01

    ing approach called Reward/Utility-Based Impact ( RUBI ). RUBI nds an e ective partitioning of agents while requir- ing no prior domain knowledge...provides better performance by discovering a non-trivial agent partitioning, and leads to faster simulations. We test RUBI in the Air Tra c Flow Management...partitioning with RUBI in the ATFMP, there is a 37% increase in per- formance, with a 510x speed up per simulation step over non-partitioning approaches

  12. Blood-brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood-central nervous system interface.

    PubMed

    Phan, Duc Tt; Bender, R Hugh F; Andrejecsk, Jillian W; Sobrino, Agua; Hachey, Stephanie J; George, Steven C; Hughes, Christopher Cw

    2017-01-01

    The blood-brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood-brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer's disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood-brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood-brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood-brain barrier pathology, recent advances in the development of novel 3D blood-brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood-brain barrier, and provide an outlook on how these blood-brain barrier-on-a-chip systems can be used for central nervous system disease modeling.

  13. Transfer of opiorphin through a blood-brain barrier culture model.

    PubMed

    Bocsik, Alexandra; Darula, Zsuzsanna; Tóth, Géza; Deli, Mária A; Wollemann, Mária

    2015-08-01

    Opioid peptides are potent analgesics with therapeutic potential in the treatment of acute and chronic pain. Their efficacy is limited by peptidases (enkephalinases). Opiorphin pentapeptide (QRFSR) is the first characterized human endogenous inhibitor of enkephalinases. The peptide is able to increase the binding and affinity of endogenous opiates to mu opioid receptors; thus, the mechanism of opiorphin may provide a new therapeutic approach in pain management. The analgesic effect of opiorphin was proven in several earlier published in vitro and in vivo studies. Our aim was to test the transfer of opiorphin through a blood-brain barrier model for the first time. The flux of opiorphin was tested on a blood-brain barrier culture model consisting of rat brain endothelial, glial and pericyte cells. Brain endothelial cells in this triple co-culture model form tight monolayers characterized by transendothelial electrical resistance measurement. Relative quantity of the peptide was estimated by mass spectrometry. The transfer of opiorphin through the blood-brain barrier model was estimated to be ∼3%, whereas the permeability coefficient was 0.53 ± 1.36 × 10(-6) cm/s (n = 4). We also observed rapid conversion of N-terminal glutamine into pyroglutamic acid during the transfer experiments. Our results indicate that opiorphin crosses cultured brain endothelial cells in the absence of serum factors in a significant amount. This is in agreement with previous in vivo data showing potentiation of enkephalin-mediated antinociception. We suggest that opiorphin may have a potential as a centrally acting novel drug to treat pain.

  14. Restraint Stress-Induced Morphological Changes at the Blood-Brain Barrier in Adult Rats

    PubMed Central

    Sántha, Petra; Veszelka, Szilvia; Hoyk, Zsófia; Mészáros, Mária; Walter, Fruzsina R.; Tóth, Andrea E.; Kiss, Lóránd; Kincses, András; Oláh, Zita; Seprényi, György; Rákhely, Gábor; Dér, András; Pákáski, Magdolna; Kálmán, János; Kittel, Ágnes; Deli, Mária A.

    2016-01-01

    Stress is well-known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognized in the development of neurodegenerative disorders, such as Alzheimer's disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3, and 21 days) were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occluding, and glucose transporter-1) and astroglia (GFAP). Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, 1-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5, and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes, cognitive and

  15. Gap Junction Proteins in the Blood-Brain Barrier Control Nutrient-Dependent Reactivation of Drosophila Neural Stem Cells

    PubMed Central

    Spéder, Pauline; Brand, Andrea H.

    2014-01-01

    Summary Neural stem cells in the adult brain exist primarily in a quiescent state but are reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila CNS, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/insulin-like growth factor pathway in underlying neural stem cells and stimulating their growth and proliferation. Here we show that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behavior, enabling glia to respond to nutritional signals and reactivate quiescent stem cells. We propose that gap junctions in the blood-brain barrier are required to translate metabolic signals into synchronized calcium pulses and insulin secretion. PMID:25065772

  16. 47 CFR 27.904 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 2 2011-10-01 2011-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1670-1675 MHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  17. 47 CFR 27.805 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 2 2011-10-01 2011-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1.4 GHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  18. 47 CFR 90.911 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.911 Partitioned licenses and disaggregated spectrum. (a) Eligibility...) that constitute the partitioned area. (2) Disaggregation. Spectrum may be disaggregated in any...

  19. 47 CFR 27.805 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 2 2012-10-01 2012-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1.4 GHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  20. 47 CFR 90.911 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.911 Partitioned licenses and disaggregated spectrum. (a) Eligibility...) that constitute the partitioned area. (2) Disaggregation. Spectrum may be disaggregated in any...

  1. 47 CFR 90.911 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.911 Partitioned licenses and disaggregated spectrum. (a) Eligibility...) that constitute the partitioned area. (2) Disaggregation. Spectrum may be disaggregated in any...

  2. 47 CFR 95.823 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. Parties seeking Commission approval of geographic partitioning or spectrum disaggregation of 218-219 MHz Service system licenses shall request...

  3. 47 CFR 27.904 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 2 2012-10-01 2012-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1670-1675 MHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  4. 47 CFR 27.904 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 2 2010-10-01 2010-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1670-1675 MHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  5. 47 CFR 27.805 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 2 2013-10-01 2013-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1.4 GHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  6. 47 CFR 27.904 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 2 2014-10-01 2014-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1670-1675 MHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  7. 47 CFR 95.823 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. Parties seeking Commission approval of geographic partitioning or spectrum disaggregation of 218-219 MHz Service system licenses shall request...

  8. 47 CFR 90.813 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.813 Partitioned licenses and disaggregated spectrum. (a) Eligibility.... Spectrum may be disaggregated in any amount. (3) Combined partitioning and disaggregation. The...

  9. 47 CFR 90.813 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.813 Partitioned licenses and disaggregated spectrum. (a) Eligibility.... Spectrum may be disaggregated in any amount. (3) Combined partitioning and disaggregation. The...

  10. 47 CFR 90.911 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.911 Partitioned licenses and disaggregated spectrum. (a) Eligibility...) that constitute the partitioned area. (2) Disaggregation. Spectrum may be disaggregated in any...

  11. 47 CFR 90.813 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.813 Partitioned licenses and disaggregated spectrum. (a) Eligibility.... Spectrum may be disaggregated in any amount. (3) Combined partitioning and disaggregation. The...

  12. 47 CFR 27.904 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 2 2013-10-01 2013-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1670-1675 MHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  13. 47 CFR 95.823 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. Parties seeking Commission approval of geographic partitioning or spectrum disaggregation of 218-219 MHz Service system licenses shall request...

  14. 47 CFR 90.813 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.813 Partitioned licenses and disaggregated spectrum. (a) Eligibility.... Spectrum may be disaggregated in any amount. (3) Combined partitioning and disaggregation. The...

  15. 47 CFR 90.911 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.911 Partitioned licenses and disaggregated spectrum. (a) Eligibility...) that constitute the partitioned area. (2) Disaggregation. Spectrum may be disaggregated in any...

  16. 47 CFR 95.823 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. Parties seeking Commission approval of geographic partitioning or spectrum disaggregation of 218-219 MHz Service system licenses shall request...

  17. 47 CFR 27.805 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 2 2014-10-01 2014-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1.4 GHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  18. 47 CFR 95.823 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. Parties seeking Commission approval of geographic partitioning or spectrum disaggregation of 218-219 MHz Service system licenses shall request...

  19. 47 CFR 90.813 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Partitioned licenses and disaggregated spectrum... Specialized Mobile Radio Service § 90.813 Partitioned licenses and disaggregated spectrum. (a) Eligibility.... Spectrum may be disaggregated in any amount. (3) Combined partitioning and disaggregation. The...

  20. 47 CFR 27.805 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 2 2010-10-01 2010-10-01 false Geographic partitioning and spectrum... partitioning and spectrum disaggregation. An entity that acquires a portion of a 1.4 GHz band licensee's geographic area or spectrum subject to a geographic partitioning or spectrum disaggregation agreement...

  1. 33. Elevation of Doors / Typical Cement Toilet Partitions / ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    33. Elevation of Doors / Typical Cement Toilet Partitions / Typical Cement Shower Bath Partitions / Typical Marble Shower Bath Partitions / Dispensary Cupboard Supply Room Cupboard Similar / Section / Kitchen Cupboard and Sink / Screened Porch Cupboard (drawing 10) - Whittier State School, Hospital & Receiving Building, 11850 East Whittier Boulevard, Whittier, Los Angeles County, CA

  2. Chronic systemic IL-1β exacerbates central neuroinflammation independently of the blood-brain barrier integrity.

    PubMed

    Murta, Verónica; Farías, María Isabel; Pitossi, Fernando Juan; Ferrari, Carina Cintia

    2015-01-15

    Peripheral circulating cytokines are involved in immune to brain communication and systemic inflammation is considered a risk factor for flaring up the symptoms in most neurodegenerative diseases. We induced both central inflammatory demyelinating lesion, and systemic inflammation with an interleukin-1β expressing adenovector. The peripheral pro-inflammatory stimulus aggravated the ongoing central lesion independently of the blood-brain barrier (BBB) integrity. This model allows studying the role of specific molecules and cells (neutrophils) from the innate immune system, in the relationship between central and peripheral communication, and on relapsing episodes of demyelinating lesions, along with the role of BBB integrity.

  3. Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier.

    PubMed

    Miner, Jonathan J; Diamond, Michael S

    2016-02-01

    The blood-brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS.

  4. Endothelial Progenitor Cells Physiology and Metabolic Plasticity in Brain Angiogenesis and Blood-Brain Barrier Modeling

    PubMed Central

    Malinovskaya, Natalia A.; Komleva, Yulia K.; Salmin, Vladimir V.; Morgun, Andrey V.; Shuvaev, Anton N.; Panina, Yulia A.; Boitsova, Elizaveta B.; Salmina, Alla B.

    2016-01-01

    Currently, there is a considerable interest to the assessment of blood-brain barrier (BBB) development as a part of cerebral angiogenesis developmental program. Embryonic and adult angiogenesis in the brain is governed by the coordinated activity of endothelial progenitor cells, brain microvascular endothelial cells, and non-endothelial cells contributing to the establishment of the BBB (pericytes, astrocytes, neurons). Metabolic and functional plasticity of endothelial progenitor cells controls their timely recruitment, precise homing to the brain microvessels, and efficient support of brain angiogenesis. Deciphering endothelial progenitor cells physiology would provide novel engineering approaches to establish adequate microfluidically-supported BBB models and brain microphysiological systems for translational studies. PMID:27990124

  5. Measuring blood-brain barrier penetration using the NeuroCart, a CNS test battery.

    PubMed

    Groeneveld, Geert Jan; Hay, Justin Luke; Van Gerven, Johannes Marinus

    2016-06-01

    To systematically study the pharmacodynamics of a CNS drug early in the development process, we developed and validated a battery of drug-sensitive CNS tests, which we call NeuroCart. Using this test battery, data-intensive phase 1 studies in healthy subjects can be performed to demonstrate the specific, time- and dose-dependent, neurophysiological and/or neuropsychological effects of a compound, thereby confirming whether the test compound reaches its intended target in the CNS - or does not reach its intended target. We use this test battery to demonstrate that a compound passes the blood-brain barrier.

  6. Blood-brain barrier P-glycoprotein function in Alzheimer's disease.

    PubMed

    van Assema, Daniëlle M E; Lubberink, Mark; Bauer, Martin; van der Flier, Wiesje M; Schuit, Robert C; Windhorst, Albert D; Comans, Emile F I; Hoetjes, Nikie J; Tolboom, Nelleke; Langer, Oliver; Müller, Markus; Scheltens, Philip; Lammertsma, Adriaan A; van Berckel, Bart N M

    2012-01-01

    A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic

  7. Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis.

    PubMed

    Kim, Soo Young; Buckwalter, Marion; Soreq, Hermona; Vezzani, Annamaria; Kaufer, Daniela

    2012-11-01

    The protection of the brain from blood-borne toxins, proteins, and cells is critical to the brain's normal function. Accordingly, a compromise in the blood-brain barrier (BBB) function accompanies many neurologic disorders, and is tightly associated with brain inflammatory processes initiated by both infiltrating leukocytes from the blood, and activation of glial cells. Those inflammatory processes contribute to determining the severity and prognosis of numerous neurologic disorders, and can both cause, and result from BBB dysfunction. In this review we examine the role of BBB and inflammatory responses, in particular activation of transforming grown factor β (TGFβ) signaling, in epilepsy, stroke, and Parkinson's disease.

  8. Role of histaminergic system in blood-brain barrier dysfunction associated with neurological disorders.

    PubMed

    Bañuelos-Cabrera, Ivette; Valle-Dorado, María Guadalupe; Aldana, Blanca Irene; Orozco-Suárez, Sandra Adela; Rocha, Luisa

    2014-11-01

    Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. This represents a critical situation because damaged integrity of the BBB is related to the influx of immune mediators, plasma proteins and other outside elements from blood to the central nervous system (CNS) that may trigger a cascade of events that leads to neuroinflammation. In this review, evidence that mast cells and the release of factors such as histamine play an important role in the neuroinflammatory process associated with brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy is presented.

  9. Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity.

    PubMed

    Unhavaithaya, Yingdee; Orr-Weaver, Terry L

    2012-01-01

    Proper development requires coordination in growth of the cell types composing an organ. Many plant and animal cells are polyploid, but how these polyploid tissues contribute to organ growth is not well understood. We found the Drosophila melanogaster subperineurial glia (SPG) to be polyploid, and ploidy is coordinated with brain mass. Inhibition of SPG polyploidy caused rupture of the septate junctions necessary for the blood-brain barrier. Thus, the increased SPG cell size resulting from polyploidization is required to maintain the SPG envelope surrounding the growing brain. Polyploidization likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples.

  10. The Benefits of Adaptive Partitioning for Parallel AMR Applications

    SciTech Connect

    Steensland, Johan

    2008-07-01

    Parallel adaptive mesh refinement methods potentially lead to realistic modeling of complex three-dimensional physical phenomena. However, the dynamics inherent in these methods present significant challenges in data partitioning and load balancing. Significant human resources, including time, effort, experience, and knowledge, are required for determining the optimal partitioning technique for each new simulation. In reality, scientists resort to using the on-board partitioner of the computational framework, or to using the partitioning industry standard, ParMetis. Adaptive partitioning refers to repeatedly selecting, configuring and invoking the optimal partitioning technique at run-time, based on the current state of the computer and application. In theory, adaptive partitioning automatically delivers superior performance and eliminates the need for repeatedly spending valuable human resources for determining the optimal static partitioning technique. In practice, however, enabling frameworks are non-existent due to the inherent significant inter-disciplinary research challenges. This paper presents a study of a simple implementation of adaptive partitioning and discusses implied potential benefits from the perspective of common groups of users within computational science. The study is based on a large set of data derived from experiments including six real-life, multi-time-step adaptive applications from various scientific domains, five complementing and fundamentally different partitioning techniques, a large set of parameters corresponding to a wide spectrum of computing environments, and a flexible cost function that considers the relative impact of multiple partitioning metrics and diverse partitioning objectives. The results show that even a simple implementation of adaptive partitioning can automatically generate results statistically equivalent to the best static partitioning. Thus, it is possible to effectively eliminate the problem of determining the

  11. Measurement of the iodine partition coefficient

    SciTech Connect

    Furrer, M.; Cripps, R.C.; Gubler, R.

    1985-08-01

    The hydrolysis of iodine is complicated because it involves a number of species that differ considerably in their individual volatilities. Large uncertainties exist in the thermodynamic data of some of the iodine species, especially at temperatures above 25C. Because of this, an experiment was undertaken to measure the partition coefficient under varying physical and chemical conditions. Measurements of P were made for a temperature range of 21 to 113C under well-defined conditions (liquid molar concentration, pH, and redox potential) for inorganic iodine. The experimental results are interpreted with the aid of an analytical model and published thermodynamic data. A good agreement between calculated and measured values was found. The experimental setup allows the determination of very high partition coefficients up to a value of 2.0 X 10W. This is demonstrated by adding cesium-iodide to the fuel pool water of a boiling water reactor.

  12. Number Partitioning via Quantum Adiabatic Computation

    NASA Technical Reports Server (NTRS)

    Smelyanskiy, Vadim N.; Toussaint, Udo; Clancy, Daniel (Technical Monitor)

    2002-01-01

    We study both analytically and numerically the complexity of the adiabatic quantum evolution algorithm applied to random instances of combinatorial optimization problems. We use as an example the NP-complete set partition problem and obtain an asymptotic expression for the minimal gap separating the ground and exited states of a system during the execution of the algorithm. We show that for computationally hard problem instances the size of the minimal gap scales exponentially with the problem size. This result is in qualitative agreement with the direct numerical simulation of the algorithm for small instances of the set partition problem. We describe the statistical properties of the optimization problem that are responsible for the exponential behavior of the algorithm.

  13. Analysis of fractals with combined partition

    NASA Astrophysics Data System (ADS)

    Dedovich, T. G.; Tokarev, M. V.

    2016-03-01

    The space—time properties in the general theory of relativity, as well as the discreteness and non-Archimedean property of space in the quantum theory of gravitation, are discussed. It is emphasized that the properties of bodies in non-Archimedean spaces coincide with the properties of the field of P-adic numbers and fractals. It is suggested that parton showers, used for describing interactions between particles and nuclei at high energies, have a fractal structure. A mechanism of fractal formation with combined partition is considered. The modified SePaC method is offered for the analysis of such fractals. The BC, PaC, and SePaC methods for determining a fractal dimension and other fractal characteristics (numbers of levels and values of a base of forming a fractal) are considered. It is found that the SePaC method has advantages for the analysis of fractals with combined partition.

  14. Dynamic criteria for partitioning and transmutation

    SciTech Connect

    Lu, A.H. )

    1991-11-01

    Because of the slow progress being made in the national geologic repository program, the idea of partitioning and transmuting (P-T) long-lived radionuclides resurfaces as a potential improvement in high-level radioactive waste management. It seems theoretically possible to reduce the overall problems of radioactive waste by repeatedly partitioning and recycling wastes into actinide-free wastes, but there are recognizable difficulties and negative consequences that may overshadow the long-term benefits. This paper addresses some of the criteria that might be used to achieve an optimal P-T concept development, i.e., to minimize the negative short-term impact and to maximize both short-term and long-term benefits.

  15. Partition-DFT on the water dimer.

    PubMed

    Gómez, Sara; Nafziger, Jonathan; Restrepo, Albeiro; Wasserman, Adam

    2017-02-21

    As is well known, the ground-state symmetry group of the water dimer switches from its equilibrium Cs-character to C2h-character as the distance between the two oxygen atoms of the dimer decreases below RO-O∼2.5 Å. For a range of RO-O between 1 and 5 Å, and for both symmetries, we apply Partition Density Functional Theory (PDFT) to find the unique monomer densities that sum to the correct dimer densities while minimizing the sum of the monomer energies. We calculate the work involved in deforming the isolated monomer densities and find that it is slightly larger for the Cs geometry for all RO-O. We discuss how the PDFT densities and the corresponding partition potentials support the orbital-interaction picture of hydrogen-bond formation.

  16. Bipartite graph partitioning and data clustering

    SciTech Connect

    Zha, Hongyuan; He, Xiaofeng; Ding, Chris; Gu, Ming; Simon, Horst D.

    2001-05-07

    Many data types arising from data mining applications can be modeled as bipartite graphs, examples include terms and documents in a text corpus, customers and purchasing items in market basket analysis and reviewers and movies in a movie recommender system. In this paper, the authors propose a new data clustering method based on partitioning the underlying biopartite graph. The partition is constructed by minimizing a normalized sum of edge weights between unmatched pairs of vertices of the bipartite graph. They show that an approximate solution to the minimization problem can be obtained by computing a partial singular value decomposition (SVD) of the associated edge weight matrix of the bipartite graph. They point out the connection of their clustering algorithm to correspondence analysis used in multivariate analysis. They also briefly discuss the issue of assigning data objects to multiple clusters. In the experimental results, they apply their clustering algorithm to the problem of document clustering to illustrate its effectiveness and efficiency.

  17. Partition algebraic design of asynchronous sequential circuits

    NASA Technical Reports Server (NTRS)

    Maki, Gary K.; Chen, Kristen Q.; Gopalakrishnan, Suresh K.

    1993-01-01

    Tracey's Theorem has long been recognized as essential in generating state assignments for asynchronous sequential circuits. This paper shows that partitioning variables derived from Tracey's Theorem also has a significant impact in generating the design equations. Moreover, this theorem is important to the fundamental understanding of asynchronous sequential operation. The results of this work simplify asynchronous logic design. Moreover, detection of safe circuits is made easier.

  18. Partitioning coefficients between olivine and silicate melts

    NASA Astrophysics Data System (ADS)

    Bédard, J. H.

    2005-08-01

    Variation of Nernst partition coefficients ( D) between olivine and silicate melts cannot be neglected when modeling partial melting and fractional crystallization. Published natural and experimental olivine/liquidD data were examined for covariation with pressure, temperature, olivine forsterite content, and melt SiO 2, H 2O, MgO and MgO/MgO + FeO total. Values of olivine/liquidD generally increase with decreasing temperature and melt MgO content, and with increasing melt SiO 2 content, but generally show poor correlations with other variables. Multi-element olivine/liquidD profiles calculated from regressions of D REE-Sc-Y vs. melt MgO content are compared to results of the Lattice Strain Model to link melt MgO and: D0 (the strain compensated partition coefficient), EM3+ (Young's Modulus), and r0 (the size of the M site). Ln D0 varies linearly with Ln MgO in the melt; EM3+ varies linearly with melt MgO, with a dog-leg at ca. 1.5% MgO; and r0 remains constant at 0.807 Å. These equations are then used to calculate olivine/liquidD for these elements using the Lattice Strain Model. These empirical parameterizations of olivine/liquidD variations yield results comparable to experimental or natural partitioning data, and can easily be integrated into existing trace element modeling algorithms. The olivine/liquidD data suggest that basaltic melts in equilibrium with pure olivine may acquire small negative Ta-Hf-Zr-Ti anomalies, but that negative Nb anomalies are unlikely to develop. Misfits between results of the Lattice Strain Model and most light rare earth and large ion lithophile partitioning data suggest that kinetic effects may limit the lower value of D for extremely incompatible elements in natural situations characterized by high cooling/crystallization rates.

  19. Pure Partition Functions of Multiple SLEs

    NASA Astrophysics Data System (ADS)

    Kytölä, Kalle; Peltola, Eveliina

    2016-08-01

    Multiple Schramm-Loewner Evolutions (SLE) are conformally invariant random processes of several curves, whose construction by growth processes relies on partition functions—Möbius covariant solutions to a system of second order partial differential equations. In this article, we use a quantum group technique to construct a distinguished basis of solutions, which conjecturally correspond to the extremal points of the convex set of probability measures of multiple SLEs.

  20. Hardware Index to Set Partition Converter

    DTIC Science & Technology

    2013-01-01

    www.jstatsoft.org/ 8. Knuth , D.E.: Volume 4 Generating all combinations and permutations. In: The Art of Computer Programming, Fascicle 3. Addison...especially requires high-speed enumeration of partitions. Recent research in computational molecular biology has shown the importance of par- titions...speed generation of combinations, as well as the generation of random combina- tions for use in reconfigurable computers . It can also be viewed as a

  1. Environment Partitioning and Reactivity of Polybrominated Diphenylethers

    NASA Technical Reports Server (NTRS)

    Hua, Inez; Iraci, Laura T.; Jafvert, Chad; Bezares-Cruz, Juan

    2004-01-01

    Polybrominated diphenyl ethers (PBDEs) are an important class of flame retardants. Annual global demand for these compounds was over 67,000 metric tons in 2001. PBDEs have recently been extensively investigated as environmental contaminants because they have been detected in air, sediment, and tissue samples from urban and remote areas. Important issues include quantifying PBDE partitioning in various environmental compartments, and elucidating transformation pathways. The partitioning of PBDE congeners to aerosols was estimated for 16 sites in the United States, Canada, and Mexico. The aerosol particles were PM2.5, the total suspended particle (TSP) concentration varied between 3.0 - 55.4 micro g/cubic meter, and the organic fraction ranged from 11 - 41%; these data are published values for each site. It is estimated that the largest fraction of each PBDE associated with the aerosol particles occurs in Mexico City, and the smallest fraction in Colorado Plateau. Although the organic fraction in Mexico City is about 60% of that observed in the Colorado Plateau, the TSP is larger by a factor of about 18.5, and it is the difference in TSP that strongly influences the fraction of particle-bound PBDE in this case. PBDE partitioning to PM2.5 particles also varies seasonally because of temperature variations. For the less brominated congeners the percentage that is particle-bound is relatively low, regardless of air temperature. In contrast, the heavier congeners exhibit a significant temperature dependence: as the temperature decreases (fall, winter) the percentage of PBDE that is particle-bound increases. The partitioning calculations complement experimental data indicating that decabromodiphenyl ether (DBDE) dissolved in hexane transforms very rapidly when irradiated with solar light. DBDE is the most highly brominated PBDE congener (10 bromine atoms) and occurs in the commercial formulation which is subject to the largest global demand.

  2. A straightforward implementation of in situ solution electrochemical ¹³C NMR spectroscopy for studying reactions on commercial electrocatalysts: ethanol oxidation.

    PubMed

    Huang, L; Sorte, E G; Sun, S-G; Tong, Y Y J

    2015-05-11

    Identifying and quantifying electrocatalytic-reaction-generated solution species, be they reaction intermediates or products, are highly desirable in terms of understanding the associated reaction mechanisms. We report herein a straightforward implementation of in situ solution electrochemical (13)C NMR spectroscopy for the first time that enables in situ studies of reactions on commercial fuel-cell electrocatalysts (Pt and PtRu blacks). Using ethanol oxidation reaction (EOR) as a working example, we discovered that (1) the complete oxidation of ethanol to CO2 only took place dominantly at the very beginning of a potentiostatic chronoamperometric (CA) measurement and (2) the PtRu had a much higher activity in catalysing oxygen insertion reaction that leads to acetic acid.

  3. Straightforward synthesis of a novel ring-fused pyrazole-lactam and in vitro cytotoxic activity on cancer cell lines.

    PubMed

    Bertuzzi, G; Locatelli, E; Colecchia, D; Calandro, P; Bonini, B F; Chandanshive, J Z; Mazzanti, A; Zani, P; Chiariello, M; Comes Franchini, M

    2016-07-19

    In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,β-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a "side chain" characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15-60 μM for exposure time of 24-72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.

  4. Peptide partitioning properties from direct insertion studies

    SciTech Connect

    Ulmschneider, Martin; Smith, Jeremy C; Ulmschneider, Jakob

    2010-06-01

    Partitioning properties of polypeptides are at the heart of biological membrane phenomena and their precise quantification is vital for ab-initio structure prediction and the accurate simulation of membrane protein folding and function. Recently the cellular translocon machinery has been employed to determine membrane insertion propensities and transfer energetics for a series of polyleucine segments embedded in a carrier sequence. We show here that the insertion propensity, pathway, and transfer energetics into synthetic POPC bilayers can be fully described by direct atomistic peptide partitioning simulations. The insertion probability as a function of peptide length follows two-state Boltzmann statistics, in agreement with the experiments. The simulations expose a systematic offset between translocon-mediated and direct insertion free energies. Compared to the experiment the insertion threshold is shifted toward shorter peptides by 2 leucine residues. The simulations reveal many hitherto unknown atomic-resolution details about the partitioning process and promise to provide a powerful tool for urgently needed calibration of lipid parameters to match experimentally observed peptide transfer energies.

  5. Airborne phthalate partitioning to cotton clothing

    NASA Astrophysics Data System (ADS)

    Morrison, Glenn; Li, Hongwan; Mishra, Santosh; Buechlein, Melissa

    2015-08-01

    Accumulation on indoor surfaces and fabrics can increase dermal uptake and non-dietary ingestion of semi-volatile organic compounds. To better understand the potential for dermal uptake of phthalates from clothing, we measured the mass accumulation on cotton fabrics of two phthalate esters commonly identified in indoor air: diethylphthalate (DEP) and di-n-butyl phthalate (DnBP). In 10-day chamber experiments, we observed strong air-to-cloth partitioning of these phthalates to shirts and jean material. Area-normalized partition coefficients ranged from 209 to 411 (μg/m2)/(μg/m3) for DEP and 2850 to 6580 (μg/m2)/(μg/m3) for DnBP. Clothing volume-normalized partition coefficients averaged 2.6 × 105 (μg/m3)/(μg/m3) for DEP and 3.9 × 106 (μg/m3)/(μg/m3) for DnBP. At equilibrium, we estimate that a typical set of cotton clothing can sorb DnBP from the equivalent of >10,000 m3 of indoor air, thereby substantially decreasing external mass-transfer barriers to dermal uptake. Further, we estimate that a significant fraction of a child's body burden of DnBP may come from mouthing fabric material that has been equilibrated with indoor air.

  6. Diversity partitioning during the Cambrian radiation

    PubMed Central

    Na, Lin; Kiessling, Wolfgang

    2015-01-01

    The fossil record offers unique insights into the environmental and geographic partitioning of biodiversity during global diversifications. We explored biodiversity patterns during the Cambrian radiation, the most dramatic radiation in Earth history. We assessed how the overall increase in global diversity was partitioned between within-community (alpha) and between-community (beta) components and how beta diversity was partitioned among environments and geographic regions. Changes in gamma diversity in the Cambrian were chiefly driven by changes in beta diversity. The combined trajectories of alpha and beta diversity during the initial diversification suggest low competition and high predation within communities. Beta diversity has similar trajectories both among environments and geographic regions, but turnover between adjacent paleocontinents was probably the main driver of diversification. Our study elucidates that global biodiversity during the Cambrian radiation was driven by niche contraction at local scales and vicariance at continental scales. The latter supports previous arguments for the importance of plate tectonics in the Cambrian radiation, namely the breakup of Pannotia. PMID:25825755

  7. Microbial partitioning to settleable particles in stormwater.

    PubMed

    Characklis, Gregory W; Dilts, Mackenzie J; Simmons, Otto D; Likirdopulos, Christina A; Krometis, Leigh-Anne H; Sobsey, Mark D

    2005-05-01

    The degree to which microbes in the water column associate with settleable particles has important implications for microbial transport in receiving waters, as well as for microbial removal via sedimentation (i.e. detention basins). The partitioning behavior of several bacterial, protozoan and viral indicator organisms is explored in three urban streams under both storm and dry weather conditions. The fraction of organisms associated with settleable particles in stormwater is estimated through use of a centrifugation technique which is calibrated using suspensions of standard particles (e.g., glass, latex). The fraction of organisms associated with settleable particles varies by type of microbe, and the partitioning behavior of each organism generally changes between dry weather and storm conditions. Bacterial indicator organisms (fecal coliforms, Escherichia coli, enterococci) exhibited relatively consistent behavior, with an average of 20-35% of organisms associated with these particles in background samples and 30-55% in storm samples. Clostridium perfringens spores exhibited the highest average level of particle association, with storm values varying from 50% to 70%. Results related to total coliphage partitioning were more variable, with 20-60% associated with particles during storms. These estimates should be valuable in surface water quality modeling efforts, many of which currently assume that all microbes exist as free (unattached) organisms.

  8. Phase partitioning experiment (8-IML-1)

    NASA Technical Reports Server (NTRS)

    Brooks, Donald E.

    1992-01-01

    Phase partitioning is a method of separating biological cells and macromolecules via their differential distribution in two phase aqueous polymer solutions. The ultimate goal of the experiment is to test the hypothesis that the efficiency of separation of closely related cell types, by partitioning in immiscible aqueous phases, will be enhanced in the non-convective environment provided by space. Before a cell separation experiment can be performed, the demixing of immiscible aqueous polymer solutions must be understood and controlled in order to optimize the experimental conditions for a cell separation experiment in the future. The present Phase Partitioning Experiment (PPE) is the third in a series, the first two flew on STS 51-D in Apr. 1985 and STS 26 in Oct. 1988. In those experiments the immiscible aqueous phases demixed spontaneously at different rates, the final disposition being one in which the phase which wetted the container wall surrounded the second phase which formed an 'egg yolk' in the center of the chamber.

  9. Equilibrium Partitioning Sediment Benchmarks (ESBs) for the ...

    EPA Pesticide Factsheets

    This document describes procedures to determine the concentrations of nonionic organic chemicals in sediment interstitial waters. In previous ESB documents, the general equilibrium partitioning (EqP) approach was chosen for the derivation of sediment benchmarks because it accounts for the varying bioavailability of chemicals in different sediments and allows for the incorporation of the appropriate biological effects concentration. This provides for the derivation of benchmarks that are causally linked to the specific chemical, applicable across sediments, and appropriately protective of benthic organisms.  This equilibrium partitioning sediment benchmark (ESB) document was prepared by scientists from the Atlantic Ecology Division, Mid-Continent Ecology Division, and Western Ecology Division, the Office of Water, and private consultants. The document describes procedures to determine the interstitial water concentrations of nonionic organic chemicals in contaminated sediments. Based on these concentrations, guidance is provided on the derivation of toxic units to assess whether the sediments are likely to cause adverse effects to benthic organisms. The equilibrium partitioning (EqP) approach was chosen because it is based on the concentrations of chemical(s) that are known to be harmful and bioavailable in the environment.  This document, and five others published over the last nine years, will be useful for the Program Offices, including Superfund, a

  10. Biogeography of time partitioning in mammals

    PubMed Central

    Bennie, Jonathan J.; Duffy, James P.; Inger, Richard; Gaston, Kevin J.

    2014-01-01

    Many animals regulate their activity over a 24-h sleep–wake cycle, concentrating their peak periods of activity to coincide with the hours of daylight, darkness, or twilight, or using different periods of light and darkness in more complex ways. These behavioral differences, which are in themselves functional traits, are associated with suites of physiological and morphological adaptations with implications for the ecological roles of species. The biogeography of diel time partitioning is, however, poorly understood. Here, we document basic biogeographic patterns of time partitioning by mammals and ecologically relevant large-scale patterns of natural variation in “illuminated activity time” constrained by temperature, and we determine how well the first of these are predicted by the second. Although the majority of mammals are nocturnal, the distributions of diurnal and crepuscular species richness are strongly associated with the availability of biologically useful daylight and twilight, respectively. Cathemerality is associated with relatively long hours of daylight and twilight in the northern Holarctic region, whereas the proportion of nocturnal species is highest in arid regions and lowest at extreme high altitudes. Although thermal constraints on activity have been identified as key to the distributions of organisms, constraints due to functional adaptation to the light environment are less well studied. Global patterns in diversity are constrained by the availability of the temporal niche; disruption of these constraints by the spread of artificial lighting and anthropogenic climate change, and the potential effects on time partitioning, are likely to be critical influences on species’ future distributions. PMID:25225371

  11. Biogeography of time partitioning in mammals.

    PubMed

    Bennie, Jonathan J; Duffy, James P; Inger, Richard; Gaston, Kevin J

    2014-09-23

    Many animals regulate their activity over a 24-h sleep-wake cycle, concentrating their peak periods of activity to coincide with the hours of daylight, darkness, or twilight, or using different periods of light and darkness in more complex ways. These behavioral differences, which are in themselves functional traits, are associated with suites of physiological and morphological adaptations with implications for the ecological roles of species. The biogeography of diel time partitioning is, however, poorly understood. Here, we document basic biogeographic patterns of time partitioning by mammals and ecologically relevant large-scale patterns of natural variation in "illuminated activity time" constrained by temperature, and we determine how well the first of these are predicted by the second. Although the majority of mammals are nocturnal, the distributions of diurnal and crepuscular species richness are strongly associated with the availability of biologically useful daylight and twilight, respectively. Cathemerality is associated with relatively long hours of daylight and twilight in the northern Holarctic region, whereas the proportion of nocturnal species is highest in arid regions and lowest at extreme high altitudes. Although thermal constraints on activity have been identified as key to the distributions of organisms, constraints due to functional adaptation to the light environment are less well studied. Global patterns in diversity are constrained by the availability of the temporal niche; disruption of these constraints by the spread of artificial lighting and anthropogenic climate change, and the potential effects on time partitioning, are likely to be critical influences on species' future distributions.

  12. On bottleneck partitioning k-ary n-cubes

    NASA Technical Reports Server (NTRS)

    Nicol, David M.; Mao, Weizhen

    1994-01-01

    Graph partitioning is a topic of extensive interest, with applications to parallel processing. In this context graph nodes typically represent computation, and edges represent communication. One seeks to distribute the workload by partitioning the graph so that every processor has approximately the same workload, and the communication cost (measured as a function of edges exposed by the partition) is minimized. Measures of partition quality vary; in this paper we consider a processor's cost to be the sum of its computation and communication costs, and consider the cost of a partition to be the bottleneck, or maximal processor cost induced by the partition. For a general graph the problem of finding an optimal partitioning is intractable. In this paper we restrict our attention to the class of k-art n-cube graphs with uniformly weighted nodes. Given mild restrictions on the node weight and number of processors, we identify partitions yielding the smallest bottleneck. We also demonstrate by example that some restrictions are necessary for the partitions we identify to be optimal. In particular, there exist cases where partitions that evenly partition nodes need not be optimal.

  13. Differential effect of aluminum on the blood-brain barrier transport of peptides, technetium and albumin

    SciTech Connect

    Banks, W.A.; Kastin, A.J.; Fasold, M.B.

    1988-02-01

    Aluminum is a neurotoxin capable of altering membrane structure and function. We investigated whether aluminum also can affect saturable transport across membranes using the blood-brain barrier as our model. Mice were given i.p. or i.v. aluminum (up to 100 mg/kg) as the chloride salt and the disappearance from the brain of several centrally administered substances was measured. We found that aluminum rapidly and profoundly inhibited the saturable system that transports the small, N-tyrosinated peptides Tyr-MIF-1 and the enkephalins from the brain to the blood by acting as a noncompetitive inhibitor. In contrast, the disappearance from the brain of technetium pertechnetate (a substance also transported out of the brain by a different saturable system), albumin or D-Tyr-MIF-1 (a stereoisomer of Tyr-MIF-1 that was confirmed not to be transported by the carrier system) was not affected by aluminum. Aluminum also did not alter either the saturable or nonsaturable component of the uptake of Tyr-MIF-1 by erythrocytes. These findings suggest that one mechanism by which aluminum may induce neurotoxicity is by selective alteration of the transport systems of the blood-brain barrier.

  14. Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation.

    PubMed

    Wolff, Gretchen; Davidson, Sarah J; Wrobel, Jagoda K; Toborek, Michal

    2015-08-07

    Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 ± 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression.

  15. Effect of 2450-MHz microwave energy on the blood-brain barrier to hydrophilic molecules

    SciTech Connect

    Williams, W.M.

    1983-01-01

    Microwave energy at 2450 MHz 120 Hz AM was found ineffective in increasing the permeability of the blood-brain barrier to the hydrophilic tracers HRP and (/sup 14/C) sucrose. Furthermore, a diminished permeability to HRP and sodium fluorescein was apparent after 180 minutes of exposure to microwaves at an incident power density of 20 mW/cm/sup 2/. Colonic temperature, as well as temperature within the cerebral cortex, hypothalamus, cerebellum and medulla, were elevated by less than 1/sup 0/C over those of sham-exposed rats. A significant decrease in the permeability to HRP and (/sup 14/C) sucrose occurred after exposure to an incident power density of 65 mW/cm/sup 2/ for 30 minutes. The reduction in permeability to HRP correlated with a suppressed incorporation of the tracer by pinocytosis in cerebral microvessels. Suppression of blood-brain barrier permeability to hydrophilic tracers was most pronounced at brain temperatures exceeding approx. 40/sup 0/C and is demonstrated to be temperature dependent.

  16. Nanoparticles and blood-brain barrier: the key to central nervous system diseases.

    PubMed

    Domínguez, Alazne; Suárez-Merino, Blanca; Goñi-de-Cerio, Felipe

    2014-01-01

    Major central nervous system disorders represent a significant and worldwide public health problem. In fact, the therapeutic success of many pharmaceuticals developed to treat central nervous system diseases is still moderate, since the blood-brain barrier (BBB) limits the access of systemically administered compounds to the brain. Therefore, they require the application of a large total dose of a drug, and cause numerous toxic effects. The development of nanotechnological systems are useful tools to deliver therapeutics and/or diagnostic probes to the brain due to nanocarriers having the potential to improve the therapeutic effect of drugs and to reduce their side effects. This review provides a brief overview of the variety of carriers employed for central nervous system drug and diagnostic probes delivery. Further, this paper focuses on the novel nanocarriers developed to enhance brain delivery across the blood-brain barrier. Special attention is paid to liposomes, micelles, polymeric and lipid-based nanoparticles, dendrimers and carbon nanotubes. The recent developments in nanocarrier implementation through size/charge optimization and surface modifications (PEGylation, targeting delivery, and coating with surfactants) have been discussed. And a detailed description of the nanoscaled pharmaceutical delivery devices employed for the treatment of central nervous system disorders have also been defined. The aim of the review is to evaluate the nanotechnology-based drug delivery strategies to treat different central nervous system disorders.

  17. Blood-brain barrier permeability mechanisms in view of quantitative structure-activity relationships (QSAR).

    PubMed

    Bujak, Renata; Struck-Lewicka, Wiktoria; Kaliszan, Michał; Kaliszan, Roman; Markuszewski, Michał J

    2015-04-10

    The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies.

  18. Age-associated physiological and pathological changes at the blood-brain barrier: A review.

    PubMed

    Erdő, Franciska; Denes, László; de Lange, Elizabeth

    2017-01-01

    The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of aged populations. The morphological and biochemical changes in the aging brain are the subjects of many extended research projects worldwide for a long time. However, the crucial role of the blood-brain barrier (BBB) impairment and disruption in the pathological processes in age-associated neurodegenerative disorders received special attention just for a few years. This article gives an overview on the major elements of the blood-brain barrier and its supporting mechanisms and also on their alterations during development, physiological aging process and age-associated neurodegenerative disorders (Alzheimer's disease, multiple sclerosis, Parkinson's disease, pharmacoresistant epilepsy). Besides the morphological alterations of the cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal elements) of the BBB and neurovascular unit, the changes of the barrier at molecular level (tight junction proteins, adheres junction proteins, membrane transporters, basal lamina, extracellular matrix) are also summarized. The recognition of new players and initiators of the process of neurodegeneration at the level of the BBB may offer new avenues for novel therapeutic approaches for the treatment of numerous chronic neurodegenerative disorders currently without effective medication.

  19. Interaction of ethanol and microwaves on the blood-brain barrier of rats

    SciTech Connect

    Neilly, J.P.; Lin, J.C.

    1986-01-01

    The combined effects of ethanol and microwaves on the permeation of Evans blue dye through the mammalian blood-brain barrier was studied in male Wistar rats. Anesthetized rats were infused through a cannula in the left femoral vein with 0.1, 0.3, 0.5 or 0.7 grams of absolute ethanol per kilogram of body mass. A control group was given 0.7 g/kg of isotonic saline. The left hemisphere of the brain was irradiated by 3.15-GHz microwave energy at 3.0 W/cm2 rms for 15 min. The rat's rectal temperature was maintained at 37.0 degrees C. Immediately after irradiation, 2% Evans blue dye in saline (2.0 ml/kg body mass) was injected through the cannula. The results show that as the quantity of alcohol was increased, the degree of staining was decreased or eliminated. The temperature of the irradiated area of the brain increased for the first 4 to 5 minutes of irradiation and then stabilized for the remainder of the irradiation period. The steady-state temperature was highest in animals receiving saline or the smallest dose of alcohol. As the quantity of alcohol was increased, the steady-state temperature was reduced. These results indicate that ethanol inhibits microwave-induced permeation of the blood-brain barrier through reduced heating of the brain.

  20. Methodologies to assess drug permeation through the blood-brain barrier for pharmaceutical research.

    PubMed

    Passeleu-Le Bourdonnec, Céline; Carrupt, Pierre-Alain; Scherrmann, Jean Michel; Martel, Sophie

    2013-11-01

    The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier.

  1. Polymers as Reference Partitioning Phase: Polymer Calibration for an Analytically Operational Approach To Quantify Multimedia Phase Partitioning.

    PubMed

    Gilbert, Dorothea; Witt, Gesine; Smedes, Foppe; Mayer, Philipp

    2016-06-07

    Polymers are increasingly applied for the enrichment of hydrophobic organic chemicals (HOCs) from various types of samples and media in many analytical partitioning-based measuring techniques. We propose using polymers as a reference partitioning phase and introduce polymer-polymer partitioning as the basis for a deeper insight into partitioning differences of HOCs between polymers, calibrating analytical methods, and consistency checking of existing and calculation of new partition coefficients. Polymer-polymer partition coefficients were determined for polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and organochlorine pesticides (OCPs) by equilibrating 13 silicones, including polydimethylsiloxane (PDMS) and low-density polyethylene (LDPE) in methanol-water solutions. Methanol as cosolvent ensured that all polymers reached equilibrium while its effect on the polymers' properties did not significantly affect silicone-silicone partition coefficients. However, we noticed minor cosolvent effects on determined polymer-polymer partition coefficients. Polymer-polymer partition coefficients near unity confirmed identical absorption capacities of several PDMS materials, whereas larger deviations from unity were indicated within the group of silicones and between silicones and LDPE. Uncertainty in polymer volume due to imprecise coating thickness or the presence of fillers was identified as the source of error for partition coefficients. New polymer-based (LDPE-lipid, PDMS-air) and multimedia partition coefficients (lipid-water, air-water) were calculated by applying the new concept of a polymer as reference partitioning phase and by using polymer-polymer partition coefficients as conversion factors. The present study encourages the use of polymer-polymer partition coefficients, recognizing that polymers can serve as a linking third phase for a quantitative understanding of equilibrium partitioning of HOCs between any two phases.

  2. Safety-Critical Partitioned Software Architecture: A Partitioned Software Architecture for Robotic

    NASA Technical Reports Server (NTRS)

    Horvath, Greg; Chung, Seung H.; Cilloniz-Bicchi, Ferner

    2011-01-01

    The flight software on virtually every mission currently managed by JPL has several major flaws that make it vulnerable to potentially fatal software defects. Many of these problems can be addressed by recently developed partitioned operating systems (OS). JPL has avoided adopting a partitioned operating system on its flight missions, primarily because doing so would require significant changes in flight software design, and the risks associated with changes of that magnitude cannot be accepted by an active flight project. The choice of a partitioned OS can have a dramatic effect on the overall system and software architecture, allowing for realization of benefits far beyond the concerns typically associated with the choice of OS. Specifically, we believe that a partitioned operating system, when coupled with an appropriate architecture, can provide a strong infrastructure for developing systems for which reusability, modifiability, testability, and reliability are essential qualities. By adopting a partitioned OS, projects can gain benefits throughout the entire development lifecycle, from requirements and design, all the way to implementation, testing, and operations.

  3. High dimensional data clustering by partitioning the hypergraphs using dense subgraph partition

    NASA Astrophysics Data System (ADS)

    Sun, Xili; Tian, Shoucai; Lu, Yonggang

    2015-12-01

    Due to the curse of dimensionality, traditional clustering methods usually fail to produce meaningful results for the high dimensional data. Hypergraph partition is believed to be a promising method for dealing with this challenge. In this paper, we first construct a graph G from the data by defining an adjacency relationship between the data points using Shared Reverse k Nearest Neighbors (SRNN). Then a hypergraph is created from the graph G by defining the hyperedges to be all the maximal cliques in the graph G. After the hypergraph is produced, a powerful hypergraph partitioning method called dense subgraph partition (DSP) combined with the k-medoids method is used to produce the final clustering results. The proposed method is evaluated on several real high-dimensional datasets, and the experimental results show that the proposed method can improve the clustering results of the high dimensional data compared with applying k-medoids method directly on the original data.

  4. Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link

    PubMed Central

    Velázquez-Moctezuma, J.

    2016-01-01

    Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins. PMID:27738642

  5. Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development.

    PubMed

    Bastian, T W; Duck, K A; Michalopoulos, G C; Chen, M J; Liu, Z-J; Connor, J R; Lanier, L M; Sola-Visner, M C; Georgieff, M K

    2017-03-01

    Essentials Potential neurodevelopmental side effects of thrombopoietin mimetics need to be considered. The effects of eltrombopag (ELT) on neuronal iron status and dendrite development were assessed. ELT crosses the blood-brain barrier and causes iron deficiency in developing neurons. ELT blunts dendrite maturation, indicating a need for more safety studies before neonatal use.

  6. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review.

    PubMed

    Bicker, Joana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2014-08-01

    During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood-brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood-brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood-brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood-brain barrier is also discussed.

  7. Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link.

    PubMed

    Hurtado-Alvarado, G; Domínguez-Salazar, E; Pavon, L; Velázquez-Moctezuma, J; Gómez-González, B

    2016-01-01

    Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

  8. A brief history of partitions of numbers, partition functions and their modern applications

    NASA Astrophysics Data System (ADS)

    Debnath, Lokenath

    2016-04-01

    'Number rules the universe.' The Pythagoras 'If you wish to forsee the future of mathematics our course is to study the history and present conditions of the science.' Henri Poincaré 'The primary source (Urqell) of all mathematics are integers.' Hermann Minkowski This paper is written to commemorate the centennial anniversary of the Mathematical Association of America. It deals with a short history of different kinds of natural numbers including triangular, square, pentagonal, hexagonal and k-gonal numbers, and their simple properties and their geometrical representations. Included are Euclid's and Pythagorean's main contributions to elementary number theory with the main contents of the Euclid Elements of the 13-volume masterpiece of mathematical work. This is followed by Euler's new discovery of the additive number theory based on partitions of numbers. Special attention is given to many examples, Euler's theorems on partitions of numbers with geometrical representations of Ferrers' graphs, Young's diagrams, Lagrange's four-square theorem and the celebrated Waring problem. Included are Euler's generating functions for the partitions of numbers, Euler's pentagonal number theorem, Gauss' triangular and square number theorems and the Jacobi triple product identity. Applications of the theory of partitions of numbers to different statistics such as the Bose- Einstein, Fermi- Dirac, Gentile, and Maxwell- Boltzmann statistics are briefly discussed. Special attention is given to pedagogical information through historical approach to number theory so that students and teachers at the school, college and university levels can become familiar with the basic concepts of partitions of numbers, partition functions and their modern applications, and can pursue advanced study and research in analytical and computational number theory.

  9. Boron, beryllium, and lithium, partitioning in olivine

    SciTech Connect

    Neroda, Elizabeth

    1996-05-01

    A one atmosphere experimental study was performed to determine the mineral/melt partition coefficients for B, Be, and Li in forsteritic olivine. Two compositions were chosen along the 1350{degrees}C isotherm, 1b (Fo{sub 17.3} Ab{sub 82.7} An{sub 0} by weight) and 8c (Fo{sub 30} Ab{sub 23.3} An{sub 47.8}, by weight) were then combined in equal amounts to form a composition was doped with 25ppm Li, B, Yb, Nb, Zr, Sr, and Hf, 50ppm Sm, and 100ppm Be, Nd, Ce, and Rb. Electron and ion microprobe analyses showed that the olivine crystals and surrounding glasses were homogeneous with respect to major and trace elements. Partition coefficients calculated from these analyses are as follows: 1b: D{sub B} = 4.41 ({+-} 2.3) E-03, D{sub Be} = 2.86 ({+-} 0.45) E-03, D{sub Li} = 1.54 ({+-} 0.21) E-01, 50/50: D{sub B} = 2.86 ({+-} 0.5) E-03, D{sub Be} = 2.07 ({+-} 0.09) E-03, D{sub Li} = 1.51 ({+-} 0.18) E-01, 8c: D{sub B} = 6.05 ({+-} 1.5) E-03, D{sub Be} = 1.81 ({+-} 0.03) E-03, D{sub Li} = 1.31 ({+-} 0.09) E-01. The results of this study will combined with similar data for other minerals as part of a larger study to understand the partitioning behavior of B, Be, and Li in melting of the upper mantle at subduction zones.

  10. Partitioning technique for discrete quantum systems

    SciTech Connect

    Jin, L.; Song, Z.

    2011-06-15

    We develop the partitioning technique for quantum discrete systems. The graph consists of several subgraphs: a central graph and several branch graphs, with each branch graph being rooted by an individual node on the central one. We show that the effective Hamiltonian on the central graph can be constructed by adding additional potentials on the branch-root nodes, which generates the same result as does the the original Hamiltonian on the entire graph. Exactly solvable models are presented to demonstrate the main points of this paper.

  11. Spatially-partitioned many-body vortices

    NASA Astrophysics Data System (ADS)

    Klaiman, S.; Alon, O. E.

    2016-02-01

    A vortex in Bose-Einstein condensates is a localized object which looks much like a tiny tornado storm. It is well described by mean-field theory. In the present work we go beyond the current paradigm and introduce many-body vortices. These are made of spatially- partitioned clouds, carry definite total angular momentum, and are fragmented rather than condensed objects which can only be described beyond mean-field theory. A phase diagram based on a mean-field model assists in predicting the parameters where many-body vortices occur. Implications are briefly discussed.

  12. The minimal length and quantum partition functions

    NASA Astrophysics Data System (ADS)

    Abbasiyan-Motlaq, M.; Pedram, P.

    2014-08-01

    We study the thermodynamics of various physical systems in the framework of the generalized uncertainty principle that implies a minimal length uncertainty proportional to the Planck length. We present a general scheme to analytically calculate the quantum partition function of the physical systems to first order of the deformation parameter based on the behavior of the modified energy spectrum and compare our results with the classical approach. Also, we find the modified internal energy and heat capacity of the systems for the anti-Snyder framework.

  13. Light period regulation of carbohydrate partitioning

    NASA Technical Reports Server (NTRS)

    Janes, Harry W.

    1994-01-01

    We have shown that the photosynthetic period is important in regulating carbon partitioning. Even when the same amount of carbon is fixed over a 24h period considerably more is translocated out of the leaf under the longer photosynthetic period. This is extremely important when parts of the plant other than the leaves are to be sold. It is also important to notice the amount of carbon respired in the short photosynthetic period. The light period effect on carbohydrate fixation, dark respiration, and translocation is shown in this report.

  14. Psychometric Properties of the Chinese Version of the Fear of Negative Evaluation Scale-Brief (BFNE) and the BFNE-Straightforward for Middle School Students

    PubMed Central

    Wei, Jia; Zhang, Chunyu; Li, Yadan; Xue, Song; Zhang, Jinfu

    2015-01-01

    Background The 12-item brief version of the Fear of Negative Evaluation Scale (BFNE) is one of the most widely used instruments to assess fear of negative evaluation. Recent evidence strongly supports the version composed of 8 straightforward items (BFNE-S), which possessesstronger psychometric properties. The purpose of the current study is to examine the psychometric prop-erties of the Chinese versions of the BFNE and BFNE-S for middle school students. Methodology A total of 1009 middle school students were recruited in this study. The BFNE, the BFNE-S, the Friedman-Bendas Text Anxiety Scale (FBTAS), and the Social Anxiety Scale (SAS) were administered to 497 participants, and 52 participants were re-tested after four weeks. The BFNE, the BFNE-S, the Rosenberg Self-Esteem Scale (RSES), and the Balanced Inventory of Desirable Responding (BIDR) wereadministered to 492 participants. The BFNE and BFNE-S significantly cor-related with all the scales, supporting their convergent, divergent and concurrent validity. Principal Findings The Cronbach's alpha of the BFNE (BFNE-S) was 0.864 (0.867) with 497 par-ticipants and 0.886 (0.844) with 492 participants, and the test-retest reliability coefficient was 0.791 (0.855) (ICC). Although the EFA identified a two-factor solution in which the 8 straightfor-ward items loaded on one factor and the 4 reversed items loaded on the other, the CFA, using a random intercept model to control the wording effect, supported a unidimensional factor struc-ture of the BFNE. Both EFA and CFA supported the unidimensional assumption of the BFNE-S. The correlations of the BFNE and BFNE-S were 0.929 and 0.952 in two samples. Conclusions The Chinese versions of the BFNE and BFNE-S demonstrate adequate psychometric properties for assessing fear of negative evaluation. The results support their use among the Chinese middle school students. Considering its greater parsimony and excellent reliability and validity, the BFNE-S is a better tool. PMID

  15. Bacterial plasmid partition machinery: a minimalist approach to survival.

    PubMed

    Schumacher, Maria A

    2012-02-01

    The accurate segregation or partition of replicated DNA is essential for ensuring stable genome transmission. Partition of bacterial plasmids requires only three elements: a centromere-like DNA site and two proteins, a partition NTPase, and a centromere-binding protein (CBP). Because of this simplicity, partition systems have served as tractable model systems to study the fundamental molecular mechanisms required for DNA segregation at an atomic level. In the last few years, great progress has been made in this endeavor. Surprisingly, these studies have revealed that although the basic partition components are functionally conserved between three types of plasmid partition systems, these systems employ distinct mechanisms of DNA segregation. This review summarizes the molecular insights into plasmid segregation that have been achieved through these recent structural studies.

  16. Mini review on blood-brain barrier penetration of pyridinium aldoximes.

    PubMed

    Kalász, H; Nurulain, S M; Veress, G; Antus, S; Darvas, F; Adeghate, E; Adem, A; Hashemi, F; Tekes, K

    2015-02-01

    This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are highly charged hydrophilic compounds used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase reactivators. Pyridinium aldoximes have antidotal effects against poisoning with cholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This poses a severe challenge to all innocent and peace-loving people worldwide. This review gives a brief summary of BBB transporters and description of the current in vitro and in vivo methods for the characterization of BBB penetration of established and novel pyridinium aldoximes. The authors provide a putative mechanism of penetration, outline some future ways of formulation and discuss the possible advantages and disadvantages of increasing BBB penetration.

  17. Drug transport into the central nervous system: using newer findings about the blood-brain barriers.

    PubMed

    Banks, William A

    2012-06-01

    The blood-brain barriers (BBBs) represent one of the biggest challenges for the effective delivery of drugs today. Discoveries made in the last 30 years offer new strategies for central nervous system (CNS) drug development, but have yet to be fully incorporated into the field. Here, we examine seven recently discovered aspects of the BBB and how they have been or could be developed for drug delivery. These areas are brain-to-blood (efflux) transporters, immune cell trafficking into the brain under physiologic conditions, mechanisms by which antibodies can access the CNS, Trojan horse delivery systems, blood-to-brain transport systems for biologicals, lectin interactions and ligand modifications that enhance BBB penetration, and secretory capacities of cells comprising the BBBs.

  18. The blood-brain barrier: connecting the gut and the brain.

    PubMed

    Banks, William A

    2008-08-07

    The BBB prevents the unrestricted exchange of substances between the central nervous system (CNS) and the blood. The blood-brain barrier (BBB) also conveys information between the CNS and the gastrointestinal (GI) tract through several mechanisms. Here, we review three of those mechanisms. First, the BBB selectively transports some peptides and regulatory proteins in the blood-to-brain or the brain-to-blood direction. The ability of GI hormones to affect functions of the BBB, as illustrated by the ability of insulin to alter the BBB transport of amino acids and drugs, represents a second mechanism. A third mechanism is the ability of GI hormones to affect the secretion by the BBB of substances that themselves affect feeding and appetite, such as nitric oxide and cytokines. By these and other mechanisms, the BBB regulates communications between the CNS and GI tract.

  19. Developing drugs that can cross the blood-brain barrier: applications to Alzheimer's disease.

    PubMed

    Banks, William A

    2008-12-10

    Development of therapeutics for the central nervous system is one of the most challenging areas in drug development. This is primarily because, in addition to all of the other complications one faces in developing new drugs targeting peripheral sites, one must also negotiate the blood-brain barrier (BBB). There are dozens of strategies to overcome the obstacle of the BBB, but many of these are bound to fail, barring extreme serendipity, because they are based on an inaccurate or incomplete picture of the BBB. This article therefore starts with a brief review of the BBB as it pertains to drug development. It then examines some examples of the delivery of drugs to the central nervous system that are relevant to Alzheimer's disease, placing emphasis on peptides, antibodies, and antisense oligonucleotides.

  20. Alzheimer's disease drug development and the problem of the blood-brain barrier

    PubMed Central

    Pardridge, William M.

    2009-01-01

    Alzheimer's disease (AD) drug development is limited by the presence of the blood-brain barrier (BBB). More than 98% of all small molecule drugs, and ∼100% of all large molecule drugs, do not cross the BBB. Despite the fact that the vast majority of AD drug candidates do not cross the BBB, the present-day AD drug development effort is characterized by an imbalance, whereby >99% of the drug development effort is devoted to CNS drug discovery, and <1% of drug development is devoted to CNS drug delivery. Future AD drug development needs a concerted effort to incorporate the BBB sciences early in the CNS drug discovery process. This can be accomplished by a reallocation of resources, and an expansion of the effort in the pure science of BBB biology and the applied science of brain drug targeting technology. PMID:19751922

  1. Focused ultrasound-mediated drug delivery through the blood-brain barrier

    PubMed Central

    Burgess, Alison; Shah, Kairavi; Hough, Olivia; Hynynen, Kullervo

    2015-01-01

    Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods which can be used to circumvent the BBB to promote drug delivery is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents. PMID:25936845

  2. Metabolically dependent blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis.

    PubMed

    Hawkins, C P; Munro, P M; Landon, D N; McDonald, W I

    1992-01-01

    We have studied chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of immune-mediated demyelination, using gadolinium (Gd)-enhanced magnetic resonance imaging in vivo and the blood-brain barrier (BBB) markers, lanthanum nitrate and Gd nitrate, histologically. In regions of the spinal cord showing Gd enhancement, there was evidence for vesicular transport as a mechanism of BBB breakdown in CREAE, shown by an increased number of endothelial vesicles containing lanthanide (lanthanum or Gd, whichever had been perfused) and deposition of tracer in the perivascular space; tight interendothelial junctions remained intact. Prior perfusion with 2,4-dinitrophenol, a metabolic inhibitor, suppressed the appearance of endothelial vesicles containing lanthanide and tracer in the perivascular space. We conclude that an important contribution to BBB breakdown in CREAE is mediated by a metabolic change in the endothelial cells associated with increased vesicular transport.

  3. Analytical and Biological Methods for Probing the Blood-Brain Barrier

    NASA Astrophysics Data System (ADS)

    Kuhnline, Sloan; Courtney, D.; Nandi, Pradyot; Linz, Thomas H.; Aldrich, Jane V.; Audus, Kenneth L.; Lunte, Susan M.

    2012-07-01

    The blood-brain barrier (BBB) is an important interface between the peripheral and central nervous systems. It protects the brain against the infiltration of harmful substances and regulates the permeation of beneficial endogenous substances from the blood into the extracellular fluid of the brain. It can also present a major obstacle in the development of drugs that are targeted for the central nervous system. Several methods have been developed to investigate the transport and metabolism of drugs, peptides, and endogenous compounds at the BBB. In vivo methods include intravenous injection, brain perfusion, positron emission tomography, and microdialysis sampling. Researchers have also developed in vitro cell-culture models that can be employed to investigate transport and metabolism at the BBB without the complication of systemic involvement. All these methods require sensitive and selective analytical methods to monitor the transport and metabolism of the compounds of interest at the BBB.

  4. Blood-brain barrier after resuscitation from 10-min clinical death in rats.

    PubMed

    Kapuściński, A; Kapuściński, P

    1995-01-01

    In rats 10-min clinical death was induced by intrathoracic compression of the cardiac vessel bundle. The animals were sacrificed from 15 min to 7 days after resuscitation. They were decapitated 15 sec after intracarotid injection of mixture of L-[U-14C]glutamic acid and tritiated water. Using by the dual label method the brain uptake index (BUI) and percent of injected dose of amino acid in the cerebral hemisphere were calculated. In 45% of animals an increase of amino acid transfer and rise of BUI revealed the blood-brain barrier (BBB) alterations. The most pronounced changes developed after 120 min and 1 day after resuscitation. The impaired vs. normal BBB state depends probably on uneven recovery of cerebral circulation in individual animals after resuscitation.

  5. Focused ultrasound-mediated drug delivery through the blood-brain barrier.

    PubMed

    Burgess, Alison; Shah, Kairavi; Hough, Olivia; Hynynen, Kullervo

    2015-05-01

    Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods, which can be used to circumvent the BBB to promote drug delivery, is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents.

  6. The impact of microglial activation on blood-brain barrier in brain diseases

    PubMed Central

    da Fonseca, Anna Carolina Carvalho; Matias, Diana; Garcia, Celina; Amaral, Rackele; Geraldo, Luiz Henrique; Freitas, Catarina; Lima, Flavia Regina Souza

    2014-01-01

    The blood-brain barrier (BBB), constituted by an extensive network of endothelial cells (ECs) together with neurons and glial cells, including microglia, forms the neurovascular unit (NVU). The crosstalk between these cells guarantees a proper environment for brain function. In this context, changes in the endothelium-microglia interactions are associated with a variety of inflammation-related diseases in brain, where BBB permeability is compromised. Increasing evidences indicate that activated microglia modulate expression of tight junctions, which are essential for BBB integrity and function. On the other hand, the endothelium can regulate the state of microglial activation. Here, we review recent advances that provide insights into interactions between the microglia and the vascular system in brain diseases such as infectious/inflammatory diseases, epilepsy, ischemic stroke and neurodegenerative disorders. PMID:25404894

  7. Fluorescein Isothiocyanate (FITC)-Dextran Extravasation as a Measure of Blood-Brain Barrier Permeability.

    PubMed

    Natarajan, Reka; Northrop, Nicole; Yamamoto, Bryan

    2017-04-10

    The blood-brain barrier (BBB) is formed in part by vascular endothelial cells that constitute the capillaries and microvessels of the brain. The function of this barrier is to maintain homeostasis within the brain microenvironment and buffer the brain from changes in the periphery. A dysfunction of the BBB would permit circulating molecules and pathogens typically restricted to the periphery to enter the brain and interfere with normal brain function. As increased permeability of the BBB is associated with several neuropathologies, it is important to have a reliable and sensitive method that determines BBB permeability and the degree of BBB disruption. A detailed protocol is presented for assessing the integrity of the BBB by transcardial perfusion of a 10,000 Da FITC-labeled dextran molecule and its visualization to determine the degree of extravasation from brain microvessels. © 2017 by John Wiley & Sons, Inc.

  8. Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies.

    PubMed

    Loureiro, Joana A; Gomes, Bárbara; Coelho, Manuel A N; do Carmo Pereira, Maria; Rocha, Sandra

    2014-04-01

    Development of therapeutics for brain disorders is one of the more difficult challenges to be overcome by the scientific community due to the inability of most molecules to cross the blood-brain barrier (BBB). Antibody-conjugated nanoparticles are drug carriers that can be used to target encapsulated drugs to the brain endothelial cells and have proven to be very promising. They significantly improve the accumulation of the drug in pathological sites and decrease the undesirable side effect of drugs in healthy tissues. We review the systems that have demonstrated promising results in crossing the BBB through receptor-mediated endocytic mechanisms for the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

  9. Disruption of the blood-brain barrier in Parkinson's disease: curse or route to a cure?

    PubMed

    Lee, Heyne; Pienaar, Ilse S

    2014-01-01

    The vertebrate blood-brain barrier (BBB) is critical for ensuring the maintenance of brain homeostasis, whilst protecting the brain against toxic insults. Various pathological events disrupt BBB integrity, holding several important clinical implications. In instances where the normal mechanisms controlling passage of substances into the brain are compromised, these could sensitize or even worsen endogenous pathological conditions. Recognition has grown recently that patients diagnosed with Parkinson's disease (PD) present with concurrent medical problems, including cerebrovascular lesions. However, cerebrovascular disturbances may also result from PD-related disease processes; the pathological mechanisms which could entail interaction between environment-derived and genetic factors. The current review addresses the accumulation of studies aimed at better understanding the series of processes affecting the neurovascular unit in human Parkinsonism, due in part to the BBB presenting as a formidable opponent in the effective delivery of therapeutics that have shown promise as therapeutic strategies for treating aspects of PD when tested in vitro.

  10. Blood-brain barrier P-glycoprotein function in neurodegenerative disease.

    PubMed

    Bartels, A L

    2011-01-01

    Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protection against toxic compounds. Importantly, dysfunctional BBB P-gp transport is postulated as an important factor contributing to accumulation of aggregated protein in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, P-gp is a major factor in mediating resistance to brain entry of numerous exogenous compounds, including toxins that can be involved in PD pathogenesis. This review highlights the role of altered P-gp function in the pathogenesis and progression of neurodegenerative disease. Also the implications of alterations in P-gp function for the treatment of these diseases are discussed.

  11. The gut microbiota influences blood-brain barrier permeability in mice.

    PubMed

    Braniste, Viorica; Al-Asmakh, Maha; Kowal, Czeslawa; Anuar, Farhana; Abbaspour, Afrouz; Tóth, Miklós; Korecka, Agata; Bakocevic, Nadja; Ng, Lai Guan; Guan, Ng Lai; Kundu, Parag; Gulyás, Balázs; Halldin, Christer; Hultenby, Kjell; Nilsson, Harriet; Hebert, Hans; Volpe, Bruce T; Diamond, Betty; Pettersson, Sven

    2014-11-19

    Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.

  12. Automatic QSAR modeling of ADME properties: blood-brain barrier penetration and aqueous solubility.

    PubMed

    Obrezanova, Olga; Gola, Joelle M R; Champness, Edmund J; Segall, Matthew D

    2008-01-01

    In this article, we present an automatic model generation process for building QSAR models using Gaussian Processes, a powerful machine learning modeling method. We describe the stages of the process that ensure models are built and validated within a rigorous framework: descriptor calculation, splitting data into training, validation and test sets, descriptor filtering, application of modeling techniques and selection of the best model. We apply this automatic process to data sets of blood-brain barrier penetration and aqueous solubility and compare the resulting automatically generated models with 'manually' built models using external test sets. The results demonstrate the effectiveness of the automatic model generation process for two types of data sets commonly encountered in building ADME QSAR models, a small set of in vivo data and a large set of physico-chemical data.

  13. Bioavailability of endomorphins and the blood-brain barrier--a review.

    PubMed

    Perlikowska, Renata; Janecka, Anna

    2014-01-01

    Opioid peptides have the potential to be pharmaceutical agents for the treatment of pain because they modulate nociceptive pathways at supraspinal, spinal and peripheral levels. Unfortunately, peptides are generally hydrophilic compounds and therefore unable to cross the blood-brain barrier (BBB) by passive diffusion to reach the central nervous system (CNS) in an amount sufficient to activate appropriate receptors. Endomorphins (EMs) belong to the class of endogenous opioids eliciting the strongest analgesic effect, but only after direct administration to the CNS. Extensive research is in progress to better understand the relationships between EM structure and bioavailability. This article deals with the recent investigations that allow the design of stable and neuroactive EM analogs with enhanced brain passage and uptake.

  14. Experimental Methods and Transport Models for Drug Delivery across the Blood-Brain Barrier

    PubMed Central

    Fu, Bingmei M

    2017-01-01

    The blood-brain barrier (BBB) is a dynamic barrier essential for maintaining the micro-environment of the brain. Although the special anatomical features of the BBB determine its protective role for the central nervous system (CNS) from blood-born neurotoxins, however, the BBB extremely limits the therapeutic efficacy of drugs into the CNS, which greatly hinders the treatment of major brain diseases. This review summarized the unique structures of the BBB, described a variety of in vivo and in vitro experimental methods for determining the transport properties of the BBB, e.g., the permeability of the BBB to water, ions, and solutes including nutrients, therapeutic agents and drug carriers, and presented newly developed mathematical models which quantitatively correlate the anatomical structures of the BBB with its barrier functions. Finally, on the basis of the experimental observations and the quantitative models, several strategies for drug delivery through the BBB were proposed. PMID:22201587

  15. Changes in blood-brain barrier function modify the neuroendocrine response to circulating substances.

    PubMed

    Jezová, D; Johansson, B B; Oprsalová, Z; Vigas, M

    1989-04-01

    It is known that various experimental, pathological and even physiological situations may be accompanied by transient increases in blood-brain barrier (BBB) permeability. The hypothesis that under such conditions the blood-borne substances can reach the active sites in the brain in concentrations high enough to influence central control of hormone release was verified in these studies. A suitable experimental model of BBB opening by protamine sulfate administration in conscious rats was introduced. Using this model it was shown that the dopaminergic blocker domperidone inhibited apomorphine-induced ACTH release if permeability of the BBB was increased, but not under normal conditions. It is suggested that the changes in BBB function can modify the neuroendocrine response also to other circulating substances and this may be an important, until now unconsidered phenomenon in neuroendocrine research.

  16. Blood-brain barrier drug targeting: the future of brain drug development.

    PubMed

    Pardridge, William M

    2003-03-01

    As human longevity increases, the likelihood of the onset of diseases of the brain (and other organs) also increases. Clinical therapeutics offer useful long-term treatments, if not cures, if drugs can be delivered appropriately and effectively. Unfortunately, research in drug transport to the brain has not advanced very far. Through better characterization of the transport systems utilized within the blood-brain barrier, a greater understanding of how to exploit these systems will lead to effective treatments for brain disorders. Pardridge reviews the functions of the various known transport systems in the brain and discusses how the development of BBB drug-targeting programs in pharmaceutical and academic settings may lead to more efficacious treatments.

  17. Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

    PubMed Central

    Stamatovic, Svetlana M; Johnson, Allison M; Keep, Richard F; Andjelkovic, Anuska V

    2016-01-01

    abstract The blood-brain barrier (BBB) is a highly complex and dynamic barrier. It is formed by an interdependent network of brain capillary endothelial cells, endowed with barrier properties, and perivascular cells (astrocytes and pericytes) responsible for inducing and maintaining those properties. One of the primary properties of the BBB is a strict regulation of paracellular permeability due to the presence of junctional complexes (tight, adherens and gap junctions) between the endothelial cells. Alterations in junction assembly and function significantly affect BBB properties, particularly barrier permeability. However, such alterations are also involved in remodeling the brain endothelial cell surface and regulating brain endothelial cell phenotype. This review summarizes the characteristics of brain endothelial tight, adherens and gap junctions and highlights structural and functional alterations in junctional proteins that may contribute to BBB dysfunction. PMID:27141427

  18. Automatic partitioning of unstructured grids into connected components

    NASA Technical Reports Server (NTRS)

    Dagum, Leonardo

    1993-01-01

    This paper presents two partitioning schemes that guarantee connected components given a connected initial grid. Connected components are important for convergence of methods such as domain decomposition or multigrid. For many of the grids tested, the schemes produce partitions as good (in terms of number of cut edges) or better than spectral partitioning and require only modest computational resources. This paper describes the two schemes in detail and presents comparison results from a number of two and three dimensional unstructured grids.

  19. A straightforward method for Vacuum-Ultraviolet flux measurements: The case of the hydrogen discharge lamp and implications for solid-phase actinometry

    NASA Astrophysics Data System (ADS)

    Fulvio, D.; Brieva, A. C.; Cuylle, S. H.; Linnartz, H.; Jäger, C.; Henning, T.

    2014-07-01

    Vacuum-Ultraviolet (VUV) radiation is responsible for the photo-processing of simple and complex molecules in several terrestrial and extraterrestrial environments. In the laboratory such radiation is commonly simulated by inexpensive and easy-to-use microwave-powered hydrogen discharge lamps. However, VUV flux measurements are not trivial and the methods/devices typically used for this purpose, mainly actinometry and calibrated VUV silicon photodiodes, are not very accurate or expensive and lack of general suitability to experimental setups. Here, we present a straightforward method for measuring the VUV photon flux based on the photoelectric effect and using a gold photodetector. This method is easily applicable to most experimental setups, bypasses the major problems of the other methods, and provides reliable flux measurements. As a case study, the method is applied to a microwave-powered hydrogen discharge lamp. In addition, the comparison of these flux measurements to those obtained by O2 actinometry experiments allow us to estimate the quantum yield (QY) values QY122 = 0.44 ± 0.16 and QY160 = 0.87 ± 0.30 for solid-phase O2 actinometry.

  20. Straightforward fabrication of stable white LEDs by embedding of inorganic UV-LEDs into bulk polymerized polymethyl-methacrylate doped with organic dyes.

    PubMed

    Di Martino, Daniela; Beverina, Luca; Sassi, Mauro; Brovelli, Sergio; Tubino, Riccardo; Meinardi, Francesco

    2014-03-18

    Stable white-emitting down-converted LEDs are straightforwardly prepared by bulk polymerization of an organic dye doped polymethyl-methacrylate (PMMA) shell directly on top of a highly efficient commercial blue-emitting InGaN LED. Our optimized polymerization procedure allows for extending the form factor of achievable luminescence converter (LUCO) material beyond the conventional thin film form and to directly produce devices with light bulb design. The selected organic dyes, the blue-emitting Coumarin 30 and a red-emitting diketopyrrolopyrrole derivative, exhibit high compatibility with the free radical polymerization reaction of the PMMA matrix and ensure high stability of the final hybrid device. The control of both the thickness of the PMMA shell and the concentration of the dopant dyes allow for fine tuning of the emission color of the LUCO LED and to obtain white light with CIE chromatic coordinates x = 0.32 and y = 0.33, with rendering index as high as 80. This simple and versatile procedure is not dye-exclusive and is therefore extendable to other molecular systems for color-tunable efficient solid-state lighting sources.

  1. Straightforward and effective synthesis of γ-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes.

    PubMed

    Ma, Xiaofeng; Lubin, Hodney; Ioja, Enikő; Kékesi, Orsolya; Simon, Ágnes; Apáti, Ágota; Orbán, Tamás I; Héja, László; Kardos, Julianna; Markó, István E

    2016-01-15

    Supply of major metabolites such as γ-aminobutyric acid (GABA), β-alanine and taurine is an essential instrument that shapes signalling, proper cell functioning and survival in the brain and peripheral organs. This background motivates the synthesis of novel classes of compounds regulating their selective transport through various fluid-organ barriers via the low-affinity γ-aminobutyric acid (GABA) transporter subtype 2 (GAT2). Natural and synthetic spirocyclic compounds or therapeutics with a range of structures and biological activity are increasingly recognised in this regard. Based on pre-validated GABA transport activity, straightforward and efficient synthesis method was developed to provide an azaspiro[4.5]decane scaffold, holding a variety of charge, substituent and 3D constrain of spirocyclic amine. Investigation of the azaspiro[4.5]decane scaffold in cell lines expressing the four GABA transporter subtypes led to the discovery of a subclass of a GAT2-selective compounds with acyl-substituted azaspiro[4.5]decane core.

  2. Straightforward fabrication of stable white LEDs by embedding of inorganic UV-LEDs into bulk polymerized polymethyl-methacrylate doped with organic dyes

    NASA Astrophysics Data System (ADS)

    di Martino, Daniela; Beverina, Luca; Sassi, Mauro; Brovelli, Sergio; Tubino, Riccardo; Meinardi, Francesco

    2014-03-01

    Stable white-emitting down-converted LEDs are straightforwardly prepared by bulk polymerization of an organic dye doped polymethyl-methacrylate (PMMA) shell directly on top of a highly efficient commercial blue-emitting InGaN LED. Our optimized polymerization procedure allows for extending the form factor of achievable luminescence converter (LUCO) material beyond the conventional thin film form and to directly produce devices with light bulb design. The selected organic dyes, the blue-emitting Coumarin 30 and a red-emitting diketopyrrolopyrrole derivative, exhibit high compatibility with the free radical polymerization reaction of the PMMA matrix and ensure high stability of the final hybrid device. The control of both the thickness of the PMMA shell and the concentration of the dopant dyes allow for fine tuning of the emission color of the LUCO LED and to obtain white light with CIE chromatic coordinates x = 0.32 and y = 0.33, with rendering index as high as 80. This simple and versatile procedure is not dye-exclusive and is therefore extendable to other molecular systems for color-tunable efficient solid-state lighting sources.

  3. Straightforward synthetic protocol for the introduction of stabilized C nucleophiles in the BODIPY core for advanced sensing and photonic applications.

    PubMed

    Gutiérrez-Ramos, Brenda D; Bañuelos, Jorge; Arbeloa, Teresa; López Arbeloa, Iñigo; González-Navarro, Paulina E; Wrobel, Kazimierz; Cerdán, Luis; García-Moreno, Inmaculada; Costela, Angel; Peña-Cabrera, Eduardo

    2015-01-19

    A straightforward synthetic protocol to directly incorporate stabilized 1,3-dicarbonyl C nucleophiles to the meso position of BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) is reported. Soft nucleophiles generated by deprotonation of 1,3-dicarbonyl derivatives smoothly displace the 8-methylthio group from 8-(methylthio)BODIPY analogues in the presence of Cu(I) thiophenecarboxylate in stoichiometric amounts at room temperature. Seven highly fluorescent new derivatives are prepared with varying yields (20-92%) in short reaction times (5-30 min). The excellent photophysical properties of the new dyes allow focusing on applications never analyzed before for BODIPYs substituted with stabilized C nucleophiles such as pH sensors and lasers in liquid and solid state, highlighting the relevance of the synthetic protocol described in the present work. The attainment of these dyes, with strong UV absorption and highly efficient and stable laser emission in the green spectral region, concerns to one of the greatest challenges in the ongoing development of advanced photonic materials with relevant applications. In fact, organic dyes with emission in the green are the only ones that allow, by frequency-doubling processes, the generation of tunable ultraviolet (250-350 nm) radiation, with ultra-short pulses.

  4. A straightforward method for Vacuum-Ultraviolet flux measurements: The case of the hydrogen discharge lamp and implications for solid-phase actinometry

    SciTech Connect

    Fulvio, D. E-mail: dfu@oact.inaf.it; Brieva, A. C.; Jäger, C.; Cuylle, S. H.; Linnartz, H.; Henning, T.

    2014-07-07

    Vacuum-Ultraviolet (VUV) radiation is responsible for the photo-processing of simple and complex molecules in several terrestrial and extraterrestrial environments. In the laboratory such radiation is commonly simulated by inexpensive and easy-to-use microwave-powered hydrogen discharge lamps. However, VUV flux measurements are not trivial and the methods/devices typically used for this purpose, mainly actinometry and calibrated VUV silicon photodiodes, are not very accurate or expensive and lack of general suitability to experimental setups. Here, we present a straightforward method for measuring the VUV photon flux based on the photoelectric effect and using a gold photodetector. This method is easily applicable to most experimental setups, bypasses the major problems of the other methods, and provides reliable flux measurements. As a case study, the method is applied to a microwave-powered hydrogen discharge lamp. In addition, the comparison of these flux measurements to those obtained by O{sub 2} actinometry experiments allow us to estimate the quantum yield (QY) values QY{sub 122} = 0.44 ± 0.16 and QY{sub 160} = 0.87 ± 0.30 for solid-phase O{sub 2} actinometry.

  5. Straightforward process for removal of milk fat globule membranes and production of fat-free whey protein concentrate from cheese whey.

    PubMed

    Damodaran, Srinivasan

    2011-09-28

    A straightforward method for the separation of milk fat globule membrane (MFGM) and production of fat-free whey protein concentrate/isolate from cheese whey has been developed. Lowering of the conductivity of the whey from its initial value of about 5600 μS cm(-1) to about 2000-500 μS cm(-1) via diafiltration with water caused selective precipitation of MFGM when incubated for 30 min at pH 4.2 and 35 °C. The whey proteins remained soluble in the supernatant under these conditions. Experimental evidence suggested that precipitation of MFGM at pH 4.2 was not due to a nonspecific effect of lowering of the conductivity of the whey but due to the specific effect of removal of Ca2+ from the whey. The lipid content of whey protein isolate obtained by this process was <0.2%, and the protein loss was <14%. The method provides an industrially feasible process for the production of fat-free whey protein concentrate/isolate. The MFGM, which is reported to contain bioactive/nutraceutical lipids and proteins, is a valuable byproduct of the process.

  6. Apparatus for chemical amplification based on fluid partitioning in an immiscible liquid

    DOEpatents

    Anderson, Brian L [Lodi, CA; Colston, Bill W [San Ramon, CA; Elkin, Christopher J [San Ramon, CA

    2012-05-08

    A system for nucleic acid amplification of a sample comprises partitioning the sample into partitioned sections and performing PCR on the partitioned sections of the sample. Another embodiment of the invention provides a system for nucleic acid amplification and detection of a sample comprising partitioning the sample into partitioned sections, performing PCR on the partitioned sections of the sample, and detecting and analyzing the partitioned sections of the sample.

  7. Method for chemical amplification based on fluid partitioning in an immiscible liquid

    DOEpatents

    Anderson, Brian L.; Colston, Bill W.; Elkin, Christopher J.

    2015-06-02

    A system for nucleic acid amplification of a sample comprises partitioning the sample into partitioned sections and performing PCR on the partitioned sections of the sample. Another embodiment of the invention provides a system for nucleic acid amplification and detection of a sample comprising partitioning the sample into partitioned sections, performing PCR on the partitioned sections of the sample, and detecting and analyzing the partitioned sections of the sample.

  8. Method for chemical amplification based on fluid partitioning in an immiscible liquid

    DOEpatents

    Anderson, Brian L.; Colston, Bill W.; Elkin, Christopher J.

    2017-02-28

    A system for nucleic acid amplification of a sample comprises partitioning the sample into partitioned sections and performing PCR on the partitioned sections of the sample. Another embodiment of the invention provides a system for nucleic acid amplification and detection of a sample comprising partitioning the sample into partitioned sections, performing PCR on the partitioned sections of the sample, and detecting and analyzing the partitioned sections of the sample.

  9. Partitioning kinetic energy during freewheeling wheelchair maneuvers.

    PubMed

    Medola, Fausto O; Dao, Phuc V; Caspall, Jayme J; Sprigle, Stephen

    2014-03-01

    This paper describes a systematic method to partition the kinetic energy (KE) of a free-wheeling wheelchair. An ultralightweight rigid frame wheelchair was instrumented with two axle-mounted encoders and data acquisition equipment to accurately measure the velocity of the drive wheels. A mathematical model was created combining physical specifications and geometry of the wheelchair and its components. Two able-bodied subjects propelled the wheelchair over four courses that involved straight and turning maneuvers at differing speeds. The KE of the wheelchair was divided into three components: translational, rotational, and turning energy. This technique was sensitive to the changing contributions of the three energy components across maneuvers. Translational energy represented the major component of total KE in all maneuvers except a zero radius turn in which turning energy was dominant. Both translational and rotational energies are directly related to wheelchair speed. Partitioning KE offers a useful means of investigating the dynamics of a moving wheelchair. The described technique permits analysis of KE imparted to the wheelchair during maneuvers involving changes in speed and direction, which are most representative of mobility in everyday life. This technique can be used to study the effort required to maneuver different types and configurations of wheelchairs.

  10. Vacuole Partitioning during Meiotic Division in Yeast

    PubMed Central

    Roeder, A. D.; Shaw, J. M.

    1996-01-01

    We have examined the partitioning of the yeast vacuole during meiotic division. In pulse-chase experiments, vacuoles labeled with the lumenal ade2 fluorophore or the membrane-specific dye FM 4-64 were not inherited by haploid spores. Instead, these fluorescent markers were excluded from spores and trapped between the spore cell walls and the ascus. Serial optical sections using a confocal microscope confirmed that spores did not inherit detectable amounts of fluorescently labeled vacuoles. Moreover, indirect immunofluorescence studies established that an endogenous vacuolar membrane protein, alkaline phosphatase, and a soluable vacuolar protease, carboxypeptidase Y, were also detected outside spores after meiotic division. Spores that did not inherit ade2- or FM 4-64-labeled vacuoles did generate an organelle that could be visualized by subsequent staining with vacuole-specific fluorophores. These data contrast with genetic evidence that a soluble vacuolar protease is inherited by spores. When the partitioning of both types of markers was examined in sporulating cultures, the vacuolar protease activity was inherited by spores while fluorescently labeled vacuoles were largely excluded from spores. Our results indicate that the majority of the diploid vacuole, both soluble contents and membrane-bound components, are excluded from spores formed during meiotic division. PMID:8889511

  11. Carbon partitioning in sugarcane (Saccharum species)

    PubMed Central

    Wang, Jianping; Nayak, Spurthi; Koch, Karen; Ming, Ray

    2013-01-01

    Focus has centered on C-partitioning in stems of sugarcane (Saccharum sp.) due to their high-sucrose accumulation features, relevance to other grasses, and rising economic value. Here we review how sugarcane balances between sucrose storage, respiration, and cell wall biosynthesis. The specific topics involve (1) accumulation of exceptionally high sucrose levels (up to over 500 mM), (2) a potential, turgor-sensitive system for partitioning sucrose between storage inside (cytosol and vacuole) and outside cells, (3) mechanisms to prevent back-flow of extracellular sucrose to xylem or phloem, (4) apparent roles of sucrose-P-synthase in fructose retrieval and sucrose re-synthesis, (5) enhanced importance of invertases, and (6) control of C-flux at key points in cell wall biosynthesis (UDP-glucose dehydrogenase) and respiration (ATP- and pyrophosphate-dependent phosphofructokinases). A combination of emerging technologies is rapidly enhancing our understanding of these points and our capacity to shift C-flux between sucrose, cell wall polymers, or other C-sinks. PMID:23785381

  12. Partitioning in parallel processing of production systems

    SciTech Connect

    Oflazer, K.

    1987-01-01

    This thesis presents research on certain issues related to parallel processing of production systems. It first presents a parallel production system interpreter that has been implemented on a four-processor multiprocessor. This parallel interpreter is based on Forgy's OPS5 interpreter and exploits production-level parallelism in production systems. Runs on the multiprocessor system indicate that it is possible to obtain speed-up of around 1.7 in the match computation for certain production systems when productions are split into three sets that are processed in parallel. The next issue addressed is that of partitioning a set of rules to processors in a parallel interpreter with production-level parallelism, and the extent of additional improvement in performance. The partitioning problem is formulated and an algorithm for approximate solutions is presented. The thesis next presents a parallel processing scheme for OPS5 production systems that allows some redundancy in the match computation. This redundancy enables the processing of a production to be divided into units of medium granularity each of which can be processed in parallel. Subsequently, a parallel processor architecture for implementing the parallel processing algorithm is presented.

  13. New parallel SOR method by domain partitioning

    SciTech Connect

    Xie, Dexuan

    1996-12-31

    In this paper, we propose and analyze a new parallel SOR method, the PSOR method, formulated by using domain partitioning together with an interprocessor data-communication technique. For the 5-point approximation to the Poisson equation on a square, we show that the ordering of the PSOR based on the strip partition leads to a consistently ordered matrix, and hence the PSOR and the SOR using the row-wise ordering have the same convergence rate. However, in general, the ordering used in PSOR may not be {open_quote}consistently ordered{close_quotes}. So, there is a need to analyze the convergence of PSOR directly. In this paper, we present a PSOR theory, and show that the PSOR method can have the same asymptotic rate of convergence as the corresponding sequential SOR method for a wide class of linear systems in which the matrix is {open_quotes}consistently ordered{close_quotes}. Finally, we demonstrate the parallel performance of the PSOR method on four different message passing multiprocessors (a KSR1, the Intel Delta, an Intel Paragon and an IBM SP2), along with a comparison with the point Red-Black and four-color SOR methods.

  14. Ferrous iron partitioning in the lower mantle

    NASA Astrophysics Data System (ADS)

    Muir, Joshua M. R.; Brodholt, John P.

    2016-08-01

    We used density functional theory (DFT) to examine the partitioning of ferrous iron between periclase and bridgmanite under lower mantle conditions. To study the effects of the three major variables - pressure, temperature and concentration - these have been varied from 0 to 150 GPa, from 1000 to 4000 K and from 0 to 100% total iron content. We find that increasing temperature increases KD, increasing iron concentration decreases KD, while pressure can both increase and decrease KD. We find that KD decreases slowly from about 0.32 to 0.06 with depth under lower mantle conditions. We also find that KD increases sharply to 0.15 in the very lowermost mantle due to the strong temperature increases near the CMB. Spin transitions have a large effect on the activity of ferropericlase which causes KD to vary with pressure in a peak-like fashion. Despite the apparently large changes in KD through the mantle, this actually results in relatively small changes in total iron content in the two phases, with XFefp ranging from about 0.20 to 0.35, before decreasing again to about 0.28 at the CMB, and XFebd has a pretty constant value of about 0.04-0.07 throughout the lower mantle. For the very high Fe concentrations suggested for ULVZs, Fe partitions very strongly into ferropericlase.

  15. Recursive partitioning for heterogeneous causal effects.

    PubMed

    Athey, Susan; Imbens, Guido

    2016-07-05

    In this paper we propose methods for estimating heterogeneity in causal effects in experimental and observational studies and for conducting hypothesis tests about the magnitude of differences in treatment effects across subsets of the population. We provide a data-driven approach to partition the data into subpopulations that differ in the magnitude of their treatment effects. The approach enables the construction of valid confidence intervals for treatment effects, even with many covariates relative to the sample size, and without "sparsity" assumptions. We propose an "honest" approach to estimation, whereby one sample is used to construct the partition and another to estimate treatment effects for each subpopulation. Our approach builds on regression tree methods, modified to optimize for goodness of fit in treatment effects and to account for honest estimation. Our model selection criterion anticipates that bias will be eliminated by honest estimation and also accounts for the effect of making additional splits on the variance of treatment effect estimates within each subpopulation. We address the challenge that the "ground truth" for a causal effect is not observed for any individual unit, so that standard approaches to cross-validation must be modified. Through a simulation study, we show that for our preferred method honest estimation results in nominal coverage for 90% confidence intervals, whereas coverage ranges between 74% and 84% for nonhonest approaches. Honest estimation requires estimating the model with a smaller sample size; the cost in terms of mean squared error of treatment effects for our preferred method ranges between 7-22%.

  16. Gait Partitioning Methods: A Systematic Review

    PubMed Central

    Taborri, Juri; Palermo, Eduardo; Rossi, Stefano; Cappa, Paolo

    2016-01-01

    In the last years, gait phase partitioning has come to be a challenging research topic due to its impact on several applications related to gait technologies. A variety of sensors can be used to feed algorithms for gait phase partitioning, mainly classifiable as wearable or non-wearable. Among wearable sensors, footswitches or foot pressure insoles are generally considered as the gold standard; however, to overcome some inherent limitations of the former, inertial measurement units have become popular in recent decades. Valuable results have been achieved also though electromyography, electroneurography, and ultrasonic sensors. Non-wearable sensors, such as opto-electronic systems along with force platforms, remain the most accurate system to perform gait analysis in an indoor environment. In the present paper we identify, select, and categorize the available methodologies for gait phase detection, analyzing advantages and disadvantages of each solution. Finally, we comparatively examine the obtainable gait phase granularities, the usable computational methodologies and the optimal sensor placements on the targeted body segments. PMID:26751449

  17. Immunogold labeling reveals subcellular localisation of silica nanoparticles in a human blood-brain barrier model

    NASA Astrophysics Data System (ADS)

    Ye, Dong; Anguissola, Sergio; O'Neill, Tiina; Dawson, Kenneth A.

    2015-05-01

    Subcellular location of nanoparticles has been widely investigated with fluorescence microscopy, via fluorescently labeled antibodies to visualise target antigens in cells. However, fluorescence microscopy, such as confocal or live cell imaging, has generally limited 3D spatial resolution. Conventional electron microscopy can be useful in bridging resolution gap, but still not ideal in resolving subcellular organelle identities. Using the pre-embedding immunogold electron microscopic imaging, we performed accurate examination of the intracellular trafficking and gathered further evidence of transport mechanisms of silica nanoparticles across a human in vitro blood-brain barrier model. Our approach can effectively immunolocalise a variety of intracellular compartments and provide new insights into the uptake and subcellular transport of nanoparticles.Subcellular location of nanoparticles has been widely investigated with fluorescence microscopy, via fluorescently labeled antibodies to visualise target antigens in cells. However, fluorescence microscopy, such as confocal or live cell imaging, has generally limited 3D spatial resolution. Conventional electron microscopy can be useful in bridging resolution gap, but still not ideal in resolving subcellular organelle identities. Using the pre-embedding immunogold electron microscopic imaging, we performed accurate examination of the intracellular trafficking and gathered further evidence of transport mechanisms of silica nanoparticles across a human in vitro blood-brain barrier model. Our approach can effectively immunolocalise a variety of intracellular compartments and provide new insights into the uptake and subcellular transport of nanoparticles. Electronic supplementary information (ESI) available: Nanoparticle characterisation data, preservation of cellular structures, staining controls, optimisation of size amplification via the silver enhancement, and more imaging results from anti-clathrin and anti-caveolin 1

  18. Chromatographic behaviour predicts the ability of potential nootropics to permeate the blood-brain barrier.

    PubMed

    Farsa, Oldřich

    2013-01-01

    The log BB parameter is the logarithm of the ratio of a compound's equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k'. The second aim was to estimate the brain's absorption of 2-(azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k' were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam-type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism.

  19. Chromatographic Behaviour Predicts the Ability of Potential Nootropics to Permeate the Blood-Brain Barrier

    PubMed Central

    Farsa, Oldřich

    2013-01-01

    The log BB parameter is the logarithm of the ratio of a compound’s equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k′. The second aim was to estimate the brain’s absorption of 2-(azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k′ were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam-type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism. PMID:23641330

  20. Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors

    PubMed Central

    2014-01-01

    Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compound to feed back into the design process. A total of 17 compounds were evaluated, revealing molecules with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivatives exhibited 1–100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate molecules for small molecule probes and drugs. PMID:24780082

  1. Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins.

    PubMed

    Taevernier, Lien; Bracke, Nathalie; Veryser, Lieselotte; Wynendaele, Evelien; Gevaert, Bert; Peremans, Kathelijne; De Spiegeleer, Bart

    2016-09-06

    The cyclic depsipeptide mycotoxins beauvericin and enniatins are capable of reaching the systemic circulation through various routes of exposure and are hence capable of exerting central nervous system (CNS) effects, if they are able to pass the blood-brain barrier (BBB), which was the main objective of this study. Quantification of the mycotoxins was performed using an in-house developed and validated bio-analytical UHPLC-MS/MS method. Prior to the BBB experiments, the metabolic stability of the mycotoxins was evaluated in vitro in mouse serum and brain homogenate. The BBB permeation kinetics of beauvericin and enniatins were studied using an in vivo mice model, applying multiple time regression for studying the blood-to-brain influx. Additionally, capillary depletion was applied to obtain the fraction of the peptides really entering the brain parenchyma and the fraction loosely adhered to the brain capillary wall. Finally, also the brain-to-blood efflux transport kinetics was studied. Metabolic stability data indicated that the investigated mycotoxins were stable during the duration of the in vivo study. The brain influx study showed that beauvericin and enniatins are able to cross the blood-brain barrier in mice: using the Gjedde-Patlak biphasic model, it was shown that all investigated mycotoxins exert a high initial influx rate into the brain (K1 ranging from 11 to 53μL/(g×min)), rapidly reaching a plateau. After penetration, the mycotoxins reached the brain parenchyma (95%) with only a limited amount residing in the capillaries (5%). Negligible efflux (<0.005min(-1)) from the brain was observed in the 15min post-intracerebroventricular injection.

  2. Blood-brain barrier transport of short proline-rich antimicrobial peptides.

    PubMed

    Stalmans, Sofie; Wynendaele, Evelien; Bracke, Nathalie; Knappe, Daniel; Hoffmann, Ralf; Peremans, Kathelijne; Polis, Ingeborgh; Burvenich, Christian; De Spiegeleer, Bart

    2014-04-01

    Infections by antibiotic-resistant bacteria are becoming a great risk for human health, leading to an urgent need for new efficient antibacterial therapies. The short, proline-rich antimicrobial peptides from insects gained a lot of interest as a potential antibacterial treatment, having a low toxicity profile and being mainly active against Gram-negative bacteria. To know whether these antimicrobial peptides can be used for the treatment of cerebral infections, the blood-brain barrier transport characteristics of these peptides were investigated. This study describes the results of the in vivo blood-brain barrier experiments in mice, as well as the in vitro metabolic stability in mouse plasma and brain of apidaecin Api137, oncocin, drosocin and drosocin Pro5Hyp. The four investigated peptides showed a significant influx into the brain with a K(in) ranging between 0.37 and 0.86 µL/g x min and brain distribution volumes of 19.6 to 25.8 µL/g. Only for drosocin, a significant efflux was determined, with a k(out) of 0.22 min(-1). After entering the brain, oncocin was for approximately 80% trapped in the endothelial cells, while the other peptides reached the brain parenchyma for about 70%. All peptides were stable in plasma and brain during the experiments, with estimated metabolic half-lives ranging between 47 min and 637 min. We conclude that the investigated short, proline-rich antimicrobial peptides show an influx into the brain, which make them a promising antibacterial treatment of cerebral infections.

  3. Pharmacological modulation of blood-brain barrier increases permeability of doxorubicin into the rat brain.

    PubMed

    Sardi, Iacopo; la Marca, Giancarlo; Cardellicchio, Stefania; Giunti, Laura; Malvagia, Sabrina; Genitori, Lorenzo; Massimino, Maura; de Martino, Maurizio; Giovannini, Maria G

    2013-01-01

    Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2 mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine (P < 0.001) or ondansetron (P < 0.05) than in control tissues. The concentration of doxorubicin was significantly higher in cerebral hemispheres and brainstem (P < 0.05) but not in cerebellum of rats pretreated with dexamethasone than in control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but currently inapplicable chemotherapeutic drugs.

  4. Drug interactions at the blood-brain barrier: fact or fantasy?

    PubMed Central

    Eyal, Sara; Hsiao, Peng; Unadkat, Jashvant D.

    2009-01-01

    There is considerable interest in the therapeutic and adverse outcomes of drug interactions at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These include altered efficacy of drugs used in the treatment of CNS disorders, such as AIDS dementia and malignant tumors, and enhanced neurotoxicity of drugs that normally penetrate poorly into the brain. BBB- and BCSFB-mediated interactions are possible because these interfaces are not only passive anatomical barriers, but are also dynamic in that they express a variety of influx and efflux transporters and drug metabolizing enzymes. Based on studies in rodents, it has been widely postulated that efflux transporters play an important role at the human BBB in terms of drug delivery. Furthermore, it is assumed that chemical inhibition of transporters or their genetic ablation in rodents is predictive of the magnitude of interaction to be expected at the human BBB. However, studies in humans challenge this well-established paradigm and claim that such drug interactions will be lesser in magnitude but yet may be clinically significant. This review focuses on current known mechanisms of drug interactions at the blood-brain and blood-CSF barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies. Defining the mechanisms and the impact of drug-drug interactions at the BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing neurotoxicity of non-CNS drugs. PMID:19393264

  5. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

    PubMed Central

    Meissner, Konrad; Avram, Michael J.; Yermolenka, Viktar; Francis, Amber M.; Blood, Jane; Kharasch, Evan D.

    2013-01-01

    Background The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Methods Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Results Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p < 0.05). Analgesia testing was confounded by cyclosporine-related pain. Conclusions Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects. PMID:23851346

  6. A partitioning strategy for nonuniform problems on multiprocessors

    NASA Technical Reports Server (NTRS)

    Berger, M. J.; Bokhari, S.

    1985-01-01

    The partitioning of a problem on a domain with unequal work estimates in different subddomains is considered in a way that balances the work load across multiple processors. Such a problem arises for example in solving partial differential equations using an adaptive method that places extra grid points in certain subregions of the domain. A binary decomposition of the domain is used to partition it into rectangles requiring equal computational effort. The communication costs of mapping this partitioning onto different microprocessors: a mesh-connected array, a tree machine and a hypercube is then studied. The communication cost expressions can be used to determine the optimal depth of the above partitioning.

  7. Partition of nonionic organic compounds in aquatic systems

    USGS Publications Warehouse

    Smith, James A.; Witkowski, Patrick J.; Chiou, Cary T.

    1988-01-01

    In aqueous systems, the distribution of many nonionic organic solutes in soil-sediment, aquatic organisms, and dissolved organic matter can be explained in terms of a partition model. The nonionic organic solute is distributed between water and different organic phases that behave as bulk solvents. Factors such as polarity, composition, and molecular size of the solute and organic phase determine the relative importance of partition to the environmental distribution of the solute. This chapter reviews these factors in the context of a partition model and also examines several environmental applications of the partition model for surface- and ground-water systems.

  8. Deep eutectic solvents in countercurrent and centrifugal partition chromatography.

    PubMed

    Roehrer, Simon; Bezold, Franziska; García, Eva Marra; Minceva, Mirjana

    2016-02-19

    Deep eutectic solvents (DESs) were evaluated as solvents in centrifugal partition chromatography, a liquid-liquid chromatography separation technology. To this end, the partition coefficients of ten natural compounds of different hydrophobicity were determined in non-aqueous biphasic systems containing DES. The influence of the composition of DESs and the presence of water in the biphasic system on the partition coefficient were also examined. In addition, several process relevant physical properties of the biphasic system, such as the density and viscosity of the phases, were measured. A mixture of three to four hydrophobic compounds was successfully separated in a centrifugal partition extractor using a heptane/ethanol/DES biphasic system.

  9. Chaos synchronization basing on symbolic dynamics with nongenerating partition.

    PubMed

    Wang, Xingyuan; Wang, Mogei; Liu, Zhenzhen

    2009-06-01

    Using symbolic dynamics and information theory, we study the information transmission needed for synchronizing unidirectionally coupled oscillators. It is found that when sustaining chaos synchronization with nongenerating partition, the synchronization error will be larger than a critical value, although the required coupled channel capacity can be smaller than the case of using a generating partition. Then we show that no matter whether a generating or nongenerating partition is in use, a high-quality detector can guarantee the lead of the response oscillator, while the lag responding can make up the low precision of the detector. A practicable synchronization scheme basing on a nongenerating partition is also proposed in this paper.

  10. Partitioning planning studies: Preliminary evaluation of metal and radionuclide partitioning the high-temperature thermal treatment systems

    SciTech Connect

    Liekhus, K.; Grandy, J.; Chambers, A.

    1997-03-01

    A preliminary study of toxic metals and radionuclide partitioning during high-temperature processing of mixed waste has been conducted during Fiscal Year 1996 within the Environmental Management Technology Evaluation Project. The study included: (a) identification of relevant partitioning mechanisms that cause feed material to be distributed between the solid, molten, and gas phases within a thermal treatment system; (b) evaluations of existing test data from applicable demonstration test programs as a means to identify and understand elemental and species partitioning; and, (c) evaluation of theoretical or empirical partitioning models for use in predicting elemental or species partitioning in a thermal treatment system. This preliminary study was conducted to identify the need for and the viability of developing the tools capable of describing and predicting toxic metals and radionuclide partitioning in the most applicable mixed waste thermal treatment processes. This document presents the results and recommendations resulting from this study that may serve as an impetus for developing and implementing these predictive tools.

  11. Determining Partition Coefficient (Log P), Distribution Coefficient (Log D) and Ionization Constant (pKa) in Early Drug Discovery.

    PubMed

    Bharate, Sonali S; Kumar, Vikas; Vishwakarma, Ram A

    2016-01-01

    An early prediction of physicochemical properties is highly desirable during drug discovery to find out a viable lead candidate. Although there are several methods available to determine partition coefficient (log P), distribution coefficient (log D) and ionization constant (pKa), none of them involves simple and fixed, miniaturized protocols for diverse set of compounds. Therefore, it is necessary to establish simple, uniform and medium-throughput protocols requiring small sample quantities for the determination of these physicochemical properties. Log P and log D were determined by shake flask method, wherein, the compound was partitioned between presaturated noctanol and water phase (water/PBS pH 7.4) and the concentration of compound in each phase was determined by HPLC. The pKa determination made use of UV spectrophotometric analysis in a 96-well microtiter plate containing a series of aqueous buffers ranging from pH 1.0 to 13.0. The medium-throughput miniaturized protocols described herein, for determination of log P, log D and pKa, are straightforward to set up and require very small quantities of sample (< 5 mg for all three properties). All established protocols were validated using diverse set of compounds.

  12. Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

    PubMed

    Sırav, Bahriye; Seyhan, Nesrin

    2016-09-01

    With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (p<0.01). 1800MHz pulse modulated radio-frequency radiation exposure was found more effective on the male animals (p<0.01). For female groups; dye contents in the whole brains were 0.14±0.01mg% in the control, 0.24±0.03mg% in 900MHz exposed and 0.14±0.02mg% in 1800MHz exposed animals. No statistical variance found between the control and 1800MHz exposed animals (p>0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed

  13. Computational prediction of octanol-water partition coefficient based on the extended solvent-contact model.

    PubMed

    Kim, Taeho; Park, Hwangseo

    2015-07-01

    The logarithm of 1-octanol/water partition coefficient (LogP) is one of the most important molecular design parameters in drug discovery. Assuming that LogP can be calculated from the difference between the solvation free energy of a molecule in water and that in 1-octanol, we propose a method for predicting the molecular LogP values based on the extended solvent-contact model. To obtain the molecular solvation free energy data for the two solvents, a proper potential energy function was defined for each solvent with respect to atomic distributions and three kinds of atomic parameters. Total 205 atomic parameters were optimized with the standard genetic algorithm using the training set consisting of 139 organic molecules with varying shapes and functional groups. The LogP values estimated with the two optimized solvation free energy functions compared reasonably well with the experimental results with the associated squared correlation coefficient and root mean square error of 0.824 and 0.697, respectively. Besides the prediction accuracy, the present method has the merit in practical applications because molecular LogP values can be computed straightforwardly from the simple potential energy functions without the need to calculate various molecular descriptors. The methods for enhancing the accuracy of the present prediction model are also discussed.

  14. Interspecific resource partitioning in sympatric ursids

    USGS Publications Warehouse

    Belant, J.L.; Kielland, K.; Follmann, E.H.; Adams, L.G.

    2006-01-01

    The fundamental niche of a species is rarely if ever realized because the presence of other species restricts it to a narrower range of ecological conditions. The effects of this narrower range of conditions define how resources are partitioned. Resource partitioning has been inferred but not demonstrated previously for sympatric ursids. We estimated assimilated diet in relation to body condition (body fat and lean and total body mass) and reproduction for sympatric brown bears (Ursus arctos) and American black bears (U. americanus) in southcentral Alaska, 1998-2000. Based on isotopic analysis of blood and keratin in claws, salmon (Oncorhynchus spp.) predominated in brown bear diets (>53% annually) whereas black bears assimilated 0-25% salmon annually. Black bears did not exploit salmon during a year with below average spawning numbers, probably because brown bears deterred black bear access to salmon. Proportion of salmon in assimilated diet was consistent across years for brown bears and represented the major portion of their diet. Body size of brown bears in the study area approached mean body size of several coastal brown bear populations, demonstrating the importance of salmon availability to body condition. Black bears occurred at a comparable density (mass:mass), but body condition varied and was related directly to the amount of salmon assimilated in their diet. Both species gained most lean body mass during spring and all body fat during summer when salmon were present. Improved body condition (i.e., increased percentage body fat) from salmon consumption reduced catabolism of lean body mass during hibernation, resulting in better body condition the following spring. Further, black bear reproduction was directly related to body condition; reproductive rates were reduced when body condition was lower. High body fat content across years for brown bears was reflected in consistently high reproductive levels. We suggest that the fundamental niche of black bears

  15. Effects of poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide on blood-brain barrier and dopaminergic neurons of rats with lipopolysaccharide-induced Parkinson's disease.

    PubMed

    Wu, Xiao-li; Wang, Ping; Liu, Yun-hui; Xue, Yi-xue

    2014-05-01

    Neuro-inflammation and dysfunction of blood-brain barrier play an important role in the occurrence, development, and neuronal degeneration of Parkinson's disease (PD). Studies have demonstrated that a variety of cytokines such as TNF-α and IL-1β destroy the structure and function of blood-brain barrier. The damage to blood-brain barrier results in death of dopaminergic neurons, while protection of blood-brain barrier slows down the progression of PD. Also, it has been shown that activation of poly (ADP-ribose) polymerase (PARP) plays an important role in causing damage to blood-brain barrier. In addition, the PARP inhibitor 3-AB has been shown to protect blood-brain barrier from damage and has neuroprotective effects. In this study, using a lipopolysaccharide (LPS)-induced PD rat model, we investigated whether 3-AB protects blood-brain barrier and dopaminergic neurons from functional damage. LPS significantly increased Evans blue content in the substantia nigra which peaked at 12 h, while administration of 3-AB significantly inhibited the LPS-induced increase in Evans blue content and also significantly increased the expression of the tight junction-associated proteins claudin-5, occludin and ZO-1. 3-AB also increased the number of tyrosine hydroxylase positive cells and reduced the IL-1β and TNF-α content significantly. According to western blot analysis, 3-AB significantly reduced the p-ERK1/2 expression, while the expression of p-p38MAPK increased. These results suggest that 3-AB protects the blood-brain barrier from functional damage in an LPS-induced PD rat model and dopaminergic neurons are protected from degeneration by upregulation of tight junction-associated proteins. These protective effects of 3-AB may be related to modulation of the ERK1/2 pathway.

  16. Partitioning sparse matrices with eigenvectors of graphs

    NASA Technical Reports Server (NTRS)

    Pothen, Alex; Simon, Horst D.; Liou, Kang-Pu

    1990-01-01

    The problem of computing a small vertex separator in a graph arises in the context of computing a good ordering for the parallel factorization of sparse, symmetric matrices. An algebraic approach for computing vertex separators is considered in this paper. It is shown that lower bounds on separator sizes can be obtained in terms of the eigenvalues of the Laplacian matrix associated with a graph. The Laplacian eigenvectors of grid graphs can be computed from Kronecker products involving the eigenvectors of path graphs, and these eigenvectors can be used to compute good separators in grid graphs. A heuristic algorithm is designed to compute a vertex separator in a general graph by first computing an edge separator in the graph from an eigenvector of the Laplacian matrix, and then using a maximum matching in a subgraph to compute the vertex separator. Results on the quality of the separators computed by the spectral algorithm are presented, and these are compared with separators obtained from other algorithms for computing separators. Finally, the time required to compute the Laplacian eigenvector is reported, and the accuracy with which the eigenvector must be computed to obtain good separators is considered. The spectral algorithm has the advantage that it can be implemented on a medium-size multiprocessor in a straightforward manner.

  17. Advanced Aqueous Separation Systems for Actinide Partitioning

    SciTech Connect

    Nash, Kenneth L.; Clark, Sue; Meier, G Patrick; Alexandratos, Spiro; Paine, Robert; Hancock, Robert; Ensor, Dale

    2012-03-21

    One of the most challenging aspects of advanced processing of spent nuclear fuel is the need to isolate transuranium elements from fission product lanthanides. This project expanded the scope of earlier investigations of americium (Am) partitioning from the lanthanides with the synthesis of new separations materials and a centralized focus on radiochemical characterization of the separation systems that could be developed based on these new materials. The primary objective of this program was to explore alternative materials for actinide separations and to link the design of new reagents for actinide separations to characterizations based on actinide chemistry. In the predominant trivalent oxidation state, the chemistry of lanthanides overlaps substantially with that of the trivalent actinides and their mutual separation is quite challenging.

  18. Experimental investigation of the iodine partition coefficient

    SciTech Connect

    Kelly, J.L.; Babad, C.J.; Mulder, R.U.

    1985-11-01

    Short-term values of the iodine partition coefficient (IPC) were evaluated experimentally by an air/water system over the following ranges of conditions: temperature = 25 to 70/sup 0/C, pH = 5 to 9, and iodine concentration = 10/sup -9/ to 10/sup -2/ kg iodine/m/sup 3/ H/sub 2/O. The experimental IPC values are relatively independent of temperature over the indicated range, but show a significant dependence on pH and iodine concentration. In basic solutions the short-term values are several orders of magnitude less than the true equilibrium values; in acid solutions, the differences are much less. These results are useful for predicting the disposition of iodine shortly (i.e., 1 to 10 h) after iodine has been released into an air/water environment.

  19. Partitional Classification: A Complement to Phylogeny

    PubMed Central

    Salomon, Marc; Dassy, Bruno

    2016-01-01

    The tree of life is currently an active object of research, though next to vertical gene transmission non vertical gene transfers proved to play a significant role in the evolutionary process. To overcome this difficulty, trees of life are now constructed from genes hypothesized vital, on the assumption that these are all transmitted vertically. This view has been challenged. As a frame for this discussion, we developed a partitional taxonomical system clustering taxa at a high taxonomical rank. Our analysis (1) selects RNase P RNA sequences of bacterial, archaeal, and eucaryal genera from genetic databases, (2) submits the sequences, aligned, to k-medoid analysis to obtain clusters, (3) establishes the correspondence between clusters and taxa, (4) constructs from the taxa a new type of taxon, the genetic community (GC), and (5) classifies the GCs: Archaea–Eukaryotes contrastingly different from the six others, all bacterial. The GCs would be the broadest frame to carry out the phylogenies. PMID:27346943

  20. Exometabolite niche partitioning among sympatric soil bacteria

    PubMed Central

    Baran, Richard; Brodie, Eoin L.; Mayberry-Lewis, Jazmine; Hummel, Eric; Da Rocha, Ulisses Nunes; Chakraborty, Romy; Bowen, Benjamin P.; Karaoz, Ulas; Cadillo-Quiroz, Hinsby; Garcia-Pichel, Ferran; Northen, Trent R.

    2015-01-01

    Soils are arguably the most microbially diverse ecosystems. Physicochemical properties have been associated with the maintenance of this diversity. Yet, the role of microbial substrate specialization is largely unexplored since substrate utilization studies have focused on simple substrates, not the complex mixtures representative of the soil environment. Here we examine the exometabolite composition of desert biological soil crusts (biocrusts) and the substrate preferences of seven biocrust isolates. The biocrust's main primary producer releases a diverse array of metabolites, and isolates of physically associated taxa use unique subsets of the complex metabolite pool. Individual isolates use only 13−26% of available metabolites, with only 2 out of 470 used by all and 40% not used by any. An extension of this approach to a mesophilic soil environment also reveals high levels of microbial substrate specialization. These results suggest that exometabolite niche partitioning may be an important factor in the maintenance of microbial diversity. PMID:26392107

  1. Exometabolite niche partitioning among sympatric soil bacteria

    SciTech Connect

    Baran, Richard; Brodie, Eoin L.; Mayberry-Lewis, Jazmine; Hummel, Eric; Da Rocha, Ulisses Nunes; Chakraborty, Romy; Bowen, Benjamin P.; Karaoz, Ulas; Cadillo-Quiroz, Hinsby; Garcia-Pichel, Ferran; Northen, Trent R.

    2015-09-22

    Soils are arguably the most microbially diverse ecosystems. Physicochemical properties have been associated with the maintenance of this diversity. Yet, the role of microbial substrate specialization is largely unexplored since substrate utilization studies have focused on simple substrates, not the complex mixtures representative of the soil environment. Here we examine the exometabolite composition of desert biological soil crusts (biocrusts) and the substrate preferences of seven biocrust isolates. The biocrust's main primary producer releases a diverse array of metabolites, and isolates of physically associated taxa use unique subsets of the complex metabolite pool. Individual isolates use only 13-26% of available metabolites, with only 2 out of 470 used by all and 40% not used by any. An extension of this approach to a mesophilic soil environment also reveals high levels of microbial substrate specialization. In conclusion, these results suggest that exometabolite niche partitioning may be an important factor in the maintenance of microbial diversity.

  2. Exometabolite niche partitioning among sympatric soil bacteria

    DOE PAGES

    Baran, Richard; Brodie, Eoin L.; Mayberry-Lewis, Jazmine; ...

    2015-09-22

    Soils are arguably the most microbially diverse ecosystems. Physicochemical properties have been associated with the maintenance of this diversity. Yet, the role of microbial substrate specialization is largely unexplored since substrate utilization studies have focused on simple substrates, not the complex mixtures representative of the soil environment. Here we examine the exometabolite composition of desert biological soil crusts (biocrusts) and the substrate preferences of seven biocrust isolates. The biocrust's main primary producer releases a diverse array of metabolites, and isolates of physically associated taxa use unique subsets of the complex metabolite pool. Individual isolates use only 13-26% of available metabolites,more » with only 2 out of 470 used by all and 40% not used by any. An extension of this approach to a mesophilic soil environment also reveals high levels of microbial substrate specialization. In conclusion, these results suggest that exometabolite niche partitioning may be an important factor in the maintenance of microbial diversity.« less

  3. Metal separations using aqueous biphasic partitioning systems

    SciTech Connect

    Chaiko, D.J.; Zaslavsky, B.; Rollins, A.N.; Vojta, Y.; Gartelmann, J.; Mego, W.

    1996-05-01

    Aqueous biphasic extraction (ABE) processes offer the potential for low-cost, highly selective separations. This countercurrent extraction technique involves selective partitioning of either dissolved solutes or ultrafine particulates between two immiscible aqueous phases. The extraction systems that the authors have studied are generated by combining an aqueous salt solution with an aqueous polymer solution. They have examined a wide range of applications for ABE, including the treatment of solid and liquid nuclear wastes, decontamination of soils, and processing of mineral ores. They have also conducted fundamental studies of solution microstructure using small angle neutron scattering (SANS). In this report they review the physicochemical fundamentals of aqueous biphase formation and discuss the development and scaleup of ABE processes for environmental remediation.

  4. Recursive Partitioning Method on Competing Risk Outcomes

    PubMed Central

    Xu, Wei; Che, Jiahua; Kong, Qin

    2016-01-01

    In some cancer clinical studies, researchers have interests to explore the risk factors associated with competing risk outcomes such as recurrence-free survival. We develop a novel recursive partitioning framework on competing risk data for both prognostic and predictive model constructions. We define specific splitting rules, pruning algorithm, and final tree selection algorithm for the competing risk tree models. This methodology is quite flexible that it can corporate both semiparametric method using Cox proportional hazards model and parametric competing risk model. Both prognostic and predictive tree models are developed to adjust for potential confounding factors. Extensive simulations show that our methods have well-controlled type I error and robust power performance. Finally, we apply both Cox proportional hazards model and flexible parametric model for prognostic tree development on a retrospective clinical study on oropharyngeal cancer patients. PMID:27486300

  5. Partitioned-Interval Quantum Optical Communications Receiver

    NASA Technical Reports Server (NTRS)

    Vilnrotter, Victor A.

    2013-01-01

    The proposed quantum receiver in this innovation partitions each binary signal interval into two unequal segments: a short "pre-measurement" segment in the beginning of the symbol interval used to make an initial guess with better probability than 50/50 guessing, and a much longer segment used to make the high-sensitivity signal detection via field-cancellation and photon-counting detection. It was found that by assigning as little as 10% of the total signal energy to the pre-measurement segment, the initial 50/50 guess can be improved to about 70/30, using the best available measurements such as classical coherent or "optimized Kennedy" detection.

  6. Partitional Classification: A Complement to Phylogeny.

    PubMed

    Salomon, Marc; Dassy, Bruno

    2016-01-01

    The tree of life is currently an active object of research, though next to vertical gene transmission non vertical gene transfers proved to play a significant role in the evolutionary process. To overcome this difficulty, trees of life are now constructed from genes hypothesized vital, on the assumption that these are all transmitted vertically. This view has been challenged. As a frame for this discussion, we developed a partitional taxonomical system clustering taxa at a high taxonomical rank. Our analysis (1) selects RNase P RNA sequences of bacterial, archaeal, and eucaryal genera from genetic databases, (2) submits the sequences, aligned, to k-medoid analysis to obtain clusters, (3) establishes the correspondence between clusters and taxa, (4) constructs from the taxa a new type of taxon, the genetic community (GC), and (5) classifies the GCs: Archaea-Eukaryotes contrastingly different from the six others, all bacterial. The GCs would be the broadest frame to carry out the phylogenies.

  7. Recursive partitioning for heterogeneous causal effects

    PubMed Central

    Athey, Susan; Imbens, Guido

    2016-01-01

    In this paper we propose methods for estimating heterogeneity in causal effects in experimental and observational studies and for conducting hypothesis tests about the magnitude of differences in treatment effects across subsets of the population. We provide a data-driven approach to partition the data into subpopulations that differ in the magnitude of their treatment effects. The approach enables the construction of valid confidence intervals for treatment effects, even with many covariates relative to the sample size, and without “sparsity” assumptions. We propose an “honest” approach to estimation, whereby one sample is used to construct the partition and another to estimate treatment effects for each subpopulation. Our approach builds on regression tree methods, modified to optimize for goodness of fit in treatment effects and to account for honest estimation. Our model selection criterion anticipates that bias will be eliminated by honest estimation and also accounts for the effect of making additional splits on the variance of treatment effect estimates within each subpopulation. We address the challenge that the “ground truth” for a causal effect is not observed for any individual unit, so that standard approaches to cross-validation must be modified. Through a simulation study, we show that for our preferred method honest estimation results in nominal coverage for 90% confidence intervals, whereas coverage ranges between 74% and 84% for nonhonest approaches. Honest estimation requires estimating the model with a smaller sample size; the cost in terms of mean squared error of treatment effects for our preferred method ranges between 7–22%. PMID:27382149

  8. Partition coefficients of organic contaminants with carbohydrates.

    PubMed

    Hung, Hsu-Wen; Lin, Tsair-Fuh; Chiou, Cary T

    2010-07-15

    In view of the current lack of reliable partition coefficients for organic compounds with carbohydrates (K(ch)), carefully measured values with cellulose and starch, the two major forms of carbohydrates, are provided for a wide range of compounds: short-chain chlorinated hydrocarbons, halogenated benzenes, alkyl benzenes, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, and organochlorine pesticides. To ensure the accuracy of the K(ch) data, solute concentrations in both water and carbohydrate phases are measured by direct solvent extraction of the samples. For a given compound, the observed partition coefficient with cellulose (K(cl)) is virtually the same as that with starch (K(st)). This finding expedites the evaluation of organic contamination with different forms of carbohydrates. The presently determined K(ch) values of 13 PAHs are substantially lower (by 3-66 times) than the literature data; the latter are suspect as they were obtained with (i) presumably impure carbohydrate samples or (ii) indirectly measured equilibrium solute concentrations in carbohydrate and water phases. Although the K(ch) values are generally considerably lower than the respective K(ow) (octanol-water) or K(lipid) (lipid-water), accurate K(ch) data are duly required to accurately estimate the contamination of carbohydrates by organic compounds because of the abundance of carbohydrates over lipids in crops and plants. To overcome the current lack of reliable K(ch) data for organic compounds, a close correlation of log K(ch) with log K(ow) has been established for predicting the unavailable K(ch) data for low-polarity compounds.

  9. 47 CFR 24.104 - Partitioning and disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... their authorized spectrum at any time following grant of their geographic area authorizations. (a... names that constitute the partitioned area. (c) Disaggregation. Spectrum may be disaggregated in any... for a partitioned license area and for disaggregated spectrum shall be the remainder of the...

  10. 47 CFR 24.714 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 2 2010-10-01 2010-10-01 false Partitioned licenses and disaggregated spectrum... Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Parties seeking approval for... § 24.839. (2) Broadband PCS licensees in spectrum blocks A, B, D, and E and broadband PCS C and F...

  11. 47 CFR 24.714 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 2 2011-10-01 2011-10-01 false Partitioned licenses and disaggregated spectrum... Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Parties seeking approval for... § 24.839. (2) Broadband PCS licensees in spectrum blocks A, B, D, and E and broadband PCS C and F...

  12. 47 CFR 22.948 - Partitioning and Disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... partition or disaggregate their spectrum to other qualified entities. (2) Partitioning. During the five year... obtaining disaggregated spectrum may only use such spectrum in that portion of the cellular market encompassed by the original licensee's CGSA and may not use such spectrum to provide service to...

  13. 47 CFR 27.15 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 2 2012-10-01 2012-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. (1) Parties seeking approval for... service area or disaggregate their licensed spectrum at any time following the grant of their licenses....

  14. 47 CFR 90.365 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Partitioned licenses and disaggregated spectrum... § 90.365 Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Party seeking approval... disaggregate their licensed spectrum at any time following the grant of their licenses. Multilateration...

  15. 47 CFR 24.104 - Partitioning and disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... their authorized spectrum at any time following grant of their geographic area authorizations. (a... names that constitute the partitioned area. (c) Disaggregation. Spectrum may be disaggregated in any... for a partitioned license area and for disaggregated spectrum shall be the remainder of the...

  16. 47 CFR 24.104 - Partitioning and disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... their authorized spectrum at any time following grant of their geographic area authorizations. (a... names that constitute the partitioned area. (c) Disaggregation. Spectrum may be disaggregated in any... for a partitioned license area and for disaggregated spectrum shall be the remainder of the...

  17. 47 CFR 24.104 - Partitioning and disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... their authorized spectrum at any time following grant of their geographic area authorizations. (a... names that constitute the partitioned area. (c) Disaggregation. Spectrum may be disaggregated in any... for a partitioned license area and for disaggregated spectrum shall be the remainder of the...

  18. 47 CFR 101.1323 - Spectrum aggregation, disaggregation, and partitioning.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Spectrum aggregation, disaggregation, and... Requirements § 101.1323 Spectrum aggregation, disaggregation, and partitioning. (a) Eligibility. (1) Parties... aggregate spectrum in any MAS bands, but may not disaggregate their licensed spectrum or partition...

  19. 47 CFR 27.15 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 2 2011-10-01 2011-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. (1) Parties seeking approval for... service area or disaggregate their licensed spectrum at any time following the grant of their licenses....

  20. 47 CFR 24.714 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 2 2014-10-01 2014-10-01 false Partitioned licenses and disaggregated spectrum... Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Parties seeking approval for... § 24.839. (2) Broadband PCS licensees in spectrum blocks A, B, D, and E and broadband PCS C and F...

  1. 47 CFR 90.365 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Partitioned licenses and disaggregated spectrum... § 90.365 Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Party seeking approval... disaggregate their licensed spectrum at any time following the grant of their licenses. Multilateration...

  2. 47 CFR 90.365 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Partitioned licenses and disaggregated spectrum... § 90.365 Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Party seeking approval... disaggregate their licensed spectrum at any time following the grant of their licenses. Multilateration...

  3. 47 CFR 101.1323 - Spectrum aggregation, disaggregation, and partitioning.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Spectrum aggregation, disaggregation, and... Requirements § 101.1323 Spectrum aggregation, disaggregation, and partitioning. (a) Eligibility. (1) Parties... aggregate spectrum in any MAS bands, but may not disaggregate their licensed spectrum or partition...

  4. 47 CFR 22.948 - Partitioning and Disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... partition or disaggregate their spectrum to other qualified entities. (2) Partitioning. During the five year... obtaining disaggregated spectrum may only use such spectrum in that portion of the cellular market encompassed by the original licensee's CGSA and may not use such spectrum to provide service to...

  5. 47 CFR 101.1323 - Spectrum aggregation, disaggregation, and partitioning.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Spectrum aggregation, disaggregation, and... Requirements § 101.1323 Spectrum aggregation, disaggregation, and partitioning. (a) Eligibility. (1) Parties... aggregate spectrum in any MAS bands, but may not disaggregate their licensed spectrum or partition...

  6. 47 CFR 27.15 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 2 2010-10-01 2010-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. (1) Parties seeking approval for... service area or disaggregate their licensed spectrum at any time following the grant of their licenses....

  7. 47 CFR 22.948 - Partitioning and Disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... partition or disaggregate their spectrum to other qualified entities. (2) Partitioning. During the five year... obtaining disaggregated spectrum may only use such spectrum in that portion of the cellular market encompassed by the original licensee's CGSA and may not use such spectrum to provide service to...

  8. 47 CFR 27.15 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 2 2013-10-01 2013-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. (a) Eligibility. (1) Parties seeking approval for... service area or disaggregate their licensed spectrum at any time following the grant of their licenses....

  9. 47 CFR 22.948 - Partitioning and Disaggregation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... partition or disaggregate their spectrum to other qualified entities. (2) Partitioning. During the five year... obtaining disaggregated spectrum may only use such spectrum in that portion of the cellular market encompassed by the original licensee's CGSA and may not use such spectrum to provide service to...

  10. 47 CFR 24.714 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 2 2012-10-01 2012-10-01 false Partitioned licenses and disaggregated spectrum... Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Parties seeking approval for... § 24.839. (2) Broadband PCS licensees in spectrum blocks A, B, D, and E and broadband PCS C and F...

  11. 47 CFR 27.15 - Geographic partitioning and spectrum disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 2 2014-10-01 2014-10-01 false Geographic partitioning and spectrum... Geographic partitioning and spectrum disaggregation. Link to an amendment published at 79 FR 48537, Aug. 15... licensed spectrum at any time following the grant of their licenses. (b) Technical...

  12. 47 CFR 101.1323 - Spectrum aggregation, disaggregation, and partitioning.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Spectrum aggregation, disaggregation, and... Requirements § 101.1323 Spectrum aggregation, disaggregation, and partitioning. (a) Eligibility. (1) Parties... aggregate spectrum in any MAS bands, but may not disaggregate their licensed spectrum or partition...

  13. 47 CFR 101.1323 - Spectrum aggregation, disaggregation, and partitioning.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Spectrum aggregation, disaggregation, and... Requirements § 101.1323 Spectrum aggregation, disaggregation, and partitioning. (a) Eligibility. (1) Parties... aggregate spectrum in any MAS bands, but may not disaggregate their licensed spectrum or partition...

  14. 47 CFR 24.104 - Partitioning and disaggregation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... their authorized spectrum at any time following grant of their geographic area authorizations. (a... names that constitute the partitioned area. (c) Disaggregation. Spectrum may be disaggregated in any... for a partitioned license area and for disaggregated spectrum shall be the remainder of the...

  15. 47 CFR 22.948 - Partitioning and Disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... partition or disaggregate their spectrum to other qualified entities. (2) Partitioning. During the five year... obtaining disaggregated spectrum may only use such spectrum in that portion of the cellular market encompassed by the original licensee's CGSA and may not use such spectrum to provide service to...

  16. 47 CFR 24.714 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 2 2013-10-01 2013-10-01 false Partitioned licenses and disaggregated spectrum... Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Parties seeking approval for... § 24.839. (2) Broadband PCS licensees in spectrum blocks A, B, D, and E and broadband PCS C and F...

  17. 47 CFR 90.365 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Partitioned licenses and disaggregated spectrum... § 90.365 Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Party seeking approval... disaggregate their licensed spectrum at any time following the grant of their licenses. Multilateration...

  18. 47 CFR 90.365 - Partitioned licenses and disaggregated spectrum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Partitioned licenses and disaggregated spectrum... § 90.365 Partitioned licenses and disaggregated spectrum. (a) Eligibility. (1) Party seeking approval... disaggregate their licensed spectrum at any time following the grant of their licenses. Multilateration...

  19. 47 CFR 101.1111 - Partitioning and disaggregation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Partitioning and disaggregation. 101.1111 Section 101.1111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES Competitive Bidding Procedures for LMDS § 101.1111 Partitioning...

  20. 47 CFR 101.1111 - Partitioning and disaggregation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Partitioning and disaggregation. 101.1111 Section 101.1111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES Competitive Bidding Procedures for LMDS § 101.1111 Partitioning...

  1. 47 CFR 101.1111 - Partitioning and disaggregation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Partitioning and disaggregation. 101.1111 Section 101.1111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES Competitive Bidding Procedures for LMDS § 101.1111 Partitioning...

  2. Spatial partitioning improves the reliability of biochemical signaling

    PubMed Central

    Mugler, Andrew; Tostevin, Filipe; ten Wolde, Pieter Rein

    2013-01-01

    Spatial heterogeneity is a hallmark of living systems, even at the molecular scale in individual cells. A key example is the partitioning of membrane-bound proteins via lipid domain formation or cytoskeleton-induced corralling. However, the impact of this spatial heterogeneity on biochemical signaling processes is poorly understood. Here, we demonstrate that partitioning improves the reliability of biochemical signaling. We exactly solve a stochastic model describing a ubiquitous motif in membrane signaling. The solution reveals that partitioning improves signaling reliability via two effects: it moderates the nonlinearity of the switching response, and it reduces noise in the response by suppressing correlations between molecules. An optimal partition size arises from a trade-off between minimizing the number of proteins per partition to improve signaling reliability and ensuring sufficient proteins per partition to maintain signal propagation. The predicted optimal partition size agrees quantitatively with experimentally observed systems. These results persist in spatial simulations with explicit diffusion barriers. Our findings suggest that molecular partitioning is not merely a consequence of the complexity of cellular substructures, but also plays an important functional role in cell signaling. PMID:23530194

  3. Trace-element partitioning in pantellerites and trachytes

    SciTech Connect

    Mahood, G.A.; Stimac, J.A. )

    1990-08-01

    In order to investigate the effect of increasing melt peralkalinity on partitioning, partition coefficients have been determined using neutron activation analyses of coexisting phenocrysts and glass of five samples from Pantelleria spanning the range trachyte to pantellerite. Alkali feldspar partition coefficients for Fe, Rb, Ba, Sr, and Eu vary with melt peralkalinity due to changes in melt polymerization and to the systematic increase in X{sub or} and decrease in X{sub an} of the feldspar. In going from trachyte to pantellerite, Fe partition coefficients increase from 0.04 to 0.10, presumably because Fe{sup +3} increasingly substitutes in the feldspar tetrahedral site as melt activity of Al declines and Fe concentrations increase. Partition coefficients for trivalent light REEs (rare earth elements) decrease and the partitioning pattern becomes flatter, the most evolved samples having some of the lowest published values for feldspar. The hundredfold decline in Eu partition coefficients (2.5 to 0.024) and the decrease in the size of the positive partitioning anomaly are attributed to increasing Eu{sup 3+}/Eu{sup 2+} in the melt as it becomes more peralkaline, as well as to concomitant decrease in the Ca content of feldspar. As a result, the behavior of Eu during fractional crystallization of peralkaline suites is fundamentally different from that in metaluminous suites; absolute abundances rise and the size of the negative Eu anomaly changes little with fractionation beyond pantelleritic trachyte.

  4. Simple partitions of a hyperbolic plane of positive curvature

    SciTech Connect

    Romakina, Lyudmila N

    2012-09-30

    We construct special monohedral isotropic partitions with symmetries of the hyperbolic plane H of positive curvature with a simple 4-contour as a cell. An analogue of mosaic in these partitions called a tiling is introduced. Also we consider some fractal tilings. The existence of band tilings in each homological series with code (m, n) is proved. Bibliography: 14 titles.

  5. DOES NITROGEN PARTITIONING PROMOTE SPECIES DIVERSITY IN ARCTIC TUSSOCK TUNDRA?

    EPA Science Inventory

    We used 15N soil-labeling techniques to examine how the dominant species in a N-limited, tussock tundra plant community partitioned soil N, and how such partitioning may contribute to community organization. The five most productive species were well differentiated with respect ...

  6. PARTITION COEFFICIENTS FOR METALS IN SURFACE WATER, SOIL, AND WASTE

    EPA Science Inventory

    This report presents metal partition coefficients for the surface water pathway and for the source model used in the Multimedia, Multi-pathway, Multi-receptor Exposure and Risk Assessment (3MRA) technology under development by the U.S. Environmental Protection Agency. Partition ...

  7. ESTIMATING DISSOLVED ORGANIC CARBON PARTITION COEFFICIENTS FOR NONIONIC ORGANIC CHEMICALS

    EPA Science Inventory

    A literature search was performed for dissolved organic carbon/water partition coefficients for nonionic chemicals (Kdoc) and Kdoc data was taken from more than sixty references. The Kdoc data were evaluated as a function of the n-octanol/water partition coefficients (Kow). A pre...

  8. 47 CFR 101.1111 - Partitioning and disaggregation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Partitioning and disaggregation. 101.1111 Section 101.1111 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES Competitive Bidding Procedures for LMDS § 101.1111 Partitioning...

  9. REE and Strontium Partition Coefficients for Nakhla Pyroxenes

    NASA Technical Reports Server (NTRS)

    Oe, K.; McKay, G.; Le, L.

    2001-01-01

    We present new partition coefficients for REE and Sr determined using a synthetic melt that crystallizes pyroxenes very similar in composition to Nakhla pyroxene cores. We believe these are the most appropriate partition coefficients to use in studying Nakhla Additional information is contained in the original extended abstract..

  10. ST6GALNAC5 Expression Decreases the Interactions between Breast Cancer Cells and the Human Blood-Brain Barrier.

    PubMed

    Drolez, Aurore; Vandenhaute, Elodie; Delannoy, Clément Philippe; Dewald, Justine Hélène; Gosselet, Fabien; Cecchelli, Romeo; Julien, Sylvain; Dehouck, Marie-Pierre; Delannoy, Philippe; Mysiorek, Caroline

    2016-08-11

    The ST6GALNAC5 gene that encodes an α2,6-sialyltransferase involved in the biosynthesis of α-series gangliosides, was previously identified as one of the genes that mediate breast cancer metastasis to the brain. We have shown that the expression of ST6GALNAC5 in MDA-MB-231 breast cancer cells resulted in the expression of GD1α ganglioside at the cell surface. By using a human blood-brain barrier in vitro model recently developed, consisting in CD34⁺ derived endothelial cells co-cultivated with pericytes, we show that ST6GALNAC5 expression decreased the interactions between the breast cancer cells and the human blood-brain barrier.

  11. Breakdown of Blood-Brain and Blood-Spinal Cord Barriers During Acute Methamphetamine Intoxication: Role of Brain Temperature.

    PubMed

    Kiyatkin, Eugene A; Sharma, Hari S

    2016-01-01

    Methamphetamine (METH) is a powerful and often-abused stimulant with potent addictive and neurotoxic properties. While it is generally believed that structural brain damage induced by METH results from oxidative stress, in this work we present data suggesting robust disruption of blood-brain and blood-spinal cord barriers during acute METH intoxication in rats. We demonstrate the relationships between METH-induced brain hyperthermia and widespread but structure-specific barrier leakage, acute glial cell activation, changes in brain water and ionic homeostasis, and structural damage of different types of cells in the brain and spinal cord. Therefore, METH-induced leakage of the blood-brain and blood-spinal cord barriers is a significant contributor to different types of functional and structural brain abnormalities that determine acute toxicity of this drug and possibly neurotoxicity during its chronic use.

  12. Alzheimer's disease and blood-brain barrier function - Why have anti-β-amyloid therapies failed to prevent dementia progression?

    PubMed Central

    Pahnke, Jens; Walker, Lary C.; Scheffler, Katja; Krohn, Markus

    2009-01-01

    Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-β plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood-brain barrier function, and propose that the activation of the excretion function of the blood-brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-β aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy. PMID:19481107

  13. ST6GALNAC5 Expression Decreases the Interactions between Breast Cancer Cells and the Human Blood-Brain Barrier

    PubMed Central

    Drolez, Aurore; Vandenhaute, Elodie; Delannoy, Clément Philippe; Dewald, Justine Hélène; Gosselet, Fabien; Cecchelli, Romeo; Julien, Sylvain; Dehouck, Marie-Pierre; Delannoy, Philippe; Mysiorek, Caroline

    2016-01-01

    The ST6GALNAC5 gene that encodes an α2,6-sialyltransferase involved in the biosynthesis of α-series gangliosides, was previously identified as one of the genes that mediate breast cancer metastasis to the brain. We have shown that the expression of ST6GALNAC5 in MDA-MB-231 breast cancer cells resulted in the expression of GD1α ganglioside at the cell surface. By using a human blood-brain barrier in vitro model recently developed, consisting in CD34+ derived endothelial cells co-cultivated with pericytes, we show that ST6GALNAC5 expression decreased the interactions between the breast cancer cells and the human blood-brain barrier. PMID:27529215

  14. Dominant partition method. [based on a wave function formalism

    NASA Technical Reports Server (NTRS)

    Dixon, R. M.; Redish, E. F.

    1979-01-01

    By use of the L'Huillier, Redish, and Tandy (LRT) wave function formalism, a partially connected method, the dominant partition method (DPM) is developed for obtaining few body reductions of the many body problem in the LRT and Bencze, Redish, and Sloan (BRS) formalisms. The DPM maps the many body problem to a fewer body one by using the criterion that the truncated formalism must be such that consistency with the full Schroedinger equation is preserved. The DPM is based on a class of new forms for the irreducible cluster potential, which is introduced in the LRT formalism. Connectivity is maintained with respect to all partitions containing a given partition, which is referred to as the dominant partition. Degrees of freedom corresponding to the breakup of one or more of the clusters of the dominant partition are treated in a disconnected manner. This approach for simplifying the complicated BRS equations is appropriate for physical problems where a few body reaction mechanism prevails.

  15. Bacterial partition complexes segregate within the volume of the nucleoid

    PubMed Central

    Le Gall, Antoine; Cattoni, Diego I.; Guilhas, Baptiste; Mathieu-Demazière, Céline; Oudjedi, Laura; Fiche, Jean-Bernard; Rech, Jérôme; Abrahamsson, Sara; Murray, Heath; Bouet, Jean-Yves; Nollmann, Marcelo

    2016-01-01

    Precise and rapid DNA segregation is required for proper inheritance of genetic material. In most bacteria and archaea, this process is assured by a broadly conserved mitotic-like apparatus in which a NTPase (ParA) displaces the partition complex. Competing observations and models imply starkly different 3D localization patterns of the components of the partition machinery during segregation. Here we use super-resolution microscopies to localize in 3D each component of the segregation apparatus with respect to the bacterial chromosome. We show that Par proteins locate within the nucleoid volume and reveal that proper volumetric localization and segregation of partition complexes requires ATPase and DNA-binding activities of ParA. Finally, we find that the localization patterns of the different components of the partition system highly correlate with dense chromosomal regions. We propose a new mechanism in which the nucleoid provides a scaffold to guide the proper segregation of partition complexes. PMID:27377966

  16. Nutrient partitioning and seedling development in the genus Leucaena

    SciTech Connect

    Dovel, R.L.

    1987-01-01

    Slow establishment of the genus Leucaena from seed has been attributed to law seedling vigor and late nodulation. Observation of early seedling growth indicated that partitioning of a large proportion of resources to the root of young Leucaena seedlings could account, in part, for the slow initial shoot growth observed in this genus. Therefore, a series of experiments were conducted to examine the partitioning of stored seed reserves, photosynthate, and nitrogen in developing Leucaena seedlings. The effects of nodulation and nitrogen fertilization on partitioning of nutrients in the seedling were also examined. Seed reserves were initially used for radicle growth in dark grown seedlings; however, partitioning soon shifted to the hypocotyl. By four days after imbibition, hypocotyl weight exceeded radicle weight in both species tested (L. leucocephala and L. retusa), at all temperatures above 20/sup 0/C. Two experiments were conducted examining the carbon partitioning of L. leucocephala cultivar K-8 using /sup 14/CO/sub 2/ pulse labeling techniques.

  17. Equilibration timescale of atmospheric secondary organic aerosol partitioning

    NASA Astrophysics Data System (ADS)

    Shiraiwa, Manabu; Seinfeld, John H.

    2012-12-01

    Secondary organic aerosol (SOA) formed from partitioning of oxidation products of anthropogenic and biogenic volatile organic compounds (VOCs) accounts for a substantial portion of atmospheric particulate matter. In describing SOA formation, it is generally assumed that VOC oxidation products rapidly adopt gas-aerosol equilibrium. Here we estimate the equilibration timescale, τeq, of SOA gas-particle partitioning using a state-of-the-art kinetic flux model. τeq is found to be of order seconds to minutes for partitioning of relatively high volatility organic compounds into liquid particles, thereby adhering to equilibrium gas-particle partitioning. However, τeq increases to hours or days for organic aerosol associated with semi-solid particles, low volatility, large particle size, and low mass loadings. Instantaneous equilibrium partitioning may lead to substantial overestimation of particle mass concentration and underestimation of gas-phase concentration.

  18. Partitioning in Avionics Architectures: Requirements, Mechanisms, and Assurance

    NASA Technical Reports Server (NTRS)

    Rushby, John

    1999-01-01

    Automated aircraft control has traditionally been divided into distinct "functions" that are implemented separately (e.g., autopilot, autothrottle, flight management); each function has its own fault-tolerant computer system, and dependencies among different functions are generally limited to the exchange of sensor and control data. A by-product of this "federated" architecture is that faults are strongly contained within the computer system of the function where they occur and cannot readily propagate to affect the operation of other functions. More modern avionics architectures contemplate supporting multiple functions on a single, shared, fault-tolerant computer system where natural fault containment boundaries are less sharply defined. Partitioning uses appropriate hardware and software mechanisms to restore strong fault containment to such integrated architectures. This report examines the requirements for partitioning, mechanisms for their realization, and issues in providing assurance for partitioning. Because partitioning shares some concerns with computer security, security models are reviewed and compared with the concerns of partitioning.

  19. Crystal/liquid partitioning in augite - Effects of cooling rate

    NASA Astrophysics Data System (ADS)

    Gamble, R. P.; Taylor, L. A.

    1980-03-01

    The partitioning of major and minor elements between augite and melt was determined as a function of cooling rate for two high-titanium basalt compositions. The results of this study of lunar rock systems 10017 and 75055 were compared with the results of other kinetic studies of augite-liquid partitioning in other rock systems. It was found that the partitioning of major elements (i.e., Ca, Fe, Mg) is essentially rate independent and is insensitive to bulk rock composition and to the nature and order of appearance of coexisting phases for cooling rates of less than 100 C/hr. The partitioning behavior of minor elements (i.e., Al, Cr, Ti) for the same range of cooling rates is complex, being dependent on cooling rate and bulk rock composition. Consideration of these factors is important when augite chemistry and/or partitioning behavior are used in modeling certain magmatic processes or in estimating the thermal history of basaltic rocks.

  20. Immiscible silicate liquid partition coefficients: implications for crystal-melt element partitioning and basalt petrogenesis

    NASA Astrophysics Data System (ADS)

    Veksler, Ilya V.; Dorfman, Alexander M.; Danyushevsky, Leonid V.; Jakobsen, Jakob K.; Dingwell, Donald B.

    2006-12-01

    This study investigates partitioning of elements between immiscible aluminosilicate and borosilicate liquids using three synthetic mixtures doped with 32 trace elements. In order to get a good spatial separation of immiscible liquids, we employed a high-temperature centrifuge. Experiments were performed at 1,050-1,150°C, 1 atm, in sealed Fe and Pt containers. Quenched products were analysed by electron microprobe and LA ICP-MS. Nernst partition coefficients ( D’s) between the Fe-rich and Si-rich aluminosilicate immiscible liquids are the highest for Zn (3.3) and Fe (2.6) and the lowest for Rb and K (0.4-0.5). The plots of D values against ionic potential Z/r in all the compositions show a convex upward trend, which is typical also for element partitioning between immiscible silicate and salt melts. The results bear upon the speciation and structural position of elements in multicomponent silicate liquids. The ferrobasalt-rhyolite liquid immiscibility is observed in evolved basaltic magmas, and may play an important role in large gabbroic intrusions, such as Skaergaard, and during the generation of unusual lavas, such as ferropicrites.

  1. Cryptococcus neoformans phospholipase B1 activates host cell Rac1 for traversal across the blood-brain barrier.

    PubMed

    Maruvada, Ravi; Zhu, Longkun; Pearce, Donna; Zheng, Yi; Perfect, John; Kwon-Chung, Kyung J; Kim, Kwang Sik

    2012-10-01

    Cryptococcus neoformans penetration into the central nervous system (CNS) requires traversal of the blood-brain barrier that is composed of a single layer of human brain microvascular endothelial cells (HBMEC), but the underlying mechanisms of C. neoformans traversal remain incompletely understood. C. neoformans transcytosis of HBMEC monolayer involves rearrangements of the host cell actin cytoskeleton and small GTP-binding Rho family proteins such as Rac1 are shown to regulate host cell actin cytoskeleton. We, therefore, examined whether C. neoformans traversal of the blood-brain barrier involves host Rac1. While the levels of activated Rac1 (GTP-Rac1) in HBMEC increased significantly upon incubation with C. neoformans strains, pharmacological inhibition and down-modulation of Rac1 significantly decreased C. neoformans transcytosis of HBMEC monolayer. Also, Rac1 inhibition was efficient in preventing C. neoformans penetration into the brain. In addition, C. neoformans phospholipase B1 (Plb1) was shown to contribute to activating host cell Rac1, andSTAT3 was observed to associate with GTP-Rac1 in HBMEC that were incubated with C. neoformans strain but not with its Δplb1 mutant. These findings demonstrate for the first time that C. neoformans Plb1 aids fungal traversal across the blood-brain barrier by activating host cell Rac1 and its association with STAT3, and suggest that pharmacological intervention of host-microbial interaction contributing to traversal of the blood-brain barrier may prevent C. neoformans penetration into the brain.

  2. The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier

    PubMed Central

    Neuhaus, Winfried; Gaiser, Fabian; Mahringer, Anne; Franz, Jonas; Riethmüller, Christoph; Förster, Carola

    2014-01-01

    Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro. PMID:25389390

  3. Polyacrylate-water partitioning of biocidal compounds: enhancing the understanding of biocide partitioning between render and water.

    PubMed

    Bollmann, Ulla E; Ou, Yi; Mayer, Philipp; Trapp, Stefan; Bester, Kai

    2015-01-01

    In recent years, the application of polymer-based renders and paints for façade coatings of buildings has risen enormously due to the increased mounting of thermal insulation systems. These materials are commonly equipped with biocides - algaecides, fungicides, and bactericides - to protect the materials from biological deterioration. However, the biocides need to be present in the water phase in order to be active and, hence, they are flushed of the material by rain water. In order to increase the knowledge about the partitioning of biocides from render into the water phase, partition constants between the polymer - in this case polyacrylate - and water were studied using glass fibre filters coated with polyacrylate. The polyacrylate-water partition constants (logKAcW) of ten biocides used in construction material varied between 1.66 (isoproturon) and 3.57 (dichloro-N-octylisothiazolinone). The correlation of the polyacrylate-water partition constants with the octanol-water partition constants is significant, but the polyacrylate-water partition constants were predominantly below octanol-water partition constants (Kow). The comparison with render-water distribution constants showed that estimating the leaching of biocides from render based on polymer-water partitioning is a useful and practical tool.

  4. New Linear Partitioning Models Based on Experimental Water: Supercritical CO 2 Partitioning Data of Selected Organic Compounds

    SciTech Connect

    Burant, Aniela; Thompson, Christopher; Lowry, Gregory V.; Karamalidis, Athanasios K.

    2016-05-17

    Partitioning coefficients of organic compounds between water and supercritical CO2 (sc-CO2) are necessary to assess the risk of migration of these chemicals from subsurface CO2 storage sites. Despite the large number of potential organic contaminants, the current data set of published water-sc-CO2 partitioning coefficients is very limited. Here, the partitioning coefficients of thiophene, pyrrole, and anisole were measured in situ over a range of temperatures and pressures using a novel pressurized batch reactor system with dual spectroscopic detectors: a near infrared spectrometer for measuring the organic analyte in the CO2 phase, and a UV detector for quantifying the analyte in the aqueous phase. Our measured partitioning coefficients followed expected trends based on volatility and aqueous solubility. The partitioning coefficients and literature data were then used to update a published poly-parameter linear free energy relationship and to develop five new linear free energy relationships for predicting water-sc-CO2 partitioning coefficients. Four of the models targeted a single class of organic compounds. Unlike models that utilize Abraham solvation parameters, the new relationships use vapor pressure and aqueous solubility of the organic compound at 25 °C and CO2 density to predict partitioning coefficients over a range of temperature and pressure conditions. The compound class models provide better estimates of partitioning behavior for compounds in that class than the model built for the entire dataset.

  5. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment.

    PubMed

    van Tellingen, O; Yetkin-Arik, B; de Gooijer, M C; Wesseling, P; Wurdinger, T; de Vries, H E

    2015-03-01

    Gliomas are the most common primary brain tumors. Particularly in adult patients, the vast majority of gliomas belongs to the heterogeneous group of diffuse gliomas, i.e. glial tumors characterized by diffuse infiltrative growth in the preexistent brain tissue. Unfortunately, glioblastoma, the most aggressive (WHO grade IV) diffuse glioma is also by far the most frequent one. After standard treatment, the 2-year overall survival of glioblastoma patients is approximately only 25%. Advanced knowledge in the molecular pathology underlying malignant transformation has offered new handles and better treatments for several cancer types. Unfortunately, glioblastoma multiforme (GBM) patients have not yet profited as although numerous experimental drugs have been tested in clinical trials, all failed miserably. This grim prognosis for GBM is at least partly due to the lack of successful drug delivery across the blood-brain tumor barrier (BBTB). The human brain comprises over 100 billion capillaries with a total length of 400 miles, a total surface area of 20 m(2) and a median inter-capillary distance of about 50 μm, making it the best perfused organ in the body. The BBTB encompasses existing and newly formed blood vessels that contribute to the delivery of nutrients and oxygen to the tumor and facilitate glioma cell migration to other parts of the brain. The high metabolic demands of high-grade glioma create hypoxic areas that trigger increased expression of VEGF and angiogenesis, leading to the formation of abnormal vessels and a dysfunctional BBTB. Even though the BBTB is considered 'leaky' in the core part of glioblastomas, in large parts of glioblastomas and, even more so, in lower grade diffuse gliomas the BBTB more closely resembles the intact blood-brain barrier (BBB) and prevents efficient passage of cancer therapeutics, including small molecules and antibodies. Thus, many drugs can still be blocked from reaching the many infiltrative glioblastoma cells that

  6. Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity

    PubMed Central

    Mulac, Dennis; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

    2012-01-01

    Scope Ergot alkaloids are secondary metabolites of Claviceps spp. and they have been in the focus of research for many years. Experiments focusing on ergotamine as a former migraine drug referring to the ability to reach the brain revealed controversial results. The question to which extent ergot alkaloids are able to cross the blood-brain barrier is still not answered. Methods and results In order to answer this question we have studied the ability of ergot alkaloids to penetrate the blood-brain barrier in a well established in vitro model system using primary porcine brain endothelial cells. It could clearly be demonstrated that ergot alkaloids are able to cross the blood-brain barrier in high quantities in only a few hours. We could further identify an active transport for ergometrine as a substrate for the BCRP/ABCG2 transporter. Investigations concerning barrier integrity properties have identified ergocristinine as a potent substance to accumulate in these cells ultimately leading to a weakened barrier function. Conclusion For the first time we could show that the so far as biologically inactive described 8-(S) isomers of ergot alkaloids seem to have an influence on barrier integrity underlining the necessity for a risk assessment of ergot alkaloids in food and feed. PMID:22147614

  7. A Novel Dynamic Neonatal Blood-Brain Barrier on a Chip.

    PubMed

    Deosarkar, Sudhir P; Prabhakarpandian, Balabhaskar; Wang, Bin; Sheffield, Joel B; Krynska, Barbara; Kiani, Mohammad F

    2015-01-01

    Studies of neonatal neural pathologies and development of appropriate therapeutics are hampered by a lack of relevant in vitro models of neonatal blood-brain barrier (BBB). To establish such a model, we have developed a novel blood-brain barrier on a chip (B3C) that comprises a tissue compartment and vascular channels placed side-by-side mimicking the three-dimensional morphology, size and flow characteristics of microvessels in vivo. Rat brain endothelial cells (RBEC) isolated from neonatal rats were seeded in the vascular channels of B3C and maintained under shear flow conditions, while neonatal rat astrocytes were cultured under static conditions in the tissue compartment of the B3C. RBEC formed continuous endothelial lining with a central lumen along the length of the vascular channels of B3C and exhibited tight junction formation, as measured by the expression of zonula occludens-1 (ZO-1). ZO-1 expression significantly increased with shear flow in the vascular channels and with the presence of astrocyte conditioned medium (ACM) or astrocytes cultured in the tissue compartment. Consistent with in vivo BBB, B3C allowed endfeet-like astrocyte-endothelial cell interactions through a porous interface that separates the tissue compartment containing cultured astrocytes from the cultured RBEC in the vascular channels. The permeability of fluorescent 40 kDa dextran from vascular channel to the tissue compartment significantly decreased when RBEC were cultured in the presence of astrocytes or ACM (from 41.0 ± 0.9 x 10-6 cm/s to 2.9 ± 1.0 x 10-6 cm/s or 1.1±0.4 x 10-6 cm/s, respectively). Measurement of electrical resistance in B3C further supports that the addition of ACM significantly improves the barrier function in neonatal RBEC. Moreover, B3C exhibits significantly improved barrier characteristics compared to the transwell model and B3C permeability was not significantly different from the in vivo BBB permeability in neonatal rats. In summary, we developed a

  8. A Novel Dynamic Neonatal Blood-Brain Barrier on a Chip

    PubMed Central

    Deosarkar, Sudhir P.; Prabhakarpandian, Balabhaskar; Wang, Bin; Sheffield, Joel B.; Krynska, Barbara; Kiani, Mohammad F.

    2015-01-01

    Studies of neonatal neural pathologies and development of appropriate therapeutics are hampered by a lack of relevant in vitro models of neonatal blood-brain barrier (BBB). To establish such a model, we have developed a novel blood-brain barrier on a chip (B3C) that comprises a tissue compartment and vascular channels placed side-by-side mimicking the three-dimensional morphology, size and flow characteristics of microvessels in vivo. Rat brain endothelial cells (RBEC) isolated from neonatal rats were seeded in the vascular channels of B3C and maintained under shear flow conditions, while neonatal rat astrocytes were cultured under static conditions in the tissue compartment of the B3C. RBEC formed continuous endothelial lining with a central lumen along the length of the vascular channels of B3C and exhibited tight junction formation, as measured by the expression of zonula occludens-1 (ZO-1). ZO-1 expression significantly increased with shear flow in the vascular channels and with the presence of astrocyte conditioned medium (ACM) or astrocytes cultured in the tissue compartment. Consistent with in vivo BBB, B3C allowed endfeet-like astrocyte-endothelial cell interactions through a porous interface that separates the tissue compartment containing cultured astrocytes from the cultured RBEC in the vascular channels. The permeability of fluorescent 40 kDa dextran from vascular channel to the tissue compartment significantly decreased when RBEC were cultured in the presence of astrocytes or ACM (from 41.0±0.9 x 10−6 cm/s to 2.9±1.0 x 10−6 cm/s or 1.1±0.4 x 10−6 cm/s, respectively). Measurement of electrical resistance in B3C further supports that the addition of ACM significantly improves the barrier function in neonatal RBEC. Moreover, B3C exhibits significantly improved barrier characteristics compared to the transwell model and B3C permeability was not significantly different from the in vivo BBB permeability in neonatal rats. In summary, we developed a

  9. Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications

    NASA Astrophysics Data System (ADS)

    Su, Chia-Hao; Tsai, Ching-Yi; Tomanek, Boguslaw; Chen, Wei-Yu; Cheng, Fong-Yu

    2016-04-01

    The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy.The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c6nr00280c

  10. Potentiation of neurotoxicity of Lathyrus sativus by manganese: alterations in blood-brain barrier permeability.

    PubMed

    Mishra, Geeta; Shukla, Rakesh; Hasan, Mahdi; Khanna, Subhash K; Das, Mukul

    2009-05-01

    Environmental factors have been speculated to play an important role in potentiating the neurotoxicity of Lathyrus sativus (LS). Hence, blood-brain barrier permeability and neurotoxicity studies were carried out in manganese- and LS-exposed animals. Dietary feeding of LS (80%) plus Mn (0.4 mg/100 g diet) for 90 days to guinea pigs showed significant (p < 0.05) decrease in brain nucleotidase and ATPase activities when compared to control or LS alone treated groups. Combined treatment of LS and Mn showed a significant (p < 0.05) decrease in neuronal aryl hydrocarbon hydroxylase (36-40%), ethoxyresorufin-O-deethylase (40-45%), glutathione-S-transferase (27-31%), and quinone reductase (24-25%) activities when compared to control and LS alone treated animals. Lipid peroxidation, a marker for membrane damage, was found to be relatively more enhanced (58-141%) along with significant (p < 0.05) depletion of GSH levels in LS+Mn-treated animals when compared to control, Mn alone, and LS alone treated groups. The neuronal catalase activity of lathyrus plus Mn-treated animals showed a pronounced decrease (37-49%) when compared to control, Mn, and lathyrus alone treated groups. On the contrary, glutathione peroxidase in brain of Mn and lathyrus alone treated animals indicated a respective increase (p < 0.05) of 18% and 20%, while the combined effect of lathyrus plus Mn exhibited an increase of almost 50% when compared to control guinea pigs. Single parenteral administration of Mn (15 mg/kg b.wt) to guinea pigs followed by single oral intubation of beta-N-oxalyl-L-alpha, beta-diamino propionic acid (ODAP, 75 mg/guinea pig) resulted in a significant increase (143%) in neuronal ODAP content. ODAP (50 mg/kg,iv) treatment to mice pretreated with MnCl2 (10 mg/kg b.wt for 3 days or 40 mg/kg b.wt for 1 day), caused an enhancement in blood-brain barrier (BBB) permeability (129-196%), while ODAP and Mn alone showed relatively less enhancement (66-87%). The lumbar region of LS+Mn showed a

  11. Flow Partitioning in Fully Saturated Soil Aggregates

    SciTech Connect

    Yang, Xiaofan; Richmond, Marshall C.; Scheibe, Timothy D.; Perkins, William A.; Resat, Haluk

    2014-03-30

    Microbes play an important role in facilitating organic matter decomposition in soils, which is a major component of the global carbon cycle. Microbial dynamics are intimately coupled to environmental transport processes, which control access to labile organic matter and other nutrients that are needed for the growth and maintenance of microorganisms. Transport of soluble nutrients in the soil system is arguably most strongly impacted by preferential flow pathways in the soil. Since the physical structure of soils can be characterized as being formed from constituent micro aggregates which contain internal porosity, one pressing question is the partitioning of the flow among the “inter-aggregate” and “intra-aggregate” pores and how this may impact overall solute transport within heterogeneous soil structures. The answer to this question is particularly important in evaluating assumptions to be used in developing upscaled simulations based on highly-resolved mechanistic models. We constructed a number of diverse multi-aggregate structures with different packing ratios by stacking micro-aggregates containing internal pores and varying the size and shape of inter-aggregate pore spacing between them. We then performed pore-scale flow simulations using computational fluid dynamics methods to determine the flow patterns in these aggregate-of-aggregates structures and computed the partitioning of the flow through intra- and inter-aggregate pores as a function of the spacing between the aggregates. The results of these numerical experiments demonstrate that soluble nutrients are largely transported via flows through inter-aggregate pores. Although this result is consistent with intuition, we have also been able to quantify the relative flow capacity of the two domains under various conditions. For example, in our simulations, the flow capacity through the aggregates (intra-aggregate flow) was less than 2% of the total flow when the spacing between the aggregates

  12. Examination of the Brief Fear of Negative Evaluation Scale-Version 2 and the Brief Fear of Negative Evaluation Scale-Straightforward Items Factor Structure in a Sample of U.S. College Students

    ERIC Educational Resources Information Center

    Liu, Liu; Lowe, Patricia A.

    2016-01-01

    The current study examined the factor structure of the Brief Fear of Negative Evaluation-Straightforward Items (BFNE-S) and the Brief Fear of Negative Evaluation-Version 2 (BFNE-II) among 151 college students from the United States. Results indicated that the BFNE-S and the BFNE-II scores demonstrated excellent internal consistency reliability.…

  13. Scheduling Independent Partitions in Integrated Modular Avionics Systems

    PubMed Central

    Du, Chenglie; Han, Pengcheng

    2016-01-01

    Recently the integrated modular avionics (IMA) architecture has been widely adopted by the avionics industry due to its strong partition mechanism. Although the IMA architecture can achieve effective cost reduction and reliability enhancement in the development of avionics systems, it results in a complex allocation and scheduling problem. All partitions in an IMA system should be integrated together according to a proper schedule such that their deadlines will be met even under the worst case situations. In order to help provide a proper scheduling table for all partitions in IMA systems, we study the schedulability of independent partitions on a multiprocessor platform in this paper. We firstly present an exact formulation to calculate the maximum scaling factor and determine whether all partitions are schedulable on a limited number of processors. Then with a Game Theory analogy, we design an approximation algorithm to solve the scheduling problem of partitions, by allowing each partition to optimize its own schedule according to the allocations of the others. Finally, simulation experiments are conducted to show the efficiency and reliability of the approach proposed in terms of time consumption and acceptance ratio. PMID:27942013

  14. Graph Partitioning for Parallel Applications in Heterogeneous Grid Environments

    NASA Technical Reports Server (NTRS)

    Bisws, Rupak; Kumar, Shailendra; Das, Sajal K.; Biegel, Bryan (Technical Monitor)

    2002-01-01

    The problem of partitioning irregular graphs and meshes for parallel computations on homogeneous systems has been extensively studied. However, these partitioning schemes fail when the target system architecture exhibits heterogeneity in resource characteristics. With the emergence of technologies such as the Grid, it is imperative to study the partitioning problem taking into consideration the differing capabilities of such distributed heterogeneous systems. In our model, the heterogeneous system consists of processors with varying processing power and an underlying non-uniform communication network. We present in this paper a novel multilevel partitioning scheme for irregular graphs and meshes, that takes into account issues pertinent to Grid computing environments. Our partitioning algorithm, called MiniMax, generates and maps partitions onto a heterogeneous system with the objective of minimizing the maximum execution time of the parallel distributed application. For experimental performance study, we have considered both a realistic mesh problem from NASA as well as synthetic workloads. Simulation results demonstrate that MiniMax generates high quality partitions for various classes of applications targeted for parallel execution in a distributed heterogeneous environment.

  15. Scheduling Independent Partitions in Integrated Modular Avionics Systems.

    PubMed

    Chen, Jinchao; Du, Chenglie; Han, Pengcheng

    2016-01-01

    Recently the integrated modular avionics (IMA) architecture has been widely adopted by the avionics industry due to its strong partition mechanism. Although the IMA architecture can achieve effective cost reduction and reliability enhancement in the development of avionics systems, it results in a complex allocation and scheduling problem. All partitions in an IMA system should be integrated together according to a proper schedule such that their deadlines will be met even under the worst case situations. In order to help provide a proper scheduling table for all partitions in IMA systems, we study the schedulability of independent partitions on a multiprocessor platform in this paper. We firstly present an exact formulation to calculate the maximum scaling factor and determine whether all partitions are schedulable on a limited number of processors. Then with a Game Theory analogy, we design an approximation algorithm to solve the scheduling problem of partitions, by allowing each partition to optimize its own schedule according to the allocations of the others. Finally, simulation experiments are conducted to show the efficiency and reliability of the approach proposed in terms of time consumption and acceptance ratio.

  16. Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells.

    PubMed

    Ramirez, Servio H; Potula, Raghava; Fan, Shongshan; Eidem, Tess; Papugani, Anil; Reichenbach, Nancy; Dykstra, Holly; Weksler, Babette B; Romero, Ignacio A; Couraud, Pierre O; Persidsky, Yuri

    2009-12-01

    Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood-brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. In this study, we provide evidence that METH alters BBB function through direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins. These changes were accompanied by the enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Antioxidant treatment attenuated or completely reversed all tested aspects of METH-induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure.

  17. Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction

    PubMed Central

    Cui, Hai; Zhu, Qiong; Hua, Xing; Xia, Hongmei; Tan, Kaibin; Gao, Yunhua; Zhao, Jing

    2016-01-01

    Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p < 0.01). Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4 ± 1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery. PMID:27579317

  18. Drug delivery across the blood-brain barrier using focused ultrasound

    PubMed Central

    Burgess, Alison; Hynynen, Kullervo H.

    2015-01-01

    Introduction The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a non-invasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. Areas Covered The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. Expert Opinion The introduction of MRI guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient, and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development. PMID:24650132

  19. The blood-brain barrier as a regulatory interface in the gut-brain axes.

    PubMed

    Banks, William A

    2006-11-30

    The blood-brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation. Insulin transport is also regulated. For example, treatment of mice with lipopolysaccharide (LPS) increases insulin transport across the BBB by about threefold. Since many of the actions of CNS insulin oppose those of peripheral insulin and since LPS releases proinflammatory cytokines, enhanced transport of insulin across the BBB could be a mechanism which promotes insulin resistance in sepsis. The brain endothelial cells which comprise the BBB secrete many substances including cytokines. Such secretion can be stimulated from one side of the BBB with release into the other side. For example, it appears that adiponectin can inhibit release of interleukin-6 from brain endothelial cells. Overall, the BBB represents an important interface in mediating gut-brain axes.

  20. Role of the blood-brain barrier in the evolution of feeding and cognition.

    PubMed

    Banks, William A

    2012-08-01

    The blood-brain barrier (BBB) regulates the blood-to-brain passage of gastrointestinal hormones, thus informing the brain about feeding and nutritional status. Disruption of this communication results in dysregulation of feeding and body weight control. Leptin, which crosses the BBB to inform the CNS about adiposity, provides an example. Impaired leptin transport, especially coupled with central resistance, results in obesity. Various substances/conditions regulate leptin BBB transport. For example, triglycerides inhibit leptin transport. This may represent an evolutionary adaptation in that hypertriglyceridemia occurs during starvation. Inhibition of leptin, an anorectic, during starvation could have survival advantages. The large number of other substances that influence feeding is explained by the complexity of feeding. This complexity includes cognitive aspects; animals in the wild are faced with cost/benefit analyses to feed in the safest, most economical way. This cognitive aspect partially explains why so many feeding substances affect neurogenesis, neuroprotection, and cognition. The relation between triglycerides and cognition may be partially mediated through triglyceride's ability to regulate the BBB transport of cognitively active gastrointestinal hormones such as leptin, insulin, and ghrelin.

  1. Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

    PubMed

    Urayama, Akihiko; Dohgu, Shinya; Robinson, Sandra M; Sly, William S; Grubb, Jeffery H; Banks, William A

    2015-01-01

    The impermeability of the adult blood-brain barrier (BBB) to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse) of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.

  2. Brain meets body: the blood-brain barrier as an endocrine interface.

    PubMed

    Banks, William A

    2012-09-01

    The blood-brain barrier (BBB) separates the central nervous system (CNS) from the peripheral tissues. However, this does not prevent hormones from entering the brain, but shifts the main control of entry to the BBB. In general, steroid hormones cross the BBB by transmembrane diffusion, a nonsaturable process resulting in brain levels that reflect blood levels, whereas thyroid hormones and many peptides and regulatory proteins cross using transporters, a saturable process resulting in brain levels that reflect blood levels and transporter characteristics. Protein binding, brain-to-blood transport, and pharmacokinetics modulate BBB penetration. Some hormones have the opposite effect within the CNS than they do in the periphery, suggesting that these hormones cross the BBB to act as their own counterregulators. The cells making up the BBB are also endocrine like, both responding to circulating substances and secreting substances into the circulation and CNS. By dividing a hormone's receptors into central and peripheral pools, the former of which may not be part of the hormone's negative feed back loop, the BBB fosters the development of variable hormone resistance syndromes, as exemplified by evidence that altered insulin action in the CNS can contribute to Alzheimer's disease. In summary, the BBB acts as a regulatory interface in an endocrine-like, humoral-based communication between the CNS and peripheral tissues.

  3. Mouse models of neurological disorders: a view from the blood-brain barrier.

    PubMed

    Banks, William A

    2010-10-01

    The number of disease models that involve an aspect of blood-brain barrier (BBB) dysregulation have increased tremendously. The main factors contributing to this expansion have been an increased number of diseases in which the BBB is known to be involved, an increase in the known functions of the BBB, and an increase in the number of models and tools with which those diverse functions can be studied. In many cases, the BBB may be a target of disease; current thinking would include hypertensive encephalopathy and perhaps stroke in this category. Another category are those diseases in which special attributes of the BBB may predispose to disease; for example, the ability of a pathogen to cross the BBB often depends on the pathogen's ability to invoke transcytotic pathways in the brain endothelial or choroid plexus cell. Of special interest are those diseases in which the BBB may be the primary seat of disease or play a major role in the onset or progression of the disease. An increasing number of diseases are so categorized in which BBB dysfunction or dysregulation plays a major role; this review highlights such roles for the BBB including those proposed for Alzheimer's disease and obesity.

  4. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease.

    PubMed

    Erickson, Michelle A; Banks, William A

    2013-10-01

    The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-β (Aβ) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Aβ pathology.

  5. Drug delivery to the brain in Alzheimer's disease: consideration of the blood-brain barrier.

    PubMed

    Banks, William A

    2012-05-15

    The successful treatment of Alzheimer's disease (AD) will require drugs that can negotiate the blood-brain barrier (BBB). However, the BBB is not simply a physical barrier, but a complex interface that is in intimate communication with the rest of the central nervous system (CNS) and influenced by peripheral tissues. This review examines three aspects of the BBB in AD. First, it considers how the BBB may be contributing to the onset and progression of AD. In this regard, the BBB itself is a therapeutic target in the treatment of AD. Second, it examines how the BBB restricts drugs that might otherwise be useful in the treatment of AD and examines strategies being developed to deliver drugs to the CNS for the treatment of AD. Third, it considers how drug penetration across the AD BBB may differ from the BBB of normal aging. In this case, those differences can complicate the treatment of CNS diseases such as depression, delirium, psychoses, and pain control in the AD population.

  6. Plasma from patients with HELLP syndrome increases blood-brain barrier permeability.

    PubMed

    Wallace, Kedra; Tremble, Sarah M; Owens, Michelle Y; Morris, Rachael; Cipolla, Marilyn J

    2015-03-01

    Circulating inflammatory factors and endothelial dysfunction have been proposed to contribute to the pathophysiology of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. To date, the occurrence of neurological complications in these women has been reported, but few studies have examined whether impairment in blood-brain barrier (BBB) permeability or cerebrovascular reactivity is present in women having HELLP syndrome. We hypothesized that plasma from women with HELLP syndrome causes increased BBB permeability and cerebrovascular dysfunction. Posterior cerebral arteries from female nonpregnant rats were perfused with 20% serum from women with normal pregnancies (n = 5) or women with HELLP syndrome (n = 5), and BBB permeability and vascular reactivity were compared. Plasma from women with HELLP syndrome increased BBB permeability while not changing myogenic tone and reactivity to pressure. Addition of the nitric oxide (NO) synthase inhibitor N(ω)-nitro-L-arginine methyl ester caused constriction of arteries that was not different with the different plasmas nor was dilation to the NO donor sodium nitroprusside different between the 2 groups. However, dilation to the small- and intermediate-conductance, calcium-activated potassium channel activator NS309 was decreased in vessels exposed to HELLP plasma. Thus, increased BBB permeability in response to HELLP plasma was associated with selective endothelial dysfunction.

  7. Disruption of the blood-brain barrier exacerbates spreading depression in the locust CNS.

    PubMed

    Spong, Kristin E; Rochon-Terry, Geneviève; Money, Tomas G A; Robertson, R Meldrum

    2014-07-01

    In response to cellular stress in the nervous system of the locust (Locusta migratoria) neural function is interrupted in association with ionic disturbances propagating throughout nervous tissue (Spreading depression; SD). The insect blood-brain barrier (BBB) plays a critical role in the regulation of ion levels within the CNS. We investigated how a disruption in barrier function by transient exposure to 3M urea affects locusts' vulnerability to disturbances in ion levels. Repetitive SD was induced by bath application of ouabain and the extracellular potassium concentration ([K(+)]o) within the metathoracic ganglion (MTG) was monitored. Urea treatment increased the susceptibility to ouabain and caused a progressive impairment in the ability to maintain baseline [K(+)]o levels during episodes of repetitive SD. Additionally, using a within animal protocol we demonstrate that waves of SD, induced by high K(+), propagate throughout the MTG faster following disruption of the BBB. Lastly, we show that targeting the BBB of intact animals reduces their ability to sustain neural function during anoxic conditions. Our findings indicate that locust's ability to withstand stress is diminished following a reduction in barrier function likely due to an impairment of the ability of neural tissue to maintain ionic gradients.

  8. Transport Rankings of Non-Steroidal Antiinflammatory Drugs across Blood-Brain Barrier In Vitro Models

    PubMed Central

    Novakova, Iveta; Subileau, Eva-Anne; Toegel, Stefan; Gruber, Daniela; Lachmann, Bodo; Urban, Ernst; Chesne, Christophe; Noe, Christian R.; Neuhaus, Winfried

    2014-01-01

    The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB) in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line) for proper data comparison. PMID:24466249

  9. Iron transport across the blood-brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy.

    PubMed

    McCarthy, Ryan C; Kosman, Daniel J

    2015-02-01

    There are two barriers for iron entry into the brain: (1) the brain-cerebrospinal fluid (CSF) barrier and (2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

  10. Paving the way towards complex blood-brain barrier models using pluripotent stem cells.

    PubMed

    Lauschke, Karin; Frederiksen, Lise; Hall, Vanessa J

    2017-04-11

    A tissue with great need to be modelled in vitro is the blood-brain barrier (BBB). The BBB is a tight barrier that covers all blood vessels in the brain and separates the brain microenvironment from the blood system. It consists of three cell types (neurovascular unit (NVU)) that contribute to the unique tightness and selective permeability of the BBB and has been shown to be disrupted in many diseases and brain disorders, such as, vascular dementia, stroke, multiple sclerosis and Alzheimer's disease. Given the progress that pluripotent stem cells (PSCs) have made in the last two decades, it is now possible to produce many cell types from the BBB and even partially recapitulate this complex tissue in vitro. In this review, we summarize the most recent developments in PSC differentiation and modelling of the BBB. We also suggest how patient-specific human induced PSCs could be used to model BBB dysfunction in the future. Lastly, we provide perspectives on how to improve production of the BBB in vitro, for example by improving pericyte differentiation protocols and by better modelling the NVU in the dish.

  11. Blood-brain barrier disruption in the striatum of rats treated with 3-nitropropionic acid.

    PubMed

    Duran-Vilaregut, Joaquim; del Valle, Jaume; Camins, Antoni; Pallàs, Mercè; Pelegrí, Carme; Vilaplana, Jordi

    2009-01-01

    3-nitropropionic acid (3-NPA) is a natural toxin that is used to induce models of Huntington's disease (HD) in experimental animals. Here we injected 3-NPA into Sprague-Dawley rats in order to evaluate its effects on the blood-brain barrier (BBB). Evans blue (EB) extravasation was used to identify injured areas in the brains of the treated animals and immunostainings of endothelial brain barrier antigen (EBA), zona occludens-1 (ZO-1) and laminin were used as markers to characterize the effects of the neurotoxin on the BBB. Treated rats had a significant loss of body weight compared to controls, and a correlation between motor affectation and body weight loss was observed in the former. The lateral part of the striatum was specifically injured in treated animals and the BBB almost disappeared in the core of the injured areas, as evidenced by a high EB extravasation and severe alterations of the immunostainings of the three BBB integrity markers compared to those of control animals. We conclude that the BBB is severely affected in the 3-NPA rat model of HD and that disruption of this barrier is a crucial event during the development of this disease.

  12. Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier

    PubMed Central

    Zhang, Yanhua; Walker, Janelle Buttry; Minic, Zeljka; Liu, Fangchao; Goshgarian, Harry; Mao, Guangzhao

    2016-01-01

    Drug delivery to the central nervous system (CNS) is challenging due to the inability of many drugs to cross the blood-brain barrier (BBB). Here, we show that wheat germ agglutinin horse radish peroxidase (WGA-HRP) chemically conjugated to gold nanoparticles (AuNPs) can be transported to the spinal cord and brainstem following intramuscular injection into the diaphragm of rats. We synthesized and determined the size and chemical composition of a three-part nanoconjugate consisting of WGA-HRP, AuNPs, and drugs for the treatment of diaphragm paralysis associated with high cervical spinal cord injury (SCI). Upon injection into the diaphragm muscle of rats, we show that the nanoconjugate is capable of delivering the drug at a much lower dose than the unconjugated drug injected systemically to effectively induce respiratory recovery in rats following SCI. This study not only demonstrates a promising strategy to deliver drugs to the CNS bypassing the BBB but also contributes a potential nanotherapy for the treatment of respiratory muscle paralysis resulted from cervical SCI. PMID:27180729

  13. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

    PubMed

    Chang, Junlei; Mancuso, Michael R; Maier, Carolina; Liang, Xibin; Yuki, Kanako; Yang, Lu; Kwong, Jeffrey W; Wang, Jing; Rao, Varsha; Vallon, Mario; Kosinski, Cynthia; Zhang, J J Haijing; Mah, Amanda T; Xu, Lijun; Li, Le; Gholamin, Sharareh; Reyes, Teresa F; Li, Rui; Kuhnert, Frank; Han, Xiaoyuan; Yuan, Jenny; Chiou, Shin-Heng; Brettman, Ari D; Daly, Lauren; Corney, David C; Cheshier, Samuel H; Shortliffe, Linda D; Wu, Xiwei; Snyder, Michael; Chan, Pak; Giffard, Rona G; Chang, Howard Y; Andreasson, Katrin; Kuo, Calvin J

    2017-04-01

    Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

  14. Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction.

    PubMed

    Xu, Yali; Cui, Hai; Zhu, Qiong; Hua, Xing; Xia, Hongmei; Tan, Kaibin; Gao, Yunhua; Zhao, Jing; Liu, Zheng

    2016-01-01

    Objective. Blood-brain barrier (BBB) is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p < 0.01). Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4 ± 1, grade 2) while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

  15. Numerical study of nonlinear, transcranial focused ultrasound wave propagation for blood-brain barrier (BBB) opening

    NASA Astrophysics Data System (ADS)

    Jiménez, Noé; Roig, Bernardino; Redondo, Javier; Picó, Rubén; Marquet, Fabrice; Konofagou, Elisa E.; Camarena, Francisco

    2012-10-01

    Focused ultrasound (FUS) techniques for Blood-Brain Barrier opening are emerging for localized and safe brain drug delivery. In this work, a transcranial FUS field is computed by a numerical approach entailing nonlinear wave propagation in the time domain in order to determine the position of the true focus and the existence of reflections and resonances. A transducer with a curvature radius of 90 mm, and an aperture of 80 mm was simulated at a central frequency of 500 kHz. The computational method was a Finite-Difference Time-Domain (FDTD) implemented on nonlinear fluid model over a 2D Axis-symmetric domain. The boundary conditions were derived from the apparent density measurements based on a 3D CT scan acquisition performed on a Macaca mulatta primate. The study shows that nonlinear propagation shifts the peak pressure 3 mm away from the transducer when the pressure in the transducer increases from 2 kPa to 70 kPa. The focal shift is mainly due to the presence of the skull and dependent on the incidence angle of the ultrasonic beam. This study proposes a FDTD nonlinear numerical approach to study the propagation of ultrasonic waves through the skull, showing that nonlinear propagation can affect the position of the focal peak.

  16. Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients[S

    PubMed Central

    Fellows, Kelly; Uher, Tomas; Browne, Richard W.; Weinstock-Guttman, Bianca; Horakova, Dana; Posova, Helena; Vaneckova, Manuela; Seidl, Zdenek; Krasensky, Jan; Tyblova, Michaela; Havrdova, Eva; Zivadinov, Robert; Ramanathan, Murali

    2015-01-01

    The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon β1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P ≤ 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ (P < 0.001) and with CSF CD80+CD19+ (P = 0.007) cell frequencies. Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ and CD80+CD19+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event. PMID:26243484

  17. Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies.

    PubMed

    Zuchero, Y Joy Yu; Chen, Xiaocheng; Bien-Ly, Nga; Bumbaca, Daniela; Tong, Raymond K; Gao, Xiaoying; Zhang, Shuo; Hoyte, Kwame; Luk, Wilman; Huntley, Melanie A; Phu, Lilian; Tan, Christine; Kallop, Dara; Weimer, Robby M; Lu, Yanmei; Kirkpatrick, Donald S; Ernst, James A; Chih, Ben; Dennis, Mark S; Watts, Ryan J

    2016-01-06

    The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies for neurological diseases. Using transcriptomic and proteomic profiling, we searched for proteins in mouse brain endothelial cells (BECs) that could potentially be exploited to transport antibodies across the BBB. Due to their limited protein abundance, neither antibodies against literature-identified targets nor BBB-enriched proteins identified by microarray facilitated significant antibody brain uptake. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. Antibodies to each of these targets were significantly enriched in the brain after administration in vivo. In particular, antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain Aβ reduction. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies.

  18. Influence of silver and titanium dioxide nanoparticles on in vitro blood-brain barrier permeability.

    PubMed

    Chen, I-Chieh; Hsiao, I-Lun; Lin, Ho-Chen; Wu, Chien-Hou; Chuang, Chun-Yu; Huang, Yuh-Jeen

    2016-10-01

    An in vitro blood-brain barrier (BBB) model being composed of co-culture with endothelial (bEnd.3) and astrocyte-like (ALT) cells was established to evaluate the toxicity and permeability of Ag nanoparticles (AgNPs; 8nm) and TiO2 nanoparticles (TiO2NPs; 6nm and 35nm) in normal and inflammatory central nervous system. Lipopolysaccharide (LPS) was pre-treated to simulate the inflammatory responses. Both AgNPs and Ag ions can decrease transendothelial electrical resistance (TEER) value, and cause discontinuous tight junction proteins (claudin-5 and zonula occludens-1) of BBB. However, only the Ag ions induced inflammatory cytokines to release, and had less cell-to-cell permeability than AgNPs, which indicated that the toxicity of AgNPs was distinct from Ag ions. LPS itself disrupted BBB, while co-treatment with AgNPs and LPS dramatically enhanced the disruption and permeability coefficient. On the other hand, TiO2NPs exposure increased BBB penetration by size, and disrupted tight junction proteins without size dependence, and many of TiO2NPs accumulated in the endothelial cells were observed. This study provided the new insight of toxic potency of AgNPs and TiO2NPs in BBB.

  19. Blood-brain barrier and blood-cerebrospinal fluid barrier in normal and pathological conditions.

    PubMed

    Ueno, Masaki; Chiba, Yoichi; Murakami, Ryuta; Matsumoto, Koichi; Kawauchi, Machi; Fujihara, Ryuji

    2016-04-01

    Blood-borne substances can invade into the extracellular spaces of the brain via endothelial cells in sites without the blood-brain barrier (BBB), and can travel through the interstitial fluid (ISF) of the brain parenchyma adjacent to non-BBB sites. It has been shown that cerebrospinal fluid (CSF) drains directly into the blood via the arachnoid villi and also into lymph nodes via the subarachnoid spaces of the brain, while ISF drains into the cervical lymph nodes through perivascular drainage pathways. In addition, the glymphatic pathway of fluids, characterized by para-arterial pathways, aquaporin4-dependent passage through astroglial cytoplasm, interstitial spaces, and paravenous routes, has been established. Meningeal lymphatic vessels along the superior sagittal sinus were very recently discovered. It is known that, in mice, blood-borne substances can be transferred to areas with intact BBB function, such as the medial regions of the hippocampus, presumably through leaky vessels in non-BBB sites. In the present paper, we review the clearance mechanisms of interstitial substances, such as amyloid-β peptides, as well as summarize models of BBB deterioration in response to different types of insults, including acute ischemia followed by reperfusion, hypertension, and chronic hypoperfusion. Lastly, we discuss the relationship between perivascular clearance and brain disorders.

  20. Collagen Micro-Flow Channels as an for In vitro Blood-Brain Barrier Model

    NASA Astrophysics Data System (ADS)

    Shibata, Katsuya; Terazono, Hideyuki; Hattori, Akihiro; Yasuda, Kenji

    2008-06-01

    An in vitro blood-brain barrier (BBB) model is useful for drug discovery and efficacy measurements because it is a simple and convenient model of the in vivo BBB. However, the conventional in vitro BBB model does not account for shear stress to endotherial cell (EC) layers although in vivo ECs are exposed by shear stress. To improve this deficiency, we applied a microfluidics technique to a conventional in vitro BBB model and constructed a new in vitro BBB model. First, we confirmed that ECs can survive and proliferate on a cross-linked collagen gel and on an agarose including microbeads decorated with collagen type IV (CIV). In addition, we found that the cross-linker 1-ethyl-3carbodiimide hydrochloride (EDC) with N-hydroxysuccinimide (NHS) is less effective for EC proliferation than glutaraldehyde (GA), ethyleneglycol diglycidyl ether (EGDE), and agarose with microbeads. Applying a focused infrared laser, we fabricated microtunnels within the collagen gel, and we successfully cultured ECs on the inner tunnel wall. The results indicate the potential of gel microstructures for a microfluidic in vitro BBB model.

  1. Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications.

    PubMed

    d'Avella, D; Cicciarello, R; Angileri, F F; Lucerna, S; La Torre, D; Tomasello, F

    1998-01-01

    The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 +/- cGy/d, 5d/wk; total dose, 4,000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid (AIB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AIB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, well-defined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.

  2. Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier

    PubMed Central

    Urayama, Akihiko; Dohgu, Shinya; Robinson, Sandra M.; Sly, William S.; Grubb, Jeffery H.; Banks, William A

    2015-01-01

    The impermeability of the adult blood-brain barrier (BBB) to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse) of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy. PMID:26545208

  3. Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair.

    PubMed

    Sharma, Aruna; Menon, Preeti; Muresanu, Dafin F; Ozkizilcik, Asya; Tian, Z Ryan; Lafuente, José V; Sharma, Hari S

    2016-01-01

    The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

  4. Brain injury associated with widely abused amphetamines: neuroinflammation, neurogenesis and blood-brain barrier.

    PubMed

    Silva, Ana P; Martins, Tânia; Baptista, Sofia; Gonçalves, Joana; Agasse, Fabienne; Malva, João O

    2010-12-01

    Over the course of the 20(th) century, it became increasingly clear that amphetamine-like psychostimulants carried serious abuse liability that has resulted in sociological use patterns that have been described as epidemics. In fact, drug addiction is a brain disease with a high worldwide prevalence, and is considered the most expensive of the neuropsychiatric disorders. This review goes beyond the previously well-documented evidence demonstrating that amphetamines cause neuronal injury. Cellular and molecular mechanisms involved in the neurotoxicity of psychostimulants drugs have been extensively described giving particular attention to the role of oxidative stress and metabolic compromise. Recently, it was shown that the amphetamine class of drugs of abuse triggers an inflammatory process, emerging as a critical concept to understand the toxic effects of these drugs. Moreover, it has been suggested that psychostimulants compromise the capacity of the brain to generate new neurons (neurogenesis), and can also lead to blood-brain barrier (BBB) dysfunction. Together, these effects may contribute to brain damage, allowing the entry of pathogens into the brain parenchyma and thus decreasing the endogenous brain repair resources. The overall objective of this review is to highlight experimental evidence in an attempt to clarify the role of neuroinflammation in amphetamines-induced brain dysfunction and the effect of these drugs on both neurogenesis and BBB integrity.

  5. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.

    PubMed

    Miner, Jonathan J; Daniels, Brian P; Shrestha, Bimmi; Proenca-Modena, Jose L; Lew, Erin D; Lazear, Helen M; Gorman, Matthew J; Lemke, Greg; Klein, Robyn S; Diamond, Michael S

    2015-12-01

    The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

  6. Mast Cell - Glia Dialogue in Chronic Pain and Neuropathic Pain: Blood-Brain Barrier Implications.

    PubMed

    Skaper, Stephen D

    2016-01-01

    Mast cells and microglia, working singly and in partnership, produce proinflammatory agents which play key roles in a wide array of nervous system disorders. Such neuroinflammatory settings may compromise integrity of both the blood-nerve barrier and blood-brain barrier (BBB) and blood-spinal cord barrier. While both belong to the innate immune system mast cells are far more ubiquitous, are resident in peripheral nerves and the central nervous system, and can influence blood-nerve barrier characteristics. Mast cells, being near the perivasculature especially within the dura, on the brain side of the BBB, are strategically located to play havoc with the BBB. Mast cells and glia are endowed with homeostatic mechanisms/molecules which come into play following tissue damage. These include the N-acylethanolamine family, especially N-palmitoylethanolamine, which is posited to be a key player in maintaining cellular homeostasis against external stressors provoking, for example, inflammation. This review is intended as an overview covering the pathobiology of neuroinflammation in the context of mast cells and microglia, their role in BBB integrity, and therapeutic perspectives in targeting these cells to preserve BBB function.

  7. Gyroxin increases blood-brain barrier permeability to Evans blue dye in mice.

    PubMed

    Alves da Silva, J A; Oliveira, K C; Camillo, M A P

    2011-01-01

    Gyroxin is a serine protease enzyme component of the South American rattlesnake (Crotalus durissus terrificus) venom. This toxin displays several activities, including the induction of blood coagulation (fibrinogenolytic activity), vasodilation and neurotoxicity, resulting in an effect called barrel rotation. The mechanisms involved in this neurotoxic activity are not well known. Because gyroxin is a member of a potentially therapeutic family of enzymes, including thrombin, ancrod, batroxobin, trypsin and kallicrein, the identification of the mechanism of gyroxin's action is extremely important. In this study, gyroxin was isolated from crude venom by affinity and molecular exclusion chromatography. Analysis of the isolated gyroxin via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a single protein band with a molecular weight of approximately 28 kDa, confirming the identity of the molecule. Furthermore, intravenous administration of purified gyroxin (0.25 μg/g of body weight) to mice resulted in symptoms compatible with barrel rotation syndrome, confirming the neurotoxic activity of the toxin. Mice treated with gyroxin showed an increase in the concentration of albumin-Evans blue in brain extracts, indicating an increase in the blood-brain barrier (BBB) permeability. This gyroxin-induced increase in BBB permeability was time-dependent, reaching a peak within 15 min after exposure, similar to the time span in which the neurotoxic syndrome (barrel rotation) occurs. This work provides the first evidence of gyroxin's capacity to temporarily alter the permeability of the BBB.

  8. Microfluidic modeling of the effects of nanoparticles on the blood-brain barrier in flow

    NASA Astrophysics Data System (ADS)

    Schwait, Craig; Hartman, Ryan; Bao, Yuping; Xu, Yaolin

    2011-11-01

    The difficulty of diffusing drugs across the blood-brain barrier (BBB) has caused an impasse for many brain treatments. Nanoparticles (NPs), to which drugs can adsorb, attach, or be entrapped, have the potential to deliver drugs past the BBB. Before nanoparticles can be used, their effects on the BBB and brain must be ascertained. Previous steady-state studies fall short for closely modeling in vivo conditions . Convection of nanoparticles is ignored, and endothelial cells' (ECs) morphology differs based on loading conditions; in vitro loading with continuous flow exhibit ECs indicating a more similar in vivo phenotype. NPs interact with monocytes prior to the BBB, and their toxicity effects were measured in flow conditions using both Trypan Blue cell counting and cell proliferation assays. The microfluidic device designed to model the BBB contained a concentric PES hollow fiber porous membrane in PFA tubing. Full use of the device will include ECs adhered on the inner surface and astrocytes adhered to the outer surface of the PES membrane to model cerebrovascular capillaries. Funded by NSF REU Site 1062611.

  9. Effects of fumaric acid esters on blood-brain barrier tight junction proteins.

    PubMed

    Bénardais, Karelle; Pul, Refik; Singh, Vikramjeet; Skripuletz, Thomas; Lee, De-Hyung; Linker, Ralf A; Gudi, Viktoria; Stangel, Martin

    2013-10-25

    The blood-brain barrier (BBB) is composed of a network of tight junctions (TJ) which interconnect cerebral endothelial cells (EC). Alterations in the TJ proteins are common in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). Modulation of the BBB could thus represent a therapeutic mechanism. One pathway to modulate BBB integrity could be the induction of nuclear-factor (erythroid derived 2) related factor-2 (Nrf2) mediated oxidative stress responses which are targeted by fumaric acid esters (FAE). Here we analyze effects of FAE on the expression of TJ proteins in the human cerebral endothelial cell line hCMEC/D3 and experimental autoimmune encephalomyelitis (EAE). We show that dimethylfumarate (DMF) and its primary metabolite monomethylfumarate (MMF) induce the expression of the Nrf2/NQO1 pathway in endothelial cells. Neither MMF nor DMF had a consistent modulatory effect on the expression of TJ molecules in hCMEC/D3 cells. Tumor necrosis factor (TNFα)-induced downregulation of TJ proteins was at least partially reversed by treatment with FAE. However, DMF had no effect on claudin-5 expression in EAE, despite its effect on the clinical score and infiltration of immune cells. These data suggest that the modulation of the BBB is not a major mechanism of action of FAE in inflammatory demyelinating diseases of the CNS.

  10. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease.

    PubMed

    Argaw, Azeb Tadesse; Asp, Linnea; Zhang, Jingya; Navrazhina, Kristina; Pham, Trinh; Mariani, John N; Mahase, Sean; Dutta, Dipankar J; Seto, Jeremy; Kramer, Elisabeth G; Ferrara, Napoleone; Sofroniew, Michael V; John, Gareth R

    2012-07-01

    In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.

  11. Bypassing the blood-brain barrier: delivery of therapeutic agents by macrophages

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Baek, Seung-Kuk; Kwon, Young Jik; Sun, Chung-Ho; Madsen, Steen J.

    2010-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) and the blood brain tumor barrier (BBTB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of monocytes/macrophages (Mo/Ma) to cross the BBB in rats. This will permit access of anti-cancer agents such as nanoparticles to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: The infiltration of Mo/Ma into brain tumor spheroids in vitro was determined using fluorescent stained Mo/Ma. Tumors were also established in the brains of inbred rats and ALA-PDT was given 18 days following tumor induction. The degredation of the BBTB and quantification of the number of infiltrating Mo/Ma was examined on histological sections from removed brains. Results & Conclusion: PDT was highly effective in locally opening the BBTB and inducing macrophage migration into the irradiated portions of brain tumors.

  12. Therapeutic strategies to improve drug delivery across the blood-brain barrier

    PubMed Central

    Azad, Tej D.; Pan, James; Connolly, Ian D.; Remington, Austin; Wilson, Christy M.; Grant, Gerald A.

    2015-01-01

    Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB’s physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it. PMID:25727231

  13. Systemic Delivery of Blood-Brain Barrier Targeted Polymeric Nanoparticles Enhances Delivery to Brain Tissue

    PubMed Central

    Saucier-Sawyer, Jennifer K.; Deng, Yang; Seo, Young-Eun; Cheng, Christopher J.; Zhang, Junwei; Quijano, Elias; Saltzman, W. Mark

    2016-01-01

    Delivery of therapeutic agents to the central nervous system is a significant challenge, hindering progress in the treatment of diseases such as glioblastoma. Due to the presence of the blood-brain barrier (BBB), therapeutic agents do not readily transverse the brain endothelium to enter the parenchyma. Previous reports suggest that surface modification of polymer nanoparticles can improve their ability to cross the BBB, but it is unclear whether the observed enhancements in transport are large enough to enhance therapy. In this study, we synthesized two degradable polymer nanoparticle systems surface-modified with ligands previously suggested to improve BBB transport, and tested their ability to cross the BBB after intravenous injection in mice. All nanoparticle preparations were able to cross the BBB, although generally in low amounts (<0.5% of the injected dose), which was consistent with prior reports. One nanoparticle produced significantly higher brain uptake (~0.8% of the injected dose): a block copolymer of polylactic acid and hyperbranched polyglycerol, surface modified with adenosine (PLA-HPG-Ad). PLA-HPG-Ad nanoparticles provided controlled release of camptothecin, killing U87 glioma cells in culture. When administered intravenously in mice with intracranial U87 tumors, they failed to increase survival. These results suggest that enhancing nanoparticle transport across the BBB does not necessarily yield proportional pharmacological effects. PMID:26453169

  14. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

    PubMed

    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.

  15. Electroporation of Brain Endothelial Cells on Chip toward Permeabilizing the Blood-Brain Barrier

    PubMed Central

    Bonakdar, Mohammad; Wasson, Elisa M.; Lee, Yong W.; Davalos, Rafael V.

    2016-01-01

    The blood-brain barrier, mainly composed of brain microvascular endothelial cells, poses an obstacle to drug delivery to the brain. Controlled permeabilization of the constituent brain endothelial cells can result in overcoming this barrier and increasing transcellular transport across it. Electroporation is a biophysical phenomenon that has shown potential in permeabilizing and overcoming this barrier. In this study we developed a microengineered in vitro model to characterize the permeabilization of adhered brain endothelial cells to large molecules in response to applied pulsed electric fields. We found the distribution of affected cells by reversible and irreversible electroporation, and quantified the uptaken amount of naturally impermeable molecules into the cells as a result of applied pulse magnitude and number of pulses. We achieved 81 ± 1.7% (N = 6) electroporated cells with 17 ± 8% (N = 5) cell death using an electric-field magnitude of ∼580 V/cm and 10 pulses. Our results provide the proper range for applied electric-field intensity and number of pulses for safe permeabilization without significantly compromising cell viability. Our results demonstrate that it is possible to permeabilize the endothelial cells of the BBB in a controlled manner, therefore lending to the feasibility of using pulsed electric fields to increase drug transport across the BBB through the transcellular pathway. PMID:26789772

  16. Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

    PubMed

    Gao, Jian-Qing; Lv, Qing; Li, Li-Ming; Tang, Xin-Jiang; Li, Fan-Zhu; Hu, Yu-Lan; Han, Min

    2013-07-01

    Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.

  17. Targeting Transporters: Promoting Blood-Brain Barrier Repair in Response to Oxidative Stress Injury

    PubMed Central

    Ronaldson, Patrick T.; Davis, Thomas P.

    2015-01-01

    The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., endogenous transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. PMID:25796436

  18. Bacterial induction of Snail1 contributes to blood-brain barrier disruption

    PubMed Central

    Kim, Brandon J.; Hancock, Bryan M.; Bermudez, Andres; Cid, Natasha Del; Reyes, Efren; van Sorge, Nina M.; Lauth, Xavier; Smurthwaite, Cameron A.; Hilton, Brett J.; Stotland, Aleksandr; Banerjee, Anirban; Buchanan, John; Wolkowicz, Roland; Traver, David; Doran, Kelly S.

    2015-01-01

    Bacterial meningitis is a serious infection of the CNS that results when blood-borne bacteria are able to cross the blood-brain barrier (BBB). Group B Streptococcus (GBS) is the leading cause of neonatal meningitis; however, the molecular mechanisms that regulate bacterial BBB disruption and penetration are not well understood. Here, we found that infection of human brain microvascular endothelial cells (hBMECs) with GBS and other meningeal pathogens results in the induction of host transcriptional repressor Snail1, which impedes expression of tight junction genes. Moreover, GBS infection also induced Snail1 expression in murine and zebrafish models. Tight junction components ZO-1, claudin 5, and occludin were decreased at both the transcript and protein levels in hBMECs following GBS infection, and this repression was dependent on Snail1 induction. Bacteria-independent Snail1 expression was sufficient to facilitate tight junction disruption, promoting BBB permeability to allow bacterial passage. GBS induction of Snail1 expression was dependent on the ERK1/2/MAPK signaling cascade and bacterial cell wall components. Finally, overexpression of a dominant-negative Snail1 homolog in zebrafish elevated transcription of tight junction protein–encoding genes and increased zebrafish survival in response to GBS challenge. Taken together, our data support a Snail1-dependent mechanism of BBB disruption and penetration by meningeal pathogens. PMID:25961453

  19. Regulation of ABC Efflux Transporters at Blood-Brain Barrier in Health and Neurological Disorders

    PubMed Central

    Qosa, Hisham; Miller, David S.; Pasinelli, Piera; Trotti, Davide

    2015-01-01

    The strength of the blood-brain barrier (BBB) in providing protection to the central nervous system from exposure to circulating chemicals is maintained by tight junctions between endothelial cells and by a broad range of transporter proteins that regulate exchange between CNS and blood. The most important transporters that restrict the permeability of large number of toxins as well as therapeutic agents are the ABC transporters. Among them, P-gp, BCRP, MRP1 and MRP2 are the utmost studied. These efflux transporters are neuroprotective, limiting the brain entry of neurotoxins; however, they could also restrict the entry of many therapeutics and contribute to CNS pharmacoresistance. Characterization of several regulatory pathways that govern expression and activity of ABC efflux transporters in the endothelium of brain capillaries have led to an emerging consensus that these processes are complex and contain several cellular and molecular elements. Alterations in ABC efflux transporters expression and/or activity occur in several neurological diseases. Here, we review the signaling pathways that regulate expression and transport activity of P-gp, BCRP, MRP1 and MRP2 as well as how their expression/activity changes in neurological diseases. PMID:26187753

  20. Trojan Horse Transit Contributes to Blood-Brain Barrier Crossing of a Eukaryotic Pathogen.

    PubMed

    Santiago-Tirado, Felipe H; Onken, Michael D; Cooper, John A; Klein, Robyn S; Doering, Tamara L

    2017-01-31

    The blood-brain barrier (BBB) protects the central nervous system (CNS) by restricting the passage of molecules and microorganisms. Despite this barrier, however, the fungal pathogen Cryptococcus neoformans invades the brain, causing a meningoencephalitis that is estimated to kill over 600,000 people annually. Cryptococcal infection begins in the lung, and experimental evidence suggests that host phagocytes play a role in subsequent dissemination, although this role remains ill defined. Additionally, the disparate experimental approaches that have been used to probe various potential routes of BBB transit make it impossible to assess their relative contributions, confounding any integrated understanding of cryptococcal brain entry. Here we used an in vitro model BBB to show that a "Trojan horse" mechanism contributes significantly to fungal barrier crossing and that host factors regulate this process independently of free fungal transit. We also, for the first time, directly imaged C. neoformans-containing phagocytes crossing the BBB, showing that they do so via transendothelial pores. Finally, we found that Trojan horse crossing enables CNS entry of fungal mutants that cannot otherwise traverse the BBB, and we demonstrate additional intercellular interactions that may contribute to brain entry. Our work elucidates the mechanism of cryptococcal brain invasion and offers approaches to study other neuropathogens.