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Sample records for bloodbrain partitioning straightforward

  1. The relationship between harvest and survival rates of mallards: A straightforward approach with partitioned data sets

    USGS Publications Warehouse

    Nichols, J.D.; Hines, J.E.

    1983-01-01

    We randomly partitioned mallard (Anas platyrhynchos) bandings and recoveries from each of a number of selected reference areas into 2 groups and estimated survival and harvest rates for each area and group. This procedure produced independent vectors of survival- and harvest-rate estimates, which were used to test the general hypothesis that mallard survival and harvest rates were inversely related. We used Spearman rank correlation analysis and z-test contrasts between survival rates from years of high vs. low harvest rates. We also conducted computer simulation experiments to gain insight into the ability of these analyses to detect the relationship of interest. The data analyses suggested that survival and harvest rates of young females were inversely related, at least for the 5 areas included in the analysis. However, for young males and adults of both sexes, the analyses provided no evidence of an inverse relationship between survival and harvest rates, except possibly in a few specific areas.

  2. 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. PMID:26277183

  3. A straightforward total synthesis of (-)-chaetominine.

    PubMed

    Malgesini, Beatrice; Forte, Barbara; Borghi, Daniela; Quartieri, Francesca; Gennari, Cesare; Papeo, Gianluca

    2009-08-10

    A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available D-tryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (first step) of the quinazolinone moiety and the late stage introduction (penultimate step) of the hydroxy group allowed a synthetic strategy devoid of protective groups. The key step of the process is the a-c tricyclic ring construction via an unprecedented NCS-mediated N-acyl cyclization on an indole ring to give tetrahydro-1H-pyrido[2,3-b]indole 11. In the penultimate step, oxidation of the tetracyclic intermediate 14 with oxaziridine 15 gave only one of the four possible diastereoisomers, the cis-diastereoisomer 16 resulting from the attack of the oxaziridine to the double bond face opposite to the c-d ring substituents. In the last step, the complete stereocontrol of the Et(3)SiH/TFA reduction of compound 16, probably involving a N-acyliminium ion, can be attributed to ring constrain, which forces the b-c ring junction in the more stable cis-orientation. (-)-Chaetominine (1) showed a negligible inhibitory activity on several cancer cell lines. PMID:19562787

  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. The blood-brain barrier.

    PubMed

    Obermeier, Birgit; Verma, Ajay; Ransohoff, Richard M

    2016-01-01

    In autoimmune neurologic disorders, the blood-brain barrier (BBB) plays a central role in immunopathogenesis, since this vascular interface is an entry path for cells and effector molecules of the peripheral immune system to reach the target organ, the central nervous system (CNS). The BBB's unique anatomic structure and the tightly regulated interplay of its cellular and acellular components allow for maintenance of brain homeostasis, regulation of influx and efflux, and protection from harm; these ensure an optimal environment for the neuronal network to function properly. In both health and disease, the BBB acts as mediator between the periphery and the CNS. For example, immune cell trafficking through the cerebral vasculature is essential to clear microbes or cell debris from neural tissues, while poorly regulated cellular transmigration can underlie or worsen CNS pathology. In this chapter, we focus on the specialized multicellular structure and function of the BBB/neurovascular unit and discuss how BBB breakdown can precede or be a consequence of neuroinflammation. We introduce the blood-cerebrospinal fluid barrier and include a brief aside about evolutionary aspects of barrier formation and refinements. Lastly, since restoration of barrier function is considered key to ameliorate neurologic disease, we speculate about new therapeutic avenues to repair a damaged BBB. PMID:27112670

  6. 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.

  7. Laser Unlocks Blood-Brain Barrier for Chemotherapy, Study Shows

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_157444.html Laser Unlocks Blood-Brain Barrier for Chemotherapy, Study Shows ... 24, 2016 WEDNESDAY, Feb. 24, 2016 (HealthDay News) -- Laser surgery can open the protective blood-brain barrier, ...

  8. Straightforward and complete deposition of NMR data to the PDBe.

    PubMed

    Penkett, Christopher J; van Ginkel, Glen; Velankar, Sameer; Swaminathan, Jawahar; Ulrich, Eldon L; Mading, Steve; Stevens, Tim J; Fogh, Rasmus H; Gutmanas, Aleksandras; Kleywegt, Gerard J; Henrick, Kim; Vranken, Wim F

    2010-10-01

    We present a suite of software for the complete and easy deposition of NMR data to the PDB and BMRB. This suite uses the CCPN framework and introduces a freely downloadable, graphical desktop application called CcpNmr Entry Completion Interface (ECI) for the secure editing of experimental information and associated datasets through the lifetime of an NMR project. CCPN projects can be created within the CcpNmr Analysis software or by importing existing NMR data files using the CcpNmr FormatConverter. After further data entry and checking with the ECI, the project can then be rapidly deposited to the PDBe using AutoDep, or exported as a complete deposition NMR-STAR file. In full CCPN projects created with ECI, it is straightforward to select chemical shift lists, restraint data sets, structural ensembles and all relevant associated experimental collection details, which all are or will become mandatory when depositing to the PDB. Instructions and download information for the ECI are available from the PDBe web site at http://www.ebi.ac.uk/pdbe/nmr/deposition/eci.html . PMID:20680401

  9. 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

  10. 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

  11. The dynamic blood-brain barrier.

    PubMed

    Keaney, James; Campbell, Matthew

    2015-11-01

    With the endothelium as its central unit, the blood-brain barrier (BBB) is a complex multicellular structure separating the central nervous system (CNS) from the systemic circulation. Disruption of the BBB has now been implicated in a multitude of acute and chronic CNS disorders indicating the potentially devastating effects of BBB breakdown on brain function. However, the healthy BBB is not an impermeable wall, but rather a communication 'centre', responding to and passing signals between the CNS and blood. New studies are identifying BBB-specific transport pathways that tightly regulate the entry and exit of molecules to and from the brain. They are revealing a highly plastic barrier in which dynamic changes in BBB components like paracellular tight junction complexes can contribute to BBB maintenance. Here, we provide a succinct overview of the current state-of-play in BBB research and summarize novel findings into BBB regulation in homeostatic regulation of the brain. PMID:26277326

  12. 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).

  13. Osmotic blood-brain barrier disruption: CT and radionuclide imaging

    SciTech Connect

    Roman-Goldstein, S.; Clunie, D.A.; Stevens, J.; Hogan, R.; Monard, J.; Ramsey, F.; Neuwelt, E.A.

    1994-03-01

    The purpose of this study was to compare CT and radionuclide imaging of osmotic blood-brain barrier disruption, and to develop a quantitative method for imaging osmotic blood-brain barrier disruption and to see if iopamidol could be safety given intravenously in conjunction with blood-brain barrier disruption. Forty-five blood-brain barrier disruption procedures were imaged with CT and radionuclide scans. The scans were evaluated with visual and quantitative scales. Patients were observed for adverse effects after blood-brain barrier disruption. There was a 4% rate of seizures in this study. There was good agreement between visual CT and radionuclide grading systems. Quantitative disruption did not add useful information to visual interpretations. Nonionic iodine-based contrast medium has a lower incidence of seizures when injected intravenously in conjunction with osmotic blood-brain barrier disruption than ionic contrast material. Contrast-enhanced CT is the preferred method to image disruption because it has better spatial resolution than radionuclide techniques. 34 refs., 4 figs., 6 tabs.

  14. 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

  15. 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. PMID:25805003

  16. [Blood-brain barrier transport of opioid analgesics].

    PubMed

    Suzuki, Toyofumi

    2011-01-01

    Opioid analgesics exhibit cationic properties under physiological conditions, and the mechanism underlying permeation of the blood-brain barrier thus cannot be fully explained by simple diffusion alone. Various types of transporters that exhibit substrate specificity are localized on the blood-brain barrier, and play a role in transporting substances from circulating blood and from brain interstitial fluid. Progress is being made in explaining the mechanisms, functions, and physiological roles of polyspecific organic cation transporters, but little evidence has indicated that these previously identified organic cation transporters are involved in the transport of opioid analgesics across the blood-brain barrier. Consequently, clarifying the role of transporters in the distribution of opioid analgesics into the brain and determining their transport molecule will not only provide clues to effective drug delivery to the brain, but will also contribute to optimizing pain relief treatment, and by extension play a role in drug discovery for analgesics. Currently there are enthusiastic discussions in the literature regarding the existence of putative transporters involved in the transport of opioid analgesics across the blood-brain barrier. This review article introduces the results of our research as well as recent findings on the involvement of transporters in the blood-brain barrier transport of opioid analgesics such as morphine, morphine metabolites, oxycodone, fentanyl, codeine, and pentazocine. PMID:21963971

  17. A New Approach to Parallel Dynamic Partitioning for Adaptive Unstructured Meshes

    NASA Technical Reports Server (NTRS)

    Heber, Gerd; Biswas, Rupak; Gao, Guang R.

    1999-01-01

    Classical mesh partitioning algorithms were designed for rather static situations, and their straightforward application in a dynamical framework may lead to unsatisfactory results, e.g., excessive data migration among processors. Furthermore, special attention should be paid to their amenability to parallelization. In this paper, a novel parallel method for the dynamic partitioning of adaptive unstructured meshes is described. It is based on a linear representation of the mesh using self-avoiding walks.

  18. 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…

  19. 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…

  20. Toxoplasma gondii and the blood-brain barrier

    PubMed Central

    Feustel, Sabrina M.; Meissner, Markus; Liesenfeld, Oliver

    2012-01-01

    Infection with the protozoan parasite Toxoplasma gondii is characterized by asymptomatic latent infection in the central nervous system and skeletal muscle tissue in the majority of immunocompentent individuals. Life-threatening reactivation of the infection in immunocompromized patients originates from rupture of Toxoplasma cysts in the brain. While major progress has been made in our understanding of the immunopathogenesis of infection the mechanism(s) of neuroinvasion of the parasite remains poorly understood. The present review presents the current understanding of blood-brain barrier (patho)physiology and the interaction of Toxoplasma gondii with cells of the blood-brain barrier. PMID:22460645

  1. Continuous partition lattice

    PubMed Central

    Björner, Anders

    1987-01-01

    A continuous analogue to the partition lattices is presented. This is the metric completion of the direct limit of a system of embeddings of the finite partition lattices. The construction is analogous to von Neumann's construction of a continuous geometry over a field F from the finite-dimensional projective geometries over F. PMID:16593874

  2. 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

  3. 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.

  4. Fuzzy Partition Models for Fitting a Set of Partitions.

    ERIC Educational Resources Information Center

    Gordon, A. D.; Vichi, M.

    2001-01-01

    Describes methods for fitting a fuzzy consensus partition to a set of partitions of the same set of objects. Describes and illustrates three models defining median partitions and compares these methods to an alternative approach to obtaining a consensus fuzzy partition. Discusses interesting differences in the results. (SLD)

  5. Partitioning and parallel radiosity

    NASA Astrophysics Data System (ADS)

    Merzouk, S.; Winkler, C.; Paul, J. C.

    1996-03-01

    This paper proposes a theoretical framework, based on domain subdivision for parallel radiosity. Moreover, three various implementation approaches, taking advantage of partitioning algorithms and global shared memory architecture, are presented.

  6. Shannon information, LMC complexity and Rényi entropies: a straightforward approach.

    PubMed

    López-Ruiz, Ricardo

    2005-04-01

    The LMC complexity, an indicator of complexity based on a probabilistic description, is revisited. A straightforward approach allows us to establish the time evolution of this indicator in a near-equilibrium situation and gives us a new insight for interpreting the LMC complexity for a general non equilibrium system. Its relationship with the Rényi entropies is also explained. One of the advantages of this indicator is that its calculation does not require a considerable computational effort in many cases of physical and biological interest. PMID:15752607

  7. Straightforward synthesis of deuterated precursors to demonstrate the biogenesis of aromatic thiols in wine.

    PubMed

    Roland, Aurélie; Schneider, Rémi; Razungles, Alain; Le Guernevé, Christine; Cavelier, Florine

    2010-10-13

    Straightforward synthesis of labeled S-3-(hexan-1-ol)-glutathione and S-4-(4-methylpentan-2-one)-glutathione has been developed through a conjugate addition optimization study. Sauvignon blanc fermentation experiments with the [(2)H(10)] S-4-(4-methylpentan-2-one)-glutathione used as a tracer released the corresponding deuterated thiol, thus proving the direct relationship with the 4-mercapto-4-methylpentan-2-one under enological conditions. The conversion yield of such transformation was estimated to be close to 0.3%, opening an avenue for additional study on varietal thiol biogenesis. PMID:20825191

  8. An annulative transfer hydrogenation strategy enables straightforward access to tetrahydro fused-pyrazine derivatives.

    PubMed

    Xiong, Biao; Zhang, Shu-Di; Chen, Lu; Li, Bin; Jiang, Huan-Feng; Zhang, Min

    2016-08-23

    A ruthenium-catalysed annulative transfer hydrogenation strategy, enabling straightforward access to tetrahydro fused-pyrazine derivatives from N-heteroaryl diamines and vicinal diols, has been demonstrated for the first time. Such a synthesis proceeds with unprecedented synthetic effectiveness including high step- and atom efficiency, generation of water as the sole by-product, short reaction time and no need for external high pressure H2 gas, offering an important basis for the transformation of vicinal diols, a class of bio-mass derived resources, into functionalized products. PMID:27499170

  9. Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in Drosophila

    PubMed Central

    Mayer, Fahima; Mayer, Nasima; Chinn, Leslie; Pinsonneault, Robert L.; Kroetz, Deanna; Bainton, Roland J.

    2011-01-01

    Pharmacologic remedy of many brain diseases is difficult because of the powerful drug exclusion properties of the blood-brain barrier (BBB). Chemical isolation of the vertebrate brain is achieved through the highly integrated, anatomically compact and functionally overlapping chemical isolation processes of the BBB. These include functions that need to be coordinated between tight diffusion junctions and unidirectionally-acting xenobiotic transporters. Understanding of many of these processes has been hampered, as they are not well mimicked by ex vivo models of the BBB and have been experimentally difficult and expensive to disentangle in intact rodent models. Here we show that the Drosophila melanogaster (Dm) humoral/CNS barrier conserves the xenobiotic exclusion properties found in the vertebrate vascular endothelium. We characterize a fly ABC transporter, Mdr65, that functions similar to mammalian xenobiotic BBB transporters and show that varying its levels solely in the Dm BBB changes the inherent sensitivity of the barrier to cytotoxic pharmaceuticals. Furthermore we demonstrate orthologous function between Mdr65 and vertebrate ABC transporters by rescuing chemical protection of the Dm brain with human MDR1/Pgp. These data indicate that the ancient origins of CNS chemoprotection extend to both conserved molecular means and functionally analogous anatomic spaces that together promote CNS selective drug partition. Thus, Dm presents an experimentally tractable system for analyzing physiological properties of the BBB in an intact organism. PMID:19295159

  10. 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.

  11. Straightforward rapid spectrophotometric quantification of total cyanogenic glycosides in fresh and processed cassava products.

    PubMed

    Tivana, Lucas Daniel; Da Cruz Francisco, Jose; Zelder, Felix; Bergenståhl, Bjorn; Dejmek, Petr

    2014-09-01

    In this study, we extend pioneering studies and demonstrate straightforward applicability of the corrin-based chemosensor, aquacyanocobyrinic acid (ACCA), for the instantaneous detection and rapid quantification of endogenous cyanide in fresh and processed cassava roots. Hydrolytically liberated endogenous cyanide from cyanogenic glycosides (CNp) reacts with ACCA to form dicyanocobyrinic acid (DCCA), accompanied by a change of colour from orange to violet. The method was successfully tested on various cassava samples containing between 6 and 200 mg equiv. HCN/kg as verified with isonicotinate/1,3-dimethylbarbiturate as an independent method. The affinity of ACCA sensor to cyanide is high, coordination occurs fast and the colorimetric response can therefore be instantaneously monitored with spectrophotometric methods. Direct applications of the sensor without need of extensive and laborious extraction processes are demonstrated in water-extracted samples, in acid-extracted samples, and directly on juice drops. ACCA showed high precision with a standard deviation (STDV) between 0.03 and 0.06 and high accuracy (93-96%). Overall, the ACCA procedure is straightforward, safe and easily performed. In a proof-of-concept study, rapid screening of ten samples within 20 min has been tested. PMID:24731309

  12. 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.

  13. Partition density functional theory

    NASA Astrophysics Data System (ADS)

    Nafziger, Jonathan

    Partition density functional theory (PDFT) is a method for dividing a molecular electronic structure calculation into fragment calculations. The molecular density and energy corresponding to Kohn Sham density-functional theory (KS-DFT) may be exactly recovered from these fragments. Each fragment acts as an isolated system except for the influence of a global one-body 'partition' potential which deforms the fragment densities. In this work, the developments of PDFT are put into the context of other fragment-based density functional methods. We developed three numerical implementations of PDFT: One within the NWChem computational chemistry package using basis sets, and the other two developed from scratch using real-space grids. It is shown that all three of these programs can exactly reproduce a KS-DFT calculation via fragment calculations. The first of our in-house codes handles non-interacting electrons in arbitrary one-dimensional potentials with any number of fragments. This code is used to explore how the exact partition potential changes for different partitionings of the same system and also to study features which determine which systems yield non-integer PDFT occupations and which systems are locked into integer PDFT occupations. The second in-house code, CADMium, performs real-space calculations of diatomic molecules. Features of the exact partition potential are studied for a variety of cases and an analytical formula determining singularities in the partition potential is derived. We introduce an approximation for the non-additive kinetic energy and show how this quantity can be computed exactly. Finally a PDFT functional is developed to address the issues of static correlation and delocalization errors in approximations within DFT. The functional is applied to the dissociation of H2 + and H2.

  14. 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.

  15. Cumulants of partitions

    NASA Astrophysics Data System (ADS)

    Weiss, Christoph; Block, Martin; Holthaus, Martin; Schmieder, Gerald

    2003-02-01

    We utilize the formal equivalence between the number-partitioning problem and a harmonically trapped ideal Bose gas within the microcanonical ensemble for characterizing the probability distribution which governs the number of addends occurring in an unrestricted partition of a natural number n. By deriving accurate asymptotic formulae for its coefficients of skewness and excess, it is shown that this distribution remains non-Gaussian even when n is made arbitrarily large. Both skewness and excess vary substantially before settling to their constant-limiting values for n > 1010.

  16. New Aperture Partitioning Element

    NASA Astrophysics Data System (ADS)

    Griffin, S.; Calef, B.; Williams, S.

    Postprocessing in an optical system can be aided by adding an optical element to partition the pupil into a number of segments. When imaging through the atmosphere, the recorded data are blurred by temperature-induced variations in the index of refraction along the line of sight. Using speckle imaging techniques developed in the astronomy community, this blurring can be corrected to some degree. The effectiveness of these techniques is diminished by redundant baselines in the pupil. Partitioning the pupil reduces the degree of baseline redundancy, and therefore improves the quality of images that can be obtained from the system. It is possible to implement the described approach on an optical system with a segmented primary mirror, but not very practical. This is because most optical systems do not have segmented primary mirrors, and those that do have relatively low bandwidth positioning of segments due to their large mass and inertia. It is much more practical to position an active aperture partitioning element at an aft optics pupil of the optical system. This paper describes the design, implementation and testing of a new aperture partitioning element that is completely reflective and reconfigurable. The device uses four independent, annular segments that can be positioned with a high degree of accuracy without impacting optical wavefront of each segment. This mirror has been produced and is currently deployed and working on the 3.6 m telescope.

  17. 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.

  18. Effects of microwave radiation on the blood-brain barrier

    SciTech Connect

    Ward, T.R.; Ali, J.S.; Long, M.D.

    1986-05-01

    The authors attempted to repeat a portion of the study by Oscar and Hawkins in which pulsed and continuous-wave microwave radiation increased permeation of labeled tracers through the blood-brain barrier. At the SAR used (0.1 W/kg) the calculated average brain temperature rise is less than 0.1C. The authors found no changes in permeation; however, there were differences in experimental conditions, including type of tracers, frequency and microwave field configuration. It is possible but unlikely that one of these differences is responsible for the apparent discrepancy in results.

  19. 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. PMID:26507553

  20. Blood-Brain Glucose Transfer: Repression in Chronic Hyperglycemia

    NASA Astrophysics Data System (ADS)

    Gjedde, Albert; Crone, Christian

    1981-10-01

    Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from 400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in brain endothelial cells in response to increased plasma glucose.

  1. Protection of the blood-brain barrier by hypercapnia during acute hypertension

    SciTech Connect

    Baumbach, G.L.; Mayhan, W.G.; Heistad, D.D.

    1986-08-01

    The purpose of this study was to examine effects of hypercapnia on susceptibility of the blood-brain barrier to disruption during acute hypertension. Two methods were used to test the hypothesis that cerebral vasodilation during hypercapnia increases disruption of the blood-brain barrier. First, permeability of the blood-brain barrier was measured in anesthetized cats with SVI-labeled serum albumin. Severe hypertension markedly increased permeability of the blood-brain barrier during normocapnia, but not during hypercapnia. The protective effect of hypercapnia was not dependent on sympathetic nerves. Second, in anesthetized rats, permeability of the barrier was quantitated by clearance of fluorescent dextran. Disruption of the blood-brain barrier during hypertension was decreased by hypercapnia. Because disruption of the blood-brain barrier occurred primarily in pial venules, the authors also measured pial venular diameter and pressure. Acute hypertension increased pial venular pressure and diameter in normocapnic rats. Hypercapnia alone increased pial venular pressure and pial venular diameter, and acute hypertension during hypercapnia further increased venular pressure. The magnitude of increase in pial venular pressure during acute hypertension was significantly less in hypercapnic than in normocapnic rats. They conclude that hypercapnia protects the blood-brain barrier. Possible mechanisms of this effect include attenuation of the incremental increase in pial venular pressure by hypercapnia or a direct effect on the blood-brain barrier not related to venous pressure.

  2. 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.

  3. A straightforward approach for gated STED-FCS to investigate lipid membrane dynamics.

    PubMed

    Clausen, Mathias P; Sezgin, Erdinc; Bernardino de la Serna, Jorge; Waithe, Dominic; Lagerholm, B Christoffer; Eggeling, Christian

    2015-10-15

    Recent years have seen the development of multiple technologies to investigate, with great spatial and temporal resolution, the dynamics of lipids in cellular and model membranes. One of these approaches is the combination of far-field super-resolution stimulated-emission-depletion (STED) microscopy with fluorescence correlation spectroscopy (FCS). STED-FCS combines the diffraction-unlimited spatial resolution of STED microscopy with the statistical accuracy of FCS to determine sub-millisecond-fast molecular dynamics with single-molecule sensitivity. A unique advantage of STED-FCS is that the observation spot for the FCS data recordings can be tuned to sub-diffraction scales, i.e. <200 nm in diameter, in a gradual manner to investigate fast diffusion of membrane-incorporated labelled entities. Unfortunately, so far the STED-FCS technology has mostly been applied on a few custom-built setups optimised for far-red fluorescent emitters. Here, we summarise the basics of the STED-FCS technology and highlight how it can give novel details into molecular diffusion modes. Most importantly, we present a straightforward way for performing STED-FCS measurements on an unmodified turnkey commercial system using a time-gated detection scheme. Further, we have evaluated the STED-FCS performance of different commonly used green emitting fluorescent dyes applying freely available, custom-written analysis software. PMID:26123184

  4. Protein synthesis by native chemical ligation: expanded scope by using straightforward methodology.

    PubMed

    Hackeng, T M; Griffin, J H; Dawson, P E

    1999-08-31

    The total chemical synthesis of proteins has great potential for increasing our understanding of the molecular basis of protein function. The introduction of native chemical ligation techniques to join unprotected peptides next to a cysteine residue has greatly facilitated the synthesis of proteins of moderate size. Here, we describe a straightforward methodology that has enabled us to rapidly analyze the compatibility of the native chemical ligation strategy for X-Cys ligation sites, where X is any of the 20 naturally occurring amino acids. The simplified methodology avoids the necessity of specific amino acid thioester linkers or alkylation of C-terminal thioacid peptides. Experiments using matrix-assisted laser-desorption ionization MS analysis of combinatorial ligations of LYRAX-C-terminal thioester peptides to the peptide CRANK show that all 20 amino acids are suitable for ligation, with Val, Ile, and Pro representing less favorable choices because of slow ligation rates. To illustrate the method's utility, two 124-aa proteins were manually synthesized by using a three-step, four-piece ligation to yield a fully active human secretory phospholipase A(2) and a catalytically inactive analog. The combination of flexibility in design with general access because of simplified methodology broadens the applicability and versatility of chemical protein synthesis. PMID:10468563

  5. SPINN: a straightforward machine learning solution to the pulsar candidate selection problem

    NASA Astrophysics Data System (ADS)

    Morello, V.; Barr, E. D.; Bailes, M.; Flynn, C. M.; Keane, E. F.; van Straten, W.

    2014-09-01

    We describe SPINN (Straightforward Pulsar Identification using Neural Networks), a high-performance machine learning solution developed to process increasingly large data outputs from pulsar surveys. SPINN has been cross-validated on candidates from the southern High Time Resolution Universe (HTRU) survey and shown to identify every known pulsar found in the survey data while maintaining a false positive rate of 0.64 per cent. Furthermore, it ranks 99 per cent of pulsars among the top 0.11 per cent of candidates, and 95 per cent among the top 0.01 per cent. In conjunction with the PEASOUP pipeline, it has already discovered four new pulsars in a re-processing of the intermediate Galactic latitude area of HTRU, three of which have spin periods shorter than 5 ms. SPINN's ability to reduce the amount of candidates to visually inspect by up to four orders of magnitude makes it a very promising tool for future large-scale pulsar surveys. In an effort to provide a common testing ground for pulsar candidate selection tools and stimulate interest in their development, we also make publicly available the set of candidates on which SPINN was cross-validated.

  6. Binary breath figures for straightforward and controllable self-assembly of microspherical caps.

    PubMed

    Gong, Jianliang; Xu, Bingang; Tao, Xiaoming; Li, Lei

    2016-05-11

    The intense interest surrounding asymmetrical microparticles originates from their unique anisotropic properties and promising applications. In this work, direct self-assembly of polymeric microspherical caps without the assistance of any additives has been achieved by using low-surface-tension methanol (MeOH) and high-surface-tension water as binary breath figures (BFs). With the evaporation of polystyrene (PS) solution containing low-boiling-point solvent in the binary vapors, the formed MeOH BFs could quickly diffuse into solution, while water BFs tended to remain at the solution surface. This led to the formation of a gradient nonsolvent layer at the vapor/solution interface, which induced the formation of nuclei and guided further asymmetrical growth of polymer particles. After the spontaneous removal of MeOH, water and residual solvent by evaporation, polymeric microspherical caps were left on the substrate. Through controlling the proportion of water introduced by adjusting the ratios of MeOH and water, polymeric microspherical caps with a range of controllable shapes (divided at different positions of a sphere) were successfully obtained. The formation mechanism was explained based on the difference of vapor pressure, surface tension and miscibility between the employed solvents and nonsolvents. A solvent possessing a high vapor pressure, low surface tension and good miscibility with MeOH contributed to the formation of microspherical caps. This flexible, green and straightforward technique is a nondestructive strategy, and avoids complicated work on design, preparation and removal of hard templates and additives. PMID:27139817

  7. Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

    PubMed

    Beteck, Richard M; Coertzen, Dina; Smit, Frans J; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

    2016-07-01

    As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones. PMID:27210430

  8. Straightforward reconstruction of 3D surfaces and topography with a camera: Accuracy and geoscience application

    NASA Astrophysics Data System (ADS)

    James, M. R.; Robson, S.

    2012-09-01

    Topographic measurements for detailed studies of processes such as erosion or mass movement are usually acquired by expensive laser scanners or rigorous photogrammetry. Here, we test and use an alternative technique based on freely available computer vision software which allows general geoscientists to easily create accurate 3D models from field photographs taken with a consumer-grade camera. The approach integrates structure-from-motion (SfM) and multiview-stereo (MVS) algorithms and, in contrast to traditional photogrammetry techniques, it requires little expertise and few control measurements, and processing is automated. To assess the precision of the results, we compare SfM-MVS models spanning spatial scales of centimeters (a hand sample) to kilometers (the summit craters of Piton de la Fournaise volcano) with data acquired from laser scanning and formal close-range photogrammetry. The relative precision ratio achieved by SfM-MVS (measurement precision: observation distance) is limited by the straightforward camera calibration model used in the software, but generally exceeds 1:1000 (i.e., centimeter-level precision over measurement distances of 10 s of meters). We apply SfM-MVS at an intermediate scale, to determine erosion rates along a ˜50-m-long coastal cliff. Seven surveys carried out over a year indicate an average retreat rate of 0.70 ± 0.05 m a-1. Sequential erosion maps (at ˜0.05 m grid resolution) highlight the spatiotemporal variability in the retreat, with semivariogram analysis indicating a correlation between volume loss and length scale. Compared with a laser scanner survey of the same site, SfM-MVS produced comparable data and reduced data collection time by ˜80%.

  9. 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.

  10. Stress does not increase blood-brain barrier permeability in mice.

    PubMed

    Roszkowski, Martin; Bohacek, Johannes

    2016-07-01

    Several studies have reported that exposure to acute psychophysiological stressors can lead to an increase in blood-brain barrier permeability, but these findings remain controversial and disputed. We thoroughly examined this issue by assessing the effect of several well-established paradigms of acute stress and chronic stress on blood-brain barrier permeability in several brain areas of adult mice. Using cerebral extraction ratio for the small molecule tracer sodium fluorescein (NaF, 376 Da) as a sensitive measure of blood-brain barrier permeability, we find that neither acute swim nor restraint stress lead to increased cerebral extraction ratio. Daily 6-h restraint stress for 21 days, a model for the severe detrimental impact of chronic stress on brain function, also does not alter cerebral extraction ratio. In contrast, we find that cold forced swim and cold restraint stress both lead to a transient, pronounced decrease of cerebral extraction ratio in hippocampus and cortex, suggesting that body temperature can be an important confounding factor in studies of blood-brain barrier permeability. To additionally assess if stress could change blood-brain barrier permeability for macromolecules, we measured cerebral extraction ratio for fluorescein isothiocyanate-dextran (70 kDa). We find that neither acute restraint nor cold swim stress affected blood-brain barrier permeability for macromolecules, thus corroborating our findings that various stressors do not increase blood-brain barrier permeability. PMID:27146513

  11. Neurosurgical Techniques for Disruption of the Blood-Brain Barrier for Glioblastoma Treatment.

    PubMed

    Rodriguez, Analiz; Tatter, Stephen B; Debinski, Waldemar

    2015-01-01

    The blood-brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood-brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood-brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal. PMID:26247958

  12. 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.

  13. 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

  14. 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. PMID:26437710

  15. Blood-brain barrier in acute liver failure

    PubMed Central

    Nguyen, Justin H.

    2011-01-01

    Brain edema remains a challenging obstacle in the management of acute liver failure (ALF). Cytotoxic mechanisms associated with brain edema have been well recognized, but evidence for vasogenic mechanisms in the pathogenesis of brain edema in ALF has been lacking. Recent reports have not only shown a role of matrix metalloproteinase-9 in the pathogenesis of brain edema in experimental ALF but have also found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood-brain barrier (BBB) integrity. This article reviews and explores the role of the paracellular tight junction proteins in the increased selective BBB permeability that leads to brain edema in ALF. PMID:22100566

  16. Blood-brain barrier and neuro-AIDS.

    PubMed

    Zhang, Y-L; Ouyang, Y-B; Liu, L-G; Chen, D-X

    2015-12-01

    Neuro-AIDS is becoming a major health problem among AIDS patients who experience improved survival under combined antiretroviral therapy (cART). Neuronal injury and loss are the critical issues of neuro-AIDS that need the entry of HIV into the central nervous system (CNS) via peripheral infected monocyte/macrophage carriers or viral direct penetration of blood-brain barrier (BBB). The mechanisms of HIV enhancing BBB permeability and entering CNS and the effect of drug abuse in HIV traffic across BBB are discussed. In addition, the current anti-HIV drugs, although they are effective in reducing plasma viral level, cannot eradicate the viruses completely from CNS. The possible mechanism of BBB hindrance and anti-HIV drug efflux by transport proteins, and general methods used to deliver antiretroviral drugs into brain are also discussed. PMID:26744885

  17. 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.

  18. Blood-brain barrier and new approaches to brain drug delivery.

    PubMed Central

    Pardridge, W. M.; Boado, R. J.; Black, K. L.; Cancilla, P. A.

    1992-01-01

    Morbidity caused by brain dysfunction affects more than 50 million persons in the United States. Although new neuropharmaceuticals have the potential for treating specific brain diseases, they may not effectively enter brain from blood. Safe strategies are needed for drug delivery through the brain capillary wall, which makes up the blood-brain barrier in vivo. Two of these strategies are reviewed, as are related new developments in the molecular and cell biology of the brain capillary endothelium. The production of chimeric peptides represents a physiologic-based strategy for drug delivery. It entails the covalent coupling of the neuropharmaceutical to a brain transport vector, allowing transportation through the blood-brain barrier. Another strategy is biochemical opening of the blood-brain barrier: intracarotid leukotriene infusion is a method for selectively increasing blood-brain barrier permeability in brain tumors without affecting barrier permeability in normal brain tissue. Images PMID:1595245

  19. 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. PMID:27086967

  20. 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. PMID:26661222

  1. 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. PMID:23426527

  2. Prediction of Partition Coefficients of Organic Compounds between SPME/PDMS and Aqueous Solution

    PubMed Central

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

    2014-01-01

    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. PMID:24534804

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

    PubMed

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

    2014-01-01

    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. PMID:24534804

  4. Quantum field theory of partitions

    SciTech Connect

    Bender, C.M.; Brody, D.C.; Meister, B.K.

    1999-07-01

    Given a sequence of numbers {l_brace}a{sub n}{r_brace}, it is always possible to find a set of Feynman rules that reproduce that sequence. For the special case of the partitions of the integers, the appropriate Feynman rules give rise to graphs that represent the partitions in a clear pictorial fashion. These Feynman rules can be used to generate the Bell numbers B(n) and the Stirling numbers S(n,k) that are associated with the partitions of the integers. {copyright} {ital 1999 American Institute of Physics.}

  5. Probabilistic framework for network partition

    NASA Astrophysics Data System (ADS)

    Li, Tiejun; Liu, Jian; E, Weinan

    2009-08-01

    Given a large and complex network, we would like to find the partition of this network into a small number of clusters. This question has been addressed in many different ways. In a previous paper, we proposed a deterministic framework for an optimal partition of a network as well as the associated algorithms. In this paper, we extend this framework to a probabilistic setting, in which each node has a certain probability of belonging to a certain cluster. Two classes of numerical algorithms for such a probabilistic network partition are presented and tested. Application to three representative examples is discussed.

  6. 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. PMID:27209800

  7. 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…

  8. 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

    2015-12-01

    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

  9. Graph Partitioning and Sequencing Software

    Energy Science and Technology Software Center (ESTSC)

    1995-09-19

    Graph partitioning is a fundemental problem in many scientific contexts. CHACO2.0 is a software package designed to partition and sequence graphs. CHACO2.0 allows for recursive application of several methods for finding small edge separators in weighted graphs. These methods include inertial, spectral, Kernighan Lin and multilevel methods in addition to several simpler strategies. Each of these approaches can be used to partition the graph into two, four, or eight pieces at each level of recursion.more » In addition, the Kernighan Lin method can be used to improve partitions generated by any of the other algorithms. CHACO2.0 can also be used to address various graph sequencing problems, with applications to scientific computing, database design, gene sequencing and other problems.« less

  10. Current concepts of blood-brain barrier development.

    PubMed

    Liebner, Stefan; Czupalla, Cathrin J; Wolburg, Hartwig

    2011-01-01

    Homeostasis of the central nervous system (CNS) microenvironment is essential for its normal function and is maintained by the blood-brain barrier (BBB). The BBB proper is made up of endothelial cells (ECs) interconnected by tight junctions (TJs) that reveal a unique morphology and biochemical composition of the body's vasculature. In this article, we focus on developmental aspects of the BBB and describe morphological as well as molecular special features of the neuro-vascular unit (NVU) involved in barrier induction. Recently, we and others identified the Wnt/b-catenin pathway as crucial for brain angiogenesis, TJ and BBB formation. Based on these findings we discuss other pathways and molecular interactions for BBB establishment and maintenance. At the morphological level, our concept favors a major role for polarized astrocytes (ACs) therein. Orthogonal arrays of particles (OAPs) that are the morphological correlate of the water channel protein aquaporin-4 (AQP4) are specifically formed in the membrane of the AC endfoot. The polarized AC endfoot and hence OAPs are dependent on agrin and dystroglycan, of which agrin is a developmentally regulated extracellular matrix (ECM) component. Understanding the mechanisms leading to BBB development will be key to the understanding of barrier maintenance that is crucial for, but frequently disturbed, in the diseased adult brain. PMID:21769778

  11. The Blood-Brain Barrier: Bottleneck in Brain Drug Development

    PubMed Central

    Pardridge, William M.

    2005-01-01

    Summary: The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences. PMID:15717053

  12. Simplified, noninvasive PET measurement of blood-brain barrier permeability

    SciTech Connect

    Iannotti, F.; Fieschi, C.; Alfano, B.; Picozzi, P.; Mansi, L.; Pozzilli, C.; Punzo, A.; Del Vecchio, G.; Lenzi, G.L.; Salvatore, M.

    1987-05-01

    Blood-brain barrier (BBB) permeability to (/sup 68/Ga)EDTA was measured by positron emission tomography (PET) in four normal volunteers and in 11 patients with brain tumors. A unidirectional transfer constant, Ki, was calculated applying multiple-time graphical analysis (MTGA). This method allows the detection of backflux from brain to blood and, by generalization, the measurement of the constant Kb (brain to blood). Furthermore, the need for an independent measurement of the intravascular tracer is obviated: MTGA itself provides an estimate of the cerebral plasma volume (Vp). In the four normal volunteers the Ki was 3.0 +/- 0.8 X 10(-4) ml g-1 min-1 (mean +/- SD) and the Vp 0.034 +/- 0.007 ml g-1. A net increase in Ki up to a maximum of 121.0 X 10(-4) ml g-1 min-1 (correspondent value of Kb = 0.025 min-1) as well as an increase of Vp was observed in malignant tumors. The input function was calculated using both the (/sup 68/Ga)EDTA concentration in sequential arterial blood samples and, noninvasively, the activity derived from the superior sagittal sinus image. The values of Ki and Vp from these two calculations were in good agreement. The application of MTGA to PET permits the evaluation of passage of substances across the BBB without making assumptions about the compartments in which the tracer distributes.

  13. Drug transport across the blood-brain barrier.

    PubMed

    Pardridge, William M

    2012-11-01

    The blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood-cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight <400 Da and forms <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin-biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport. PMID:22929442

  14. Estrogen and insulin transport through the blood-brain barrier.

    PubMed

    May, Aaron A; Bedel, Nicholas D; Shen, Ling; Woods, Stephen C; Liu, Min

    2016-09-01

    Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS. PMID:27182046

  15. 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

  16. Cytokine Signaling Modulates Blood-Brain Barrier Function

    PubMed Central

    Pan, Weihong; Stone, Kirsten P.; Hsuchou, Hung; Manda, Vamshi K.; Zhang, Yan; Kastin, Abba J.

    2014-01-01

    The blood-brain barrier (BBB) provides a vast interface for cytokines to affect CNS function. The BBB is a target for therapeutic intervention. It is essential, therefore, to understand how cytokines interact with each other at the level of the BBB and how secondary signals modulate CNS functions beyond the BBB. The interactions between cytokines and lipids, however, have not been fully addressed at the level of the BBB. Here, we summarize current understanding of the localization of cytokine receptors and transporters in specific membrane microdomains, particularly lipid rafts, on the luminal (apical) surface of the microvascular endothelial cells composing the BBB. We then illustrate the clinical context of cytokine effects on the BBB by neuroendocrine regulation and amplification of inflammatory signals. Two unusual aspects discussed are signaling crosstalk by different classes of cytokines and genetic regulation of drug efflux transporters. We also introduce a novel area of focus on how cytokines may act through nuclear hormone receptors to modulate efflux transporters and other targets. A specific example discussed is the ATP-binding cassette transporter-1 (ABCA-1) that regulates lipid metabolism. Overall, cytokine signaling at the level of the BBB is a crucial feature of the dynamic regulation that can rapidly change BBB function and affect brain health and disease. PMID:21834767

  17. Blood-brain barrier disruption during spontaneous canine visceral leishmaniasis.

    PubMed

    Melo, G D; Grano, F G; Silva, J E S; Kremer, B E; Lima, V M F; Machado, G F

    2015-12-01

    Visceral leishmaniasis is a complex disease caused by Leishmania infantum, and in dogs, besides the classical symptoms, there are descriptions of inflammatory alterations in the brain. Brain inflammation is a strictly controlled process, and as the brain counts on the efficiency of the blood-brain barrier (BBB), we aimed to assess BBB integrity in dogs with spontaneous visceral leishmaniasis. Therefore, we evaluated markers in the cerebrospinal fluid (CSF) and in brain tissue related to BBB disruption and brain inflammation. Elevated albumin quota revealed BBB breakdown, corroborated by increased concentrations of anti-Leishmania antibodies in the CSF. In the brain, albumin and IgG staining formed halos around blood vessels, a classical indicator of BBB leakage. Soluble IgG was also detected in the choroid plexus and ependyma, and in these structures, IgG stained random resident cells. IgG(+) cells and Fcγ-RI(+) cells were identified in the choroid plexus, ependyma and perivascular in the brain parenchyma. The data support the occurrence of BBB disruption in dogs with spontaneous visceral leishmaniasis, and IgG as a key molecule that is capable of initiating and/or maintaining the inflammatory stimuli in the nervous milieu and the CSF as an important disseminator of inflammatory stimuli within the CNS. PMID:26434684

  18. 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. PMID:25355222

  19. 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.

  20. Rasterization and Voxelization of - and Three-Dimensional Space Partitionings

    NASA Astrophysics Data System (ADS)

    Gorte, Ben; Zlatanov, Sisi

    2016-06-01

    The paper presents a very straightforward and effective algorithm to convert a space partitioning, made up of polyhedral objects, into a 3D block of voxels, which is fully occupied, i.e. in which every voxel has a value. In addition to walls, floors, etc. there are 'air' voxels, which in turn may be distinguished as indoor and outdoor air. The method is a 3D extension of a 2D polygon-to-raster conversion algorithm. The input of the algorithm is a set of non-overlapping, closed polyhedra, which can be nested or touching. The air volume is not necessarily represented explicitly as a polyhedron (it can be treated as 'background', leading to the 'default' voxel value). The approach consists of two stages, the first being object (boundary) based, the second scan-line based. In addition to planar faces, other primitives, such as ellipsoids, can be accommodated in the first stage without affecting the second.

  1. 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

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

    PubMed Central

    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.

    2015-01-01

    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.—Zhang, J., Sadowska, G. B., Chen, X., Park, S. Y., Kim, J.-E., Bodge, C. A., Cummings, E., Lim, Y.-P., Makeyev, O., Besio, W. G., Gaitanis, J., Banks, W. A., Stonestreet, B. S. Anti–IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus. PMID:25609424

  3. 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.

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

    PubMed

    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

  5. 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:25632404

  7. 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.

  8. 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

  9. Permeation of Dopamine Sulfate through the Blood-Brain Barrier

    PubMed Central

    Suominen, Tina; Piepponen, T. Petteri; Kostiainen, Risto

    2015-01-01

    Dopamine sulfate (DA-3- and DA-4-S) have been determined in the human brain, but it is unclear whether they are locally formed in the central nervous system (CNS), or transported into the CNS from peripheral sources. In the current study, permeation of the blood-brain barrier (BBB) by DA-S was studied by injecting 13C6-labelled regioisomers of DA-S (13DA-3-S and 13DA-4-S) and dopamine (DA) subcutaneously (s.c.) in anesthetized rats, then analyzing brain microdialysis and plasma samples by UPLC-MS/MS. The results in the microdialysis samples demonstrated that brain concentrations of 13DA-S regioisomers clearly increased after the s.c. injections. The concentration of DA did not change, indicating the permeation of DA-S through an intact BBB. The analysis of plasma samples, however, showed that DA-S only permeates the BBB to a small extent, as the concentrations in plasma were substantially higher than in the microdialysis samples. The results also showed that the concentrations of DA-3-S were around three times higher than the concentrations of DA-4-S in rat brain, as well as in the plasma samples after the s.c. injections, indicating that DA-3-S and DA-4-S permeate the BBB with similar efficiency. The fate of 13DA-S in brain was followed by monitoring 13C6-labelled DA-S hydrolysis products, i.e. 13DA and its common metabolites; however, no 13C6-labelled products were detected. This suggests that DA-S either permeates through the BBB back to the peripheral circulation or is dissociated or metabolized by unexpected mechanisms. PMID:26207745

  10. 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.

  11. 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

  12. Blood-brain barrier damage in vascular dementia.

    PubMed

    Ueno, Masaki; Chiba, Yoichi; Matsumoto, Koichi; Murakami, Ryuta; Fujihara, Ryuji; Kawauchi, Machi; Miyanaka, Hiroshi; Nakagawa, Toshitaka

    2016-04-01

    New findings on flow or drainage pathways of brain interstitial fluid and cerebrospinal fluid have been made. The interstitial fluid flow has an effect on the passage of blood-borne substances in the brain parenchyma, especially in areas near blood-brain barrier (BBB)-free regions. Actually, blood-borne substances can be transferred in areas with intact BBB function, such as the hippocampus, the corpus callosum, periventricular areas, and medial portions of the amygdala, presumably through leaky vessels in the subfornical organs or the choroid plexus. Increasing evidence indicates that dysfunction of the BBB function may play a significant role in the pathogenesis of vascular dementia. Accordingly, we have examined which insults seen in patients suffering from vascular dementia have an effect on the BBB using experimental animal models exhibiting some phenotypes of vascular dementia. The BBB in the hippocampus was clearly deteriorated in Mongolian gerbils exposed to acute ischemia followed by reperfusion and also in stroke-prone spontaneously hypertensive rats (SHRSP) showing hypertension. The BBB in the corpus callosum was clearly deteriorated in Wistar rats with permanent ligation of the bilateral common carotid arteries showing chronic hypoperfusion. The BBB in the hippocampus and the olfactory bulb was mildly deteriorated in aged senescence accelerated prone mice (SAMP8) showing cognitive dysfunction. The BBB in the hippocampus was mildly deteriorated in aged animals with hydrocephalus. Mild endothelial damage was seen in hyperglycemic db/db mice. In addition, mRNA expression of osteopontin, matrix metalloproteinase-13 (MMP-13), and CD36 was increased in vessels showing BBB damage in hypertensive SHRSP. As osteopontin, MMP-13 and CD36 are known to be related to brain injury and amyloid β accumulation or clearance, BBB damage followed by increased gene expression of these molecules not only contributes to the pathogenesis of vascular dementia, but also bridges

  13. The disturbed blood-brain barrier in human glioblastoma.

    PubMed

    Wolburg, Hartwig; Noell, Susan; Fallier-Becker, Petra; Mack, Andreas F; Wolburg-Buchholz, Karen

    2012-01-01

    The aim of this article is to describe alterations of the blood-brain barrier (BBB) in gliomas. The main clinical problem of human gliomas is the edematous swelling and the dramatic increase of intracerebral pressure, also compromising healthy areas of the brain. According to our concept, one of the main reasons on the cellular level for these clinical problems is the loss or reduction of astroglial polarity. Astroglial polarity means the specific accumulation of potassium and water channels in the superficial and perivascular astroglial endfeet membranes. The most important water channel in the CNS is the astroglial water channel protein aquaporin-4 (AQP4) which is arranged in a morphologically spectacular way, the so-called orthogonal arrays of particles (OAPs) to be observed in freeze-fracture replicas. In brain tumors, but also under conditions of trauma or inflammation, these OAPs are redistributed to membrane domains apart from endfeet areas. Probably, this dislocation might be due to the degradation of the proteoglycan agrin by the matrix metalloproteinase 3 (MMP3). Agrin binds to the dystrophin-dystroglycan-complex (DDC), which in turn is connected to AQP4. As a consequence, agrin loss may lead to a redistribution of AQP4 and a compromised directionality of water transport out of the cell, finally to cytotoxic edema. This in turn is hypothesized to lead to a breakdown of the BBB characterized by disturbed tight junctions, and thus to the development of vasogenic edema. However, the mechanism how the loss of polarity is related to the disturbance of microvascular tight junctions is completely unknown so far. PMID:22387049

  14. Blood-Brain Barrier Penetration and in Vivo Activity of an NGF Conjugate

    NASA Astrophysics Data System (ADS)

    Friden, Phillip M.; Walus, Lee R.; Watson, Patricia; Doctrow, Susan R.; Kozarich, John W.; Backman, Cristina; Bergman, Hanna; Hoffer, Barry; Bloom, Floyd; Granholm, Ann-Charlotte

    1993-01-01

    Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.

  15. 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. PMID:20977045

  16. Pharmacokinetics of new nootropic acylprolyldipeptide and its penetration across the blood-brain barrier after oral administration.

    PubMed

    Boiko, S S; Ostrovskaya, R U; Zherdev, V P; Korotkov, S A; Gudasheva, T A; Voronina, T A; Seredenin, S B

    2000-04-01

    Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an unmodified state. PMID:10977920

  17. Pharmacokinetics and In Vitro Blood-Brain Barrier Screening of the Plant-Derived Alkaloid Tryptanthrin.

    PubMed

    Jähne, Evelyn A; Eigenmann, Daniela E; Sampath, Chethan; Butterweck, Veronika; Culot, Maxime; Cecchelli, Roméo; Gosselet, Fabien; Walter, Fruzsina R; Deli, Mária A; Smieško, Martin; Hamburger, Matthias; Oufir, Mouhssin

    2016-07-01

    The indolo[2,1-b]quinazoline alkaloid tryptanthrin was previously identified as a potent anti-inflammatory compound with a unique pharmacological profile. It is a potent inhibitor of cyclooxygenase-2, 5-lipooxygenase-catalyzed leukotriene synthesis, and nitric oxide production catalyzed by the inducible nitric oxide synthase. To characterize the pharmacokinetic properties of tryptanthrin, we performed a pilot in vivo study in male Sprague-Dawley rats (2 mg/kg bw i. v.). Moreover, the ability of tryptanthrin to cross the blood-brain barrier was evaluated in three in vitro human and animal blood-brain barrier models. Bioanalytical UPLC-MS/MS methods used were validated according to current international guidelines. A half-life of 40.63 ± 6.66 min and a clearance of 1.00 ± 0.36 L/h/kg were found in the in vivo pharmacokinetic study. In vitro data obtained with the two primary animal blood-brain barrier models showed a good correlation with an immortalized human monoculture blood-brain barrier model (hBMEC cell line), and were indicative of a high blood-brain barrier permeation potential of tryptanthrin. These findings were corroborated by the in silico prediction of blood-brain barrier penetration. P-glycoprotein interaction of tryptanthrin was assessed by calculation of the efflux ratio in bidirectional permeability assays. An efflux ratio below 2 indicated that tryptanthrin is not subjected to active efflux. PMID:27093249

  18. 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. PMID:25609424

  19. New Instrumentation for Phase Partitioning

    NASA Technical Reports Server (NTRS)

    Harris, J. M.

    1985-01-01

    Cells and molecules can be purified by partitioning between the two immiscible liquid phases formed by aqueous solutions of poly/ethylene glycol and dextran. Such purification can be more selective, higher yielding, and less destructive to sensitive biological materials than other available techniques. Earth's gravitational field is a hindering factor as it causes sedimentation of particles to be purified and shear-induced particle randomization. The present proposal is directed toward developing new instrumentation for performing phase partitioning both on Earth and in microgravity.

  20. Rectilinear partitioning of irregular data parallel computations

    NASA Technical Reports Server (NTRS)

    Nicol, David M.

    1991-01-01

    New mapping algorithms for domain oriented data-parallel computations, where the workload is distributed irregularly throughout the domain, but exhibits localized communication patterns are described. Researchers consider the problem of partitioning the domain for parallel processing in such a way that the workload on the most heavily loaded processor is minimized, subject to the constraint that the partition be perfectly rectilinear. Rectilinear partitions are useful on architectures that have a fast local mesh network. Discussed here is an improved algorithm for finding the optimal partitioning in one dimension, new algorithms for partitioning in two dimensions, and optimal partitioning in three dimensions. The application of these algorithms to real problems are discussed.

  1. 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.

  2. Mechanisms of methylmercury transport across the blood-brain barrier

    SciTech Connect

    Kerper, L.E.

    1993-01-01

    Methylmercury readily enters the brain of exposed individuals, and is highly neurotoxic. The goal of this research was to determine the mechanisms of methylmercury transport across both the luminal and abluminal membranes of brain capillary endothelial cells, the cells which comprise the blood-brain barrier. The rapid carotid injection technique was used in rats to investigate the uptake of methylmercury from blood into brain endothelial cells. Uptake of ([sup 203]Hg)-methylmercury complexed with L-cysteine (CH[sub 3] [sup 203]Hg-L-Cys) was more rapid than that of ([sup 203]Hg)-methylmercury complexed with D-cysteine or bovine serum albumin. Uptake of CH[sub 3][sup 203]Hg-L-Cys was saturable, and was inhibited by substrates for the L (alanine-preferring) carrier. Brain uptake of [sup 14]C-L-methionine was inhibited by CH[sub 3]Hg-L-Cys but not by CH[sub 3]HgCl. Uptake of [sup 203]Hg administered as CH[sub 3]Hg-L-Cys-glutathione (CH[sub 3][sup 203]Hg-GSH) was comparable to CH[sub 3][sup 203]Hg-L-Cys uptake at 2 [mu]M. L-Methionine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) inhibited [sup 203]Hg uptake administered as CH[sub 3][sup 203]Hg-GSH, whereas acivicin had no effect. This uptake was also inhibited by S-ethylglutathione when pH of the injection solution was allowed to rise to 8.5. In later experiments performed at pH 8.2, uptake of [sup 203]Hg administered as CH[sub 3][sup 203]Hg-GSH was inhibited only by BCH. To study mechanisms of methylmercury efflux from endothelial cells, a primary culture of bovine brain capillary endothelial cells was developed. Intracellular glutathione concentration was 2.6 [+-] 0.7 mM. Incubation of CH[sub 3][sup 203]HgCl-preloaded cells with GSH depletors decreased ([sup 203]Hg)-methylmercury efflux in a dose-dependent manner which correlated with intracellular GSH concentrations. ([sup 203]Hg)-Methylmercury efflux was also inhibited by GSH-S-conjugates an GSH analogs, but not by amino acids.

  3. Effects of partitioning and scheduling sparse matrix factorization on communication and load balance. Final Report

    SciTech Connect

    Venugopal, S.; Naik, V.K.

    1991-10-01

    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.

  4. 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.

  5. Monomial Crystals and Partition Crystals

    NASA Astrophysics Data System (ADS)

    Tingley, Peter

    2010-04-01

    Recently Fayers introduced a large family of combinatorial realizations of the fundamental crystal B(Λ0) for ^sln, where the vertices are indexed by certain partitions. He showed that special cases of this construction agree with the Misra-Miwa realization and with Berg's ladder crystal. Here we show that another special case is naturally isomorphic to a realization using Nakajima's monomial crystal.

  6. Set covering, partition and packing

    SciTech Connect

    Hulme, B.L.; Baca, L.S.

    1984-03-01

    Set covering problems are known to be solvable by Boolean algebraic methods. This report shows that set partition and set packing problems can be solved by the same algebraic methods because these problems can be converted into covering problems. Many applications are possible including security patrol assignment which is used as an example.

  7. 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...

  8. Analysis of the anomalous scale-dependent behavior of dispersivity using straightforward analytical equations: Flow variance vs. dispersion

    SciTech Connect

    Looney, B.B.; Scott, M.T.

    1988-12-31

    Recent field and laboratory data have confirmed that apparent dispersivity is a function of the flow distance of the measurement. This scale effect is not consistent with classical advection dispersion modeling often used to describe the transport of solutes in saturated porous media. Many investigators attribute this anomalous behavior to the fact that the spreading of solute is actually the result of the heterogeneity of subsurface materials and the wide distribution of flow paths and velocities available in such systems. An analysis using straightforward analytical equations confirms this hypothesis. An analytical equation based on a flow variance approach matches available field data when a variance description of approximately 0.4 is employed. Also, current field data provide a basis for statistical selection of the variance parameter based on the level of concern related to the resulting calculated concentration. While the advection dispersion approach often yielded reasonable predictions, continued development of statistical and stochastic techniques will provide more defendable and mechanistically descriptive models.

  9. Correlative cryo-fluorescence and cryo-scanning electron microscopy as a straightforward tool to study host-pathogen interactions

    PubMed Central

    Strnad, Martin; Elsterová, Jana; Schrenková, Jana; Vancová, Marie; Rego, Ryan O. M.; Grubhoffer, Libor; Nebesářová, Jana

    2015-01-01

    Correlative light and electron microscopy is an imaging technique that enables identification and targeting of fluorescently tagged structures with subsequent imaging at near-to-nanometer resolution. We established a novel correlative cryo-fluorescence microscopy and cryo-scanning electron microscopy workflow, which enables imaging of the studied object of interest very close to its natural state, devoid of artifacts caused for instance by slow chemical fixation. This system was tested by investigating the interaction of the zoonotic bacterium Borrelia burgdorferi with two mammalian cell lines of neural origin in order to broaden our knowledge about the cell-association mechanisms that precedes the entry of the bacteria into the cell. This method appears to be an unprecedentedly fast (<3 hours), straightforward, and reliable solution to study the finer details of pathogen-host cell interactions and provides important insights into the complex and dynamic relationship between a pathogen and a host. PMID:26658551

  10. Correlative cryo-fluorescence and cryo-scanning electron microscopy as a straightforward tool to study host-pathogen interactions.

    PubMed

    Strnad, Martin; Elsterová, Jana; Schrenková, Jana; Vancová, Marie; Rego, Ryan O M; Grubhoffer, Libor; Nebesářová, Jana

    2015-01-01

    Correlative light and electron microscopy is an imaging technique that enables identification and targeting of fluorescently tagged structures with subsequent imaging at near-to-nanometer resolution. We established a novel correlative cryo-fluorescence microscopy and cryo-scanning electron microscopy workflow, which enables imaging of the studied object of interest very close to its natural state, devoid of artifacts caused for instance by slow chemical fixation. This system was tested by investigating the interaction of the zoonotic bacterium Borrelia burgdorferi with two mammalian cell lines of neural origin in order to broaden our knowledge about the cell-association mechanisms that precedes the entry of the bacteria into the cell. This method appears to be an unprecedentedly fast (<3 hours), straightforward, and reliable solution to study the finer details of pathogen-host cell interactions and provides important insights into the complex and dynamic relationship between a pathogen and a host. PMID:26658551

  11. 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.

  12. Terminology for trace-element partitioning

    SciTech Connect

    Beattie, P. ); Drake, M. ); Jones, J.; McKay, G. ); Leeman, W. ); Longhi, J. ); Nielsen, R. ); Palme, H. ); Shaw, D. ); Takahashi, E. ); Watson, B. )

    1993-04-01

    A self-consistent terminology for partitioning data is presented. Ratios of the concentration of a component in two phases are termed partition coefficients and given the symbol D. Ratios of partition coefficients are termed exchange coefficients and given the symbol K[sub D]. The prefix bulk implies that these coefficients are weighted according to the proportions of coexisting phases. Bulk partition and bulk exchange coefficients are denoted by [bar D] and [ovr K[sub D

  13. 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

  14. 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…

  15. 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. PMID:26406936

  16. Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability

    PubMed Central

    Mooney, Skyler J.; Shah, Kairavi; Yeung, Sharon; Burgess, Alison; Aubert, Isabelle; Hynynen, Kullervo

    2016-01-01

    Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier. PMID:27459643

  17. Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability.

    PubMed

    Mooney, Skyler J; Shah, Kairavi; Yeung, Sharon; Burgess, Alison; Aubert, Isabelle; Hynynen, Kullervo

    2016-01-01

    Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier. PMID:27459643

  18. Blood-Brain Barrier Breakdown Determines Differential Therapeutic Outcome in Genetically Diverse Forms of Medulloblastoma.

    PubMed

    Guerit, Sylvaine; Liebner, Stefan

    2016-04-11

    Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix and colleagues (2016) report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models. PMID:27070693

  19. 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

  20. Next generation of non-mammalian blood-brain barrier models to study parasitic infections of the central nervous system

    PubMed Central

    Siddiqui, Ruqaiyyah; Edwards-Smallbone, James; Flynn, Robin; Khan, Naveed Ahmed

    2012-01-01

    Transmigration of neuropathogens across the blood-brain barrier is a key step in the development of central nervous system infections, making it a prime target for drug development. The ability of neuropathogens to traverse the blood-brain barrier continues to inspire researchers to understand the specific strategies and molecular mechanisms that allow them to enter the brain. The availability of models of the blood-brain barrier that closely mimic the situation in vivo offers unprecedented opportunities for the development of novel therapeutics. PMID:21921682

  1. 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. PMID:23220906

  2. 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. PMID:24328099

  3. About Thinning Invariant Partition Structures

    NASA Astrophysics Data System (ADS)

    Starr, Shannon; Vermesi, Brigitta; Wei, Ang

    2012-08-01

    Bernoulli- p thinning has been well-studied for point processes. Here we consider three other cases: (1) sequences ( X 1, X 2,…); (2) gaps of such sequences ( X n+1- X 1) n∈ℕ; (3) partition structures. For the first case we characterize the distributions which are simultaneously invariant under Bernoulli- p thinning for all p∈(0,1]. Based on this, we make conjectures for the latter two cases, and provide a potential approach for proof. We explain the relation to spin glasses, which is complementary to important previous work of Aizenman and Ruzmaikina, Arguin, and Shkolnikov.

  4. 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.

  5. Blood-brain barrier permeability of bioactive withanamides present in Withania somnifera fruit extract.

    PubMed

    Vareed, Shaiju K; Bauer, Alison K; Nair, Kavitha M; Liu, Yunbao; Jayaprakasam, Bolleddula; Nair, Muraleedharan G

    2014-08-01

    The neuroprotective effect of Withania somnifera L. Dunal fruit extract, in rodent models, is known. Withanamides, the primary active constituents in W.somnifera fruit extract exhibited neuroprotective effects against β-amyloid-induced cytotoxicity in neuronal cell culture studies. Therefore, we investigated the blood-brain barrier permeability of withanamides in W.somnifera fruit extract in mice using HPLC coupled with high resolution quadrupole time of flight mass spectrometer (Q-TOF/MS) detection. Mice were administered with 250 mg/kg of W.somnifera extract by intraperitoneal injection, and the blood and brain samples analyzed by Q-TOF/MS detection. Four major withanamides were detected in brain and blood of mice administered with W.somnifera extract. The results suggested that the withanamides crossed the blood-brain barrier. These results may help to develop W.somnifera fruit extract as a preventive or therapeutic botanical drug for stress-induced neurological disorders. PMID:24458838

  6. 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.

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:25904743

  8. A dynamic model of the blood-brain barrier "in vitro".

    PubMed

    Stanness, K A; Guatteo, E; Janigro, D

    1996-01-01

    Cell culture models have been widely used for screening of neurotoxicants and represent a viable alternative to direct in vivo experiments. We have developed a dynamic in vitro blood-brain barrier model designed to allow for extensive toxicological, pharmacological and physiological testing. Induction of blood-brain barrier properties in a tri-dimensional hollow fiber culturing apparatus was investigated by co-culturing a bovine aortic endothelial cell line (or rat brain endothelial cells) with rat brain astrocytes (or C6 rat glioma cells) under pulsatile flow conditions to mimic intraluminal blood flow. Cell growth was monitored over time by measuring glucose consumption and lactate production: these experiments confirmed that the hollow fiber cell culturing systems can maintain viable cells in culture for extended (> 1 month) periods of time. Cells were visually inspected after culturing and dissociation from the hollow fiber cartridge and identified as endothelial (by fluorescent Dil-Ac-LDL uptake) or glial (by GFAP immunoreactivity). Blood-brain barrier properties were tested by intraluminal injection of horse-radish peroxidase (HRP, mol. weight 44,000), glucose (m.w. 180) or potassium. Either procedure demonstrated that aortic cells co-cultured with astrocytes (or C6 cells) developed a selective barrier with an estimated electrical resistance of 2,900 omega/cm2. The electrophysiological and morphological properties of BAEC were also affected by the co-culturing process, suggesting that astrocytes induced CNS properties in these cells. These results demonstrate that the hollow fiber cell co-culturing system may be used as a dynamic model of the mammalian blood-brain barrier. PMID:8856743

  9. 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. PMID:25904743

  10. Efflux transporters in blood-brain interfaces of the developing brain

    PubMed Central

    Strazielle, Nathalie; Ghersi-Egea, Jean-François

    2015-01-01

    The cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-CSF barrier (BCSFB) operate as gatekeepers for the central nervous system. Exposure of the vulnerable developing brain to chemical insults can have dramatic consequences for brain maturation and lead to life-long neurological diseases. The ability of blood-brain interfaces to efficiently protect the immature brain is therefore an important pathophysiological issue. This is also key to our understanding of drug entry into the brain of neonatal and pediatric patients. Non-specific paracellular diffusion through barriers is restricted early during development, but other neuroprotective properties of these interfaces differ between the developing and adult brains. This review focuses on the developmental expression and function of various classes of efflux transporters. These include the multispecific transporters of the ATP-binding cassette transporter families ABCB, ABCC, ABCG, the organic anion and cation transporters of the solute carrier families SLC21/SLCO and SLC22, and the peptide transporters of the SLC15 family. These transporters play a key role in preventing brain entry of blood-borne molecules such as drugs, environmental toxicants, and endogenous metabolites, or else in increasing the clearance of potentially harmful organic ions from the brain. The limited data available for laboratory animals and human highlight transporter-specific developmental patterns of expression and function, which differ between blood-brain interfaces. The BCSFB achieves an adult phenotype earlier than BBB. Efflux transporters at the BBB appear to be regulated by various factors subsequently secreted by neural progenitors and astrocytes during development. Their expression is also modulated by oxidative stress, inflammation, and exposure to xenobiotic inducers. A better understanding of these regulatory pathways during development, in particular

  11. 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

  12. A multitheragnostic nanobubble system to induce blood-brain barrier disruption with magnetically guided focused ultrasound.

    PubMed

    Huang, Hsin-Yang; Liu, Hao-Li; Hsu, Po-Hung; Chiang, Chih-Sheng; Tsai, Chih-Hung; Chi, Huei-Shang; Chen, San-Yuan; Chen, You-Yin

    2015-01-27

    A novel magnetically guidable nanobubble is designed for disrupting the blood-brain barrier (BBB) by combining magnetic guidance with focused ultrasound in vivo. The magnetic-nanobubble platform also demonstrates the potential to serve as a unique theranostic tool via performing focused ultrasound (FUS)-induced BBB disruption and magnetic resonance imaging (MRI)/ultrasound dual-modality contrast-agent imaging to improve the drug delivery of therapeutic substances or gene therapy into the central nervous system. PMID:25472627

  13. Effects of chronic metrifonate treatment on cholinergic enzymes and the blood-brain barrier.

    PubMed

    Rakonczay, Z; Papp, H

    2001-07-01

    After an acute (4 h) treatment with an irreversible cholinesterase inhibitor organophosphate, metrifonate (100 mg/kg i.p.), the activities of both acetyl- and butyrylcholinesterase were inhibited (66.0-70.7% of the control level) in the rat brain cortex and hippocampus. There were no significant changes in the acetyl- and butyrylcholinesterase activities in the olfactory bulb, or in the choline acetyltransferase activity in all three brain areas. After chronic (2 or 5 week) metrifonate treatment (100 mg/kg daily i.p.), the activities of both cholinesterases were substantially inhibited in the rat brain cortex and hippocampus (15.8-31.8% of the control levels), but there was no inhibition of the choline acetyltransferase activity. Moreover, chronic metrifonate treatment did not have any effect on the distribution of the acetylcholinesterase molecular forms. In vitro, metrifonate proved to be a more potent inhibitor of butyryl- than of acetylcholinesterase in both the cortex and the hippocampus. In the hippocampus, the butyrylcholinesterase activity was twice as sensitive to metrifonate inhibition as that in the cortex (IC50 values 0.22 and 0.46 microM, respectively). The effects of chronic (5 week) metrifonate treatment on the blood-brain barrier of the adult rat were examined. The damage to the blood-brain barrier was judged by the extravasation of Evans' blue dye in three brain regions: the cerebral cortex, the hippocampus, and the striatum. No extravasation of Evans' blue dye was found in the brain by fluorometric quantitation. These data indicate that chronic metrifonate treatment may increase the extracellular acetylcholine level via cholinesterase inhibition, but it does not have any effects on the blood-brain barrier. Therefore, it appears reasonable to hypothesize that cholinesterase activities do not play a role in the blood-brain barrier permeability. PMID:11311445

  14. 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.

  15. 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.

  16. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier

    SciTech Connect

    Friden, P.M.; Walus, L.R.; Musso, G.F.; Taylor, M.A.; Malfroy, B.; Starzyk, R.M. )

    1991-06-01

    Delivery of nonlipophilic drugs to the brain is hindered by the tightly apposed capillary endothelial cells that make up the blood-brain barrier. The authors have examined the ability of a monoclonal antibody (OX-26), which recognizes the rat transferrin receptor, to function as a carrier for the delivery of drugs across the blood-brain barrier. This antibody, which was previously shown to bind preferentially to capillary endothelial cells in the brain after intravenous administration, labels the entire cerebrovascular bed in a dose-dependent manner. The initially uniform labeling of brain capillaries becomes extremely punctate {approximately} 4 hr after injection, suggesting a time-dependent sequestering of the antibody. Capillary-depletion experiments, in which the brain is separated into capillary and parenchymal fractions, show a time-dependent migration of radiolabeled antibody from the capillaries into the brain parenchyma, which is consistent with the transcytosis of compounds across the blood-brain barrier. Antibody-methotrexate conjugates were tested in vivo to assess the carrier ability of this antibody. Immunohistochemical staining for either component of an OX-26-methotrexate conjugate revealed patterns of cerebrovascular labeling identical to those observed with the unaltered antibody. Accumulation of radiolabeled methotrexate in the brain parenchyma is greatly enhanced when the drug is conjugated to OX-26.

  17. 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

    2015-02-01

    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. PMID:25482664

  18. Parameters of photosynthetic energy partitioning.

    PubMed

    Lazár, Dušan

    2015-03-01

    Almost every laboratory dealing with plant physiology, photosynthesis research, remote sensing, and plant phenotyping possesses a fluorometer to measure a kind of chlorophyll (Chl) fluorescence induction (FLI). When the slow Chl FLI is measured with addition of saturating pulses and far-red illumination, the so-called quenching analysis followed by the so-called relaxation analysis in darkness can be realized. These measurements then serve for evaluation of the so-called energy partitioning, that is, calculation of quantum yields of photochemical and of different types of non-photochemical processes. Several theories have been suggested for photosynthetic energy partitioning. The current work aims to summarize all the existing theories, namely their equations for the quantum yields, their meaning and their assumptions. In the framework of these theories it is also found here that the well-known NPQ parameter ( [Formula: see text] ; Bilger and Björkman, 1990) equals the ratio of the quantum yield of regulatory light-induced non-photochemical quenching to the quantum yield of constitutive non-regulatory non-photochemical quenching (ΦNPQ/Φf,D). A similar relationship is also found here for the PQ parameter (ΦP/Φf,D). PMID:25569797

  19. Mass partitioning effects in diffusion transport.

    PubMed

    Kojic, Milos; Milosevic, Miljan; Wu, Suhong; Blanco, Elvin; Ferrari, Mauro; Ziemys, Arturas

    2015-08-28

    Frequent mass exchange takes place in a heterogeneous environment among several phases, where mass partitioning may occur at the interface of phases. Analytical and computational methods for diffusion do not usually incorporate molecule partitioning masking the true picture of mass transport. Here we present a computational finite element methodology to calculate diffusion mass transport with a partitioning phenomenon included and the analysis of the effects of partitioning. Our numerical results showed that partitioning controls equilibrated mass distribution as expected from analytical solutions. The experimental validation of mass release from drug-loaded nanoparticles showed that partitioning might even dominate in some cases with respect to diffusion itself. The analysis of diffusion kinetics in the parameter space of partitioning and diffusivity showed that partitioning is an extremely important parameter in systems, where mass diffusivity is fast and that the concentration of nanoparticles can control payload retention inside nanoparticles. The computational and experimental results suggest that partitioning and physiochemical properties of phases play an important, if not crucial, role in diffusion transport and should be included in the studies of mass transport processes. PMID:26204522

  20. 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. PMID:25783995

  1. 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.

  2. 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…

  3. A Partitioning Technique for Defining Instructional Groups.

    ERIC Educational Resources Information Center

    Baker, Frank B.; Hubert, Lawrence J.

    1979-01-01

    A technique is presented for partitioning N students into K groups of fixed sizes using a given measure of proximity for all student pairs. The measure of proximity is typically calculated from a set of variables and constitutes the data needed for a criterion of partition "fit." (Author)

  4. 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

  5. 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.

  6. Bicriterion methods for partitioning dissimilarity matrices.

    PubMed

    Brusco, Michael J; Cradit, J Dennis

    2005-11-01

    Partitioning indices associated with the within-cluster sums of pairwise dissimilarities often exhibit a systematic bias towards clusters of a particular size, whereas minimization of the partition diameter (i.e. the maximum dissimilarity element across all pairs of objects within the same cluster) does not typically have this problem. However, when the partition-diameter criterion is used, there is often a myriad of alternative optimal solutions that can vary significantly with respect to their substantive interpretation. We propose a bicriterion partitioning approach that considers both diameter and within-cluster sums in the optimization problem and facilitates selection from among the alternative optima. We developed several MATLAB-based exchange algorithms that rapidly provide excellent solutions to bicriterion partitioning problems. These algorithms were evaluated using synthetic data sets, as well as an empirical dissimilarity matrix. PMID:16293203

  7. 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.

  8. Dense Subgraph Partition of Positive Hypergraphs.

    PubMed

    Liu, Hairong; Latecki, Longin Jan; Yan, Shuicheng

    2015-03-01

    In this paper, we present a novel partition framework, called dense subgraph partition (DSP), to automatically, precisely and efficiently decompose a positive hypergraph into dense subgraphs. A positive hypergraph is a graph or hypergraph whose edges, except self-loops, have positive weights. We first define the concepts of core subgraph, conditional core subgraph, and disjoint partition of a conditional core subgraph, then define DSP based on them. The result of DSP is an ordered list of dense subgraphs with decreasing densities, which uncovers all underlying clusters, as well as outliers. A divide-and-conquer algorithm, called min-partition evolution, is proposed to efficiently compute the partition. DSP has many appealing properties. First, it is a nonparametric partition and it reveals all meaningful clusters in a bottom-up way. Second, it has an exact and efficient solution, called min-partition evolution algorithm. The min-partition evolution algorithm is a divide-and-conquer algorithm, thus time-efficient and memory-friendly, and suitable for parallel processing. Third, it is a unified partition framework for a broad range of graphs and hypergraphs. We also establish its relationship with the densest k-subgraph problem (DkS), an NP-hard but fundamental problem in graph theory, and prove that DSP gives precise solutions to DkS for all kin a graph-dependent set, called critical k-set. To our best knowledge, this is a strong result which has not been reported before. Moreover, as our experimental results show, for sparse graphs, especially web graphs, the size of critical k-set is close to the number of vertices in the graph. We test the proposed partition framework on various tasks, and the experimental results clearly illustrate its advantages. PMID:26353260

  9. 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. PMID:26343337

  10. Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered

    PubMed Central

    Eizayaga, Francisco; Scorticati, Camila; Prestifilippo, Juan P; Romay, Salvador; Fernandez, Maria A; Castro, José L; Lemberg, Abraham; Perazzo, Juan C

    2006-01-01

    AIM: To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 d after ligation when portal pressure is spontaneously normalized. METHODS: Adult male Wistar rats were divided into four groups: Group I: Sham14d , sham operated; Group II: PH14d , portal vein stenosis; (both groups were used 14 days after surgery); Group III: Sham40d, Sham operated and Group IV: PH40d Portal vein stenosis (Groups II and IV used 40 d after surgery). Plasma ammonia, plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. RESULTS: Forty days after stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION: The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment. PMID:16552803

  11. Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier

    PubMed Central

    Xing, Ying; Wen, Chun-yan; Li, Song-tao; Xia, Zong-xin

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in the repair of central nervous system injury, but cannot directly traverse the blood-brain barrier. Liposomes are a new type of non-viral vector, able to carry macromolecules across the blood-brain barrier and into the brain. Here, we investigate whether BDNF could be transported across the blood-brain barrier by tail-vein injection of liposomes conjugated to transferrin (Tf) and polyethylene glycol (PEG), and carrying BDNF modified with cytomegalovirus promoter (pCMV) or glial fibrillary acidic protein promoter (pGFAP) (Tf-pCMV-BDNF-PEG and Tf-pGFAP-BDNF-PEG, respectively). Both liposomes were able to traverse the blood-brain barrier, and BDNF was mainly expressed in the cerebral cortex. BDNF expression in the cerebral cortex was higher in the Tf-pGFAP-BDNF-PEG group than in the Tf-pCMV-BDNF-PEG group. This study demonstrates the successful construction of a non-virus targeted liposome, Tf-pGFAP-BDNF-PEG, which crosses the blood-brain barrier and is distributed in the cerebral cortex. Our work provides an experimental basis for BDNF-related targeted drug delivery in the brain. PMID:27212923

  12. Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier.

    PubMed

    Xing, Ying; Wen, Chun-Yan; Li, Song-Tao; Xia, Zong-Xin

    2016-04-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in the repair of central nervous system injury, but cannot directly traverse the blood-brain barrier. Liposomes are a new type of non-viral vector, able to carry macromolecules across the blood-brain barrier and into the brain. Here, we investigate whether BDNF could be transported across the blood-brain barrier by tail-vein injection of liposomes conjugated to transferrin (Tf) and polyethylene glycol (PEG), and carrying BDNF modified with cytomegalovirus promoter (pCMV) or glial fibrillary acidic protein promoter (pGFAP) (Tf-pCMV-BDNF-PEG and Tf-pGFAP-BDNF-PEG, respectively). Both liposomes were able to traverse the blood-brain barrier, and BDNF was mainly expressed in the cerebral cortex. BDNF expression in the cerebral cortex was higher in the Tf-pGFAP-BDNF-PEG group than in the Tf-pCMV-BDNF-PEG group. This study demonstrates the successful construction of a non-virus targeted liposome, Tf-pGFAP-BDNF-PEG, which crosses the blood-brain barrier and is distributed in the cerebral cortex. Our work provides an experimental basis for BDNF-related targeted drug delivery in the brain. PMID:27212923

  13. Selecting optimal partitioning schemes for phylogenomic datasets

    PubMed Central

    2014-01-01

    Background Partitioning involves estimating independent models of molecular evolution for different subsets of sites in a sequence alignment, and has been shown to improve phylogenetic inference. Current methods for estimating best-fit partitioning schemes, however, are only computationally feasible with datasets of fewer than 100 loci. This is a problem because datasets with thousands of loci are increasingly common in phylogenetics. Methods We develop two novel methods for estimating best-fit partitioning schemes on large phylogenomic datasets: strict and relaxed hierarchical clustering. These methods use information from the underlying data to cluster together similar subsets of sites in an alignment, and build on clustering approaches that have been proposed elsewhere. Results We compare the performance of our methods to each other, and to existing methods for selecting partitioning schemes. We demonstrate that while strict hierarchical clustering has the best computational efficiency on very large datasets, relaxed hierarchical clustering provides scalable efficiency and returns dramatically better partitioning schemes as assessed by common criteria such as AICc and BIC scores. Conclusions These two methods provide the best current approaches to inferring partitioning schemes for very large datasets. We provide free open-source implementations of the methods in the PartitionFinder software. We hope that the use of these methods will help to improve the inferences made from large phylogenomic datasets. PMID:24742000

  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. 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.

  16. Convex Regression with Interpretable Sharp Partitions

    PubMed Central

    Petersen, Ashley; Simon, Noah; Witten, Daniela

    2016-01-01

    We consider the problem of predicting an outcome variable on the basis of a small number of covariates, using an interpretable yet non-additive model. We propose convex regression with interpretable sharp partitions (CRISP) for this task. CRISP partitions the covariate space into blocks in a data-adaptive way, and fits a mean model within each block. Unlike other partitioning methods, CRISP is fit using a non-greedy approach by solving a convex optimization problem, resulting in low-variance fits. We explore the properties of CRISP, and evaluate its performance in a simulation study and on a housing price data set.

  17. Quantum Dilogarithms and Partition q-Series

    NASA Astrophysics Data System (ADS)

    Kato, Akishi; Terashima, Yuji

    2015-08-01

    In our previous work (Kato and Terashima, Commun Math Phys. arXiv:1403.6569, 2014), we introduced the partition q-series for mutation loop γ—a loop in exchange quiver. In this paper, we show that for a certain class of mutation sequences, called reddening sequences, the graded version of partition q-series essentially coincides with the ordered product of quantum dilogarithm associated with each mutation; the partition q-series provides a state-sum description of combinatorial Donaldson-Thomas invariants introduced by Keller.

  18. How pervasive is the Hirshfeld partitioning?

    SciTech Connect

    Heidar-Zadeh, Farnaz; Ayers, Paul W.

    2015-01-28

    One can partition the molecular density into its atomic contributions by minimizing the divergence of the atom-in-molecule densities from their corresponding reference pro-atomic densities, subject to the constraint that the sum of the atom-in-molecule densities is the total molecular density. We expose conditions on the divergence measure that are necessary, and sufficient, to recover the popular Hirshfeld partitioning. Specifically, among all local measures of the divergence between two probability distribution functions, the Hirshfeld partitioning is obtained only for f-divergences.

  19. Radiographic quantitation of reversible blood-brain barrier disruption in vivo. [Dogs

    SciTech Connect

    Drayer, B.P.; Schmeckel, D.E.; Hedlund, L.W.; Lischko, M.M.; Sage, M.R.; Heinz, E.R.; Dubois, P.J.; Goulding, P.L.

    1982-04-01

    Cranial computed tomography (CT) was used to quantitate disruption of the blood-brain barrier (BBB) in dogs in vivo following intracarotid infusion of hypertonic mannitol. The degree of opening varied with the same dose and infusion rate. The ratio of contrast enhancement in brain vs. venous blood was elevated in 4 of 5 mannitol-treated animals, with the ipsilateral basal ganglia and cortical gray matter. The statistical significance and reproducibility of the derived CT numbers used for brain and venous blood calculations, as well as the linear relationship between iodine concentration and CT enhancement, was affirmed by obtaining multiple consecutive scans.

  20. 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. PMID:26590675

  1. Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery.

    PubMed

    Oller-Salvia, Benjamí; Sánchez-Navarro, Macarena; Giralt, Ernest; Teixidó, Meritxell

    2016-08-22

    Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although the blood-brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors - known as BBB shuttles - offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins. PMID:27188322

  2. 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. PMID:25446620

  3. Targeted delivery of protein and gene medicines through the blood-brain barrier.

    PubMed

    Pardridge, W M

    2015-04-01

    The development of biologic drugs (recombinant proteins, therapeutic antibodies, peptides, nucleic acid therapeutics) as new treatments of brain disorders has been difficult, and a major reason is the lack of transport through the blood-brain barrier (BBB) of these large molecule pharmaceuticals. Biologic drugs can be re-engineered as brain-penetrating neuropharmaceuticals using BBB molecular Trojan horse technology. Certain peptidomimetic monoclonal antibodies that target endogenous receptors on the BBB, such as the insulin or transferrin receptor, enable the re-engineering of biologic drugs that cross the BBB. PMID:25669455

  4. 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. PMID:25595250

  5. 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

  6. Adult human dental pulp stem cells promote blood-brain barrier permeability through vascular endothelial growth factor-a expression.

    PubMed

    Winderlich, Joshua N; Kremer, Karlea L; Koblar, Simon A

    2016-06-01

    Stem cell therapy is a promising new treatment option for stroke. Intravascular administration of stem cells is a valid approach as stem cells have been shown to transmigrate the blood-brain barrier. The mechanism that causes this effect has not yet been elucidated. We hypothesized that stem cells would mediate localized discontinuities in the blood-brain barrier, which would allow passage into the brain parenchyma. Here, we demonstrate that adult human dental pulp stem cells express a soluble factor that increases permeability across an in vitro model of the blood-brain barrier. This effect was shown to be the result of vascular endothelial growth factor-a. The effect could be amplified by exposing dental pulp stem cell to stromal-derived factor 1, which stimulates vascular endothelial growth factor-a expression. These findings support the use of dental pulp stem cell in therapy for stroke. PMID:26661186

  7. Partitioning technique for open systems

    NASA Astrophysics Data System (ADS)

    Brändas, Erkki J.

    2010-11-01

    The focus of the present contribution is essentially confined to three research areas carried out during the author's turns as visiting (assistant, associate and full) professor at the University of Florida's Quantum Theory Project, QTP. The first two topics relate to perturbation theory and spectral theory for self-adjoint operators in Hilbert space. The third subject concerns analytic extensions to non-self-adjoint problems, where particular consequences of the occurrence of continuous energy spectra are measured. In these studies general partitioning methods serve as general cover for perturbation-, variational- and general matrix theory. In addition we follow up associated inferences for the time dependent problem as well as recent results and conclusions of a rather general yet surprising character. Although the author spent most of his times at QTP during visits in the 1970s and 1980s, collaborations with department members and shorter stays continued through later decades. Nevertheless the impact must be somewhat fragmentary, yet it is hoped that the present account is sufficiently self-contained to be realistic and constructive.

  8. Lipid partitioning during cardiac stress.

    PubMed

    Kolwicz, Stephen C

    2016-10-01

    It is well documented that fatty acids serve as the primary fuel substrate for the contracting myocardium. However, extensive research has identified significant changes in the myocardial oxidation of fatty acids during acute or chronic cardiac stress. As a result, the redistribution or partitioning of fatty acids due to metabolic derangements could have biological implications. Fatty acids can be stored as triacylglycerols, serve as critical components for biosynthesis of phospholipid membranes, and form the potent signaling molecules, diacylglycerol and ceramides. Therefore, the contribution of lipid metabolism to health and disease is more intricate than a balance of uptake and oxidation. In this review, the available data regarding alterations that occur in endogenous cardiac lipid pathways during the pathological stressors of ischemia-reperfusion and pathological hypertrophy/heart failure are highlighted. In addition, changes in endogenous lipids observed in exercise training models are presented for comparison. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk. PMID:27040509

  9. HPAM: Hirshfeld Partitioned Atomic Multipoles

    PubMed Central

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

    2011-01-01

    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 lmax 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 lmax = 0 (atomic charges) to lmax = 4 (atomic hexadecapoles). Both HD and HD-I atomic multipoles up to rank lmax are shown to exactly reproduce ab initio molecular multipole moments of rank L for L ≤ lmax. In addition, molecular dipole moments calculated by HD, HD-I, and ChelpG atomic charges only (lmax = 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. PMID:22140274

  10. 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.

  11. Energy partitioning schemes: a dilemma.

    PubMed

    Mayer, I

    2007-01-01

    Two closely related energy partitioning schemes, in which the total energy is presented as a sum of atomic and diatomic contributions by using the "atomic decomposition of identity", are compared on the example of N,N-dimethylformamide, a simple but chemically rich molecule. Both schemes account for different intramolecular interactions, for instance they identify the weak C-H...O intramolecular interactions, but give completely different numbers. (The energy decomposition scheme based on the virial theorem is also considered.) The comparison of the two schemes resulted in a dilemma which is especially striking when these schemes are applied for molecules distorted from their equilibrium structures: one either gets numbers which are "on the chemical scale" and have quite appealing values at the equilibrium molecular geometries, but exhibiting a counter-intuitive distance dependence (the two-center energy components increase in absolute value with the increase of the interatomic distances)--or numbers with too large absolute values but "correct" distance behaviour. The problem is connected with the quick decay of the diatomic kinetic energy components. PMID:17328441

  12. A straightforward entry to chiral carbocyclic nucleoside analogues via the enantioselective [3+2] cycloaddition of α-nucleobase substituted acrylates.

    PubMed

    Xie, Ming-Sheng; Wang, Yong; Li, Jian-Ping; Du, Cong; Zhang, Yan-Yan; Hao, Er-Jun; Zhang, Yi-Ming; Qu, Gui-Rong; Guo, Hai-Ming

    2015-08-11

    A straightforward entry to chiral carbocyclic nucleoside analogues has been realized via the enantioselective [3+2] cycloaddition of α-nucleobase substituted acrylates to vinyl cyclopropanes for the first time. With Pd2(dba)3-L5 as the catalyst, carbocyclic purine, uracil, and thymine nucleoside analogues with quaternary stereocenters were obtained in excellent yields (up to 99% yield) and good enantioselectivities (up to 92% ee). PMID:26145719

  13. Trace and Minor Elements in Magmas at High Pressure: In Situ Structural Insights on Partitioning at Depth

    NASA Astrophysics Data System (ADS)

    Sanloup, C.; Cochain, B.; de Grouchy, C.; Leroy, C.; Bureau, H.; Schmidt, B.; Konopkova, Z.; Kantor, I.; Irifune, T.; Daisenberg, D.

    2014-12-01

    Trace element partitioning between crystals and silicate melts has been successfully modelled using crystal-chemistry rules [1], although these models do not explicitly include melt's properties. However, melt composition has been shown to strongly influence element partitioning [2], implying a control from the 'melt-chemistry' as well. Additionally, element partitioning can be pressure-dependent, in which case it is a useful marker of depth for planetary processes such as mantle melting, and crust or core formation. To assess the effect of melt structure on partitioning at depth, we have investigated the local structure around trace and minor elements in melts at high pressure using two in situ techniques, high energy x-ray diffraction and EXAFS. X-ray diffraction data, once converted into pair distribution functions, are straightforward to interpret and give access to the full structure although overlaps between different contributions occur. In contrast, EXAFS is a chemically-sensitive probe that describes the local structure around a given element, but is model-dependent. Both methods will be illustrated by results obtained on two types of elements, some volatiles and some lithophiles. References: [1] Blundy JD and Wood BJ, Nature 372:452, 1999. [2] Schmidt MW et al., Science 312:1646, 2006.

  14. 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.

  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. 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. PMID:27463671

  17. 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.

  18. 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.

  19. Isorropia Partitioning and Load Balancing Package

    Energy Science and Technology Software Center (ESTSC)

    2006-09-01

    Isorropia is a partitioning and load balancing package which interfaces with the Zoltan library. Isorropia can accept input objects such as matrices and matrix-graphs, and repartition/redistribute them into a better data distribution on parallel computers. Isorropia is primarily an interface package, utilizing graph and hypergraph partitioning algorithms that are in the Zoltan library which is a third-party library to Tilinos.

  20. Deriving the Hirshfeld partitioning using distance metrics

    NASA Astrophysics Data System (ADS)

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

    2014-09-01

    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.

  1. 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.

  2. Cerebral circulation, metabolism, and blood-brain barrier of rats in hypocapnic hypoxia

    SciTech Connect

    Beck, T.; Krieglstein, J.

    1987-03-01

    The effects of hypoxic hypoxia on physiological variables, cerebral circulation, cerebral metabolism, and blood-brain barrier were investigated in conscious, spontaneously breathing rats by exposing them to an atmosphere containing 7% O/sub 2/. Hypoxia affected a marked hypotension, hypocapnia and alkalosis. Cortical tissue high-energy phosphates and glucose content were not affected by hypoxia, glucose 6-phosphate lactate, and pyruvate levels were significantly increased. Blood-brain barrier permeability, regional brain glucose content and lumped constant were not changed by hypoxia. Local cerebral glucose utilization (LCGU) rose by 40-70% of control values in gray matter and by 80-90% in white matter. Under hypoxia, columns of increased and decreased LCGU and were detectable in cortical gray matter. Color-coded (/sup 14/C)2-deoxy-D-glucose autoradiograms of rat brain are shown. Local cerebral blood flow (LCBF) increased by 50-90% in gray matter and by up to 180% in white matter. Coupling between LCGU and LCBF in hypoxia remained unchanged. The data suggests a stimulation of glycolysis, increased glucose transport into the cell, and increased hexokinase activity. The physiological response of gray and white matter to hypoxia obviously differs. Uncoupling of the relation between LCGU and LCBF does not occur.

  3. 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.

  4. Viral interactions with the blood-brain barrier: old dog, new tricks.

    PubMed

    Hou, Jianghui; Baker, Lane A; Zhou, Lushan; Klein, Robyn S

    2016-01-01

    Brain endothelial cells form a unique cellular structure known as the tight junction to regulate the exchanges between the blood and the parenchyma by limiting the paracellular diffusion of blood-borne substance. Together with the restricted pathway of transcytosis, the tight junction in the brain endothelial cells provides the central nervous system (CNS) with effective protection against both the foreign pathogens and the host immune cells, which is also termed the "blood-brain barrier." The blood-brain barrier is particularly important for defending against neurotropic viral infections that have become a major source of diseases worldwide. Many neurotropic viruses are able to cross the BBB and infect the CNS through very poorly understood processes. This review focuses upon the structural and functional changes of the brain endothelial tight junction in response to viral infections in the CNS and how the tight junction changes may be studied with advanced imaging and recording approaches to reveal novel processes used by the viruses to cross the barrier system. Additional emphasis is placed upon new countermeasures that can act directly upon the tight junction to improve the pathogen clearance and minimize the inflammatory damage. PMID:27141421

  5. Rapid high-affinity transport of a chemotherapeutic amino acid across the blood-brain barrier.

    PubMed

    Takada, Y; Vistica, D T; Greig, N H; Purdon, D; Rapoport, S I; Smith, Q R

    1992-04-15

    The therapeutic efficacy of many anticancer drugs against intracerebral tumors is limited by poor uptake into the central nervous system. One way to enhance brain delivery is to design agents that are transported into the brain by the saturable nutrient carriers of the blood-brain barrier. In this paper, we describe a nitrogen mustard amino acid, DL-2-amino-7-bis[(2-chloroethyl)amino/bd-1,2,3,4-tetrahydro-2-napthoi c acid, that is taken up into brain with high affinity by the large neutral amino acid carrier of the blood-brain barrier. Brain transport of DL-2-amino-7-bis[(2-chloroethyl)aminol-1,2,3,4-tetrahydro-2-naphth oic acid in the rat was found to be rapid (cerebrovascular permeability-surface area product approximately 2 x 10(-2) ml/s/g), saturable and inhibitable by large neutral amino acids. Maximal influx rate (Vmax) and half-saturation (Km) constants equaled 0.26 nmol/min/g and 0.19 microM, respectively, in the parietal cortex. Regional brain uptake of acid exceeded that of the clinical analogue, melphalan, by greater than 20-fold. The results demonstrate that drug modification to produce high-affinity ligands for the cerebrovascular nutrient carriers is a viable means to enhance drug delivery to brain for the treatment of brain tumors and other central nervous system disorders. PMID:1559223

  6. Effect of rapid correction of hyponatremia on the blood-brain barrier of rats.

    PubMed

    Adler, S; Verbalis, J G; Williams, D

    1995-05-01

    Brain demyelination sometimes follows rapid correction of hyponatremia, especially if the hyponatremia is chronic. During correction brain water decreases and the brain shrinks. The present study examined whether such shrinkage might be sufficient to disrupt the tight junctions of the blood-brain barrier. Barrier intactness was evaluated using magnetic resonance imaging and intravenous gadolinium contrast administration. Hypertonic saline infusion rapidly increased the plasma sodium concentration and caused barrier disruption more frequently in chronic than in acute hyponatremic rats. Similar increases in plasma sodium concentration did not disrupt the barrier in normonatremic rats. The disruption appeared to be due to altered plasma osmolality since infusion of hypertonic mannitol, which raised plasma osmolality without changing the plasma sodium concentration, disrupted the barrier in hyponatremic but not normonatremic rats. Moreover, the osmotic threshold for barrier disruption was lowest in chronic hyponatremia, intermediate in acute hyponatremia, and highest in normonatremia. The greater susceptibility to osmotic disruption in chronic hyponatremia suggests that blood-brain barrier disruption may play a significant role in causing the demyelination sometimes found following too rapid correction of hyponatremia, possibly through exposure of oligodendrocytes to plasma macromolecules such as complement. PMID:7648255

  7. Novel delivery methods bypassing the blood-brain and blood-tumor barriers.

    PubMed

    Hendricks, Benjamin K; Cohen-Gadol, Aaron A; Miller, James C

    2015-03-01

    Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications. PMID:25727219

  8. Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications.

    PubMed

    Rapoport, S I

    2000-04-01

    1. Osmotic opening of the blood-brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 A. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton. 2. The marked increase in apparent blood-brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min. 3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity. PMID:10696511

  9. Blood-brain barrier changes with kainic acid-induced limbic seizures

    SciTech Connect

    Zucker, D.K.; Wooten, G.F.; Lothman, E.W.

    1983-02-01

    Rats were treated with kainic acid (KA) i.v. to produce increasingly severe limbic seizures that were monitored with a behavioral rating scale. At various times after the induction of seizures, the animals; blood-brain barriers (B-BB) were studied with alpha-(/sup 14/C)aminoisobutyric acid ((/sup 14/C)AIBA) autoradiography. Using optical density ratios, a coefficient was devised to assess the functional integrity of the B-BB in discrete anatomic regions and to quantitatively compare these measurements among different groups of experimental animals. In animals that exhibited only mild seizures, the B-BB was not different from controls. Animals with severe limbic seizures, however, showed alterations. For as long as 2 h after delivery of KA, the B-BB appeared normal; from 2 to 24 h, the permeability to (/sup 14/C)AIBA was markedly increased throughout the brain, especially in limbic regions; from 24 h to 7 days the B-BB returned to normal except for a small residual change in limbic structures. These findings were confirmed with Evans blue dye studies of the B-BB. A correlation between focal accentuation of B-BB alterations and neuropathologic changes was found. These experiments indicted that recurrent limbic seizures may lead to a breakdown in the B-BB independent of systemic metabolic derangements. Marked focal metabolic and electrical changes, however, occurred in several limbic structures several hours before the blood-brain barrier was altered.

  10. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism.

    PubMed

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik; Olsson, Roger

    2016-05-18

    The metabolism of drugs in the brain is difficult to study in most species because of enzymatic instability in vitro and interference from peripheral metabolism in vivo. A locust ex vivo model that combines brain barrier penetration, efflux, metabolism, and analysis of the unbound fraction in intact brains was evaluated using known drugs. Clozapine was analyzed, and its major metabolites, clozapine N-oxide (CNO) and N-desmethylclozapine (NDMC), were identified and quantified. The back-transformation of CNO into clozapine observed in humans was also observed in locusts. In addition, risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data in the literature for mammals except for the stated fact that CNO is a highly blood-brain barrier permeant compound. Overall, the experiments indicated that invertebrates might be useful for screening of blood-brain barrier permeation, efflux, metabolism, and analysis of the unbound fraction of drugs in the brain in early drug discovery. PMID:26930271

  11. Software Partitioning Schemes for Advanced Simulation Computer Systems. Final Report.

    ERIC Educational Resources Information Center

    Clymer, S. J.

    Conducted to design software partitioning techniques for use by the Air Force to partition a large flight simulator program for optimal execution on alternative configurations, this study resulted in a mathematical model which defines characteristics for an optimal partition, and a manually demonstrated partitioning algorithm design which…

  12. Partitioning and kinetics of methylmercury among organs in captive mink (Neovison vison): A stable isotope tracer study.

    PubMed

    Evans, R Douglas; Hickie, Brendan; Rouvinen-Watt, Kirsti; Wang, Wei

    2016-03-01

    Despite the importance of methylmercury (MeHg) as a neurotoxin, we have relatively few good data on partitioning and kinetics of MeHg among organs, particularly across the blood-brain barrier, for mammals that consume large quantities of fish. The objective of this study was to determine the partition coefficients between blood and brain, liver and kidney and fur for MeHg under steady-state conditions and to measure the half-lives for MeHg in these organs. Captive mink (Neovison vison) were fed a diet enriched with two stable isotopes of Hg, Me(199)Hg and Me(201)Hg for a period of 60 days. After a period of 10 days the diet was changed to contain only Me(201)Hg so that, between days 10 and 60, we were able to measure both uptake and elimination rates from blood, brain, liver kidney and fur. Liver and kidney response was very rapid, closely following changes in blood concentrations but there was a small lag time between peak blood concentrations and peak brain concentrations. Half-lives for MeHg were 15.4, 10.2 and 13.4 days for brain, liver and kidney, respectively. There was no measurable conversion of the MeHg to inorganic Hg (IHg) in the brain over the 60 day period, unlike in liver and kidney. PMID:26855415

  13. 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. PMID:24686194

  14. BLOOD-BRAIN BARRIER PERMEATION IN THE RAT DURING EXPOSURE TO LOW-POWER 1.7-GHZ MICROWAVE RADIATION

    EPA Science Inventory

    The permeability of the blood-brain barrier to high-and low-molecular-weight compounds has been measured as a function of continuous wave (CW) and pulsed microwave radiation. Adult rats, anesthetized with pentobarbital and injected intravenously with a mixture of (14C) sucrose an...

  15. Differential uptake of MRI contrast agents indicates charge-selective blood-brain interface in the crayfish.

    PubMed

    Otopalik, Adriane G; Shin, Jane; Beltz, Barbara S; Sandeman, David C; Kolodny, Nancy H

    2012-08-01

    This study provides a new perspective on the long-standing problem of the nature of the decapod crustacean blood-brain interface. Previous studies of crustacean blood-brain interface permeability have relied on invasive histological, immunohistochemical and electrophysiological techniques, indicating a leaky non-selective blood-brain barrier. The present investigation involves the use of magnetic resonance imaging (MRI), a method for non-invasive longitudinal tracking of tracers in real-time. Differential uptake rates of two molecularly distinct MRI contrast agents, namely manganese (Mn(II)) and Magnevist® (Gd-DTPA), were observed and quantified in the crayfish, Cherax destructor. Contrast agents were injected into the pericardium and uptake was observed with longitudinal MRI for approximately 14.5 h. Mn(II) was taken up quickly into neural tissue (within 6.5 min), whereas Gd-DTPA was not taken up into neural tissue and was instead restricted to the intracerebral vasculature or excreted into nearby sinuses. Our results provide evidence for a charge-selective intracerebral blood-brain interface in the crustacean nervous system, a structural characteristic once considered too complex for a lower-order arthropod. PMID:22526631

  16. Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.

    PubMed

    Nahirney, Patrick C; Reeson, Patrick; Brown, Craig E

    2016-02-01

    Following ischemia, the blood-brain barrier is compromised in the peri-infarct zone leading to secondary injury and dysfunction that can limit recovery. Currently, it is uncertain what structural changes could account for blood-brain barrier permeability, particularly with aging. Here we examined the ultrastructure of early and delayed changes (3 versus 72 h) to the blood-brain barrier in young adult and aged mice (3-4 versus 18 months) subjected to photothrombotic stroke. At both time points and ages, permeability was associated with a striking increase in endothelial caveolae and vacuoles. Tight junctions were generally intact although small spaces were detected in a few cases. In young mice, ischemia led to a significant increase in pericyte process area and vessel coverage whereas these changes were attenuated with aging. Stroke led to an expansion of the basement membrane region that peaked at 3 h and partially recovered by 72 h in both age groups. Astrocyte endfeet and their mitochondria were severely swollen at both times points and ages. Our results suggest that blood-brain barrier permeability in young and aged animals is mediated by transcellular pathways (caveolae/vacuoles), rather than tight junction loss. Further, our data indicate that the effects of ischemia on pericytes and basement membrane are affected by aging. PMID:26661190

  17. Physiology of blood-brain interfaces in relation to brain disposition of small compounds and macromolecules.

    PubMed

    Strazielle, N; Ghersi-Egea, J F

    2013-05-01

    The brain develops and functions within a strictly controlled environment resulting from the coordinated action of different cellular interfaces located between the blood and the extracellular fluids of the brain, which include the interstitial fluid and the cerebrospinal fluid (CSF). As a correlate, the delivery of pharmacologically active molecules and especially macromolecules to the brain is challenged by the barrier properties of these interfaces. Blood-brain interfaces comprise both the blood-brain barrier located at the endothelium of the brain microvessels and the blood-CSF barrier located at the epithelium of the choroid plexuses. Although both barriers develop extensive surface areas of exchange between the blood and the neuropil or the CSF, the molecular fluxes across these interfaces are tightly regulated. Cerebral microvessels acquire a barrier phenotype early during cerebral vasculogenesis under the influence of the Wnt/β-catenin pathway, and of recruited pericytes. Later in development, astrocytes also play a role in blood-brain barrier maintenance. The tight choroid plexus epithelium develops very early during embryogenesis. It is specified by various signaling molecules from the embryonic dorsal midline, such as bone morphogenic proteins, and grows under the influence of Sonic hedgehog protein. Tight junctions at each barrier comprise a distinctive set of claudins from the pore-forming and tightening categories that determine their respective paracellular barrier characteristics. Vesicular traffic is limited in the cerebral endothelium and abundant in the choroidal epithelium, yet without evidence of active fluid phase transcytosis. Inorganic ion transport is highly regulated across the barriers. Small organic compounds such as nutrients, micronutrients and hormones are transported into the brain by specific solute carriers. Other bioactive metabolites, lipophilic toxic xenobiotics or pharmacological agents are restrained from accumulating in the

  18. Multi-A Graph Patrolling and Partitioning

    NASA Astrophysics Data System (ADS)

    Elor, Y.; Bruckstein, A. M.

    2012-12-01

    We introduce a novel multi agent patrolling algorithm inspired by the behavior of gas filled balloons. Very low capability ant-like agents are considered with the task of patrolling an unknown area modeled as a graph. While executing the proposed algorithm, the agents dynamically partition the graph between them using simple local interactions, every agent assuming the responsibility for patrolling his subgraph. Balanced graph partition is an emergent behavior due to the local interactions between the agents in the swarm. Extensive simulations on various graphs (environments) showed that the average time to reach a balanced partition is linear with the graph size. The simulations yielded a convincing argument for conjecturing that if the graph being patrolled contains a balanced partition, the agents will find it. However, we could not prove this. Nevertheless, we have proved that if a balanced partition is reached, the maximum time lag between two successive visits to any vertex using the proposed strategy is at most twice the optimal so the patrol quality is at least half the optimal. In case of weighted graphs the patrol quality is at least (1)/(2){lmin}/{lmax} of the optimal where lmax (lmin) is the longest (shortest) edge in the graph.

  19. Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study

    PubMed Central

    Palmela, Inês; Correia, Leonor; Silva, Rui F. M.; Sasaki, Hiroyuki; Kim, Kwang S.; Brites, Dora; Brito, Maria A.

    2015-01-01

    Ursodeoxycholic acid and its main conjugate glycoursodeoxycholic acid are bile acids with neuroprotective properties. Our previous studies demonstrated their anti-apoptotic, anti-inflammatory, and antioxidant properties in neural cells exposed to elevated levels of unconjugated bilirubin (UCB) as in severe jaundice. In a simplified model of the blood-brain barrier, formed by confluent monolayers of a cell line of human brain microvascular endothelial cells, UCB has shown to induce caspase-3 activation and cell death, as well as interleukin-6 release and a loss of blood-brain barrier integrity. Here, we tested the preventive and restorative effects of these bile acids regarding the disruption of blood-brain barrier properties by UCB in in vitro conditions mimicking severe neonatal hyperbilirubinemia and using the same experimental blood-brain barrier model. Both bile acids reduced the apoptotic cell death induced by UCB, but only glycoursodeoxycholic acid significantly counteracted caspase-3 activation. Bile acids also prevented the upregulation of interleukin-6 mRNA, whereas only ursodeoxycholic acid abrogated cytokine release. Regarding barrier integrity, only ursodeoxycholic acid abrogated UCB-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after UCB treatment. Finally, both bile acids showed ability to cross confluent monolayers of human brain microvascular endothelial cells in a time-dependent manner. Collectively, data disclose a therapeutic time-window for preventive and restorative effects of ursodeoxycholic acid and glycoursodeoxycholic acid against UCB-induced blood-brain barrier disruption and damage to human brain microvascular endothelial cells. PMID:25821432

  20. Are fluorine-rich pharmaceuticals lost by partition into fluorous phases?

    PubMed

    Sun, Shuwen; Zawatzky, Kerstin; Regalado, Erik L; Mangion, Ian K; Welch, Christopher J

    2016-09-01

    The recently developed technology of droplet microfluidics has demonstrated great potential for many applications such as biochemical assay, high throughput screening, cell culture, directed evolution, and chemical synthesis. Intrigued by its capabilities for miniaturization, flexible manipulation, rapid reagent mixing and high throughput experimentation and analysis, the pharmaceutical industry has begun to investigate droplet microfluidic implementation in medicinal and process chemistry. Segmented by an immiscible secondary phase, usually perfluorinated oil, aqueous or organic droplets serve as individual micro-reactors without suffering cross-contamination. As many drug molecules contain fluorines, it is necessary to investigate whether such compounds will be preferentially extracted into the fluorous phase via fluorophilic solvation, which could lead to erroneous analytical results. In this work, we chose drugs with up to 10 fluorines to probe their partition into perfluorodecalin (PFD) from a variety of organic solvents. A fast and straightforward MISER (Multiple Injections in a Single Experimental Run) LC-MS method was applied to measure the loss of drug after mixing with PFD. We found that no significant partition occurred, with the concentration of drugs in the 'experimental' group measured as ±10% of the 'control' group. The RSD% of multiple injections is <5%. The finding was further validated by the conventional LC-MS approach. PMID:27239759

  1. 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.

  2. Fourier transform spectrometer controller for partitioned architectures

    NASA Astrophysics Data System (ADS)

    Tamas-Selicean, D.; Keymeulen, D.; Berisford, D.; Carlson, R.; Hand, K.; Pop, P.; Wadsworth, W.; Levy, R.

    The current trend in spacecraft computing is to integrate applications of different criticality levels on the same platform using no separation. This approach increases the complexity of the development, verification and integration processes, with an impact on the whole system life cycle. Researchers at ESA and NASA advocated for the use of partitioned architecture to reduce this complexity. Partitioned architectures rely on platform mechanisms to provide robust temporal and spatial separation between applications. Such architectures have been successfully implemented in several industries, such as avionics and automotive. In this paper we investigate the challenges of developing and the benefits of integrating a scientific instrument, namely a Fourier Transform Spectrometer, in such a partitioned architecture.

  3. 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.

  4. Some comments on molecular partition functions

    SciTech Connect

    Sharp, C.M.

    1987-03-01

    In models of cool stellar atmospheres where molecules are important, molecular spectroscopic data can be used to calculate partition functions, from which equilibrium constants hence abundances can be obtained. In this report, it is shown that simple analytic approximations can be used to calculate very easily the partition functions of diatomic molecules, and comparisons are made for the two particularly important astrophysical molecules, H/sub 2/ and CO, with other work where the partition functions are calculated by explicitly summing over a very large number of energy levels. It is found that these analytic approximations give excellent agreement with more detailed calculations and are certainly adequate for many purposes. This method is very convenient, as only a few spectroscopic constants are needed, and the analytic formulae are very easily evaluated.

  5. 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

  6. 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. PMID:25936845

  7. Pathways and Progress in Improving Drug Delivery through the Intestinal Mucosa and Blood-Brain Barriers

    PubMed Central

    Laksitorini, Marlyn; Prasasty, Vivitri D.; Kiptoo, Paul K.; Siahaan, Teruna J.

    2015-01-01

    One of the major hurdles in developing therapeutic agents is the difficulty in delivering drugs through the intestinal mucosa and blood-brain barriers (BBB). The goal here is to describe the general structures of the biological barriers and the strategies to enhance drug delivery across these barriers. Prodrug methods used to improve drug penetration via the transcellular pathway have been successfully developed, and some prodrugs have been used to treat patients. The use of transporters to improve absorption of some drugs (e.g., antiviral agents) has also been successful in treating patients. Other methods, including (a) blocking the efflux pumps to improve transcellular delivery and (b) modulation of cell-cell adhesion in the intercellular junctions to improve paracellular delivery across biological barriers are still in the investigational stage. PMID:25418271

  8. Is the Blood-Brain Barrier Relevant in Metastatic Germ Cell Tumor?

    SciTech Connect

    Azar, Jose M. Schneider, Bryan P.; Einhorn, Lawrence H.

    2007-09-01

    Purpose: Germ cell tumors are uniquely chemosensitive and curable, even with advanced metastatic disease. Central nervous system recurrence can terminate a complete remission in other chemosensitive tumors, such as small cell lung cancer, because of the blood-brain barrier (BBB). We propose to document that the BBB is also relevant in germ cell tumors despite their dramatic chemosensitivity. Methods and Materials: We present five cases illustrating the concept of the BBB in patients with metastatic testicular cancer treated with chemotherapy. Results: In our large series of patients with metastatic testicular cancer treated with chemotherapy, we identified 5 unique patients. These patients were rendered free of disease only to experience relapse in the brain alone. This included 1 patient who initially had good-risk metastatic disease by means of the International Germ Cell Collaborative Group staging system at the onset of chemotherapy. Conclusions: The BBB is relevant in patients with metastatic testicular cancer.

  9. Molecular targets in radiation-induced blood-brain barrier disruption

    SciTech Connect

    Nordal, Robert A.; Wong, C. Shun . E-mail: shun.wang@sw.ca

    2005-05-01

    Disruption of the blood-brain barrier (BBB) is a key feature of radiation injury to the central nervous system. Studies suggest that endothelial cell apoptosis, gene expression changes, and alteration of the microenvironment are important in initiation and progression of injury. Although substantial effort has been directed at understanding the impact of radiation on endothelial cells and oligodendrocytes, growing evidence suggests that other cell types, including astrocytes, are important in responses that include induced gene expression and microenvironmental changes. Endothelial apoptosis is important in early BBB disruption. Hypoxia and oxidative stress in the later period that precedes tissue damage might lead to astrocytic responses that impact cell survival and cell interactions. Cell death, gene expression changes, and a toxic microenvironment can be viewed as interacting elements in a model of radiation-induced disruption of the BBB. These processes implicate particular genes and proteins as targets in potential strategies for neuroprotection.

  10. Signaled drug delivery and transport across the blood-brain barrier.

    PubMed

    Hinow, Peter; Radunskaya, Ami; Mackay, Sean M; Reynolds, John N J; Schroeder, Morgan; Tan, Eng Wui; Tucker, Ian G

    2016-09-01

    We use a mathematical model to describe the delivery of a drug to a specific region of the brain. The drug is carried by liposomes that can release their cargo by application of focused ultrasound (US). Thereupon, the drug is absorbed through the endothelial cells that line the brain capillaries and form the physiologically important blood-brain barrier (BBB). We present a compartmental model of a capillary that is able to capture the complex binding and transport processes the drug undergoes in the blood plasma and at the BBB. We apply this model to the delivery of levodopa (L-dopa, used to treat Parkinson's disease) and doxorubicin (an anticancer agent). The goal is to optimize the delivery of drug while at the same time minimizing possible side effects of the US. PMID:26572864

  11. Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

    PubMed Central

    2012-01-01

    SB-3CT, a potent and selective inhibitor of matrix metalloproteinase-2 and -9, has shown efficacy in several animal models of neurological diseases. One of the greatest challenges in the development of therapeutics for neurological diseases is the inability of drugs to cross the blood-brain barrier. A sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection was developed to measure levels of SB-3CT, its active metabolite, the α-methyl analogue, and its p-hydroxy metabolite in plasma and brain. The compounds are rapidly absorbed and are readily distributed to the brain. The pharmacokinetic properties of these gelatinase inhibitors and the efficacy shown by SB-3CT in animal models of stroke, subarachnoid hemorrhage, and spinal cord injury indicate that this class of compounds holds considerable promise in the treatment of diseases of the central nervous system. PMID:23077716

  12. 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. PMID:25291712

  13. Tumor necrosis factor and stroke: role of the blood-brain barrier

    PubMed Central

    Pan, Weihong; Kastin, Abba J.

    2008-01-01

    The progression and outcome of stroke is affected by the intricate relationship between the blood-brain barrier (BBB) and tumor necrosis factor α (TNFα). TNFα crosses the intact BBB by a receptor-mediated transport system that is upregulated by CNS trauma and inflammation. In this review, we discuss intracellular trafficking and transcytosis of TNFα, regulation of TNFα transport after stroke, and the effects of TNFα on stroke preconditioning. TNFα can activate cytoprotective pathways by pretreatment or persistent exposure to low doses. This explains the paradoxical observation that transport of this proinflammatory cytokine improves the survival and function of hypoxic cells and of mice with stroke. The dual effects of TNFα may be related to differential regulation of TNFα trafficking downstream to TNFR1 and TNFR2 receptors. As we better understand how peripheral TNFα affects its own transport and modulates neuroregeneration, we may be in a better position to pharmacologically manipulate its regulatory transport system to treat stroke. PMID:17913328

  14. Capture, crawl, cross: the T cell code to breach the blood-brain barriers.

    PubMed

    Engelhardt, Britta; Ransohoff, Richard M

    2012-12-01

    The central nervous system (CNS) is an immunologically privileged site to which access of circulating immune cells is tightly controlled by the endothelial blood-brain barrier (BBB; see Glossary) localized in CNS microvessels, and the epithelial blood-cerebrospinal fluid barrier (BCSFB) within the choroid plexus. As a result of the specialized structure of the CNS barriers, immune cell entry into the CNS parenchyma involves two differently regulated steps: migration of immune cells across the BBB or BCSFB into the cerebrospinal fluid (CSF)-drained spaces of the CNS, followed by progression across the glia limitans into the CNS parenchyma. With a focus on multiple sclerosis (MS) and its animal models, this review summarizes the distinct molecular mechanisms required for immune cell migration across the different CNS barriers. PMID:22926201

  15. 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.

  16. 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

  17. Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier.

    PubMed

    Lajoie, Jason M; Shusta, Eric V

    2015-01-01

    Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence the therapeutic potential of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo. PMID:25340933

  18. 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. PMID:25411471

  19. Measurement of blood-brain barrier permeability with positron emission tomography and (68Ga)EDTA

    SciTech Connect

    Kessler, R.M.; Goble, J.C.; Bird, J.H.; Girton, M.E.; Doppman, J.L.; Rapoport, S.I.; Barranger, J.A.

    1984-09-01

    Positron emission tomography (PET) was employed to examine time-dependent changes in blood-brain barrier (BBB) permeability to (68Ga)ethylenediaminetetraacetate (EDTA) in the rhesus monkey, following reversible barrier opening by intracarotid infusion of a hypertonic mannitol solution. The PET technique, when combined with measurements of plasma radioactivity, provided a quantitative measure of the cerebrovascular permeability-area product (PA) at different times following mannitol infusion. Hypertonic mannitol treatment reversibly increased PA to (68Ga)EDTA more than 10-fold; much of the barrier effect was over by 10 min after mannitol treatment. The results show that PET can be used to measure transient changes in BBB integrity in specific brain regions, under in vivo, noninvasive conditions.

  20. 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. PMID:2541363

  1. In Vitro and In Vivo Blood-Brain Barrier Models to Study West Nile Virus Pathogenesis.

    PubMed

    Kumar, Mukesh; Nerurkar, Vivek R

    2016-01-01

    The blood-brain barrier (BBB), a specialized interface between the peripheral blood circulation and the central nervous system, specifically regulates molecular and cellular flux between the two. It plays a critical role in the maintenance of brain hemostasis. The BBB restricts the entry of pathogens into the brain, and thus its permeability is a critical factor that determines their central effects. Once the permeability of BBB is compromised, it has serious implications in the etiology of many brain pathologies including West Nile virus (WNV) disease. In this chapter, we describe protocols for preparation, maintenance, infection and permeability measurement of monolayer and bilayer in vitro BBB models to study WNV pathogenesis. We also describe Evans blue dye assay, a well-established method to test vascular permeability in vivo after WNV infection. PMID:27188553

  2. 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

  3. Increased blood-brain transfer in a rabbit model of acute liver failure

    SciTech Connect

    Horowitz, M.E.; Schafer, D.F.; Molnar, P.; Jones, E.A.; Blasberg, R.G.; Patlak, C.S.; Waggoner, J.; Fenstermacher, J.D.

    1983-05-01

    The blood-to-brain transfer of (/sup 14/C)alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of (/sup 14/C)alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of (/sup 14/C)galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy.

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

    PubMed

    Farsa, Oldřich

    2013-03-01

    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

  5. 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

  6. 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

    2016-09-01

    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. PMID:27349679

  7. 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

  8. DNA Partitioning in Confining Nanofluidic Slits

    NASA Astrophysics Data System (ADS)

    Greenier, Madeline; Levy, Stephen

    We measure the partitioning of double stranded DNA molecules in moderately and strongly confining nanofluidic slit-like structures. Using fluorescent microscopy, the free energy penalty of confinement is inferred by comparing the concentration of DNA molecules in adjoining slits of different depths. These depths range in size from several persistence lengths to the DNA molecule's radius of gyration. The partition coefficient is determined as a function of the slit depth, DNA contour length, and DNA topology. We compare our results to theory and Monte Carlo simulations that predict the loss of free energy for ideal and semiflexible excluded volume polymers confined between parallel plates.

  9. Partition signed social networks via clustering dynamics

    NASA Astrophysics Data System (ADS)

    Wu, Jianshe; Zhang, Long; Li, Yong; Jiao, Yang

    2016-02-01

    Inspired by the dynamics phenomenon occurred in social networks, the WJJLGS model is modified to imitate the clustering dynamics of signed social networks. Analyses show that the clustering dynamics of the model can be applied to partition signed social networks. Traditionally, blockmodel is applied to partition signed networks. In this paper, a detailed dynamics-based algorithm for signed social networks (DBAS) is presented. Simulations on several typical real-world and illustrative networks that have been analyzed by the blockmodel verify the correctness of the proposed algorithm. The efficiency of the algorithm is verified on large scale synthetic networks.

  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. Influence of carbon partitioning kinetics on final Austenite fraction during quenching and partitioning

    SciTech Connect

    Clarke, Amy J; Speer, John G; Matlock, David K; Rizzo, F C; Edmonds, David V; Santofimia, Maria J

    2009-01-01

    The quenching and partitioning (Q&P) process is a two-stage heat-treatment procedure proposed for producing steel microstructures that contain carbon-enriched retained austenite. In Q&P processing, austenite stabilization is accomplished by carbon partitioning from supersaturated martensite. A quench temperature selection methodology was developed to predict an optimum process quench temperature; extension of this methodology to include carbon partitioning kinetics is developed here. Final austenite fraction is less sensitive to quench temperature than previously predicted, in agreement with experimental results.

  12. 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

  13. 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

  14. PARTITIONING OF METALS IN ROTARY KILN INCINERATION

    EPA Science Inventory

    This research project investigated the fate of trace metals in rotary kiln incineration with venturi- and packed tower-scrubber particulate- and acid gas-control. est plan was developed, using a factorial experimental design, to study the partitioning of metals among kiln ash, sc...

  15. Lipid metabolism and nutrient partitioning strategies.

    PubMed

    Morris, A M; Calsbeek, D J; Eckel, R H

    2004-10-01

    The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task. PMID:15544448

  16. Hydrologic transport and partitioning of phosphorus fractions

    NASA Astrophysics Data System (ADS)

    Berretta, C.; Sansalone, J.

    2011-06-01

    SummaryPhosphorus (P) in rainfall-runoff partitions between dissolved and particulate matter (PM) bound phases. This study investigates the transport and partitioning of P to PM fractions in runoff from a landscaped and biogenically-loaded carpark in Gainesville, FL (GNV). Additionally, partitioning and concentration results are compared to a similarly-sized concrete-paved source area of a similar rainfall depth frequency distribution in Baton Rouge, LA (BTR), where in contrast vehicular traffic represents the main source of pollutants. Results illustrate that concentrations of P fractions (dissolved, suspended, settleable and sediment) for GNV are one to two orders of magnitude higher than BTR. Despite these differences the dissolved fraction ( f d) and partitioning coefficient ( K d) distributions are similar, illustrating that P is predominantly bound to PM fractions. Examining PM size fractions, specific capacity for P (PSC) indicates that the P concentration order is suspended > settleable > sediment for GNV, similarly to BTR. For GNV the dominant PM mass fraction is sediment (>75 μm), while the mass of P is distributed predominantly between sediment and suspended (<25 μm) fractions since these PM mass fractions dominated the settleable one. With respect to transport of PM and P fractions the predominance of events for both areas is mass-limited first-flush, although each fraction illustrated unique washoff parameters. However, while transport is predominantly mass-limited, the transport of each PM and P fraction is influenced by separate hydrologic parameters.

  17. 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…

  18. UNCERTAINTY IN SOURCE PARTITIONING USING STABLE ISOTOPES

    EPA Science Inventory

    Stable isotope analyses are often used to quantify the contribution of multiple sources to a mixture, such as proportions of food sources in an animal's diet, C3 vs. C4 plant inputs to soil organic carbon, etc. Linear mixing models can be used to partition two sources with a sin...

  19. 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...

  20. Measure-theoretic sensitivity via finite partitions

    NASA Astrophysics Data System (ADS)

    Li, Jian

    2016-07-01

    For every positive integer n≥slant 2 , we introduce the concept of measure-theoretic n-sensitivity for measure-theoretic dynamical systems via finite measurable partitions, and show that an ergodic system is measure-theoretically n-sensitive but not (n  +  1)-sensitive if and only if its maximal pattern entropy is log n .

  1. hydrogen partitioning between postperovskite and bridgmanite

    NASA Astrophysics Data System (ADS)

    Townsend, J. P.; Jacobsen, S. D.; Bina, C. R.; Tsuchiya, J.

    2015-12-01

    We present new results from first-principles calculations of phonon spectra of lower mantle phases of MgSiO3 bridgmanite (brg) and postperovskite (ppv) including hydrous defects, and alumino-hydrous defects. We compute the partition coefficient of hydrogen between ppv and brg for hydrous and alumino-hydrous compositions at D" pressures and temperatures from first-principles lattice dynamics simulations and free energy calculations computed under the quasiharmonic approximation. We find that for aluminum free hydrous conditions the hydrogen partition coefficient between ppv and brg ranges from 0.2-0.8 within D". However, in the presence of aluminum the aluminum-hydrogen partition coefficient between ppv and brg is approximately 1.5. In general for a given pressure, lower temperature increases the partitioning of hydrogen into ppv for the aluminous models, but not for the aluminum free models. Because aluminum is is expected to occur in both natural slab and mantle compositions this suggests aluminous-hydrous ppv may be a host for water in D".

  2. 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...

  3. Creep-fatigue analysis by Strainrange Partitioning

    NASA Technical Reports Server (NTRS)

    Manson, S. S.; Halford, G. R.; Hirschbere, M. H.

    1973-01-01

    Strainrange Partitioning provides unifying framework for characterizing high-temperature, low-cycle, creep-fatigue properties of metals and alloys. Method offers distinct advantage to designers of immediately providing reliable upper and lower bounds on cyclic life for any type of inelastic strain cycle that may be encountered in service.

  4. Uranium and rare earth partitioning in Synroc

    SciTech Connect

    Smith, K.L.; Lumpkin, G.R.; Blackford, M.G.

    1993-12-31

    Improved AEM techniques were used to investigate three Synrocs containing 10 wt% simulated HLW and a fourth sample with {approximately}18 wt% simulated HLW. One of the 10 wt% loaded Synrocs also contained an addition of 1.0 wt% Na{sub 2}O and another contained an addition of 2.0 wt% Fe{sub 2}O{sub 3}. This work is part of a larger study initiated with the objective of determining if the bulk composition of Synroc affects the partitioning of elements between individual phases. Results from the four samples in this study show that, as expected, elemental partitioning is mainly controlled by the ionic radius criterion, with smaller Y, Gd, and U ions having a preference for zirconolite and the larger Ce and Nd ions favouring perovskite. Additions of Na and Fe lead to the formation of CAT and loveringite at the expense of rutile or Magneli phases, but only have minor effects on partitioning coefficients. Partitioning coefficients, D{sup Z/P}, for REE, Y, and U in the four Synrocs are the same (within experimental error).

  5. Partition function of interacting calorons ensemble

    NASA Astrophysics Data System (ADS)

    Deldar, S.; Kiamari, M.

    2016-01-01

    We present a method for computing the partition function of a caloron ensemble taking into account the interaction of calorons. We focus on caloron-Dirac string interaction and show that the metric that Diakonov and Petrov offered, works well in the limit where this interaction occurs. We suggest computing the correlation function of two polyakov loops by applying Ewald's method.

  6. 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...

  7. A straightforward approximate analysis of Kerr nonlinear processes in sub-wavelength diameter optical fiber with better accuracy over variational technique

    NASA Astrophysics Data System (ADS)

    Sadhu, Arunangshu; Sarkar, Somenath

    2016-05-01

    We report a simple and straightforward approximate analysis to investigate the effect of Kerr type nonlinear optical processes in sub-wavelength diameter step index optical fibers based on Marcuse method in single mode region. Optimum core diameters of such fibers, predicted by us, together with relevant core nonlinearity coefficient and effective area are seen to be compatible with the analytical values indicating the validity of this novel application of the elegant approximate method. However, the corresponding values, obtained by earlier variational method, show larger discrepancy with analytical findings in comparison with ours. Also, maximum enhancement of nonlinear processes within single mode region, confirming almost the analytical method, assures less diffraction. Formulations, coupled with simplicity and novelty of the present analysis, should find wide use by system users and experimentalists in this emerging area.

  8. 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. PMID:27081742

  9. 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. PMID:25868425

  10. Optimising query execution time in LHCb Bookkeeping System using partition pruning and Partition-Wise joins

    NASA Astrophysics Data System (ADS)

    Mathe, Zoltan; Charpentier, Philippe

    2014-06-01

    The LHCb experiment produces a huge amount of data which has associated metadata such as run number, data taking condition (detector status when the data was taken), simulation condition, etc. The data are stored in files, replicated on the Computing Grid around the world. The LHCb Bookkeeping System provides methods for retrieving datasets based on their metadata. The metadata is stored in a hybrid database model, which is a mixture of Relational and Hierarchical database models and is based on the Oracle Relational Database Management System (RDBMS). The database access has to be reliable and fast. In order to achieve a high timing performance, the tables are partitioned and the queries are executed in parallel. When we store large amounts of data the partition pruning is essential for database performance, because it reduces the amount of data retrieved from the disk and optimises the resource utilisation. This research presented here is focusing on the extended composite partitioning strategy such as range-hash partition, partition pruning and usage of the Partition-Wise joins. The system has to serve thousands of queries per minute, the performance and capability of the system is measured when the above performance optimization techniques are used.

  11. Disruption of the blood-brain barrier in pigs naturally infected with Taenia solium, untreated and after anthelmintic treatment.

    PubMed

    Guerra-Giraldez, Cristina; Marzal, Miguel; Cangalaya, Carla; Balboa, Diana; Orrego, Miguel Ángel; Paredes, Adriana; Gonzales-Gustavson, Eloy; Arroyo, Gianfranco; García, Hector H; González, Armando E; Mahanty, Siddhartha; Nash, Theodore E

    2013-08-01

    Neurocysticercosis is a widely prevalent disease in the tropics that causes seizures and a variety into of neurological symptoms in most of the world. Experimental models are limited and do not allow assessment of the degree of inflammation around brain cysts. The vital dye Evans Blue (EB) was injected to 11 pigs naturally infected with Taenia solium cysts to visually identify the extent of disruption of the blood-brain barrier. A total of 369 cysts were recovered from the 11 brains and classified according to the staining of their capsules as blue or unstained. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120h before the EB infusion, indicating a greater compromise of the blood-brain barrier due to treatment. The model could be useful for understanding the pathology of treatment-induced inflammation in neurocysticercosis. PMID:23684909

  12. 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

  13. 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

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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

  17. MR assessment of radiation-induced blood-brain barrier permeability changes in a rat glioma model

    SciTech Connect

    Krueck, W.G. Univ. of Washington School of Medicine, Seattle, WA ); Schmiedl, U.P.; Maravilla, K.R.; Starr, F.L.; Kenney, J. )

    1994-04-01

    To assess the potential of a T1-weighted, gadolinium-enhanced MR technique for quantifying radiation-induced changes of blood-brain barrier permeability in a model of stereotactically implanted intracerebral gliomas in rats. We calculated the gadolinium blood-to-tissue transport coefficient for gadopentetate dimeglumine from signal intensities in sequential MR images in nine control animals that were not irradiated and in five and three animals that had received 2500 cGy and 1500 cGy whole-brain irradiation, respectively, at 2 days before imaging. The average blood-to-tissue transport coefficient values were 9.76 mL[center dot]kg[sup [minus]1][center dot]min[sup [minus]1] in the control group, 23.41 mL[center dot]kg[sup [minus]1][center dot]min[sup [minus]1] in the 2500-cGy group, and 25.63 mL[center dot]kg[sup [minus]1][center dot]min[sup [minus]1] in the 1500-cGy group. Blood-to-tissue transport coefficients were significantly higher after irradiation, indicating increased radiation-induced blood-brain barrier permeability. Similar increased blood-brain barrier leakiness in brain tumors after high-dose irradiation has been shown by previous nuclear medicine studies using quantitative autoradiography. Contrast-enhanced dynamic MR of brain gliomas is a sensitive method to document radiation-induced blood-brain barrier breakdown. Quantitative gadolinium-enhanced MR may become a useful tool for the management of patients with brain tumors undergoing radiation therapy. 28 refs., 4 figs., 1 tab.

  18. 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

  19. Blood-brain barrier alteration after microwave-induced hyperthermia is purely a thermal effect: I. Temperature and power measurements

    SciTech Connect

    Moriyama, E.; Salcman, M.; Broadwell, R.D. )

    1991-03-01

    The effect of microwave-induced hyperthermia on the blood-brain barrier was studied in 21 Sprague-Dawley rats. Under sodium pentobarbital anesthesia, animals were place in a stereotactic frame, and an interstitial microwave antenna operating at 2450 MHz was inserted in a bony groove drilled parallel to the sagittal suture. Some antennae were equipped with an external cooling jacket. Temperature measurements were made lateral to the antenna by fluoroptical thermometry, and power was calculated from the time-temperature profile. Five minutes prior to termination of microwave irradiation, horseradish peroxidase (1 mg/20 g body weight) was injected intravenously. Extravasation of horseradish peroxidase was observed in brain tissue heated above 44.3 degrees C for 30 minutes and at 42.5 degrees C for 60 minutes. Microwave irradiation failed to open the blood-brain barrier when brain temperatures were sustained below 40.3 degrees C by the cooling system. Extravasation of blood-borne peroxidase occurred at sites of maximal temperature elevation, even when these did not coincide with the site of maximum power density. The data suggest that microwave-induced hyperthermia is an effective means for opening the blood-brain barrier and that the mechanism is not related to the nonthermal effect of microwaves.

  20. Commentary on “Alzheimer’s disease drug development and the problem of the blood-brain barrier”

    PubMed Central

    Simpkins, James W.

    2016-01-01

    The perspective by Dr. William Pardridge entitled “Alzheimer’s Disease Drug Discovery and the Problem of the Blood-Brain Barrier” makes a strong case for the imbalance in resource distribution to the drug-discovery and brain drug delivery processes, where the latter received less than 1% of the investment of the former. My own calculations are consistent with this striking imbalance. Dr. Pardridge predicts that current trials of passive immunity against β-amyloid peptide will likely fail, whereas past trials of active immunization exhibited trial-ending side effects, in part because of disruption of the integrity of the blood-brain barrier. To bring an assessment of the physiology of the blood-brain barrier and the brain delivery of drugs to the fore, several changes are needed in the way we perceive the problem, train our young scientists, organize research efforts, and incentivize reaching our common goals of effective drug therapy for Alzheimer’s disease. PMID:19751923

  1. 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

  2. Is Peripheral Immunity Regulated by Blood-Brain Barrier Permeability Changes?

    PubMed Central

    Bargerstock, Erin; Puvenna, Vikram; Iffland, Philip; Falcone, Tatiana; Hossain, Mohammad; Vetter, Stephen; Man, Shumei; Dickstein, Leah; Marchi, Nicola; Ghosh, Chaitali; Carvalho-Tavares, Juliana; Janigro, Damir

    2014-01-01

    S100B is a reporter of blood-brain barrier (BBB) integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD). Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient). After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain) but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc.) and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses. PMID:24988410

  3. Development of an in vitro blood-brain barrier model-cytotoxicity of mercury and aluminum.

    PubMed

    Toimela, Tarja; Mäenpää, Hanna; Mannerström, Marika; Tähti, Hanna

    2004-02-15

    In this study, in vitro blood-brain barrier (BBB) models composed of two different cell types were compared. The aim of our study was to find an alternative human cell line that could be used in BBB models. Inorganic and organic mercury and aluminum were studied as model chemicals in the testing of the system. BBB models were composed of endothelial RBE4 cell line or retinal pigment epithelial (RPE) cell line ARPE-19 and neuronal SH-SY5Y cells as target cells. Glial U-373 MG cells were included in part of the tests to induce the formation of a tighter barrier. Millicell CM filter inserts were coated with rat-tail collagen, and RBE4 or ARPE-19 cells were placed on the filters at the density of 3.5-4 x 10(5) cells/filter. During culture, the state of confluency was microscopically observed and confirmed by the measurement of electrical resistance caused by the developing cell layer. The target cells, SH-SY5Y neuroblastoma cells, were plated on the bottom of cell culture wells at the density of 100000 cells/cm(2). In part of the studies, glial U-373 MG cells were placed on the under side of the membrane filter. When confluent filters with ARPE-19 or RBE4 cells were placed on top of the SH-SY5Y cells, different concentrations of mercuric chloride, methyl mercury chloride, and aluminum chloride were added into the filter cups along with a fluorescent tracer. Exposure time was 24 h, after which the cytotoxicity in the SH-SY5Y cell layer, as well as in the ARPE-19 or RBE4 cell layer, was evaluated by the luminescent measurement of total ATP. The leakage of the fluorescent tracer was also monitored. The results showed that both barrier cell types were induced by glial cells. Inorganic and organic mercury caused a leakage of the dye and cytotoxicity in SH-SY5Y cells. Especially, methyl mercury chloride could exert an effect on target cells before any profound cytotoxicity in barrier cells could be seen. Aluminum did not cause any leakage in the barrier cell layer, and even

  4. 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

  5. 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.

  6. Partition coefficients of three new anticonvulsants.

    PubMed

    Hernandez-Gallegos, Z; Lehmann, P A

    1990-11-01

    The partition coefficients of three homologous anticonvulsant phenylalkylamides [racemic alpha-hydroxy-alpha-ethyl-alpha-phenylacetamide (HEPA); beta-hydroxy-beta-ethyl-beta-phenylpropionamide (HEPP); and gamma-hydroxy-gamma-ethyl-gamma-phenylbutyramide (HEPB)] were determined by reversed-phase high-performance liquid chromatography (RP-HPLC). The system was calibrated with a series of simple amines and amides, using their published log P values. The log kw values (methanol:water, extrapolated to 100% water) were 1.260 for HEPA, 1.670 for HEPP, and 1.852 for HEPB. From these results, the partition coefficients (log P) were calculated by regression as 1.20, 1.83, and 2.11, respectively. The log P values were essentially equal to those calculated by the Leo-Hansch fragmental method. Since the potency of the three anticonvulsants is approximately the same in a variety of tests, no dependence on lipophilicity could be established. PMID:2292764

  7. 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.

  8. 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.

  9. Rotational partition functions for linear molecules

    NASA Astrophysics Data System (ADS)

    McDowell, Robin S.

    1988-01-01

    An accurate closed-form expression for the rotational partition function of linear polyatomic molecules in 1Sigma electronic states is derived, including the effect of nuclear spin (significant at very low temperatures) and of quartic and sextic centrifugal distortion terms (significant at moderate and high temperatures). The proper first-order quantum correction to the classical rigid-rotator partition function is shown to yield Qr = about 1/beta exp beta/3, where beta is defined as hcB / kT and B is the rotational constant in per cm; for beta of 0.2 or greater additional power-series terms in beta are necessary. Comparison between the results of this treatment and exact summations are made for HCN and C2H2 at temperatures from 2 to 5000 K, including separate evaluation of the conributions of nuclear spin and centrifugal distortion.

  10. Mantle Mineral/Silicate Melt Partitioning

    NASA Astrophysics Data System (ADS)

    McFarlane, E. A.; Drake, M. J.

    1992-07-01

    Introduction: The partitioning of elements among mantle phases and silicate melts is of interest in unraveling the early thermal history of the Earth. It has been proposed that the elevated Mg/Si ratio of the upper mantle of the Earth is a consequence of the flotation of olivine into the upper mantle (Agee and Walker, 1988). Agee and Walker (1988) have generated a model via mass balance by assuming average mineral compositions to generate upper mantle peridotite. This model determines that upper mantle peridotite could result from the addition of 32.7% olivine and 0.9% majorite garnet into the upper mantle, and subtraction of 27.6% perovskite from the upper mantle (Agee and Walker, 1988). The present contribution uses experimental data to examine the consequences of such multiple phase fractionations enabling an independent evaluation of the above mentioned model. Here we use Mg-perovskite/melt partition coefficients from both a synthetic and a natural system (KLB-1) obtained from this laboratory. Also used are partition coefficient values for majorite garnet/melt, beta spinel/melt and olivine/melt partitioning (McFarlane et al., 1991b; McFarlane et al., 1992). Multiple phase fractionations are examined using the equilibrium crystallization equation and partition coefficient values. The mineral proportions determined by Agee and Walker (1988) are converted into weight fractions and used to compute a bulk partition coefficient value. Discussion: There has been a significant debate concerning whether measured values of trace element partition coefficients permit large-scale fractionation of liquidus phases from an early terrestrial magma ocean (Kato et al., 1988a,b; Walker and Agee, 1989; Drake, 1989; Drake et al., 1991; McFarlane et al., 1990, 1991). It should be noted that it is unclear which, if any, numerical values of partition coefficients are appropriate for examining this question, and certainly the assumptions for the current model must be more fully

  11. Grid-based partitioning for comparing attractors

    NASA Astrophysics Data System (ADS)

    Carroll, T. L.; Byers, J. M.

    2016-04-01

    Stationary dynamical systems have invariant measures (or densities) that are characteristic of the particular dynamical system. We develop a method to characterize this density by partitioning the attractor into the smallest regions in phase space that contain information about the structure of the attractor. To accomplish this, we develop a statistic that tells us if we get more information about our data by dividing a set of data points into partitions rather than just lumping all the points together. We use this method to show that not only can we detect small changes in an attractor from a circuit experiment, but we can also distinguish between a large set of numerically generated chaotic attractors designed by Sprott. These comparisons are not limited to chaotic attractors—they should work for signals from any finite-dimensional dynamical system.

  12. 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.

  13. Metal partitioning and toxicity in sewage sludge

    SciTech Connect

    Carlson-Ekvall, C.E.A.; Morrison, G.M.

    1995-12-31

    Over 20 years of research has failed to provide an unequivocal correlation between chemically extracted metals in sewage sludge applied to agricultural soil and either metal toxicity to soil organisms or crop uptake. Partitioning of metals between phases and species can provide a better estimation of mobility and potential bioavailability. Partition coefficients, K{sub D} for Cd, Cu, Pb and Zn in a sludge/water solution were determined considering the sludge/water solution as a three-phase system (particulate, colloidal and electrochemically available) over a range of pH values, ionic strengths, contact times and sludge/water ratios and compared with the KD values for sludge/water solution as a two-phase system (aqueous phase and particulate phase). Partitioning results were interpreted in terms of metal mobility from sludge to colloids and in terms of potential bioavailability from colloids to electrochemically available. The results show that both mobility and potential bioavailability are high for Zn, while Cu partitions into the mobile colloidal phase which is relatively non-bioavailable. Lead is almost completely bound to the solid phase, and is neither mobile nor bioavailable. A comparison between K, values and toxicity shows that Zn in sludge is more toxic than can be accounted for in the aqueous phase, which can be due to synergistic effects between sludge organics and Zn. Copper demonstrates clear synergism which can be attributed to the formation of lipid-soluble Cu complexes with known sludge components such as LAS, caffeine, myristic acid and nonylphenol.

  14. 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.

  15. GPS/INS integration by functional partitioning

    NASA Astrophysics Data System (ADS)

    Diesel, John W.

    It is shown that a GPS/INS system integrated by functional partitioning can satisfy all of the RTCA navigation requirements and goals. This is accomplished by accurately calibrating the INS using GPS after the inertial instruments are thermally stabilized and by exploiting the very slow subsequent error growth in the INS information. In this way, autonomous integrity monitoring can be achieved using only existing or presently planned systems.

  16. Pure Partition Functions of Multiple SLEs

    NASA Astrophysics Data System (ADS)

    Kytölä, Kalle; Peltola, Eveliina

    2016-05-01

    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.

  17. Partitioning networks into communities by message passing.

    PubMed

    Lai, Darong; Nardini, Christine; Lu, Hongtao

    2011-01-01

    Community structures are found to exist ubiquitously in a number of systems conveniently represented as complex networks. Partitioning networks into communities is thus important and crucial to both capture and simplify these systems' complexity. The prevalent and standard approach to meet this goal is related to the maximization of a quality function, modularity, which measures the goodness of a partition of a network into communities. However, it has recently been found that modularity maximization suffers from a resolution limit, which prevents its effectiveness and range of applications. Even when neglecting the resolution limit, methods designed for detecting communities in undirected networks cannot always be easily extended, and even less directly applied, to directed networks (for which specifically designed community detection methods are very limited). Furthermore, real-world networks are frequently found to possess hierarchical structure and the problem of revealing such type of structure is far from being addressed. In this paper, we propose a scheme that partitions networks into communities by electing community leaders via message passing between nodes. Using random walk on networks, this scheme derives an effective similarity measure between nodes, which is closely related to community memberships of nodes. Importantly, this approach can be applied to a very broad range of networks types. In fact, the successful validation of the proposed scheme on real and synthetic networks shows that this approach can effectively (i) address the problem of resolution limit and (ii) find communities in both directed and undirected networks within a unified framework, including revealing multiple levels of robust community partitions. PMID:21405752

  18. Scheduling and process migration in partitioned multiprocessors

    SciTech Connect

    Gait, J. )

    1990-03-01

    A partitioned multiprocessor (PM) has a shared global bus and nonshared local memories. This paper studies a process scheduler, called the two-tier scheduler (TTS), for a PM. In a PM local scheduling amortizes the cost of loading processes in local memory. Global scheduling migrates processes to balance load. A tunable time quantum is adjusted so the average process completes execution on the processor on which it is first scheduled, and only relatively long lived processes are rescheduled globally.

  19. Phase partitioning in space and on earth

    NASA Technical Reports Server (NTRS)

    Van Alstine, James M.; Karr, Laurel J.; Snyder, Robert S.; Matsos, Helen C.; Curreri, Peter A.; Harris, J. Milton; Bamberger, Stephan B.; Boyce, John; Brooks, Donald E.

    1987-01-01

    The influence of gravity on the efficiency and quality of the impressive separations achievable by bioparticle partitioning is investigated by demixing polymer phase systems in microgravity. The study involves the neutral polymers dextran and polyethylene glycol, which form a two-phase system in aqueous solution at low concentrations. It is found that demixing in low-gravity occurs primarily by coalescence, whereas on earth the demixing occurs because of density differences between the phases.

  20. 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.

  1. 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.

  2. Diversity partitioning during the Cambrian radiation.

    PubMed

    Na, Lin; Kiessling, Wolfgang

    2015-04-14

    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

  3. 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

  4. 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

  5. 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.

  6. 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

    2016-06-01

    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. PMID:27115830

  7. Reversible Opening of the Blood-Brain Barrier by Anti-Bacterial Antibodies

    NASA Astrophysics Data System (ADS)

    Tuomanen, Elaine I.; Prasad, Sudha M.; George, Jonathan S.; Hoepelman, Andy I. M.; Ibsen, Per; Heron, Iver; Starzyk, Ruth M.

    1993-08-01

    The leukocyte adhesion molecule CR3 (CD11b/CD18, Mac-1) promotes leukocyte transmigration into tissues by engaging an unknown cognate ligand on the surface of vascular endothelial cells. Filamentous hemagglutinin (FHA), an adhesin of the bacterium Bordetella pertussis, binds to CR3. We hypothesized that FHA mimics the native ligand for the CR3 integrin on endothelial cells and predicted that anti-FHA antibodies should bind to endothelial cells, interfere with leukocyte recruitment, and induce endothelial permeability. Anti-FHA monoclonal antibodies bound to cerebral microvessels in sections from human brain and upon intravenous injection into rabbits. Antibody binding correlated with the ability to recognize two polypeptides in extracts of human cerebral vessels that were also bound by CD18. In vivo, antibody binding not only interfered with transmigration of leukocytes into cerebrospinal fluid but also induced a dose-dependent reversible increase in blood-brain barrier permeability sufficient to improve delivery of intravenously administered therapeutic agents to brain parenchyma.

  8. Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier.

    PubMed

    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

  9. Blood-Brain Barrier Dysfunction and Cerebral Small Vessel Disease (Arteriolosclerosis) in Brains of Older People

    PubMed Central

    Khoong, Cheryl H.L.; Poon, Wayne; Esiri, Margaret M.; Markus, Hugh S.; Hainsworth, Atticus H.

    2014-01-01

    The blood-brain barrier (BBB) protects brain tissue from potentially harmful plasma components. Small vessel disease ([SVD], arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and IgG, which are assumed to reflect BBB dysfunction, in deep grey matter (anterior caudate-putamen, [DGM]) and deep subcortical white matter (DWM) in the brains of a well-characterized patient cohort with minimal Alzheimer disease pathology (Braak stage 0-II) (n = 84; age ≥65 years). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and IgG was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that in aged brains plasma extravasation and hence local BBB dysfunction is common but do not support an association with SVD. PMID:25289893

  10. Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications.

    PubMed

    Su, Chia-Hao; Tsai, Ching-Yi; Tomanek, Boguslaw; Chen, Wei-Yu; Cheng, Fong-Yu

    2016-04-14

    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. PMID:27035391

  11. Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.

    PubMed

    Couch, Jessica A; Yu, Y Joy; Zhang, Yin; Tarrant, Jacqueline M; Fuji, Reina N; Meilandt, William J; Solanoy, Hilda; Tong, Raymond K; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Gadkar, Kapil; Prabhu, Saileta; Ordonia, Benjamin A; Nguyen, Quyen; Lin, Yuwen; Lin, Zhonghua; Balazs, Mercedesz; Scearce-Levie, Kimberly; Ernst, James A; Dennis, Mark S; Watts, Ryan J

    2013-05-01

    Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier. PMID:23636093

  12. Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

    PubMed Central

    Keaney, James; Walsh, Dominic M.; O’Malley, Tiernan; Hudson, Natalie; Crosbie, Darragh E.; Loftus, Teresa; Sheehan, Florike; McDaid, Jacqueline; Humphries, Marian M.; Callanan, John J.; Brett, Francesca M.; Farrell, Michael A.; Humphries, Peter; Campbell, Matthew

    2015-01-01

    The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain. PMID:26491725

  13. Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy.

    PubMed

    Doherty, Colin P; O'Keefe, Eoin; Wallace, Eugene; Loftus, Teresa; Keaney, James; Kealy, John; Humphries, Marian M; Molloy, Michael G; Meaney, James F; Farrell, Michael; Campbell, Matthew

    2016-07-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE. PMID:27245243

  14. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology.

    PubMed

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H K; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H; Irimia, Daniel

    2015-01-01

    Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. PMID:26503597

  15. Iron transport across the blood-brain barrier; Development, neurovascular regulation and cerebral amyloid angiopathy

    PubMed Central

    McCarthy, Ryan C; Kosman, Daniel J

    2014-01-01

    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. PMID:25355056

  16. Blood-Brain Barrier Impairment in an Animal Model of MPS III B

    PubMed Central

    Garbuzova-Davis, Svitlana; Louis, Michael K.; Haller, Edward M.; Derasari, Hiranya M.; Rawls, Ashley E.; Sanberg, Paul R.

    2011-01-01

    Background Sanfilippo syndrome type B (MPS III B) is caused by a deficiency of α-N-acetylglucosaminidase enzyme, leading to accumulation of heparan sulfate within lysosomes and eventual progressive cerebral and systemic multiple organ abnormalities. However, little is known about the competence of the blood-brain barrier (BBB) in MPS III B. BBB dysfunction in this devastating disorder could contribute to neuropathological disease manifestations. Methodology/Principal Findings In the present study, we investigated structural (electron microscope) and functional (vascular leakage) integrity of the BBB in a mouse model of MPS III B at different stages of disease, focusing on brain structures known to experience neuropathological changes. Major findings of our study were: (1) endothelial cell damage in capillary ultrastructure, compromising the BBB and resulting in vascular leakage, (2) formation of numerous large vacuoles in endothelial cells and perivascular cells (pericytes and perivascular macrophages) in the large majority of vessels, (3) edematous space around microvessels, (4) microaneurysm adjacent to a ruptured endothelium, (6) Evans Blue and albumin microvascular leakage in various brain structures, (7) GM3 ganglioside accumulation in endothelium of the brain microvasculature. Conclusions/Significance These new findings of BBB structural and function impairment in MPS III B mice even at early disease stage may have implications for disease pathogenesis and should be considered in current and future development of treatments for MPS III B. PMID:21408219

  17. Blood-ocular and blood-brain barrier function in streptozocin-induced diabetes in rats

    SciTech Connect

    Maeepea, O.; Karlsson, C.; Alm, A.

    1984-09-01

    Edetic acid labeled with chromium 51 was injected intravenously in normal rats and in rats with streptozocin-induced diabetes. One hour after the injection the animals were killed and the concentrations of edetic acid 51Cr in vitreous body, retina, and brain were determined. No significant difference was observed between the two groups for either tissue. In a second series, a mixture of tritiated 1-glucose and aminohippuric acid tagged with carbon 14 was injected instead of edetic acid. A substantial accumulation of aminohippuric acid 14C compared with tritiated 1-glucose was observed in the vitreous body and the brain of diabetic rats in comparison with the control group. It is concluded that untreated streptozocin-induced diabetes in rats for one to two weeks will not cause a generalized increase in the permeability of the blood-ocular or the blood-brain barriers, but organic acids may accumulate in the vitreous body as well as in the brain as a consequence of reduced outward transport through these barriers.

  18. Glucose transporter of the human brain and blood-brain barrier

    SciTech Connect

    Kalaria, R.N.; Gravina, S.A.; Schmidley, J.W.; Perry, G.; Harik, S.I.

    1988-12-01

    We identified and characterized the glucose transporter in the human cerebral cortex, cerebral microvessels, and choroid plexus by specific D-glucose-displaceable (3H)cytochalasin B binding. The binding was saturable, with a dissociation constant less than 1 microM. Maximal binding capacity was approximately 7 pmol/mg protein in the cerebral cortex, approximately 42 pmol/mg protein in brain microvessels, and approximately 27 pmol/mg protein in the choroid plexus. Several hexoses displaced specific (3H)cytochalasin B binding to microvessels in a rank-order that correlated well with their known ability to cross the blood-brain barrier; the only exception was 2-deoxy-D-glucose, which had much higher affinity for the glucose transporter than the natural substrate, D-glucose. Irreversible photoaffinity labeling of the glucose transporter of microvessels with (3H)cytochalasin B, followed by solubilization and polyacrylamide gel electrophoresis, labeled a protein band with an average molecular weight of approximately 55,000. Monoclonal and polyclonal antibodies specific to the human erythrocyte glucose transporter immunocytochemically stained brain blood vessels and the few trapped erythrocytes in situ, with minimal staining of the neuropil. In the choroid plexus, blood vessels did not stain, but the epithelium reacted positively. We conclude that human brain microvessels are richly endowed with a glucose transport moiety similar in molecular weight and antigenic characteristics to that of human erythrocytes and brain microvessels of other mammalian species.

  19. Aluminum permeation of the blood-brain barrier occurs primarily across brain capillaries

    SciTech Connect

    Allen, D.D.; Yokel, R.A. )

    1991-03-11

    Aluminum has been demonstrated to be neurotoxic and has been implicated in several neurobehavioral disorders. The primary site(s) and mechanism(s) of Al flux across the blood-brain barrier (BBB) have not been elucidated. Aluminum (Al) permeation of the BBB was assessed in male Sprague-Dawley rats. Utilizing the in vivo microdialysis technique, unbound extracellular Al concentrations were ascertained at the two potential sites of flux across the BBB; the choroid plexus and brain capillaries. Microdialysis probes were implanted in the lateral ventricle and in the frontal cortex to elucidate flux across the choroid plexus and brain capillaries, respectively. A microdialysis probe was also implanted in the jugular vein to reveal blood Al concentrations. Aluminum citrate was administered via the femoral vein. Peak frontal cortex and blood Al concentration were seen within the first two 5 minute sampling periods. When concentrations were measurable for lateral ventricle, the peak concentrations were also seen within the first two 5 minute sampling periods. Area under the curve (AUC) (concentrations vs. time to last sample time point) values were calculated using RSTRIP. Brain and cerebrospinal fluid AUCs were divided by blood AUC within animal to calculate tissue/blood ratios (TBRs). Frontal cortex TBRs were significantly higher than those calculated for lateral ventricle. The results indicate that the primary site of Al flux across the BBB occurs at brain capillaries.

  20. 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. PMID:27579317

  1. Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology

    NASA Astrophysics Data System (ADS)

    Cho, Hansang; Seo, Ji Hae; Wong, Keith H. K.; Terasaki, Yasukazu; Park, Joseph; Bong, Kiwan; Arai, Ken; Lo, Eng H.; Irimia, Daniel

    2015-10-01

    Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.

  2. Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications

    NASA Astrophysics Data System (ADS)

    Shilo, Malka; Motiei, Menachem; Hana, Panet; Popovtzer, Rachela

    2014-01-01

    A critical problem in the treatment of neurodegenerative disorders and diseases, such as Alzheimer's and Parkinson's, is the incapability to overcome the restrictive mechanism of the blood-brain barrier (BBB) and to deliver important therapeutic agents to the brain. During the last decade, nanoparticles have gained attention as promising drug delivery agents that can transport across the BBB and increase the uptake of appropriate drugs in the brain. In this study we have developed insulin-targeted gold nanoparticles (INS-GNPs) and investigated quantitatively the amount of INS-GNPs that cross the BBB by the receptor-mediated endocytosis process. For this purpose, INS-GNPs and control GNPs were injected into the tail vein of male BALB/c mice. Major organs were then extracted and a blood sample was taken from the mice, and thereafter analyzed for gold content by flame atomic absorption spectroscopy. Results show that two hours post-intravenous injection, the amount of INS-GNPs found in mouse brains is over 5 times greater than that of the control, untargeted GNPs. Results of further experimentation on a rat model show that INS-GNPs can also serve as CT contrast agents to highlight specific brain regions in which they accumulate. Due to the fact that they can overcome the restrictive mechanism of the BBB, this approach could be a potentially valuable tool, helping to confront the great challenge of delivering important imaging and therapeutic agents to the brain for detection and treatment of neurodegenerative disorders and diseases.

  3. Aging and sex influence the permeability of the blood-brain barrier in the rat

    SciTech Connect

    Saija, A.; Princi, P.; D'Amico, N.; De Pasquale, R.; Costa, G.

    1990-01-01

    The aim of the present study was to investigate the existence of aging- and sex-related alterations in the permeability of the blood-brain barrier (BBB) in the rat, by calculating a unidirectional blood-to-brain transfer constant (Ki) for the circulating tracer ({sup 14}C)-{alpha}-aminoisobutyric acid. The authors observed that: (a) the permeability of the BBB significantly increased within the frontal and temporo-parietal cortex, hypothalamus and cerebellum in 28-30 week old rats, in comparison with younger animals; (b) in several brain areas of female intact rats higher Ki values (even though not significantly different) were calculated at oestrus than at proestrus; (c) in 1-week ovariectomized rats there was a marked increase of Ki values at the level of the frontal, temporo-parietal and occipital cortex, cerebellum and brain-stem. One can speculate that aging and sex-related alterations in thee permeability of the BBB reflect respectively changes in brain neurochemical system activity and in plasma steroid hormone levels.

  4. Correlation between astrocyte activity and recovery from blood-brain barrier breakdown caused by brain injury.

    PubMed

    Ikeshima-Kataoka, Hiroko; Yasui, Masato

    2016-08-17

    Glial activation is associated with cell proliferation and upregulation of astrocyte marker expression following traumatic injury in the brain. However, the biological significance of these processes remains unclear. In the present study, astrocyte activation was investigated in a murine brain injury model. Brain injury induces blood-brain barrier (BBB) breakdown and immunoglobulin G (IgG) leak into the brain parenchyma. The recovery of BBB breakdown was evaluated by analyzing immunofluorescent staining with mouse IgG antibody. IgG leakage was greatest at 1 day after stab wound injury and decreased thereafter, and almost diminished after 7 days. Bromodeoxy uridine incorporation was used, and astrocyte proliferation rates were examined by coimmunostaining with anti-bromodeoxy uridine and anti-glial fibrillary acid protein antibodies. Consistent with IgG leakage assays, astrocyte activation was the highest at day 3 and decreased after 7 days. Moreover, in reverse transcriptase-quantitative-PCR experiments, genes associated with BBB integrity were downregulated immediately after BBB breakdown and recovered to basal expression levels within 7 days. These data indicated that astrocyte activation correlated with BBB recovery from breakdown following brain injury. PMID:27362437

  5. Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

    PubMed

    Carpentier, Alexandre; Canney, Michael; Vignot, Alexandre; Reina, Vincent; Beccaria, Kevin; Horodyckid, Catherine; Karachi, Carine; Leclercq, Delphine; Lafon, Cyril; Chapelon, Jean-Yves; Capelle, Laurent; Cornu, Philippe; Sanson, Marc; Hoang-Xuan, Khê; Delattre, Jean-Yves; Idbaih, Ahmed

    2016-06-15

    The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain. PMID:27306666

  6. 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.

  7. 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

  8. Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

    PubMed Central

    Lakhan, Shaheen E.; Kirchgessner, Annette; Tepper, Deborah; Leonard, Aidan

    2013-01-01

    Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. In this review we discuss the role of matrix metalloproteinases (MMPs) in blood-brain barrier (BBB) disruption as a consequence of ischemic stroke. MMP-9 in particular appears to play an important role in tPA-associated hemorrhagic complications. Reactive oxygen species can enhance the effects of tPA on MMP activation through the loss of caveolin-1 (cav-1), a protein encoded in the cav-1 gene that serves as a critical determinant of BBB permeability. This review provides an overview of MMPs’ role in BBB breakdown during acute ischemic stroke. The possible role of MMPs in combination treatment of acute ischemic stroke is also examined. PMID:23565108

  9. 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. PMID:23628475

  10. Nafamostat mesilate protects against acute cerebral ischemia via blood-brain barrier protection.

    PubMed

    Wang, Jing; Li, Chenhui; Chen, Tao; Fang, Yinquan; Shi, Xinzhong; Pang, Tao; Zhang, Luyong; Liao, Hong

    2016-06-01

    Serine proteases, such as thrombin, are contributors to the disruption of the blood-brain barrier (BBB) and exacerbate brain damage during ischemic stroke, for which the current clinical therapy remains unsatisfactory. However, the effect of nafamostat mesilate (NM), a synthetic serine protease inhibitor, on BBB disruption following cerebral ischemia is unknown. Here, we investigated the in vivo effect of NM on BBB integrity in rats subjected to transient middle cerebral artery occlusion (MCAO) and explored the possible mechanism in an in vitro BBB model comprising rat brain microvascular endothelial cells and astrocytes after oxygen and glucose deprivation (OGD) in the presence of thrombin. The results showed that NM treatment remarkably attenuated transient MCAO-induced brain infarcts, brain oedema and motor dysfunction in addition to BBB disruption, which might be related to changes in tight junction protein expression and localization. Meanwhile, NM preserved BBB integrity and alleviated the changes in tight junction protein expression and localization and cytoskeleton rearrangement in rat brain microvascular endothelial cells via thrombin inhibition. Our findings suggest that NM treatment can preserve BBB integrity through the inhibition of thrombin, which might be correlated with the regulation of PKCα/RhoA/MLC2 pathway components. PMID:26861077

  11. Polymeric nanoparticles assembled with microfluidics for drug delivery across the blood-brain barrier

    NASA Astrophysics Data System (ADS)

    Tavares, M. R.; de Menezes, L. R.; do Nascimento, D. F.; Souza, D. H. S.; Reynaud, F.; Marques, M. F. V.; Tavares, M. I. B.

    2016-07-01

    The blood-brain barrier (BBB) is a challenge in the treatment of some diseases, since it prevents many drugs from reaching therapeutic concentrations in the brain. In this context, there is a growing interest in nanoparticles for drug delivery, since they are able to cross this barrier and target the brain. The use of polymeric materials in the development of these nanoparticles has been extensively studied. It has already been demonstrated that these nanosystems have the ability to cross the BBB, which allows effective drug release into the brain. Biodegradable polymers provide a great advantage in the development of nanosystems, but modifications of the nanoparticles' surface is essential. The traditional batch methods lack precise control over the processes of nucleation and growth, resulting in poor control over final properties of the nanoparticles. Therefore, microfluidics could be used to achieve a better production environment for the fabrication of nano- structured drug delivery systems. This study provides a brief review of: the BBB, the polymeric nanoparticles with the ability to overcome the barrier, the properties of the most used polymeric matrices, and the nanostructured drug delivery systems assembled with microfluidics.

  12. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

    PubMed

    Saraiva, Cláudia; Praça, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

    2016-08-10

    The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed. PMID:27208862

  13. 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. PMID:24837786

  14. 'À la carte' peptide shuttles: tools to increase their passage across the blood-brain barrier.

    PubMed

    Malakoutikhah, Morteza; Guixer, Bernat; Arranz-Gibert, Pol; Teixidó, Meritxell; Giralt, Ernest

    2014-07-01

    Noninvasive methods for efficient drug delivery to the brain is an unmet need. Molecular access to the brain is regulated by the blood-brain barrier (BBB) established by the endothelial cells of brain vessels. Passive diffusion is one of the main mechanisms that organic compounds use to travel through these endothelial cells. This passage across the BBB is determined mainly by certain physicochemical properties of the molecule such as lipophilicity, size, and the presence of hydrogen bond donors and acceptors. One emerging strategy to facilitate the passage of organic compounds across the BBB is the use of peptide shuttles.1 In using this approach the permeability in front the BBB is, clearly, determined by the combined physicochemical properties of both the cargo and the shuttle. Herein we report the synthesis of a series of variations of one of the more efficient peptide shuttles, (N-MePhe)n . These include diverse structural features such as various backbone stereochemistries or the presence of non-natural amino acids, including halogenated residues. In several cases, we assessed the BBB permeability of both the shuttles alone and linked to a few cargos. Our results show how factors such as stereochemistry or halogen content influences the passage across the BBB and, more importantly, opens the way to a strategy of peptide shuttles 'à la carte', in which a particular fine-tuned shuttle is used for each specific cargo. PMID:24665021

  15. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier.

    PubMed

    Lou, Nanhong; Takano, Takahiro; Pei, Yong; Xavier, Anna L; Goldman, Steven A; Nedergaard, Maiken

    2016-01-26

    Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition. PMID:26755608

  16. 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. PMID:22653056

  17. Recent advances in the brain-to-blood efflux transport across the blood-brain barrier.

    PubMed

    Hosoya, Ken-ichi; Ohtsuki, Sumio; Terasaki, Tetsuya

    2002-11-01

    Elucidating the details of the blood-brain barrier (BBB) transport mechanism is a very important step towards successful drug targeting to the brain and understanding what happens in the brain. Although several brain uptake methods have been developed to characterize transport at the BBB, these are mainly useful for investigating influx transport across the BBB. In 1992, P-glycoprotein was found to act as an efflux pump for anti-cancer drugs at the BBB using primary cultured bovine brain endothelial cells. In order to determine the direct efflux transport from the brain to the circulating blood of exogenous compounds in vivo, the Brain Efflux Index method was developed to characterize several BBB efflux transport systems. Recently, we have established conditionally immortalized rat (TR-BBB) and mouse (TM-BBB) brain capillary endothelial cell lines from transgenic rats and mice harboring temperature-sensitive simian virus 40 large T-antigen gene to characterize the transport mechanisms at the BBB in vitro. TR-BBB and TM-BBB cells possess certain in vivo transport functions and express mRNAs for the BBB. Using a combination of newly developed in vivo and in vitro methods, we have elucidated the efflux transport mechanism at the BBB for neurosteroids, excitatory neurotransmitters, suppressive neurotransmitters, amino acids, and other organic anions to understand the physiological role played by the BBB as a detoxifying organ for the brain. PMID:12429456

  18. 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. PMID:26523970

  19. Immune evasion by rabies viruses through the maintenance of blood-brain barrier integrity.

    PubMed

    Roy, Anirban; Hooper, D Craig

    2008-10-01

    The attenuated rabies virus (RV) strain Challenge Virus Standard (CVS)-F3 and a highly pathogenic strain associated with the silver-haired bats (SHBRV) can both be cleared from the central nervous system (CNS) tissues by appropriate antiviral immune mechanisms if the effectors are provided access across the blood-brain barrier (BBB). In the case of SHBRV infection, antiviral immunity develops normally in the periphery but fails to open the BBB, generally resulting in a lethal outcome. To determine whether or not an absence in the CNS targeted immune response is associated with the infection with other pathogenic RV strains, we have assessed the development of immunity, BBB permeability, and immune cell infiltration into the CNS tissues of mice infected with a variety of RV strains, including the dog variants responsible for the majority of human rabies cases. We demonstrate that the lethal outcomes of infection with a variety of known pathogenic RV strains are indeed associated with the inability to deliver immune effectors across the BBB. Survival from infection with certain of these viruses is improved in mice prone to CNS inflammation. The results suggest that competition between the activity of the immune effectors reaching CNS tissues and the inherent pathological attributes of the virus dictates the outcome and that intervention to deliver RV-specific immune effectors into CNS tissues may have general therapeutic value in rabies. PMID:19016377

  20. Ultrastructural and ultracytochemical studies on the blood-brain barrier in chronic relapsing experimental allergic encephalomyelitis.

    PubMed

    Kato, S; Nakamura, H

    1989-01-01

    We induced chronic relapsing experimental allergic encephalomyelitis (EAE), and studied the ultrastructural and ultracytochemical changes of the blood-brain barrier (BBB) in the demyelinating lesions of various stages of EAE. In the chronic, inactive stage with gliosis and perivascular fibrosis, the basal lamina (BL) of the perivascular processes of astrocytes was formed only partially, and neural parenchyma was not fully separated from the perivascular mesenchymal tissues by the BL of astrocytic processes. Vascular permeability of the BBB was studied using exogenous horseradish peroxidase (HRP) as the tracer: HRP extravasation was marked during the stages of both active myelin breakdown and removal of debris, and was recognized even at the inactive stage, although the degree was reduced to a very low level. The functions of the endothelia, assessed by ouabain-sensitive, K+-dependent p-nitrophenylphosphatase activity, were impaired as EAE progressed. The decrease in HRP leakage at the inactive stage suggests the endothelial impairment of active transport of metabolites including HRP. Along with the development of inflammatory demyelination in EAE, the BBB in affected areas became more and more altered, and gradual morphological and functional impairment of the BBB developed. PMID:2718744

  1. Blood-brain barrier dysfunction in disorders of the developing brain

    PubMed Central

    Moretti, Raffaella; Pansiot, Julien; Bettati, Donatella; Strazielle, Nathalie; Ghersi-Egea, Jean-François; Damante, Giuseppe; Fleiss, Bobbi; Titomanlio, Luigi; Gressens, Pierre

    2015-01-01

    Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data. PMID:25741233

  2. Regulation of CovR expression in Group B Streptococcus impacts blood-brain barrier penetration.

    PubMed

    Lembo, Annalisa; Gurney, Michael A; Burnside, Kellie; Banerjee, Anirban; de los Reyes, Melissa; Connelly, James E; Lin, Wan-Jung; Jewell, Kelsea A; Vo, Anthony; Renken, Christian W; Doran, Kelly S; Rajagopal, Lakshmi

    2010-07-01

    Group B Streptococcus (GBS) is an important cause of invasive infections in humans. The pathogen encodes a number of virulence factors including the pluripotent beta-haemolysin/cytolysin (beta-H/C). As GBS has the disposition of both a commensal organism and an invasive pathogen, it is important for the organism to appropriately regulate beta-H/C and other virulence factors in response to the environment. GBS can repress transcription of beta-H/C using the two-component system, CovR/CovS. Recently, we described that the serine/threonine kinase Stk1 can phosphorylate CovR at threonine 65 to relieve repression of beta-H/C. In this study, we show that infection with CovR-deficient GBS strains resulted in increased sepsis. Although CovR-deficient GBS showed decreased ability to invade the brain endothelium in vitro, they were more proficient in induction of permeability and pro-inflammatory signalling pathways in brain endothelium and penetration of the blood-brain barrier (BBB) in vivo. Microarray analysis revealed that CovR positively regulates its own expression and regulates the expression of 153 genes. Collectively, our results suggest that the positive feedback loop which regulates CovR transcription modulates host cell interaction and immune defence and may facilitate the transition of GBS from a commensal organism to a virulent meningeal pathogen. PMID:20497331

  3. A Genetic Algorithm Based Support Vector Machine Model for Blood-Brain Barrier Penetration Prediction

    PubMed Central

    Zhang, Daqing; Xiao, Jianfeng; Zhou, Nannan; Zheng, Mingyue; Luo, Xiaomin; Jiang, Hualiang; Chen, Kaixian

    2015-01-01

    Blood-brain barrier (BBB) is a highly complex physical barrier determining what substances are allowed to enter the brain. Support vector machine (SVM) is a kernel-based machine learning method that is widely used in QSAR study. For a successful SVM model, the kernel parameters for SVM and feature subset selection are the most important factors affecting prediction accuracy. In most studies, they are treated as two independent problems, but it has been proven that they could affect each other. We designed and implemented genetic algorithm (GA) to optimize kernel parameters and feature subset selection for SVM regression and applied it to the BBB penetration prediction. The results show that our GA/SVM model is more accurate than other currently available log BB models. Therefore, to optimize both SVM parameters and feature subset simultaneously with genetic algorithm is a better approach than other methods that treat the two problems separately. Analysis of our log BB model suggests that carboxylic acid group, polar surface area (PSA)/hydrogen-bonding ability, lipophilicity, and molecular charge play important role in BBB penetration. Among those properties relevant to BBB penetration, lipophilicity could enhance the BBB penetration while all the others are negatively correlated with BBB penetration. PMID:26504797

  4. Electroporation of Brain Endothelial Cells on Chip toward Permeabilizing the Blood-Brain Barrier.

    PubMed

    Bonakdar, Mohammad; Wasson, Elisa M; Lee, Yong W; Davalos, Rafael V

    2016-01-19

    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

  5. Blood-brain barrier properties in vitro depend on composition and assembly of endogenous extracellular matrices.

    PubMed

    Zobel, Kathrin; Hansen, Uwe; Galla, Hans-Joachim

    2016-08-01

    Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), are enveloped by the extracellular matrix (ECM) produced by endothelial cells, pericytes and astrocytes. The contribution of matrix components secreted by the various cell types at the neurovascular unit, however, remains unclear with respect to their effect on endothelial barrier function. In this study, a new in vitro model was established by growing endothelial cells on an ECM produced by pericytes, astrocytes or a serial combination of both. The last-mentioned was found to be more in vivo-like. We investigated the role of the composition and morphology of ECM supra-structures in maintaining BBB function. The composition was analysed by protein analysis (enzyme-linked immunosorbent assay) and the ultrastructure of generated matrices was analysed by transmission electron microscopy including immunogold labelling. We could show by electric cell-substrate impedance sensing measurements that pericytes and combined matrices significantly improved the barrier tightness of porcine brain capillary endothelial cells (PBCEC). The increase of the resistance was verified by enhanced expression of tight junction proteins. Thus, for the first time, we have shown that barrier integrity is strictly controlled by the ECM, which is a product of all cells involved in the secretion of ECM components and their modification by corresponding cells. Moreover, we have demonstrated that complex matrices by the various cells of the BBB induce barrier marker enzymes in PBCEC, such as alkaline phosphatase. PMID:27053246

  6. Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier

    PubMed Central

    Villaseñor, Roberto; Ozmen, Laurence; Messaddeq, Nadia; Grüninger, Fiona; Loetscher, Hansruedi; Keller, Annika; Betsholtz, Christer; Freskgård, Per-Ola; Collin, Ludovic

    2016-01-01

    The Blood-Brain Barrier (BBB) restricts access of large molecules to the brain. The low endocytic activity of brain endothelial cells (BECs) is believed to limit delivery of immunoglobulins (IgG) to the brain parenchyma. Here, we report that endogenous mouse IgG are localized within intracellular vesicles at steady state in BECs in vivo. Using high-resolution quantitative microscopy, we found a fraction of endocytosed IgG in lysosomes. We observed that loss of pericytes (key components of the BBB) in pdgf-bret/ret mice affects the intracellular distribution of endogenous mouse IgG in BECs. In these mice, endogenous IgG was not detected within lysosomes but instead accumulate at the basement membrane and brain parenchyma. Such IgG accumulation could be due to reduced lysosomal clearance and increased sorting to the abluminal membrane of BECs. Our results suggest that, in addition to low uptake from circulation, IgG lysosomal degradation may be a downstream mechanism by which BECs further restrict IgG access to the brain. PMID:27149947

  7. 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

  8. 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

  9. Systemic delivery of blood-brain barrier-targeted polymeric nanoparticles enhances delivery to brain tissue.

    PubMed

    Saucier-Sawyer, Jennifer K; Deng, Yang; Seo, Young-Eun; Cheng, Christopher J; Zhang, Junwei; Quijano, Elias; Saltzman, W Mark

    2015-01-01

    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 (NPs) 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 NP 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 the NP 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 NP 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 NPs 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 NP transport across the BBB does not necessarily yield proportional pharmacological effects. PMID:26453169

  10. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity.

    PubMed

    Kunze, Reiner; Urrutia, Andrés; Hoffmann, Angelika; Liu, Hui; Helluy, Xavier; Pham, Mirko; Reischl, Stefan; Korff, Thomas; Marti, Hugo H

    2015-04-01

    Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema. PMID:25725349

  11. Oligodendrocyte Precursor Cells Support Blood-Brain Barrier Integrity via TGF-β Signaling

    PubMed Central

    Maeda, Mitsuyo; Miyamoto, Nobukazu; Liang, Anna C.; Hayakawa, Kazuhide; Pham, Loc-Duyen D.; Suwa, Fumihiko; Taguchi, Akihiko; Matsuyama, Tomohiro; Ihara, Masafumi; Kim, Kyu-Won; Lo, Eng H.; Arai, Ken

    2014-01-01

    Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity. PMID:25078775

  12. Reversible opening of the blood-brain barrier by anti-bacterial antibodies.

    PubMed Central

    Tuomanen, E I; Prasad, S M; George, J S; Hoepelman, A I; Ibsen, P; Heron, I; Starzyk, R M

    1993-01-01

    The leukocyte adhesion molecule CR3 (CD11b/CD18, Mac-1) promotes leukocyte transmigration into tissues by engaging an unknown cognate ligand on the surface of vascular endothelial cells. Filamentous hemagglutinin (FHA), an adhesin of the bacterium Bordetella pertussis, binds to CR3. We hypothesized that FHA mimics the native ligand for the CR3 integrin on endothelial cells and predicted that anti-FHA antibodies should bind to endothelial cells, interfere with leukocyte recruitment, and induce endothelial permeability. Anti-FHA monoclonal antibodies bound to cerebral microvessels in sections from human brain and upon intravenous injection into rabbits. Antibody binding correlated with the ability to recognize two polypeptides in extracts of human cerebral vessels that were also bound by CD18. In vivo, antibody binding not only interfered with transmigration of leukocytes into cerebrospinal fluid but also induced a dose-dependent reversible increase in blood-brain barrier permeability sufficient to improve delivery of intravenously administered therapeutic agents to brain parenchyma. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8102802

  13. Microfluidic organ-on-chip technology for blood-brain barrier research

    PubMed Central

    van der Helm, Marinke W; van der Meer, Andries D; Eijkel, Jan C T; van den Berg, Albert; Segerink, Loes I

    2016-01-01

    ABSTRACT Organs-on-chips are a new class of microengineered laboratory models that combine several of the advantages of current in vivo and in vitro models. In this review, we summarize the advances that have been made in the development of organ-on-chip models of the blood-brain barrier (BBBs-on-chips) and the challenges that are still ahead. The BBB is formed by specialized e3ndothelial cells and separates blood from brain tissue. It protects the brain from harmful compounds from the blood and provides homeostasis for optimal neuronal function. Studying BBB function and dysfunction is important for drug development and biomedical research. Microfluidic BBBs-on-chips enable real-time study of (human) cells in an engineered physiological microenvironment, for example incorporating small geometries and fluid flow as well as sensors. Examples of BBBs-on-chips in literature already show the potential of more realistic microenvironments and the study of organ-level functions. A key challenge in the field of BBB-on-chip development is the current lack of standardized quantification of parameters such as barrier permeability and shear stress. This limits the potential for direct comparison of the performance of different BBB-on-chip models to each other and existing models. We give recommendations for further standardization in model characterization and conclude that the rapidly emerging field of BBB-on-chip models holds great promise for further studies in BBB biology and drug development. PMID:27141422

  14. Role of Microfluidics in Blood-Brain Barrier Permeability Cell Culture Modeling: Relevance to CNS Disorders.

    PubMed

    Rusanov, Alexander L; Luzgina, Natalia G; Barreto, George E; Aliev, Gjumrakch

    2016-01-01

    In vitro modeling of the human blood-brain barrier (BBB) is critical for pre-clinical evaluation and predicting the permeability of newly developed potentially neurotoxic and neurotrophic drugs. Here we summarize the specific structural and functional features of endothelial cells as a key component of the BBB and compare analysis of different cell culture models in reflecting these features. Particular attention is paid to cellular models of the BBB in microfluidic devices capable of circulating nutrient media to simulate the blood flow of the brain. In these conditions, it is possible to reproduce a number of factors affecting endothelial cells under physiological conditions, including shear stress. In comparison with static cell models, concentration gradients, which determine the velocity of transport of substances, reproduce more accurately conditions of nutrient medium flow, since they eliminate the accumulation of substances near the basal membrane of cells, not typical for the situation in vivo. Co-cultivation of different types of cells forming the BBB, in separate cell chambers connected by microchannels, allows to evaluate the mutual influences of cells under normal conditions and when exposed to the test substance. New experimental possibilities that can be achieved through modeling of BBB in microfluidic devices determine the feasibility of their use in the practice for pre-clinical studies of novel drugs against neurodegenerative diseases. PMID:26831260

  15. Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders.

    PubMed

    Qosa, Hisham; Miller, David S; Pasinelli, Piera; Trotti, Davide

    2015-12-01

    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. This article is part of a Special Issue entitled SI: Neuroprotection. PMID:26187753

  16. Neuromodulation accompanying focused ultrasound-induced blood-brain barrier opening

    PubMed Central

    Chu, Po-Chun; Liu, Hao-Li; Lai, Hsin-Yi; Lin, Chung-Yin; Tsai, Hong-Chieh; Pei, Yu-Cheng

    2015-01-01

    Burst-mode focused ultrasound (FUS) induces microbubble cavitation in the vasculature and temporarily disrupts the blood-brain barrier (BBB) to enable therapeutic agent delivery. However, it remains unclear whether FUS-induced BBB opening is accompanied by neuromodulation. Here we characterized the functional effects of FUS-induced BBB opening by measuring changes in somatosensory evoked potentials (SSEPs) and blood-oxygen-level dependent (BOLD) responses. Rats underwent burst-mode FUS (mechanical index (MI) of 0.3, 0.55 or 0.8) to the forelimb region in the left primary somatosensory cortex to induce BBB opening. Longitudinal measurements were followed for up to 1 week to characterize the temporal dynamics of neuromodulation. We observed that 0.8-MI FUS profoundly suppressed SSEP amplitude and prolonged latency, and this effect lasted 7 days. 0.55-MI FUS resulted in minimal and short-term suppression of SSEP for less than 60 minutes and didn’t affect latency. BOLD responses were also suppressed in an MI-dependent manner, mirroring the effect on SSEPs. Furthermore, repetitive delivery of 0.55-MI FUS every 3 days elicited no accumulative effects on SSEPs or tissue integrity. This is the first evidence that FUS-induced BBB opening is accompanied by reversible changes in neuron responses, and may provide valuable insight toward the development of FUS-induced BBB opening for clinical applications. PMID:26490653

  17. 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

  18. Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-Brain Barrier Breakdown in Stroke

    PubMed Central

    Knowland, Daniel; Arac, Ahmet; Sekiguchi, Kohei; Hsu, Martin; Lutz, Sarah E.; Perrino, John; Steinberg, Gary K.; Barres, Ben A.; Nimmerjahn, Axel; Agalliu, Dritan

    2014-01-01

    SUMMARY Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a novel transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 h post-stroke, TJs display profound structural defects only after two days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 h post-stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke. PMID:24746419

  19. 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.

  20. Role of the blood-brain barrier in the nutrition of the central nervous system.

    PubMed

    Campos-Bedolla, Patricia; Walter, Fruzsina R; Veszelka, Szilvia; Deli, Mária A

    2014-11-01

    The blood-brain barrier (BBB) is a dynamic and complex interface between the blood and the central nervous system regulating brain homeostasis. Major functions of the BBB include the transport of nutrients and protection of the brain from toxic compounds. This review summarizes the most important transport pathways contributing to the nutrition of the brain. Carrier-mediated transport selectively delivers small molecules like sugars, amino acids, vitamins, and trace elements. Large biomolecules, lipoproteins, peptide and protein hormones cross the BBB by receptor-mediated transport. Active efflux transporters participate in the brain efflux of endogenous metabolites as well as toxins, xenobiotics and drugs. Dysfunction in the transport of nutrients at the BBB is described in several neurological disorders and diseases. The BBB penetration of neuroprotective nutrients, especially plant polyphenols and alkaloids, their potential protective effect on brain endothelium and the interaction of nutraceuticals with active efflux transporters at the BBB are discussed. In vitro BBB models to examine nutrient transport are also presented. PMID:25481827

  1. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury.

    PubMed

    Shlosberg, Dan; Benifla, Mony; Kaufer, Daniela; Friedman, Alon

    2010-07-01

    Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood-brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI. PMID:20551947

  2. The blood-brain barrier: geriatric relevance of a critical brain-body interface.

    PubMed

    Zeevi, Neer; Pachter, Joel; McCullough, Louise D; Wolfson, Leslie; Kuchel, George A

    2010-09-01

    The blood-brain barrier (BBB) represents the interface between the brain and other body tissues. Its ability to protect the brain from harmful compounds has attracted the attention of clinicians and investigators, but far from being a simple physical barrier, the BBB is a complex, heterogeneous, and dynamic tissue. The integrated function of the cerebral microvasculature, tight junction proteins, brain microvascular endothelial cells (BMECs), cellular transport pathways, and enzymatic machinery jointly contribute to normal BBB integrity. Aging, systemic diseases, and ischemic injury can disrupt these processes, resulting in a decline in overall BBB function and integrity. Based on the published literature, this study proposes that age- and disease-related BBB alterations play a key role in diminishing the ability of older patients to recover from acute ischemic stroke. Evidence linking deficits in the cerebral microvasculature and BBB integrity to dementia, medication-related cognitive decline, white matter disease (WMD or leukoaraiosis), and related geriatric syndromes including delirium, gait disorders, and urinary incontinence is also reviewed. Priority areas for a future research agenda include strategies to improve clinicians' ability to diagnose, prevent, and manage BBB abnormalities. In future years, in vivo measures such as functional and contrast-enhanced neuroimaging will be used to evaluate BBB integrity in older adults while also assessing the effectiveness of interventions, some targeting inflammatory pathways known to disrupt the BBB, for their ability to prevent or slow the progression of these complex multifactorial geriatric syndromes. PMID:20863334

  3. Oxidative stress and blood-brain barrier dysfunction under particular consideration of matrix metalloproteinases.

    PubMed

    Lehner, Christine; Gehwolf, Renate; Tempfer, Herbert; Krizbai, Istvan; Hennig, Bernhard; Bauer, Hans-Christian; Bauer, Hannelore

    2011-09-01

    A cell's "redox" (oxidation and reduction) state is determined by the sum of all redox processes yielding reactive oxygen species (ROS), reactive nitrogen species (RNS), and other reactive intermediates. Low amounts of ROS/RNS are generated by different mechanisms in every cell and are important regulatory mediators in many signaling processes (redox signaling). When the physiological balance between the generation and elimination of ROS/RNS is disrupted, oxidative/nitrosative stress with persistent oxidative damage of the organism occurs. Oxidative stress has been suggested to act as initiator and/or mediator of many human diseases. The cerebral vasculature is particularly susceptible to oxidative stress, which is critical since cerebral endothelial cells play a major role in the creation and maintenance of the blood-brain barrier (BBB). This article will only contain a focused introduction on the biochemical background of redox signaling, since this has been reported already in a series of excellent recent reviews. The goal of this work is to increase the understanding of basic mechanisms underlying ROS/RNS-induced BBB disruption, with a focus on the role of matrix metalloproteinases, which, after all, appear to be a key mediator in the initiation and progression of BBB damage elicited by oxidative stress. PMID:21294658

  4. Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier.

    PubMed

    Villaseñor, Roberto; Ozmen, Laurence; Messaddeq, Nadia; Grüninger, Fiona; Loetscher, Hansruedi; Keller, Annika; Betsholtz, Christer; Freskgård, Per-Ola; Collin, Ludovic

    2016-01-01

    The Blood-Brain Barrier (BBB) restricts access of large molecules to the brain. The low endocytic activity of brain endothelial cells (BECs) is believed to limit delivery of immunoglobulins (IgG) to the brain parenchyma. Here, we report that endogenous mouse IgG are localized within intracellular vesicles at steady state in BECs in vivo. Using high-resolution quantitative microscopy, we found a fraction of endocytosed IgG in lysosomes. We observed that loss of pericytes (key components of the BBB) in pdgf-b(ret/ret) mice affects the intracellular distribution of endogenous mouse IgG in BECs. In these mice, endogenous IgG was not detected within lysosomes but instead accumulate at the basement membrane and brain parenchyma. Such IgG accumulation could be due to reduced lysosomal clearance and increased sorting to the abluminal membrane of BECs. Our results suggest that, in addition to low uptake from circulation, IgG lysosomal degradation may be a downstream mechanism by which BECs further restrict IgG access to the brain. PMID:27149947

  5. Pathways for Small Molecule Delivery to the Central Nervous System Across the Blood-Brain Barrier

    PubMed Central

    Mikitsh, John L; Chacko, Ann-Marie

    2014-01-01

    The treatment of central nervous system (CNS) disease has long been difficult due to the ineffectiveness of drug delivery across the blood-brain barrier (BBB). This review summarizes important concepts of the BBB in normal versus pathophysiology and how this physical, enzymatic, and efflux barrier provides necessary protection to the CNS during drug delivery, and consequently treatment challenging. Small molecules account for the vast majority of available CNS drugs primarily due to their ability to penetrate the phospholipid membrane of the BBB by passive or carrier-mediated mechanisms. Physiochemical and biological factors relevant for designing small molecules with optimal capabilities for BBB permeability are discussed, as well as the most promising classes of transporters suitable for small-molecule drug delivery. Clinically translatable imaging methodologies for detecting and quantifying drug uptake and targeting in the brain are discussed as a means of further understanding and refining delivery parameters for both drugs and imaging probes in preclinical and clinical domains. This information can be used as a guide to design drugs with preserved drug action and better delivery profiles for improved treatment outcomes over existing therapeutic approaches. PMID:24963272

  6. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells

    PubMed Central

    Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F.; Robert, Stephanie M.; Ellis-Davies, Graham; Sontheimer, Harald

    2014-01-01

    Astrocytic endfeet cover the entire cerebral vasculature and serve as exchange sites for ions, metabolites, and energy substrates from the blood to the brain. They maintain endothelial tight junctions that form the blood-brain barrier (BBB) and release vasoactive molecules that regulate vascular tone. Malignant gliomas are highly invasive tumors that use the perivascular space for invasion and co-opt existing vessels as satellite tumors form. Here we use a clinically relevant mouse model of glioma and find that glioma cells, as they populate the perivascular space of pre-existing vessels, displace astrocytic endfeet from endothelial or vascular smooth muscle cells. This causes a focal breach in the BBB. Furthermore, astrocyte-mediated gliovascular coupling is lost, and glioma cells seize control over regulation of vascular tone through Ca2+-dependent release of K+. These findings have important clinical implications regarding blood flow in the tumor-associated brain and the ability to locally deliver chemotherapeutic drugs in disease. PMID:24943270

  7. 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

  8. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity

    PubMed Central

    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.

    2015-01-01

    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 down-regulation 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 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 IFN-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. PMID:26523970

  9. Angiogenesis of the blood-brain barrier in vitro and the function of cerebral pericytes.

    PubMed

    Ramsauer, Markus; Krause, Dorothee; Dermietzel, Rolf

    2002-08-01

    Cerebral pericytes constitute an essential component of the blood-brain barrier (BBB) and are involved in blood vessel assembly. Recently, we reported on the induction of a BBB-specific enzyme expressed by cerebral pericytes (pericytic aminopeptidase N/pAPN) in coculture with cerebral endothelial cells. We completed this in vitro BBB system by adding astrocytes to these mixed cultures of endothelial cells and pericytes. Under these triculture conditions, endothelial cells and pericytes reorganize into capillary-like structures (CLSs). Capillary formation can also be achieved by the application of transforming growth factor beta 1 (TGF-b1) in the culture medium of endothelial-pericyte cultures lacking astrocytes. In contrast to the effect achieved by astrocytes, pericytes did not assemble with endothelial cells. In both cases (application of astrocytes or TGF-b1), endothelial cells underwent apoptosis. However, endothelial cells that form CLSs in the presence of pericytes appeared to be resistant to induction of apoptosis. On the basis of these observations, we concluded that astrocytes have a profound influence on the morphogenetic events underlying the organization of the vessel wall; that the effect of TGF-b1 is different from the astrocytic effect because it lacks induction of endothelial-pericyte association; and that pericytes stabilize CLSs formed by endothelial cells in coculture with astrocytes. PMID:12153997

  10. Evolution of blood-brain barrier damage associated with changes in brain metabolites following acute ischemia.

    PubMed

    Yan, Gen; Xuan, Yinghua; Dai, Zhuozhi; Zhang, Guishan; Xu, Haiyun; Mikulis, David; Wu, Renhua

    2015-11-11

    Stroke is a serious medical condition that requires emergency care. In the case of ischemic stroke, ischemia may lead to damage to the blood-brain barrier (BBB); the damage in turn may exacerbate the condition. Therefore, noninvasive detection of BBB damage represents a challenge for experimental and clinical researchers. In this study, we assessed the onset of BBB disruption by means of T1-weighted images with administration of the contrast enhancement agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and related BBB breakdown to brain metabolite changes in proton magnetic resonance spectrum (H-MRS) in the infarcted site following middle cerebral artery occlusion (MCAO) in rats. It was shown that MCAO for 30 min and 1.5 h caused no Gd-DTPA signal change in the T1-weighted images, whereas MCAO for 1 h significantly altered some of H-MRS brain metabolites, suggesting that brain metabolite changes occurred earlier than BBB damage after ischemic stroke. MCAO for 2 h caused BBB breakdown, which was related to changes in the levels of some brain metabolites detected by H-MRS. Between the second and the third hour after MCAO, brain metabolite changes continued as the result of BBB breakdown and the concurrent overperfusion to the infarcted site, which may ameliorate the metabolite changes, thus compensating for the functional failures of the brain after stroke. PMID:26366833

  11. Blood-brain barrier transport of choline is reduced in the aged rat.

    PubMed

    Mooradian, A D

    1988-02-01

    An age-related impairment in choline transport across the blood-brain barrier (BBB) may contribute to the cholinergic mechanisms of geriatric memory dysfunction. To test this hypothesis, the brain choline uptake in male Fisher 344 rats at 2, 18 and 24 months of age was studied using the Oldendorf technique. The Vmax of choline transport in the 24-month-old rats (0.05 +/- 0.04 nmol/min/g) was significantly lower than that in the 2-month-old rat (2.5 +/- 1.0 nmol/min/g) (P less than 0.05). The Km of transport in old rats (13 +/- 35 microM) was also significantly smaller than the value in 24-month-old rats (450 +/- 195 microM), while the constant of the non-saturable component of the transport, Kd, was not significantly different in older rats (1.2 +/- 0.3 vs 0.6 +/- 0.1 microliter/min/g). These results indicate that the carrier in old rats has reduced capacity and increased affinity to choline. The reduced choline carrier capacity explains the significant decrease in BBB choline transport in aged rats. PMID:3359216

  12. Blood-Brain Barrier Alterations Provide Evidence of Subacute Diaschisis in an Ischemic Stroke Rat Model

    PubMed Central

    Garbuzova-Davis, Svitlana; Rodrigues, Maria C. O.; Hernandez-Ontiveros, Diana G.; Tajiri, Naoki; Frisina-Deyo, Aric; Boffeli, Sean M.; Abraham, Jerry V.; Pabon, Mibel; Wagner, Andrew; Ishikawa, Hiroto; Shinozuka, Kazutaka; Haller, Edward; Sanberg, Paul R.; Kaneko, Yuji; Borlongan, Cesario V.

    2013-01-01

    Background Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB) competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas. Methodology/Principal Findings In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO), significant BBB alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices. Conclusions/Significance These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke. PMID:23675488

  13. A Quantitative MRI Method for Imaging Blood-Brain Barrier Leakage in Experimental Traumatic Brain Injury

    PubMed Central

    Watts, Lora Talley; Jiang, Zhao; Shen, Qiang; Li, Yunxia; Duong, Timothy Q.

    2014-01-01

    Blood-brain barrier (BBB) disruption is common following traumatic brain injury (TBI). Dynamic contrast enhanced (DCE) MRI can longitudinally measure the transport coefficient Ktrans which reflects BBB permeability. Ktrans measurements however are not widely used in TBI research because it is generally considered to be noisy and possesses low spatial resolution. We improved spatiotemporal resolution and signal sensitivity of Ktrans MRI in rats by using a high-sensitivity surface transceiver coil. To overcome the signal drop off profile of the surface coil, a pre-scan module was used to map the flip angle (B1 field) and magnetization (M0) distributions. A series of T1-weighted gradient echo images were acquired and fitted to the extended Kety model with reversible or irreversible leakage, and the best model was selected using F-statistics. We applied this method to study the rat brain one hour following controlled cortical impact (mild to moderate TBI), and observed clear depiction of the BBB damage around the impact regions, which matched that outlined by Evans Blue extravasation. Unlike the relatively uniform T2 contrast showing cerebral edema, Ktrans shows a pronounced heterogeneous spatial profile in and around the impact regions, displaying a nonlinear relationship with T2. This improved Ktrans MRI method is also compatible with the use of high-sensitivity surface coil and the high-contrast two-coil arterial spin-labeling method for cerebral blood flow measurement, enabling more comprehensive investigation of the pathophysiology in TBI. PMID:25478693

  14. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

    PubMed

    Lopez-Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Simpson, Julie E; Reijerkerk, Arie; King-Robson, Josh; Kay, Oliver; de Vries, Helga E; Hirst, Mark C; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J; Romero, Ignacio Andres

    2014-06-01

    Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders. PMID:24604078

  15. Blood-brain barrier dysfunction after primary blast injury in vitro.

    PubMed

    Hue, Christopher D; Cao, Siqi; Haider, Syed F; Vo, Kiet V; Effgen, Gwen B; Vogel, Edward; Panzer, Matthew B; Bass, Cameron R Dale; Meaney, David F; Morrison, Barclay

    2013-10-01

    The incidence of blast-induced traumatic brain injury (bTBI) has increased substantially in recent military conflicts. However, the consequences of bTBI on the blood-brain barrier (BBB), a specialized cerebrovascular structure essential for brain homeostasis, remain unknown. In this study, we utilized a shock tube driven by compressed gas to generate operationally relevant, ideal pressure profiles consistent with improvised explosive devices (IEDs). By multiple measures, the barrier function of an in vitro BBB model was disrupted following exposure to a range of controlled blast loading conditions. Trans-endothelial electrical resistance (TEER) decreased acutely in a dose-dependent manner that was most strongly correlated with impulse, as opposed to peak overpressure or duration. Significantly increased hydraulic conductivity and solute permeability post-injury further confirmed acute alterations in barrier function. Compromised ZO-1 immunostaining identified a structural basis for BBB breakdown. After blast exposure, TEER remained significantly depressed 2 days post-injury, followed by spontaneous recovery to pre-injury control levels at day 3. This study is the first to report immediate disruption of an in vitro BBB model following primary blast exposure, which may be important for the development of novel helmet designs to help mitigate the effects of blast on the BBB. PMID:23581482

  16. Vascular Endothelial Growth Factors Enhance the Permeability of the Mouse Blood-brain Barrier

    PubMed Central

    Jiang, Shize; Xia, Rui; Jiang, Yong; Wang, Lei; Gao, Fabao

    2014-01-01

    The blood-brain barrier (BBB) impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS) drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF) on BBB permeability in Kunming (KM) mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse), while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI). Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001). Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI) or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS. PMID:24551038

  17. Borrelia burgdorferi, Host-Derived Proteases, and the Blood-Brain Barrier

    PubMed Central

    Grab, Dennis J.; Perides, George; Dumler, J. Stephen; Kim, Kee Jun; Park, Jinho; Kim, Yuri V.; Nikolskaia, Olga; Choi, Kyoung Seong; Stins, Monique F.; Kim, Kwang Sik

    2005-01-01

    Neurological manifestations of Lyme disease in humans are attributed in part to penetration of the blood-brain barrier (BBB) and invasion of the central nervous system (CNS) by Borrelia burgdorferi. However, how the spirochetes cross the BBB remains an unresolved issue. We examined the traversal of B. burgdorferi across the human BBB and systemic endothelial cell barriers using in vitro model systems constructed of human brain microvascular endothelial cells (BMEC) and EA.hy 926, a human umbilical vein endothelial cell (HUVEC) line grown on Costar Transwell inserts. These studies showed that B. burgdorferi differentially crosses human BMEC and HUVEC and that the human BMEC form a barrier to traversal. During the transmigration by the spirochetes, it was found that the integrity of the endothelial cell monolayers was maintained, as assessed by transendothelial electrical resistance measurements at the end of the experimental period, and that B. burgdorferi appeared to bind human BMEC by their tips near or at cell borders, suggesting a paracellular route of transmigration. Importantly, traversal of B. burgdorferi across human BMEC induces the expression of plasminogen activators, plasminogen activator receptors, and matrix metalloproteinases. Thus, the fibrinolytic system linked by an activation cascade may lead to focal and transient degradation of tight junction proteins that allows B. burgdorferi to invade the CNS. PMID:15664945

  18. TLR4 induces CCR7-dependent monocytes transmigration through the blood-brain barrier.

    PubMed

    Paradis, Alexandre; Bernier, Stéphane; Dumais, Nancy

    2016-06-15

    In this study, we examined whether bacterial pathogen-associated molecular patterns recognized by toll-like receptors (TLRs) can modify the CCR7-dependent migration of human monocytes. MonoMac-1 (MM-1) cells and freshly isolated human monocytes were cultivated in the presence of agonists for TLR4 (which senses lipopolysaccharides from gram-negative bacteria), TLR1/2 (which senses peptidoglycan from gram-positive bacteria), and TLR9 (which recognizes bacterial DNA rich in unmethylated CpG DNA). CCR7 mRNA transcription was measured using quantitative reverse transcription polymerase chain reaction and protein expression was examined using flow cytometry. CCR7 function was monitored using migration and transmigration assays in response to CCL19/CCL21, which are natural ligands for CCR7. Our results show that TLR4 strongly increases monocyte migratory capacity in response to CCL19 in chemotaxis and transmigration assays in a model that mimics the human blood-brain barrier, whereas TLR1/2 and 9 have no effect. Examination of monocyte migration in response to TLRs that are activated by bacterial components would contribute to understanding the excessive monocyte migration that characterizes the pathogenesis of bacterial infections and/or neuroinflammatory diseases. PMID:27235343

  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. PMID:26920424

  20. Membrane configuration optimization for a murine in vitro blood-brain barrier model.

    PubMed

    Wuest, Diane M; Wing, Allison M; Lee, Kelvin H

    2013-01-30

    A powerful experimental tool used to study the dynamic functions of the blood-brain barrier (BBB) is an in vitro cellular based system utilizing cell culture inserts in multi-well plates. Currently, usage of divergent model configurations without explanation of selected variable set points renders data comparisons difficult and limits widespread understanding. This work presents for the first time in literature a comprehensive screening study to optimize membrane configuration, with aims to unveil influential membrane effects on the ability of cerebral endothelial cells to form a tight monolayer. First, primary murine brain endothelial cells and astrocytes were co-cultured in contact and non-contact orientations on membranes of pore diameter sizes ranging from 0.4 μm to 8.0 μm, and the non-contact orientation and smallest pore diameter size were shown to support a significantly tighter monolayer formation. Then, membranes made from polyethylene terephthalate (PET) and polycarbonate (PC) purchased from three different commercial sources were compared, and PET membranes purchased from two manufacturers facilitated a significantly tighter monolayer formation. Models were characterized by transendothelial electrical resistance (TEER), sodium fluorescein permeability, and immunocytochemical labeling of tight junction proteins. Finally, a murine brain endothelial cell line, bEnd.3, was grown on the different membranes, and similar results were obtained with respect to optimal membrane configuration selection. The results and methodology presented here on high throughput 24-well plate inserts can be translated to other BBB systems to advance model understanding. PMID:23131353

  1. Endothelial cell heterogeneity of blood-brain barrier gene expression along the cerebral microvasculature.

    PubMed

    Macdonald, Jennifer A; Murugesan, Nivetha; Pachter, Joel S

    2010-05-15

    The blood-brain barrier (BBB) refers to the network of microvessels that selectively restricts the passage of substances between the circulation and the central nervous system (CNS). This microvascular network is comprised of arterioles, capillaries and venules, yet the respective contribution of each of these to the BBB awaits clarification. In this regard, it has been postulated that brain microvascular endothelial cells (BMEC) from these different tributaries might exhibit considerable heterogeneity in form and function, with such diversity underlying unique roles in physiological and pathophysiological processes. Means to begin exploring such endothelial differences in situ, free from caveats associated with cell isolation and culturing procedures, are crucial to comprehending the nature and treatment of CNS diseases with vascular involvement. Here, the recently validated approach of immuno-laser capture microdissection (immuno-LCM) coupled to quantitative real-time PCR (qRT-PCR) was used to analyze gene expression patterns of BMEC retrieved in situ from either capillaries or venules. From profiling 87 genes known to play a role in BBB function and/or be enriched in isolated brain microvessels, results imply that most BBB properties reside in both segments, but that capillaries preferentially express some genes related to solute transport, while venules tend toward higher expression of an assortment of genes involved in inflammatory-related tasks. Fuller appreciation of such heterogeneity will be critical for efficient therapeutic targeting of the endothelium and the management of CNS disease. PMID:20025060

  2. Blood-brain barrier dysfunction in disorders of the developing brain.

    PubMed

    Moretti, Raffaella; Pansiot, Julien; Bettati, Donatella; Strazielle, Nathalie; Ghersi-Egea, Jean-François; Damante, Giuseppe; Fleiss, Bobbi; Titomanlio, Luigi; Gressens, Pierre

    2015-01-01

    Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data. PMID:25741233

  3. Blood-brain barrier proteomics: towards the understanding of neurodegenerative diseases.

    PubMed

    Karamanos, Yannis; Gosselet, Fabien; Dehouck, Marie-Pierre; Cecchelli, Roméo

    2014-11-01

    The blood-brain barrier (BBB) regulates the passage of endogenous and exogenous compounds and thus contributes to the brain homeostasis with the help of well-known proteins such as tight junction proteins, plasma membrane transporters and metabolic barrier proteins. In the last decade, proteomics have emerged as supplementary tools for BBB research. The development of proteomic technologies has provided several means to extend knowledge on the BBB and to investigate additional routes for the bypass of this barrier. Proteomics approaches have been used in vivo and also using in vitro BBB models to decipher the physiological characteristics and, under stress conditions, to understand the molecular mechanisms of brain diseases. This work has demonstrated that both quantitative global and targeted proteomics approaches are powerful and provide significant information on the brain microvessel endothelium. However, current knowledge is only partial and it is necessary to increase the studies using proteomics tools that will provide additional information concerning brain pathologies or BBB metabolism. Highly sensitive, accurate and specific protein quantification by quantitative targeted proteomics appears as an essential methodology for human BBB studies. PMID:25446619

  4. Scutellaria baicalensis attenuates blood-brain barrier disruption after intracerebral hemorrhage in rats.

    PubMed

    Shin, Jung-Won; Kang, Ho-Chang; Shim, Jaewon; Sohn, Nak-Won

    2012-01-01

    Disruption of the blood-brain barrier (BBB) contributes to the inflammatory response and edema formation in the brain, exacerbating brain damage. The present study evaluated the effects of Scutellaria baicalensis (SR) water extracts on BBB disruption after intracerebral hemorrhage (ICH) in rats. ICH was induced by stereotaxic intrastriatal injection of bacterial type VII collagenase, and SR was administrated orally three times (50 mg/ml/kg) during the 48 h after ICH onset. SR treatment significantly reduced the degree of (1) hemorrhage volume and edema percentage of the ipsilateral hemisphere, (2) brain water content, (3) MPO-positive neutrophil infiltration in the peri-hematoma, and (4) BBB permeability measured by Evans blue leakage. In addition, expression of matrix metalloproteinase (MMP)-9, MMP-12, and tissue inhibitor of MMPs (TIMP)-1 were investigated with immunohistochemistry. SR treatment reduced MMP-9 and MMP-12 expression in the peri-hematoma after ICH. These results indicate that SR attenuates the BBB disruption through anti-inflammatory effects and suppression of MMP expression. These findings provide a pharmacological basis for the use of SR in the treatment of the BBB disruption following stroke and trauma. PMID:22298450

  5. Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance.

    PubMed

    Zhao, Zhen; Sagare, Abhay P; Ma, Qingyi; Halliday, Matthew R; Kong, Pan; Kisler, Kassandra; Winkler, Ethan A; Ramanathan, Anita; Kanekiyo, Takahisa; Bu, Guojun; Owens, Nelly Chuqui; Rege, Sanket V; Si, Gabriel; Ahuja, Ashim; Zhu, Donghui; Miller, Carol A; Schneider, Julie A; Maeda, Manami; Maeda, Takahiro; Sugawara, Tohru; Ichida, Justin K; Zlokovic, Berislav V

    2015-07-01

    PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided Aβ trafficking to Rab5 and Rab11, leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance, which has implications for Aβ brain homeostasis and clearance therapy. PMID:26005850

  6. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.

    PubMed

    Smith, Ernest S; Jonason, Alan; Reilly, Christine; Veeraraghavan, Janaki; Fisher, Terrence; Doherty, Michael; Klimatcheva, Ekaterina; Mallow, Crystal; Cornelius, Chad; Leonard, John E; Marchi, Nicola; Janigro, Damir; Argaw, Azeb Tadesse; Pham, Trinh; Seils, Jennifer; Bussler, Holm; Torno, Sebold; Kirk, Renee; Howell, Alan; Evans, Elizabeth E; Paris, Mark; Bowers, William J; John, Gareth; Zauderer, Maurice

    2015-01-01

    Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit. PMID:25461192

  7. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier.

    PubMed

    Wolburg, Hartwig; Noell, Susan; Wolburg-Buchholz, Karen; Mack, Andreas; Fallier-Becker, Petra

    2009-04-01

    The blood-brain barrier (BBB) does not exclusively refer to brain endothelial cells, which are the site of the barrier proper. In the past few years, it has become increasingly clear that BBB endothelial cells depend considerably on the brain microenvironment to a degree exceeding the environmental influence in other organs. The concept of the BBB has been continuously developed over the decades, culminating now in the recognition that endothelial cell function in the brain is not limited to simply mediating energy and oxygen transfer between blood and neural tissue. Endothelial cells are rather "Janus-headed beings" that are active partners of both luminal molecules and cells, as well as subendothelial cells such as pericytes, astrocytes, and neurons. In this overview, the authors present and discuss both the role of astroglial cells in managing the BBB and aspects of pathological alterations in the brain as far as the BBB is involved. After a brief introduction of the BBB that describes the structure and function of the brain capillary endothelial cells, the authors report on both the water channel protein aquaporin-4 (AQP4) in astrocytes and the extracellular matrix between astrocytes/pericytes and endothelial cells. The AQP4 has an important impact on the homeostasis in the brain parenchyma; however, the mechanistic cascade from the composition of the astrocyte membrane to the maintenance of BBB properties in the endothelial cells, including their tight junction formation, is still completely unknown. PMID:19307424

  8. CB2 Receptor Activation Inhibits Melanoma Cell Transmigration through the Blood-Brain Barrier

    PubMed Central

    Haskó, János; Fazakas, Csilla; Molnár, Judit; Nyúl-Tóth, Ádám; Herman, Hildegard; Hermenean, Anca; Wilhelm, Imola; Persidsky, Yuri; Krizbai, István A.

    2014-01-01

    During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB). The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2); therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A), GPR18 (transcriptional variant 1) and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A), GPR18 (transcriptional variants 1 and 2), GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma. PMID:24815068

  9. Pyruvate blocks blood-brain barrier disruption, lymphocyte infiltration and immune response in excitotoxic brain injury

    PubMed Central

    Ryu, Jae K; McLarnon, James G

    2016-01-01

    The effects of pyruvate, the end metabolite of glycolysis, on blood-brain barrier (BBB) impairment and immune reactivity were examined in the quinolinic acid (QA)-injected rat striatum. Extensive disruption of BBB was observed at 7 d post QA-injection as demonstrated by increased immunohistochemical staining using antibody against immunoglobulin G (IgG). Animals receiving pyruvate administration (500 mg/kg) with QA-injection exhibited reduced lgG immunoreactivity (by 45%) relative to QA alone. QA intrastriatal injection also resulted in marked increases in the number of infiltrating T-lymphocytes (by 70-fold) and expression of major histocompatibility complex (MHC-class II) (by 45-fold) relative to unlesioned control. Treatment with pyruvate significantly reduced infiltration of T-cells (by 68%) and MHC class II expression (by 48%) induced by QA. These results indicate that QA injection into rat striatum leads to impairment in BBB function with pyruvate administration reducing immune response and BBB leakiness in excitotoxic injury. PMID:27073744

  10. 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

  11. Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity.

    PubMed

    Banks, W A

    2001-01-01

    Leptin has emerged as a major regulator of adiposity. Leptin is released into the blood from fat cells and circulates to the brain where it crosses the blood-brain barrier (BBB) to act at receptors within the central nervous system to affect appetite, thermogenesis, and a number of other actions. In humans and in many rodent models, resistance to leptin appears to be a chief cause of obesity. Determining the cause of leptin resistance is fundamental to developing strategies for the use of leptin in obesity. The literature characterizing the transport of leptin across the BBB is reviewed. This literature strongly suggests that the cause of leptin resistance is due a decreased transport of leptin across the BBB in obese humans and rodents. The main cause of this resistance appears to be an impairment in the activity of the transporter rather than just simply saturation at higher doses. Strategies to overcome impaired BBB transport are reviewed, including the use of allosteric regulators and the delivery of material by the intrathecal route. PMID:11172704

  12. Regulation of ABC transporters blood-brain barrier: the good, the bad, and the ugly.

    PubMed

    Miller, David S

    2015-01-01

    The brain capillary endothelial cells that constitute the blood-brain barrier express multiple ABC transport proteins on the luminal, blood-facing, plasma membrane. These transporters function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites. High expression of these ABC transporters at the barrier is a major obstacle to the delivery of therapeutics, including chemotherapeutics, to the CNS. Here, I review the signals that alter ABC transporter expression and transport function with an emphasis on P-glycoprotein, Mrp2, and breast cancer resistance protein (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced (potentially bad and ugly). In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways that involve events in and on the brain capillary endothelial cells. Targeting these signaling events provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are substrates for the transporters (potentially good). The clinical usefulness of targeting signaling to reduce efflux transporter activity and improve drug delivery to the CNS remains to be established. PMID:25640266

  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. 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.

  15. 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

  16. Flux Partitioning by Isotopic Eddy Covariance

    NASA Astrophysics Data System (ADS)

    Wehr, R.; Munger, J. W.; Nelson, D. D.; McManus, J. B.; Zahniser, M. S.; Wofsy, S. C.; Saleska, S. R.

    2011-12-01

    Net ecosystem-atmosphere exchange of CO2 is routinely measured by eddy covariance at sites around the world, but studies of ecosystem processes are more interested in the gross photosynthetic and respiratory fluxes that comprise the net flux. The standard method of partitioning the net flux into these components has been to extrapolate nighttime respiration into daytime based on a relationship between nighttime respiration, temperature, and sometimes moisture. However, such relationships generally account for only a small portion of the variation in nighttime respiration, and the assumption that they can predict respiration throughout the day is dubious. A promising alternate method, known as isotopic flux partitioning, works by identifying the stable isotopic signatures of photosynthesis and respiration in the CO2 flux. We have used this method to partition the net flux at Harvard Forest, MA, based on eddy covariance measurements of the net 12CO2 and 13CO2 fluxes (as well as measurements of the sensible and latent heat fluxes and other meteorological variables). The CO2 isotopologues were measured at 4 Hz by an Aerodyne quantum cascade laser spectrometer with a δ13C precision of 0.4 % in 0.25 sec and 0.02 % in 100 sec. In the absence of such high-frequency, high-precision isotopic measurements, past attempts at isotopic flux partitioning have combined isotopic flask measurements with high-frequency (total) CO2 measurements to estimate the isoflux (the EC/flask approach). Others have used a conditional flask sampling approach called hyperbolic relaxed eddy accumulation (HREA). We 'sampled' our data according to each of these approaches, for comparison, and found disagreement in the calculated fluxes of ~10% for the EC/flask approach, and ~30% for HREA, at midday. To our knowledge, this is the first example of flux partitioning by isotopic eddy covariance. Wider use of this method, enabled by a new generation of laser spectrometers, promises to open a new window

  17. 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.

  18. 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. PMID:26706177

  19. Specific and straightforward molecular investigation of β-thalassemia mutations in the Malaysian Malays and Chinese using direct TaqMan genotyping assays.

    PubMed

    Kho, S L; Chua, K H; George, E; Tan, J A M A

    2013-01-01

    Beta-thalassemia is a life-threatening inherited blood disorder. Rapid characterization of β-globin gene mutations is necessary because of the high frequency of Malaysian β-thalassemia carriers. A combination real-time polymerase chain reaction genotyping assay using TaqMan probes was developed to confirm β-globin gene mutations. In this study, primers and probes were designed to specifically identify 8 common β-thalassemia mutations in the Malaysian Malay and Chinese ethnic groups using the Primer Express software. "Blind tests" using DNA samples from healthy individuals and β-thalassemia patients with different genotypes were performed to determine the specificity and sensitivity of this newly designed assay. Our results showed 100% sensitivity and specificity for this novel assay. In conclusion, the TaqMan genotyping assay is a straightforward assay that allows detection of β-globin gene mutations in less than 40 min. The simplicity and reproducibility of the TaqMan genotyping assay permit its use in laboratories as a rapid and cost-effective diagnostic tool for confirmation of common β-thalassemia mutations in Malaysia. PMID:23479149

  20. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24638041

  2. 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

    2014-01-01

    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. PMID:24638041

  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. PMID:25470456

  4. 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.

  5. 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.

  6. A Partitioning Algorithm for Block-Diagonal Matrices With Overlap

    SciTech Connect

    Guy Antoine Atenekeng Kahou; Laura Grigori; Masha Sosonkina

    2008-02-02

    We present a graph partitioning algorithm that aims at partitioning a sparse matrix into a block-diagonal form, such that any two consecutive blocks overlap. We denote this form of the matrix as the overlapped block-diagonal matrix. The partitioned matrix is suitable for applying the explicit formulation of Multiplicative Schwarz preconditioner (EFMS) described in [3]. The graph partitioning algorithm partitions the graph of the input matrix into K partitions, such that every partition {Omega}{sub i} has at most two neighbors {Omega}{sub i-1} and {Omega}{sub i+1}. First, an ordering algorithm, such as the reverse Cuthill-McKee algorithm, that reduces the matrix profile is performed. An initial overlapped block-diagonal partition is obtained from the profile of the matrix. An iterative strategy is then used to further refine the partitioning by allowing nodes to be transferred between neighboring partitions. Experiments are performed on matrices arising from real-world applications to show the feasibility and usefulness of this approach.

  7. BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease.

    PubMed

    Devraj, Kavi; Poznanovic, Slobodan; Spahn, Christoph; Schwall, Gerhard; Harter, Patrick N; Mittelbronn, Michel; Antoniello, Katia; Paganetti, Paolo; Muhs, Andreas; Heilemann, Mike; Hawkins, Richard A; Schrattenholz, André; Liebner, Stefan

    2016-07-01

    Endothelial cells of the blood-brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood-brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer's disease, current treatment approaches include inhibitors of BACE-1 (β-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic β-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood-brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D-dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer's disease mouse model we show that BACE-1 is upregulated at the blood-brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood-brain barrier in β-amyloid generation and in vascular aspects of Alzheimer's disease, particularly in the development of cerebral amyloid angiopathy. PMID:26661166

  8. Knowledge base rule partitioning design for CLIPS

    NASA Technical Reports Server (NTRS)

    Mainardi, Joseph D.; Szatkowski, G. P.

    1990-01-01

    This describes a knowledge base (KB) partitioning approach to solve the problem of real-time performance using the CLIPS AI shell when containing large numbers of rules and facts. This work is funded under the joint USAF/NASA Advanced Launch System (ALS) Program as applied research in expert systems to perform vehicle checkout for real-time controller and diagnostic monitoring tasks. The Expert System advanced development project (ADP-2302) main objective is to provide robust systems responding to new data frames of 0.1 to 1.0 second intervals. The intelligent system control must be performed within the specified real-time window, in order to meet the demands of the given application. Partitioning the KB reduces the complexity of the inferencing Rete net at any given time. This reduced complexity improves performance but without undo impacts during load and unload cycles. The second objective is to produce highly reliable intelligent systems. This requires simple and automated approaches to the KB verification & validation task. Partitioning the KB reduces rule interaction complexity overall. Reduced interaction simplifies the V&V testing necessary by focusing attention only on individual areas of interest. Many systems require a robustness that involves a large number of rules, most of which are mutually exclusive under different phases or conditions. The ideal solution is to control the knowledge base by loading rules that directly apply for that condition, while stripping out all rules and facts that are not used during that cycle. The practical approach is to cluster rules and facts into associated 'blocks'. A simple approach has been designed to control the addition and deletion of 'blocks' of rules and facts, while allowing real-time operations to run freely. Timing tests for real-time performance for specific machines under R/T operating systems have not been completed but are planned as part of the analysis process to validate the design.

  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. Entanglement concentration of three-partite states

    SciTech Connect

    Groisman, Berry; Linden, Noah; Popescu, Sandu

    2005-12-15

    We investigate the concentration of multiparty entanglement by focusing on a simple family of three-partite pure states, superpositions of Greenberger-Horne-Zeilinger states and singlets. Despite the simplicity of the states, we show that they cannot be reversibly concentrated by the standard entanglement concentration procedure, to which they seem ideally suited. Our results cast doubt on the idea that for each N there might be a finite set of N-party states into which any pure state can be reversibly transformed. We further relate our results to the concept of locking of entanglement of formation.

  11. 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.

  12. Evaporative partitioning in a unified land model

    NASA Astrophysics Data System (ADS)

    Livneh, B.; Lettenmaier, D. P.; Restrepo, P. J.

    2009-12-01

    Accurate partitioning of precipitation into evapotranspiration and runoff, and more generally estimation of the surface water balance, is crucial both for hydrologic forecasting and numerical weather and climate prediction. One important aspect of this issue is the partitioning of evapotranspiration into soil evaporation, canopy evaporation, and plant transpiration, which in turn has implications for other terms in the surface water balance. In the first part of the study, we tested several well known land surface models in multi-year simulations over the continental U.S. Among the models, which included the Variable Infiltration Capacity (VIC) model, the Community Land Model (CLM), the Noah Land Surface Model (Noah LSM), and the NASA Catchment model, there were substantial variations in the partitioning. These results motivated a more detailed evaluation, using data for two catchments that were a part of the second phase of the Distributed Model Intercomparison Project (DMIP-2), the East Fork Carson River Basin and the Illinois River Basin. In this portion of the study, we evaluated a unified land model (ULM) which is a merger of the NWS Sacramento Soil Moisture Accounting model (SAC-SMA), which is used operationally for flood and seasonal streamflow prediction, and the Noah LSM, which is the land scheme used in NOAA’s suite of weather and climate prediction models. Our overall objective is to leverage the operational strengths of each model, specifically to improve streamflow prediction and soil moisture states within the Noah LSM framework, and to add a vegetation component to the SAC-SMA model. Partitioning of evapotranspiration into its three components is a key part of the ULM performance, and controls our ability to use calibrated SAC-SMA parameters within the ULM framework. In our evaluations at the DMIP-2 sites, we examined sensitivities of soil moisture and evaporative components in ULM to changes in vegetation cover, root zone depth, canopy

  13. 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.

  14. 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.

  15. 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.

  16. Transport of treosulfan and temozolomide across an in-vitro blood-brain barrier model.

    PubMed

    Linz, Ute; Hupert, Michelle; Santiago-Schübel, Beatrix; Wien, Sascha; Stab, Julia; Wagner, Sylvia

    2015-08-01

    In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood-brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in-vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors. PMID:25919318

  17. Effects of colistin on amino acid neurotransmitters and blood-brain barrier in the mouse brain.

    PubMed

    Wang, Jian; Yi, Meishuang; Chen, Xueping; Muhammad, Ishfaq; Liu, Fangping; Li, Rui; Li, Jian; Li, Jichang

    2016-01-01

    Neurotoxicity is one of the major potential side effects of colistin therapy. However, the mechanistic aspects of colistin-induced neurotoxicity remain largely unknown. The objective of this study was to examine the effects of colistin on the blood-brain barrier (BBB) and amino acid neurotransmitters in the cerebral cortex of mouse. Mice were divided into four groups (n=5) and were administrated intravenously with 15mg/kg/day of colistin sulfate for 1, 3 and 7days successively while the control group was administrated intravenously with saline solution. The permeability and ultrastructure of the BBB were detected using the Evans blue (EB) dye and transmission electron microscopy (TEM), and the expression of Claudin-5 were determined by real-time PCR examination and western blotting. The brain uptake of colistin was measured by high-performance liquid chromatography (HPLC). The effects of colistin on amino acid neurotransmitters and their receptors were also examined by HPLC and real-time PCR. The results of EB extravasation, TEM and expression of Claudin-5 showed that colistin treatment did not affect the BBB integrity. In addition, multiple doses of colistin could induce accumulation of this compound in the brain parenchyma although there was poor brain uptake of colistin. Moreover, colistin exposure significantly increased the contents of glutamate (Glu) and gamma aminobutyric acid (GABA), and enhanced the mRNA expression levels of gamma aminobutyric acid type A receptor (GABAAR), gamma aminobutyric acid type B receptor (GABABR), N-methyl-d-aspartate 1 receptor (NR1), N-methyl-d-aspartate 2A receptor (NR2A) and N-methyl-d-aspartate 2B receptor (NR2B) in the cerebral cortex. Our data demonstrate that colistin is able to accumulate in the mouse brain and elevate the levels of amino acid neurotransmitters. These findings may be associated with colistin-induced neurotoxicity. PMID:27018023

  18. Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis.

    PubMed

    Leech, S; Kirk, J; Plumb, J; McQuaid, S

    2007-02-01

    Epithelial and endothelial tight junctions are pathologically altered in infectious, inflammatory, neoplastic and other diseases. Previously, we described such abnormalities, associated with serum protein leak, in tight junctions of the blood-brain barrier endothelium, in lesional and normal-appearing white matter (NAWM) in secondary progressive (SP) and acute multiple sclerosis (MS). This work is extended here to lesions and NAWM in primary progressive multiple sclerosis (PPMS) and to cortical grey matter in PPMS and SPMS. Immunocytochemistry and semiquantitative confocal microscopy for the tight junction protein zonula occludens 1 (ZO-1) was performed on snap-frozen sections from PPMS (n = 6) and controls (n = 5). Data on 2103 blood vessels were acquired from active lesions (n = 10), inactive lesions (n = 15), NAWM (n = 42) and controls (n = 20). Data on 1218 vessels were acquired from normal-appearing grey matter (PPMS, 5; SPMS, 6; controls, 5). In PPMS abnormal ZO-1 expression in active white matter lesions and NAWM, was found in 42% and 13% of blood vessels, respectively, comparable to previous data from acute and SPMS. In chronic white matter plaques, however, abnormalities were considerably more frequent (37%) in PPMS than in SPMS. Abnormality was also more frequent in normal-appearing grey matter in SPMS (23%) than in PPMS (10%). In summary, abnormal tight junctions in both SPMS and PPMS are most frequent in active white matter lesions but persist in inactive lesions, particularly in PPMS. Abnormal tight junctions are also common in normal-appearing grey matter in SPMS. Persistent endothelial abnormality with leak (PEAL) is therefore widespread but variably expressed in MS and may contribute to disease progression. PMID:17239011

  19. Fingolimod Prevents Blood-Brain Barrier Disruption Induced by the Sera from Patients with Multiple Sclerosis

    PubMed Central

    Nishihara, Hideaki; Shimizu, Fumitaka; Sano, Yasuteru; Takeshita, Yukio; Maeda, Toshihiko; Abe, Masaaki; Koga, Michiaki; Kanda, Takashi

    2015-01-01

    Objective Effect of fingolimod in multiple sclerosis (MS) is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB). However, brain microvascular endothelial cells (BMECs) represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera. Methods Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER) in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR) MS, stable phase of RRMS and secondary progressive MS (SPMS), on the function of BBB in the presence of fingolimod-phosphate were assessed. Results Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera. Conclusions Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients. PMID:25774903

  20. Blood-brain barrier transport kinetics of the neuromedin peptides NMU, NMN, NMB and NT.

    PubMed

    Gevaert, Bert; Wynendaele, Evelien; Stalmans, Sofie; Bracke, Nathalie; D'Hondt, Matthias; Smolders, Ilse; van Eeckhaut, Ann; De Spiegeleer, Bart

    2016-08-01

    The neuromedin peptides are peripherally and centrally produced, but until now, it is generally believed that they only function as locally acting compounds without any quantitative knowledge about their blood-brain barrier (BBB) passage. Here, we characterize the transport kinetics of four neuromedins (NMU, NMN, NMB and NT) across the BBB, as well as their metabolization profile, and evaluate if they can act as endocrine hormones. Using the in vivo mouse model, multiple time regression (MTR), capillary depletion (CD) and brain efflux studies were performed. Data was fitted using linear (NMU, NT and NMB) or biphasic modeling (NMU and NMN). Three of the four investigated peptides, i.e. NMU, NT and NMN, showed a significant influx into the brain with unidirectional influx rate constants of 1.31 and 0.75 μL/(g × min) for NMU and NT respectively and initial influx constants (K1) of 72.14 and 7.55 μL/(g × min) and net influx constants (K) of 1.28 and 1.36 × 10(-16) μL/(g×min) for NMU and NMN respectively. The influx of NMB was negligible. Only NMN and NT showed a significant efflux out of the brain with an efflux constant (kout) of 0.042 min(-1) and 0.053 min(-1) respectively. Our results indicate that locally produced neuromedin peptides and/or fragments can be transported through the whole body, including passing the BBB, and taken up by different organs/tissues, supporting the idea that the neuromedins could have a much bigger role in the regulation of biological processes than currently assumed. PMID:27040796

  1. Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro*

    PubMed Central

    Matthes, Frank; Wölte, Philipp; Böckenhoff, Annika; Hüwel, Sabine; Schulz, Mareike; Hyden, Pia; Fogh, Jens; Gieselmann, Volkmar; Galla, Hans-Joachim; Matzner, Ulrich

    2011-01-01

    Enzyme replacement therapy is an option to treat lysosomal storage diseases caused by functional deficiencies of lysosomal hydrolases as intravenous injection of therapeutic enzymes can correct the catabolic defect within many organ systems. However, beneficial effects on central nervous system manifestations are very limited because the blood-brain barrier (BBB) prevents the transfer of enzyme from the circulation to the brain parenchyma. Preclinical studies in mouse models of metachromatic leukodystrophy, however, showed that arylsulfatase A (ASA) is able to cross the BBB to some extent, thus reducing lysosomal storage in brain microglial cells. The present study aims to investigate the routing of ASA across the BBB and to improve the transfer in vitro using a well established cell culture model consisting of primary porcine brain capillary endothelial cells cultured on Transwell filter inserts. Passive apical-to-basolateral ASA transfer was observed, which was not saturable up to high ASA concentrations. No active transport could be determined. The passive transendothelial transfer was, however, charge-dependent as reduced concentrations of negatively charged monosaccharides in the N-glycans of ASA or the addition of polycations increased basolateral ASA levels. Adsorptive transcytosis is therefore considered to be the major transport pathway. Partial inhibition of the transcellular ASA transfer by mannose 6-phosphate indicated a second route depending on the insulin-like growth factor II/mannose 6-phosphate receptor, MPR300. We conclude that cationization of ASA and an increase of the mannose 6-phosphate content of the enzyme may promote blood-to-brain transfer of ASA, thus leading to an improved therapeutic efficacy of enzyme replacement therapy behind the BBB. PMID:21454621

  2. Transport of arylsulfatase A across the blood-brain barrier in vitro.

    PubMed

    Matthes, Frank; Wölte, Philipp; Böckenhoff, Annika; Hüwel, Sabine; Schulz, Mareike; Hyden, Pia; Fogh, Jens; Gieselmann, Volkmar; Galla, Hans-Joachim; Matzner, Ulrich

    2011-05-20

    Enzyme replacement therapy is an option to treat lysosomal storage diseases caused by functional deficiencies of lysosomal hydrolases as intravenous injection of therapeutic enzymes can correct the catabolic defect within many organ systems. However, beneficial effects on central nervous system manifestations are very limited because the blood-brain barrier (BBB) prevents the transfer of enzyme from the circulation to the brain parenchyma. Preclinical studies in mouse models of metachromatic leukodystrophy, however, showed that arylsulfatase A (ASA) is able to cross the BBB to some extent, thus reducing lysosomal storage in brain microglial cells. The present study aims to investigate the routing of ASA across the BBB and to improve the transfer in vitro using a well established cell culture model consisting of primary porcine brain capillary endothelial cells cultured on Transwell filter inserts. Passive apical-to-basolateral ASA transfer was observed, which was not saturable up to high ASA concentrations. No active transport could be determined. The passive transendothelial transfer was, however, charge-dependent as reduced concentrations of negatively charged monosaccharides in the N-glycans of ASA or the addition of polycations increased basolateral ASA levels. Adsorptive transcytosis is therefore considered to be the major transport pathway. Partial inhibition of the transcellular ASA transfer by mannose 6-phosphate indicated a second route depending on the insulin-like growth factor II/mannose 6-phosphate receptor, MPR300. We conclude that cationization of ASA and an increase of the mannose 6-phosphate content of the enzyme may promote blood-to-brain transfer of ASA, thus leading to an improved therapeutic efficacy of enzyme replacement therapy behind the BBB. PMID:21454621

  3. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier.

    PubMed

    Pardridge, William M; Boado, Ruben J

    2012-01-01

    Recombinant protein therapeutics cannot enter brain drug development because these large molecule drugs do not cross the blood-brain barrier (BBB). However, recombinant proteins can be reengineered as BBB-penetrating IgG fusion proteins, where the IgG part is a genetically engineered monoclonal antibody (MAb) against an endogenous BBB receptor, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The IgG binds the endogenous insulin receptor or TfR to trigger transport across the BBB and acts as a molecular Trojan horse (MTH) to ferry into brain the fused protein therapeutic. The most potent MTH to date is a MAb against the HIR, designated the HIRMAb, which is active in humans and Old World primates, such as the Rhesus monkey. There is no known MAb against the mouse insulin receptor. For drug delivery in the mouse, protein therapeutics are fused to a chimeric MAb against the mouse TfR, designated the cTfRMAb. The HIRMAb or cTfRMAb Trojan horses have been engineered and expressed as fusion proteins with multiple classes of protein therapeutics, including lysosomal enzymes, neurotrophins, decoy receptors, single chain Fv therapeutic antibodies, and avidin. The pharmacokinetic (PK) properties of the IgG fusion proteins differ from that of typical MAb drugs and resemble the PK profiles of small molecules due to rapid uptake by peripheral tissues, as well as brain. The brain uptake of the IgG fusion proteins, 2-3% of injected dose/brain, is comparable to the brain uptake of small molecules. The IgG fusion proteins have been administered chronically in mouse models, and the immune response is low titer and has no effect on the fusion protein clearance from blood or brain uptake in vivo. The BBB MTH technology enables the reengineering of a wide spectrum of recombinant protein therapeutics for targeted drug delivery to the brain. PMID:22230573

  4. Myeloperoxidase-Derived Oxidants Induce Blood-Brain Barrier Dysfunction In Vitro and In Vivo

    PubMed Central

    Üllen, Andreas; Singewald, Evelin; Konya, Viktoria; Fauler, Günter; Reicher, Helga; Nusshold, Christoph; Hammer, Astrid; Kratky, Dagmar; Heinemann, Akos; Holzer, Peter; Malle, Ernst; Sattler, Wolfgang

    2013-01-01

    Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB) function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) formed via the myeloperoxidase (MPO)-H2O2-Cl− system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS)-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl− system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC) that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl− system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA) severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively) protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuro)inflammatory conditions. PMID:23691142

  5. Iron supplement prevents lead-induced disruption of the blood-brain barrier during rat development

    SciTech Connect

    Wang Qiang; Luo Wenjing; Zheng Wei; Liu Yiping; Xu Hui; Zheng Gang; Dai Zhongming; Zhang Wenbin; Chen Yaoming; Chen Jingyuan . E-mail: jy_chen@fmmu.edu.cn

    2007-02-15

    Children are known to be venerable to lead (Pb) toxicity. The blood-brain barrier (BBB) in immature brain is particularly vulnerable to Pb insults. This study was designed to test the hypothesis that Pb exposure damaged the integrity of the BBB in young animals and iron (Fe) supplement may prevent against Pb-induced BBB disruption. Male weanling Sprague-Dawley rats were divided into four groups. Three groups of rats were exposed to Pb in drinking water containing 342 {mu}g Pb/mL as Pb acetate, among which two groups were concurrently administered by oral gavage once every other day with 7 mg Fe/kg and 14 mg Fe/kg as FeSO{sub 4} solution as the low and high Fe treatment group, respectively, for 6 weeks. The control group received sodium acetate in drinking water. Pb exposure significantly increased Pb concentrations in blood by 6.6-folds (p < 0.05) and brain tissues by 1.5-2.0-folds (p < 0.05) as compared to controls. Under the electron microscope, Pb exposure in young animals caused an extensive extravascular staining of lanthanum nitrate in brain parenchyma, suggesting a leakage of cerebral vasculature. Western blot showed that Pb treatment led to 29-68% reduction (p < 0.05) in the expression of occludin as compared to the controls. Fe supplement among Pb-exposed rats maintained the normal ultra-structure of the BBB and restored the expression of occludin to normal levels. Moreover, the low dose Fe supplement significantly reduced Pb levels in blood and brain tissues. These data suggest that Pb exposure disrupts the structure of the BBB in young animals. The increased BBB permeability may facilitate the accumulation of Pb. Fe supplement appears to protect the integrity of the BBB against Pb insults, a beneficial effect that may have significant clinical implications.

  6. Enhanced blood-brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

    NASA Astrophysics Data System (ADS)

    Ding, Hong; Sagar, Vidya; Agudelo, Marisela; Pilakka-Kanthikeel, Sudheesh; Subba Rao Atluri, Venkata; Raymond, Andrea; Samikkannu, Thangavel; Nair, Madhavan P.

    2014-02-01

    The blood-brain barrier (BBB) is considered as the primary impediment barrier for most drugs. Delivering therapeutic agents to the brain is still a big challenge to date. In our study, a dual mechanism, receptor mediation combined with external non-invasive magnetic force, was incorporated into ferrous magnet-based liposomes for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs), with a size of ˜10 nm, were synthesized and confirmed by TEM and XRD respectively. The classical magnetism assay showed the presence of the characteristic superparamagnetic property. These MNPs encapsulated in PEGylated fluorescent liposomes as magneto-liposomes (MLs) showed mono-dispersion, ˜130 ± 10 nm diameter, by dynamic laser scattering (DLS) using the lipid-extrusion technique. Remarkably, a magnetite encapsulation efficiency of nearly 60% was achieved. Moreover, the luminescence and hydrodynamic size of the MLs was stable for over two months at 4 ° C. Additionally, the integrity of the ML structure remained unaffected through 120 rounds of circulation mimicking human blood fluid. After biocompatibility confirmation by cytotoxicity evaluation, these fluorescent MLs were further embedded with transferrin and applied to an in vitro BBB transmigration study in the presence or absence of external magnetic force. Comparing with magnetic force- or transferrin receptor-mediated transportation alone, their synergy resulted in 50-100% increased transmigration without affecting the BBB integrity. Consequently, confocal microscopy and iron concentration in BBB-composed cells further confirmed the higher cellular uptake of ML particles due to the synergic effect. Thus, our multifunctional liposomal magnetic nanocarriers possess great potential in particle transmigration across the BBB and may have a bright future in drug delivery to the brain.

  7. A novel platform for engineering blood-brain barrier-crossing bispecific biologics.

    PubMed

    Farrington, Graham K; Caram-Salas, Nadia; Haqqani, Arsalan S; Brunette, Eric; Eldredge, John; Pepinsky, Blake; Antognetti, Giovanna; Baumann, Ewa; Ding, Wen; Garber, Ellen; Jiang, Susan; Delaney, Christie; Boileau, Eve; Sisk, William P; Stanimirovic, Danica B

    2014-11-01

    The blood-brain barrier (BBB) prevents the access of therapeutic antibodies to central nervous system (CNS) targets. The engineering of bispecific antibodies in which a therapeutic "arm" is combined with a BBB-transcytosing arm can significantly enhance their brain delivery. The BBB-permeable single-domain antibody FC5 was previously isolated by phenotypic panning of a naive llama single-domain antibody phage display library. In this study, FC5 was engineered as a mono- and bivalent fusion with the human Fc domain to optimize it as a modular brain delivery platform. In vitro studies demonstrated that the bivalent fusion of FC5 with Fc increased the rate of transcytosis (Papp) across brain endothelial monolayer by 25% compared with monovalent fusion. Up to a 30-fold enhanced apparent brain exposure (derived from serum and cerebrospinal fluid pharmacokinetic profiles) of FC5- compared with control domain antibody-Fc fusions after systemic dosing in rats was observed. Systemic pharmacological potency was evaluated in the Hargreaves model of inflammatory pain using the BBB-impermeable neuropeptides dalargin and neuropeptide Y chemically conjugated with FC5-Fc fusion proteins. Improved serum pharmacokinetics of Fc-fused FC5 contributed to a 60-fold increase in pharmacological potency compared with the single-domain version of FC5; bivalent and monovalent FC5 fusions with Fc exhibited similar systemic pharmacological potency. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications. PMID:25070367

  8. Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier

    PubMed Central

    Storck, Steffen E.; Meister, Sabrina; Nahrath, Julius; Meißner, Julius N.; Schubert, Nils; Di Spiezio, Alessandro; Baches, Sandra; Vandenbroucke, Roosmarijn E.; Bouter, Yvonne; Prikulis, Ingrid; Korth, Carsten; Weggen, Sascha; Heimann, Axel; Schwaninger, Markus; Bayer, Thomas A.; Pietrzik, Claus U.

    2015-01-01

    According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor–related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-β (Aβ) brain accumulation and drives Alzheimer’s disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aβ transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aβ clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreERT2 Lrp1fl/fl mice) and used these mice to accurately evaluate LRP1-mediated Aβ BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Aβ1–42. Additionally, in the 5xFAD mouse model of AD, brain endothelial–specific Lrp1 deletion reduced plasma Aβ levels and elevated soluble brain Aβ, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aβ elimination via the BBB. Together, our results suggest that receptor-mediated Aβ BBB clearance may be a potential target for treatment and prevention of Aβ brain accumulation in AD. PMID:26619118

  9. Mosquito repellent (pyrethroid-based) induced dysfunction of blood-brain barrier permeability in developing brain.

    PubMed

    Sinha, C; Agrawal, A K; Islam, F; Seth, K; Chaturvedi, R K; Shukla, S; Seth, P K

    2004-02-01

    Pyrethroid-based mosquito repellents (MR) are commonly used to protect humans against mosquito vector. New born babies and children are often exposed to pyrethroids for long periods by the use of liquid vaporizers. Occupational and experimental studies indicate that pyrethroids can cause clinical, biochemical and neurological changes, and that exposure to pyrethroids during organogenesis and early developmental period is especially harmful. The neurotoxicity caused by MR has aroused concern among public regarding their use. In the present study, the effect of exposure of rat pups during early developmental stages to a pyrethroid-based MR (allethrin, 3.6% w/v, 8h per day through inhalation) on blood-brain barrier (BBB) permeability was investigated. Sodium fluororescein (SF) and Evan's blue (EB) were used as micromolecular and macromolecular tracers, respectively. Exposure during prenatal (gestation days 1-20), postnatal (PND1-30) and perinatal (gestation days 1-20 + PND1-30) periods showed significant increase in the brain uptake index (BUI) of SF by 54% (P < 0.01), 70% (P < 0.01), 79% (P < 0.01), respectively. This increase persisted (68%, P < 0.01) even 1 week after withdrawal of exposure (as assessed on PND37). EB did not exhibit significant change in BBB permeability in any of the group. The results suggest that MR inhalation during early prenatal/postnatal/perinatal life may have adverse effects on infants leading to central nervous system (CNS) abnormalities, if a mechanism operates in humans similar to that in rat pups. PMID:15013076

  10. Methamphetamine is not Toxic but Disrupts the Cell Cycle of Blood-Brain Barrier Endothelial Cells.

    PubMed

    Fisher, D; Gamieldien, K; Mafunda, P S

    2015-07-01

    The cytotoxic effects of methamphetamine (MA) are well established to be caused via induced oxidative stress which in turn compromises the core function of the blood-brain barrier (BBB) by reducing its ability to regulate the homeostatic environment of the brain. While most studies were conducted over a period of 24-48 h, this study investigated the mechanisms by which chronic exposure of MA adversely affect the endothelial cells of BBB over an extended period of 96 h. MA induced significant depression of cell numbers at 96 h. This result was supported by flow cytometric data on the cell cycle which showed that brain endothelial cells (bEnd5) at 96 h were significantly suppressed in the S-phase of the cell cycle. In contrast, at 24-72 h control cell numbers for G1, S and G2-M phases were similar to MA-exposed cells. MA (0-1,000 µM) did not, however, statistically affect the viability and cytotoxicity of the bEnd5 cells, and the profile of ATP production and DNA synthesis (BrdU) across 96 h did not provide a rationale for the suppression of cell division. Our study reports for the first time that chronic exposure to MA results in long-term disruption of the cell cycle phases which eventuates in the attenuation of brain capillary endothelial cell growth after 96 h, compounding and contributing to the already well-known adverse short-term permeability effects of MA exposure on the BBB. PMID:25666340

  11. Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor

    PubMed Central

    Brown, Jacquelyn A.; Pensabene, Virginia; Markov, Dmitry A.; Allwardt, Vanessa; Neely, M. Diana; Shi, Mingjian; Britt, Clayton M.; Hoilett, Orlando S.; Yang, Qing; Brewer, Bryson M.; Samson, Philip C.; McCawley, Lisa J.; May, James M.; Webb, Donna J.; Li, Deyu; Bowman, Aaron B.; Reiserer, Ronald S.; Wikswo, John P.

    2015-01-01

    The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier. PMID:26576206

  12. Surfactants, not size or zeta-potential influence blood-brain barrier passage of polymeric nanoparticles.

    PubMed

    Voigt, Nadine; Henrich-Noack, Petra; Kockentiedt, Sarah; Hintz, Werner; Tomas, Jürgen; Sabel, Bernhard A

    2014-05-01

    Nanoparticles (NP) can deliver drugs across the blood-brain barrier (BBB), but little is known which of the factors surfactant, size and zeta-potential are essential for allowing BBB passage. To this end we designed purpose-built fluorescent polybutylcyanoacrylate (PBCA) NP and imaged the NP's passage over the blood-retina barrier - which is a model of the BBB - in live animals. Rats received intravenous injections of fluorescent PBCA-NP fabricated by mini-emulsion polymerisation to obtain various NP's compositions that varied in surfactants (non-ionic, anionic, cationic), size (67-464nm) and zeta-potential. Real-time imaging of retinal blood vessels and retinal tissue was carried out with in vivo confocal neuroimaging (ICON) before, during and after NP's injection. Successful BBB passage with subsequent cellular labelling was achieved if NP were fabricated with non-ionic surfactants or cationic stabilizers but not when anionic compounds were added. NP's size and charge had no influence on BBB passage and cell labelling. This transport was not caused by an unspecific opening of the BBB because control experiments with injections of unlabelled NP and fluorescent dye (to test a "door-opener" effect) did not lead to parenchymal labelling. Thus, neither NP's size nor chemo-electric charge, but particle surface is the key factor determining BBB passage. This result has important implications for NP engineering in medicine: depending on the surfactant, NP can serve one of two opposite functions: while non-ionic tensides enhance brain up-take, addition of anionic tensides prevents it. NP can now be designed to specifically enhance drug delivery to the brain or, alternatively, to prevent brain penetration so to reduce unwanted psychoactive effects of drugs or prevent environmental nanoparticles from entering tissue of the central nervous system. PMID:24607790

  13. Effects of radiofrequency radiation exposure on blood-brain barrier permeability in male and female rats.

    PubMed

    Sirav, Bahriye; Seyhan, Nesrin

    2011-12-01

    During the last several decades, numerous studies have been performed aiming at the question of whether or not exposure to radiofrequency radiation (RFR) influences the permeability of the blood-brain barrier (BBB). The objective of this study was to investigate the effect of RFR on the permeability of BBB in male and female Wistar albino rats. Right brain, left brain, cerebellum, and total brain were analyzed separately in the study. Rats were exposed to 0.9 and 1.8 GHz continuous-wave (CW) RFR for 20 min (at SARs of 4.26 mW/kg and 1.46 mW/kg, respectively) while under anesthesia. Control rats were sham-exposed. Disruption of BBB integrity was detected spectrophotometrically using the Evans-blue dye, which has been used as a BBB tracer and is known to be bound to serum albumin. Right brain, left brain, cerebellum, and total brain were evaluated for BBB permeability. In female rats, no albumin extravasation was found in in the brain after RFR exposure. A significant increase in albumin was found in the brains of the RF-exposed male rats when compared to sham-exposed male brains. These results suggest that exposure to 0.9 and 1.8 GHz CW RFR at levels below the international limits can affect the vascular permeability in the brain of male rats. The possible risk of RFR exposure in humans is a major concern for the society. Thus, this topic should be investigated more thoroughly in the future. PMID:22047463

  14. The Role of Autophagy during Group B Streptococcus Infection of Blood-Brain Barrier Endothelium*

    PubMed Central

    Cutting, Andrew S.; Del Rosario, Yvette; Mu, Rong; Rodriguez, Anthony; Till, Andreas; Subramani, Suresh; Gottlieb, Roberta A.; Doran, Kelly S.

    2014-01-01

    Bacterial meningitis occurs when bloodborne pathogens invade and penetrate the blood-brain barrier (BBB), provoking inflammation and disease. Group B Streptococcus (GBS), the leading cause of neonatal meningitis, can enter human brain microvascular endothelial cells (hBMECs), but the host response to intracellular GBS has not been characterized. Here we sought to determine whether antibacterial autophagy, which involves selective recognition of intracellular organisms and their targeting to autophagosomes for degradation, is activated in BBB endothelium during bacterial infection. GBS infection resulted in increased punctate distribution of GFP-microtubule-associated protein 1 light chain 3 (LC3) and increased levels of endogenous LC3-II and p62 turnover, two hallmark indicators of active autophagic flux. Infection with GBS mutants revealed that bacterial invasion and the GBS pore-forming β-hemolysin/cytolysin (β-h/c) trigger autophagic activation. Cell-free bacterial extracts containing β-h/c activity induced LC3-II conversion, identifying this toxin as a principal provocative factor for autophagy activation. These results were confirmed in vivo using a mouse model of GBS meningitis as infection with WT GBS induced autophagy in brain tissue more frequently than a β-h/c-deficient mutant. Elimination of autophagy using Atg5-deficient fibroblasts or siRNA-mediated impairment of autophagy in hBMECs led to increased recovery of intracellular GBS. However, electron microscopy revealed that GBS was rarely found within double membrane autophagic structures even though we observed GBS-LC3 co-localization. These results suggest that although autophagy may act as a BBB cellular defense mechanism in response to invading and toxin-producing bacteria, GBS may actively thwart the autophagic pathway. PMID:25371213

  15. Blood-Brain Barrier Experiments with Clinical Magnetic Resonance Imaging and an Immunohistochemical Study

    PubMed Central

    Park, Jun Woo; Kim, Hak Jin; Han, Hyung Soo

    2010-01-01

    Objective The purpose of study was to evaluate the feasibility of brain magnetic resonance (MR) images of the rat obtained using a 1.5T MR machine in several blood-brain barrier (BBB) experiments. Methods Male Sprague-Dawley rats were used. MR images were obtained using a clinical 1.5T MR machine. A microcatheter was introduced via the femoral artery to the carotid artery. Normal saline (group 1, n = 4), clotted autologous blood (group 2, n = 4), triolein emulsion (group 3, n = 4), and oleic acid emulsion (group 4, n = 4) were infused into the carotid artery through a microcatheter. Conventional and diffusion-weighted images, the apparent coefficient map, perfusion-weighted images, and contrast-enhanced MR images were obtained. Brain tissue was obtained and triphenyltetrazolium chloride (TTC) staining was performed in group 2. Fluorescein isothiocyanate (FITC)-labeled dextran images and endothelial barrier antigen (EBA) studies were performed in group 4. Results The MR images in group 1 were of good quality. The MR images in group 2 revealed typical findings of acute cerebral infarction. Perfusion defects were noted on the perfusion-weighted images. The MR images in group 3 showed vasogenic edema and contrast enhancement, representing vascular damage. The rats in group 4 had vasogenic edema on the MR images and leakage of dextran on the FITC-labeled dextran image, representing increased vascular permeability. The immune reaction was decreased on the EBA study. Conclusion Clinical 1.5T MR images using a rat depicted many informative results in the present study. These results can be used in further researches of the BBB using combined clinical MR machines and immunohistochemical examinations. PMID:20379473

  16. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    PubMed

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease. PMID:26321046

  17. Glycodermorphins: opioid peptides with potent and prolonged analgesic activity and enhanced blood-brain barrier penetration.

    PubMed

    Negri, L; Lattanzi, R; Tabacco, F; Scolaro, B; Rocchi, R

    1998-08-01

    1. In order to improve the in vivo stability of the opioid peptide dermorphin we synthesized O-betaglucosylated analogs ([Ser7-O-betaGlc]dermorphin and [Ser7-O-betaGlc(Ac)4]-dermorphin) and C-alphagalactosylated analogs ([Ala7-C-alphaGal]dermorphin and [Ala7-C-alphaGal(Ac)4]-dermorphin). 2. O- and C-glycosylation of dermorphin halved the peptide affinity for brain mu-opioid receptors and the biological potency in guinea-pig ileum assay (GPI). Despite their lower opioid receptor affinity, when administered intracerebroventricularly (i.c.v., 8-40 pmol) and subcutaneously (s.c., 0.5-3 micromol kg(-1)) in rats, glycosylated analogs were two times more potent than dermorphin in reducing the nociceptive response to radiant heat. Acetylation of sugar hydroxyl groups reduces 5-10 times both biological activity on GPI and mu-receptor affinity, whereas the antinociceptive potency was equal to (i.c.v.) or only two-three times lower (s.c.) than dermorphin potency. 3. Blood-Brain Barrier Permeability Index (BBB-PI) of the glycodermorphins was significantly higher than that of dermorphin, indicating a facilitated entry into the brain: O-beta-linked glucoconiugates are expected to enter CNS by the glucose transporter GLUT-1 of the endothelial barrier. However the calculated BBB-PI for the C-alphagalactoside was about two times higher than that of the O-betaglucoside, excluding the implication of GLUT-1 that is known to be selective for O-beta-links and preferring for the exose glucose. 4. The enhanced brain permeability with the subsequent decrease in peripheral dosage of these opioid peptides did not result in lowering constipation. PMID:9723966

  18. Effects of acute hyperosmolality on blood-brain barrier function in ovine fetuses and lambs.

    PubMed

    Stonestreet, Barbara S; Sadowska, Grazyna B; Leeman, Joanne; Hanumara, R Choudary; Petersson, Katherine H; Patlak, Clifford S

    2006-10-01

    We examined the effects of hyperosmolality on blood-brain barrier (BBB) permeability during development to test the vulnerability of the immature barrier to stress. The BBB response to hyperosmolality was quantified using the blood-to-brain transfer constant (Ki) with alpha-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Ki plotted against osmolality increased as a function of increases in osmolality in all groups and brain regions. The relationship was described (P < 0.05) by a segmented regression model. At lower osmolalities, changes in Ki were minimal, but after a break point (threshold) was reached, the increase (P < 0.05) was linear. We examined the responses of Ki to hyperosmolality within each brain region by comparing the thresholds and slopes of the second regression segment. Lower thresholds and higher slopes imply greater vulnerability to hyperosmolality in the younger groups. Thresholds increased (P < 0.05) with development in the thalamus, superior colliculus, pons, and spinal cord, and slopes of the second regression segment decreased (P < 0.05) in the cerebellum, hippocampus, inferior colliculus, medulla, and spinal cord. BBB resistance to hyperosmolality increased (P < 0.05) with development in most brain regions. The pattern of the Ki plotted against osmolality was (P < 0.05) heterogenous among brain regions in fetuses and premature and newborn lambs, but not in older lambs. We conclude that 1) BBB permeability increased as a function of changes in osmolality, 2) the barrier becomes more resistant to hyperosmolality during development, and 3) the permeability response to hyperosmolality is heterogenous among brain regions in fetuses and premature and newborn lambs. PMID:16690764

  19. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    PubMed

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. PMID:27018328

  20. Selective disruption of the blood-brain barrier by photochemical internalization

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Zhang, Michelle J.; Gach, Michael H.; Uzal, Francisco A.; Chighvinadze, David; Madsen, Steen J.

    2009-02-01

    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) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of photochemical internalization (PCI) to selectively disrupt the BBB in rats. This will permit access of anti-cancer drugs to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: PCI treatment, coupling a macromolecule therapy of Clostridium perfringens (Cl p) epsilon prototoxin with AlPcS2a-PDT, was performed on non-tumor bearing inbred Fisher rats. T1-weighted post-contrast magnetic resonance imaging (MRI) scans were used to evaluate the extent of BBB disruption which can be inferred from the volume contrast enhancement. Results: The synergistic effect of PCI to disrupt the BBB was observed at a fluence level of 1 J with an intraperitoneal injection of Cl p prototoxin. At the fluence level of 2.5J, the extent of BBB opening induced by PCI was similar to the result of PDT suggesting no synergistic effect evoked under these conditions. Conclusion: PCI was found to be highly effective and efficient for inducing selective and localized disruption of the BBB. The extent of BBB opening peaked on day 3 and the BBB was completed restored by day 18 post treatment.

  1. Use of Ultrasound Pulses Combined with Definity for Targeted Blood-Brain Barrier Disruption

    NASA Astrophysics Data System (ADS)

    McDannold, Nathan; Vykhodtseva, Natalia; Hynynen, Kullervo

    2007-05-01

    We have developed a method to combine an ultrasound contrast agent (USCA) with low-intensity focused ultrasound pulses combined to produce temporary blood-brain barrier disruption (BBBD), a potential non-invasive means for targeted drug delivery in the brain. All of our previous work used the USCA Optison. The purpose of this work was to test the feasibility of using the USCA Definity for BBBD. Thirty-six non-overlapping locations were sonicated through a craniotomy in experiments in the brains of nine rabbits (4 locations per rabbit; US frequency: 0.69MHz, burst: 10ms, PRF: 1Hz, duration: 20s; pressure amplitude: 0.2-1.5 MPa). Eleven locations were sonicated using Optison at 0.5 MPa. For both agents, the probability for BBBD was estimated to be 50% at 0.4 MPa using probit regression. In histology, small isolated areas of extravasated erythrocytes were observed in some locations. At 0.8 MPa and above, this extravasation was sometimes accompanied by tiny (dimensions of 100 μm or less) regions of damaged brain parenchyma. The magnitude of the BBBD was larger with Optison than with Definity at 0.5 MPa (P=0.04), and more areas with extravasated erythrocytes were observed (P=0.03). We conclude that BBBD is possible using Definity for the dosage of USCA and the acoustic parameters tested in this study. While the probability for BBBD as a function of pressure amplitude and the type of acute tissue effects was similar to findings with Optison, under these experimental conditions, Optison produced a larger effect.

  2. Control of the blood-brain barrier function in cancer cell metastasis.

    PubMed

    Blecharz, Kinga G; Colla, Ruben; Rohde, Veit; Vajkoczy, Peter

    2015-10-01

    Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain-metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood-brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis. PMID:26032862

  3. Separation methods that are capable of revealing blood-brain barrier permeability.

    PubMed

    Dash, Alekha K; Elmquist, William F

    2003-11-25

    The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the

  4. Longitudinal Motor and Behavioral Assessment of Blood-Brain Barrier Opening with Transcranial Focused Ultrasound.

    PubMed

    Olumolade, Oluyemi O; Wang, Shutao; Samiotaki, Gesthimani; Konofagou, Elisa E

    2016-09-01

    Focused ultrasound (FUS), in combination with microbubbles, has been found to open the blood-brain barrier (BBB) non-invasively. When this technique is used for drug delivery, repeated drug administration and BBB opening are likely required. Therefore, it is worth investigating the long-term effects of FUS-induced BBB opening. In this study, we focused on the assessment of potential behavior changes in mice that could be attributed to repeated BBB opening for up to 6 months. The striatum of animals was unilaterally sonicated either monthly or biweekly throughout the monitoring period. Behavioral assessments were conducted using open-field and rotarod performance tests. Upon completion of each sonication, mice underwent magnetic resonance imaging (MRI) to confirm and assess the volume of the BBB opening. No differences in locomotor activity between BBB-opened and control groups in both biweekly and monthly treated mice were evident up to 6 months. Similarly, there was no affinity for a particular turn angle in the sonicated mice compared with the control animals. However, the positive control group exhibited a significant decrease in locomotor activity, as well as rotation ipsilateral to the sonicated hemisphere. Our results based on the assessment using open-field and rotarod tests indicated that repeated opening of the BBB in the striatum using FUS in conjunction with microbubbles over a period of 6 mo and under the parameters used here did not cause motor impairment, behavioral changes or morphologic alterations. This reinforces the tolerability of repeated and long-term drug delivery using FUS-induced BBB opening. PMID:27339763

  5. Impact of diabetes in blood-testis and blood-brain barriers: resemblances and differences.

    PubMed

    Alves, Marco G; Oliveira, Pedro F; Socorro, Silvia; Moreira, Paula I

    2012-11-01

    Blood-tissue barriers prevent an uncontrolled exchange of large molecules between adjacent but metabolically separated compartments. There are several known barriers and two of the most important and tightest blood-tissue barriers are the blood-testis barrier (BTB) and the blood-brain barrier (BBB). Under normal conditions these barriers, formed by tight junctions between adjacent cells, control the entry of substances and metabolites. However, hyperglycemia and other diabetes-related complications, such as hypertension, impair the function of these biological barriers with dramatic consequences. Although both, BBB and BTB, are responsible for the maintenance of different biological processes, they have some remarkable similarities not always explored when looking at metabolic-related diseases such as diabetes. These barriers possess their own glucose sensing machinery, suffer a tied hormonal control and have specific mechanisms to counteract hyper- and hypoglycemia. In BBB and BTB the insulin signaling is also distinct from other tissues and organs thus evidencing their importance in protecting against or exacerbating the effects of diabetes on glucose metabolism. The control of glucose and lactate levels in brain and testis highlights the role of these barriers in protecting against peripheral glucose and lactate fluctuations that occur in the diabetic individual. We review the role of BBB and BTB in the control of glucose and metabolic dysfunction caused by diabetes in the brain and seminiferous epithelium. Gaining a better understanding of the molecular mechanisms through which glucose metabolism disrupts BBB and BTB function may highlight new opportunities for the treatment of diabetic complications in brain and male reproductive function. PMID:22934551

  6. The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

    PubMed Central

    DeSalvo, Michael K.; Hindle, Samantha J.; Rusan, Zeid M.; Orng, Souvinh; Eddison, Mark; Halliwill, Kyle; Bainton, Roland J.

    2014-01-01

    Central nervous system (CNS) function is dependent on the stringent regulation of metabolites, drugs, cells, and pathogens exposed to the CNS space. Cellular blood-brain barrier (BBB) structures are highly specific checkpoints governing entry and exit of all small molecules to and from the brain interstitial space, but the precise mechanisms that regulate the BBB are not well understood. In addition, the BBB has long been a challenging obstacle to the pharmacologic treatment of CNS diseases; thus model systems that can parse the functions of the BBB are highly desirable. In this study, we sought to define the transcriptome of the adult Drosophila melanogaster BBB by isolating the BBB surface glia with fluorescence activated cell sorting (FACS) and profiling their gene expression with microarrays. By comparing the transcriptome of these surface glia to that of all brain glia, brain neurons, and whole brains, we present a catalog of transcripts that are selectively enriched at the Drosophila BBB. We found that the fly surface glia show high expression of many ATP-binding cassette (ABC) and solute carrier (SLC) transporters, cell adhesion molecules, metabolic enzymes, signaling molecules, and components of xenobiotic metabolism pathways. Using gene sequence-based alignments, we compare the Drosophila and Murine BBB transcriptomes and discover many shared chemoprotective and small molecule control pathways, thus affirming the relevance of invertebrate models for studying evolutionary conserved BBB properties. The Drosophila BBB transcriptome is valuable to vertebrate and insect biologists alike as a resource for studying proteins underlying diffusion barrier development and maintenance, glial biology, and regulation of drug transport at tissue barriers. PMID:25426014

  7. The Blood-brain Barrier in Neuroimmunology: Tales of Separation and Assimilation

    PubMed Central

    Banks, W. A.

    2014-01-01

    Neuroimmunology is concerned with the relations between the central nervous and immune systems and with the mechanisms that drive those relations. The blood-brain barrier (BBB) employs mechanisms that both separate and connect these two systems. In fact, the relative immune privilege of the central nervous system (CNS) is largely attributable to the BBB's ability to prevent the unregulated exchange of immune cells and their secretions between the CNS and blood. Having separated the two systems, the BBB then participates in mechanisms that allow them to influence, communicate, and interact with one another. Likewise, the BBB itself is influenced by immune events that are occurring in the periphery and in the CNS so that these three components (the BBB, the immune system, and the CNS) form neuroimmune axes that adapt to physiological and pathological conditions. To date, four major themes have emerged by which the BBB participates in these neuroimmune axes. The first of these four, the formation of the barrier, acts to separate the immune and central nervous systems. The other three themes provide mechanisms for re-establishing communication: response of the BBB to immunomodulatory molecules (e.g., prostaglandins, cytokines, chemokines, nitric oxide) secreted by immune and CNS cells; the controlled, regulated exchange of chemokines, cytokines, and immune cells between the CNS and the blood (i.e., transport across the BBB); the secretion of immunomodulatory molecules by the BBB, often in a polarized fashion. Taken together, these mechanisms reveal the BBB to be a dynamic, interactive, and adaptable interface between the immune system and the CNS, separating them on the one hand and fostering their interaction on the other hand, adjusting to physiological changes, while being a target for disease processes. This review examines specific examples by which the BBB plays an interactive, defining role in neuroimmunology. PMID:25172555

  8. Consequences of Repeated Blood-Brain Barrier Disruption in Football Players

    PubMed Central

    Puvenna, Vikram; Janigro, Mattia; Ghosh, Chaitali; Zhong, Jianhui; Zhu, Tong; Blackman, Eric; Stewart, Desiree; Ellis, Jasmina; Butler, Robert; Janigro, Damir

    2013-01-01

    The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes. PMID:23483891

  9. Into rather unexplored terrain-transcellular transport across the blood-brain barrier.

    PubMed

    De Bock, Marijke; Van Haver, Valérie; Vandenbroucke, Roosmarijn E; Decrock, Elke; Wang, Nan; Leybaert, Luc

    2016-07-01

    Efficient neuronal signaling in the central nervous system strictly depends on a well-balanced microenvironment around glial cells, synapses, and axons. Unique features of the blood-brain barrier (BBB) endothelium largely determine the composition of this micro-milieu and are dependent on the tight interplay with surrounding astrocytes and pericytes. BBB endothelial cells are endowed with a highly restrictive junctional complex that occludes the intercellular cleft, thereby preventing paracellular diffusion. The paracellular pathway is subject to extensive research as integrity loss of the junctional complex is associated with many neuropathologies, inflammation, and edema. Another important feature of the BBB endothelium is the low prevalence of nonspecific, transcytotic events, including (macro)pinocytosis, clathrin-dependent and caveolin-dependent endocytosis and the subsequent trafficking of vesicles to the opposite membrane. Although less studied, evidence is accruing that this pathway importantly contributes to increased BBB permeability, often when the junctional complex remains intact. Here, we review current knowledge on the contribution of the transcellular pathway to the BBB leak observed in different pathologic conditions. In addition, we hypothesize that nonselective, large pore connexin and pannexin channels may contribute to transcellular transport, either by providing a direct diffusion pathway across the endothelial monolayer, or indirectly, by exerting control over intracellular levels of the signaling ion Ca(2+) that is involved in many steps of the vesicular pathway. We conclude that transcytotic events at the BBB, despite being less acknowledged, cannot be simply dismissed as done in the past, but actively contribute to BBB leakage in many different pathologies. GLIA 2016;64:1097-1123. PMID:26852907

  10. Chirp- and random-based coded ultrasonic excitation for localized blood-brain barrier opening.

    PubMed

    Kamimura, H A S; Wang, S; Wu, S-Y; Karakatsani, M E; Acosta, C; Carneiro, A A O; Konofagou, E E

    2015-10-01

    Chirp- and random-based coded excitation methods have been proposed to reduce standing wave formation and improve focusing of transcranial ultrasound. However, no clear evidence has been shown to support the benefits of these ultrasonic excitation sequences in vivo. This study evaluates the chirp and periodic selection of random frequency (PSRF) coded-excitation methods for opening the blood-brain barrier (BBB) in mice. Three groups of mice (n  =  15) were injected with polydisperse microbubbles and sonicated in the caudate putamen using the chirp/PSRF coded (bandwidth: 1.5–1.9 MHz, peak negative pressure: 0.52 MPa, duration: 30 s) or standard ultrasound (frequency: 1.5 MHz, pressure: 0.52 MPa, burst duration: 20 ms, duration: 5 min) sequences. T1-weighted contrast-enhanced MRI scans were performed to quantitatively analyze focused ultrasound induced BBB opening. The mean opening volumes evaluated from the MRI were mm3, mm3and mm3 for the chirp, random and regular sonications, respectively. The mean cavitation levels were V.s, V.s and V.s for the chirp, random and regular sonications, respectively. The chirp and PSRF coded pulsing sequences improved the BBB opening localization by inducing lower cavitation levels and smaller opening volumes compared to results of the regular sonication technique. Larger bandwidths were associated with more focused targeting but were limited by the frequency response of the transducer, the skull attenuation and the microbubbles optimal frequency range. The coded methods could therefore facilitate highly localized drug delivery as well as benefit other transcranial ultrasound techniques that use higher pressure levels and higher precision to induce the necessary bioeffects in a brain region while avoiding damage to the surrounding healthy tissue. PMID:26394091

  11. Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain.

    PubMed

    Saeed, Ahmed A; Genové, Guillem; Li, Tian; Lütjohann, Dieter; Olin, Maria; Mast, Natalia; Pikuleva, Irina A; Crick, Peter; Wang, Yuqin; Griffiths, William; Betsholtz, Christer; Björkhem, Ingemar

    2014-08-22

    The presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism have not been studied previously. Here we used a pericyte-deficient mouse model, Pdgfb(ret/ret), shown to have increased permeability of the BBB to a range of low-molecular mass and high-molecular mass tracers. There was a significant accumulation of plant sterols in the brains of the Pdgfb(ret/ret) mice. By dietary treatment with 0.3% deuterium-labeled cholesterol, we could demonstrate a significant flux of cholesterol from the circulation into the brains of the mutant mice roughly corresponding to about half of the measured turnover of cholesterol in the brain. We expected the cholesterol flux into the brain to cause a down-regulation of cholesterol synthesis. Instead, cholesterol synthesis was increased by about 60%. The levels of 24(S)-hydroxycholesterol (24S-OHC) were significantly reduced in the brains of the pericyte-deficient mice but increased in the circulation. After treatment with 1% cholesterol in diet, the difference in cholesterol synthesis between mutants and controls disappeared. The findings are consistent with increased leakage of 24S-OHC from the brain into the circulation in the pericyte-deficient mice. This oxysterol is an efficient suppressor of cholesterol synthesis, and the results are consistent with a regulatory role of 24S-OHC in the brain. To our knowledge, this is the first demonstration that a defective BBB may lead to increased flux of a lipophilic compound out from the brain. The relevance of the findings for the human situation is discussed. PMID:24973215

  12. Consequences of repeated blood-brain barrier disruption in football players.

    PubMed

    Marchi, Nicola; Bazarian, Jeffrey J; Puvenna, Vikram; Janigro, Mattia; Ghosh, Chaitali; Zhong, Jianhui; Zhu, Tong; Blackman, Eric; Stewart, Desiree; Ellis, Jasmina; Butler, Robert; Janigro, Damir

    2013-01-01

    The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes. PMID:23483891

  13. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy.

    PubMed

    Rigau, Valérie; Morin, Mélanie; Rousset, Marie-Claude; de Bock, Frédéric; Lebrun, Aurore; Coubes, Philippe; Picot, Marie-Christine; Baldy-Moulinier, Michel; Bockaert, Joël; Crespel, Arielle; Lerner-Natoli, Mireille

    2007-07-01

    Previous studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies. We compared hippocampi from TLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood-brain barrier (BBB) leakage. We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events. In humans, the vessel density was significantly higher in TLE than in NE patients. This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated. Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE, VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures. We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring in TLE. PMID:17533168

  14. Permeability of the blood-brain barrier depends on brain temperature

    PubMed Central

    Kiyatkin, Eugene A.; Sharma, Hari S.

    2009-01-01

    Increased permeability of the blood-brain barrier (BBB) has been reported in different conditions accompanied by hyperthermia, but the role of brain temperature per se in modulating brain barrier functions has not been directly examined. To delineate the contribution of this factor, we examined albumin immunoreactivity in several brain structures (cortex, hippocampus, thalamus and hypothalamus) of pentobarbital-anesthetized rats (50 mg/kg, ip), which were passively warmed to different levels of brain temperature (32–42°C). Similar brain structures were also examined for the expression of glial fibrillary acidic protein (GFAP), an index of astrocytic activation, water and ion content, and morphological cell abnormalities. Data were compared with those obtained from drug-free awake rats with normal brain temperatures (36–37°C). The numbers of albumin- and GFAP-positive cells strongly correlates with brain temperature, gradually increasing from ~38.5°C and plateauing at 41–42°C. Brains maintained at hyperthermia also showed larger content of brain water and Na+, K+ and Cl− as well as structural abnormalities of brain cells, all suggesting acute brain edema. The latter alterations were seen at ~39°C, gradually progressed with temperature increase, and peaked at maximum hyperthermia. Temperature-dependent changes in albumin immunoreactivity tightly correlated with GFAP immunoreactivity, brain water, and numbers of abnormal cells; they were found in each tested area, but showed some structural specificity. Notably, a mild BBB leakage, selective glial activation, and specific cellular abnormalities were also found in the hypothalamus and piriform cortex during extreme hypothermia (32–33°C); in contrast to hyperthermia these changes were associated with decreased levels of brain water, Na+ and K+, suggesting acute brain dehydration. Therefore, brain temperature per se is an important factor in regulating BBB permeability, alterations in brain water

  15. Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier.

    PubMed

    Wang, Jing-Zhang; Xiao, Ning; Zhang, Ying-Zhou; Zhao, Chao-Xian; Guo, Xin-Hua; Lu, Li-Min

    2016-02-01

    The blood-brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain-microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a-based strategies for carrying drugs from blood to the CNS. First, the reversible inhibition of Mfsd2a may temporarily induce a general disinhibition of the transcytosis in BMECs to transport macromolecular drugs across the BBB (Strategy One). Second, Mfsd2a could be used for the transport of some small-molecule drugs chemically coupled to LPC across the BBB (Strategy Two), which is quite similar to the carrier-mediated transport (CMT) via the glucose transporter (GluT1) and the L-type amino acid transporter 1 (LAT1). We here analyze and discuss the clinical significance of the two Mfsd2a-based strategies, including therapeutic potential, available pharmaceuticals, side effects, administration procedures, and disease types. In summary, the regulatory role of Mfsd2a deepens our knowledge of the function of the BBB, potentially contributing to the effective drug delivery in the treatments for neurodegenerative diseases, brain tumors, and life-threatening infections in the CNS. PMID:26747400

  16. Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier.

    PubMed

    Banks, William A; Dohgu, Shinya; Lynch, Jessica L; Fleegal-DeMotta, Melissa A; Erickson, Michelle A; Nakaoke, Ryota; Vo, Than Q

    2008-04-01

    Insulin transported across the blood-brain barrier (BBB) has many effects within the central nervous system. Insulin transport is not static but altered by obesity and inflammation. Lipopolysaccharide (LPS), derived from the cell walls of Gram-negative bacteria, enhances insulin transport across the BBB but also releases nitric oxide (NO), which opposes LPS-enhanced insulin transport. Here we determined the role of NO synthase (NOS) in mediating the effects of LPS on insulin BBB transport. The activity of all three NOS isoenzymes was stimulated in vivo by LPS. Endothelial NOS and inducible NOS together mediated the LPS-enhanced transport of insulin, whereas neuronal NOS (nNOS) opposed LPS-enhanced insulin transport. This dual pattern of NOS action was found in most brain regions with the exception of the striatum, which did not respond to LPS, and the parietal cortex, hippocampus, and pons medulla, which did not respond to nNOS inhibition. In vitro studies of a brain endothelial cell (BEC) monolayer BBB model showed that LPS did not directly affect insulin transport, whereas NO inhibited insulin transport. This suggests that the stimulatory effect of LPS and NOS on insulin transport is mediated through cells of the neurovascular unit other than BECs. Protein and mRNA levels of the isoenzymes indicated that the effects of LPS are mainly posttranslational. In conclusion, LPS affects insulin transport across the BBB by modulating NOS isoenzyme activity. NO released by endothelial NOS and inducible NOS acts indirectly to stimulate insulin transport, whereas NO released by nNOS acts directly on BECs to inhibit insulin transport. PMID:18187549

  17. Modular properties of full 5D SYM partition function

    NASA Astrophysics Data System (ADS)

    Qiu, Jian; Tizzano, Luigi; Winding, Jacob; Zabzine, Maxim

    2016-03-01

    We study properties of the full partition function for the U(1) 5D N = {2}^{ast } gauge theory with adjoint hypermultiplet of mass M . This theory is ultimately related to abelian 6D (2,0) theory. We construct the full non-perturbative partition function on toric Sasaki-Einstein manifolds by gluing flat copies of the Nekrasov partition function and we express the full partition function in terms of the generalized double elliptic gamma function G 2 C associated with a certain moment map cone C. The answer exhibits a curious SL(4 , ℤ) modular property. Finally, we propose a set of rules to construct the partition function that resembles the calculation of 5d supersymmetric partition function with the insert ion of defects of various co-dimensions.

  18. A Robustness Testing Campaign for IMA-SP Partitioning Kernels

    NASA Astrophysics Data System (ADS)

    Grixti, Stephen; Lopez Trecastro, Jorge; Sammut, Nicholas; Zammit-Mangion, David

    2015-09-01

    With time and space partitioned architectures becoming increasingly appealing to the European space sector, the dependability of partitioning kernel technology is a key factor to its applicability in European Space Agency projects. This paper explores the potential of the data type fault model, which injects faults through the Application Program Interface, in partitioning kernel robustness testing. This fault injection methodology has been tailored to investigate its relevance in uncovering vulnerabilities within partitioning kernels and potentially contributing towards fault removal campaigns within this domain. This is demonstrated through a robustness testing case study of the XtratuM partitioning kernel for SPARC LEON3 processors. The robustness campaign exposed a number of vulnerabilities in XtratuM, exhibiting the potential benefits of using such a methodology for the robustness assessment of partitioning kernels.

  19. 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.

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

    DOEpatents

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

    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.

  1. A straightforward wet-chemistry method for the determination of solid and gaseous mercury fractions in Backlight Cold Cathode Fluorescence Lamps.

    PubMed

    Figi, Renato; Nagel, Oliver; Hagendorfer, Harald

    2012-10-15

    Backlight Cold Cathode Fluorescence Lamps (B-CCFLs) are already applied in many electronic consumer products such as LCD screens, flat screen TVs, and laptop monitors. In consequence, an increase of such products entering the waste streams can be expected in the near future. As a result of the mercury (Hg) employed in such lamps, the development of recycling techniques to create a best practical environmental option for appropriate end-of-life strategies are necessary. For this purpose the knowledge about speciation in terms of solid and gaseous state of Hg in such lamps is inevitable. However, analytical techniques to discriminate solid and gaseous Hg require a special setup, not available in most routine laboratories. Thus a straightforward and cost efficient analytical technique is of need. In this work we describe sample preparation procedures and analysis techniques, which only require equipment already available in most routine laboratories. The volatile fraction is extracted with a KMnO(4) solution utilizing a novel approach, taking the advantage that the B-CCFL glass tubes have a negative pressure. Thus the extraction solution is directly sucked into the tube where the volatile Hg-fraction is immediately extracted. Subsequently, the solid fraction is dissolved via microwave assisted pressure acid digestion after cryo-milling. Analysis for both fractions took place employing a cold vapor atomic absorption system. To prove the new method is fit for purpose, spiking experiments and analysis of reference materials (when available) was performed with recoveries being between 90% and 110%. First results obtained for a stack of lamps from an used LCD-TV display reveal that solid Hg fractions in all lamps show a variation of 20% between samples whereas the gaseous Hg content can vary up to 600%. PMID:23141320

  2. TAP - Tools for Adaptive Partitioning v. 0.99 Beta

    Energy Science and Technology Software Center (ESTSC)

    2008-11-19

    TAP is a set of tools which are essential for conducting research on adaptive partitioners. The basic premise is that a single partitioner may not be a good choice for adaptive mesh simulations; rather one must match a partitioner (obtained from a partitioning package like Zoltan, ParMetis etc) with the mesh being partitioned. TAP provides the tools that can judge the suitability of a partitioning algorithm to a given mesh.

  3. Vector-Mediated Delivery of a Polyamide ("Peptide") Nucleic Acid Analogue through the Blood-Brain Barrier in vivo

    NASA Astrophysics Data System (ADS)

    Pardridge, William M.; Boado, Ruben J.; Kang, Young-Sook

    1995-06-01

    Polyamide ("peptide") nucleic acids (PNAs) are molecules with antigene and antisense effects that may prove to be effective neuropharmaceuticals if these molecules are enabled to undergo transport through the brain capillary endothelial wall, which makes up the blood-brain barrier in vivo. The model PNA used in the present studies is an 18-mer that is antisense to the rev gene of human immunodeficiency virus type 1 and is biotinylated at the amino terminus and iodinated at a tyrosine residue near the carboxyl terminus. The biotinylated PNA was linked to a conjugate of streptavidin (SA) and the OX26 murine monoclonal antibody to the rat transferrin receptor. The blood-brain barrier is endowed with high transferrin receptor concentrations, enabling the OX26-SA conjugate to deliver the biotinylated PNA to the brain. Although the brain uptake of the free PNA was negligible following intravenous administration, the brain uptake of the PNA was increased at least 28-fold when the PNA was bound to the OX26-SA vector. The brain uptake of the PNA bound to the OX26-SA vector was 0.1% of the injected dose per gram of brain at 60 min after an intravenous injection, approximating the brain uptake of intravenously injected morphine. The PNA bound to the OX26-SA vector retained the ability to bind to synthetic rev mRNA as shown by RNase protection assays. In summary, the present studies show that while the transport of PNAs across the blood-brain barrier is negligible, delivery of these potential neuropharmaceutical drugs to the brain may be achieved by coupling them to vector-mediated peptide-drug delivery systems.

  4. Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain

    PubMed Central

    Behrens, Matthias; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

    2015-01-01

    Background Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects. Methods Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients. Results Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport. PMID:26600019

  5. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

    PubMed

    Hammer, C; Stepniak, B; Schneider, A; Papiol, S; Tantra, M; Begemann, M; Sirén, A-L; Pardo, L A; Sperling, S; Mohd Jofrry, S; Gurvich, A; Jensen, N; Ostmeier, K; Lühder, F; Probst, C; Martens, H; Gillis, M; Saher, G; Assogna, F; Spalletta, G; Stöcker, W; Schulz, T F; Nave, K-A; Ehrenreich, H

    2014-10-01

    In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function. PMID:23999527

  6. Strainrange partitioning: A total strain range version

    NASA Technical Reports Server (NTRS)

    Halford, G. R.; Saltsman, J. F.

    1983-01-01

    Procedures are presented for expressing the Strainrange Partitioning (SRP) method for creep fatigue life prediction in terms of total strain range. Inelastic and elastic strain-range - life relations are summed to give total strain-range - life relations. The life components due to inelastic strains are dealt with using conventional SRP procedures while the life components due to elastic strains are expressed as families of time-dependent terms for each type of SRP cycle. Cyclic constitutive material behavior plays an important role in establishing the elastic strain-range - life relations as well as the partitioning of the inelastic strains. To apply the approach, however, it is not necessary to have to determine the magnitude of the inelastic strain range. The total strain SRP approach is evaluated and verified using two nickel base superalloys, AF2-1DA and Rene 95. Excellent agreement is demonstrated between observed and predicted cyclic lifetimes with 70 to 80 percent of the predicted lives falling within factors of two of the observed lives. The total strain-range SRP approach should be of considerable practical value to designers who are faced with creep-fatigue problems for which the inelastic strains cannot be calculated with sufficient accuracy to make reliable life predictions by the conventional inelastic strain range SRP approach.

  7. Gait Partitioning Methods: A Systematic Review.

    PubMed

    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

  8. Inversion of hematocrit partition at microfluidic bifurcations.

    PubMed

    Shen, Zaiyi; Coupier, Gwennou; Kaoui, Badr; Polack, Benoît; Harting, Jens; Misbah, Chaouqi; Podgorski, Thomas

    2016-05-01

    Partitioning of red blood cells (RBCs) at the level of bifurcations in the microcirculatory system affects many physiological functions yet it remains poorly understood. We address this problem by using T-shaped microfluidic bifurcations as a model. Our computer simulations and in vitro experiments reveal that the hematocrit (ϕ0) partition depends strongly on RBC deformability, as long as ϕ0<20% (within the normal range in microcirculation), and can even lead to complete deprivation of RBCs in a child branch. Furthermore, we discover a deviation from the Zweifach-Fung effect which states that the child branch with lower flow rate recruits less RBCs than the higher flow rate child branch. At small enough ϕ0, we get the inverse scenario, and the hematocrit in the lower flow rate child branch is even higher than in the parent vessel. We explain this result by an intricate up-stream RBC organization and we highlight the extreme dependence of RBC transport on geometrical and cell mechanical properties. These parameters can lead to unexpected behaviors with consequences on the microcirculatory function and oxygen delivery in healthy and pathological conditions. PMID:26744089

  9. 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.

  10. Approximate algorithms for partitioning and assignment problems

    NASA Technical Reports Server (NTRS)

    Iqbal, M. A.

    1986-01-01

    The problem of optimally assigning the modules of a parallel/pipelined program over the processors of a multiple computer system under certain restrictions on the interconnection structure of the program as well as the multiple computer system was considered. For a variety of such programs it is possible to find linear time if a partition of the program exists in which the load on any processor is within a certain bound. This method, when combined with a binary search over a finite range, provides an approximate solution to the partitioning problem. The specific problems considered were: a chain structured parallel program over a chain-like computer system, multiple chain-like programs over a host-satellite system, and a tree structured parallel program over a host-satellite system. For a problem with m modules and n processors, the complexity of the algorithm is no worse than O(mnlog(W sub T/epsilon)), where W sub T is the cost of assigning all modules to one processor and epsilon the desired accuracy.

  11. Unsupervised image categorization by hypergraph partition.

    PubMed

    Huang, Yuchi; Liu, Qingshan; Lv, Fengjun; Gong, Yihong; Metaxas, Dimitris N

    2011-06-01

    We present a framework for unsupervised image categorization in which images containing specific objects are taken as vertices in a hypergraph and the task of image clustering is formulated as the problem of hypergraph partition. First, a novel method is proposed to select the region of interest (ROI) of each image, and then hyperedges are constructed based on shape and appearance features extracted from the ROIs. Each vertex (image) and its k-nearest neighbors (based on shape or appearance descriptors) form two kinds of hyperedges. The weight of a hyperedge is computed as the sum of the pairwise affinities within the hyperedge. Through all of the hyperedges, not only the local grouping relationships among the images are described, but also the merits of the shape and appearance characteristics are integrated together to enhance the clustering performance. Finally, a generalized spectral clustering technique is used to solve the hypergraph partition problem. We compare the proposed method to several methods and its effectiveness is demonstrated by extensive experiments on three image databases. PMID:21282850

  12. 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.

  13. Partitioning of on-demand electron pairs

    NASA Astrophysics Data System (ADS)

    Ubbelohde, Niels; Hohls, Frank; Kashcheyevs, Vyacheslavs; Wagner, Timo; Fricke, Lukas; Kästner, Bernd; Pierz, Klaus; Schumacher, Hans W.; Haug, Rolf J.

    2015-01-01

    The on-demand generation and separation of entangled photon pairs are key components of quantum information processing in quantum optics. In an electronic analogue, the decomposition of electron pairs represents an essential building block for using the quantum state of ballistic electrons in electron quantum optics. The scattering of electrons has been used to probe the particle statistics of stochastic sources in Hanbury Brown and Twiss experiments and the recent advent of on-demand sources further offers the possibility to achieve indistinguishability between multiple sources in Hong-Ou-Mandel experiments. Cooper pairs impinging stochastically at a mesoscopic beamsplitter have been successfully partitioned, as verified by measuring the coincidence of arrival. Here, we demonstrate the splitting of electron pairs generated on demand. Coincidence correlation measurements allow the reconstruction of the full counting statistics, revealing regimes of statistically independent, distinguishable or correlated partitioning, and have been envisioned as a source of information on the quantum state of the electron pair. The high pair-splitting fidelity opens a path to future on-demand generation of spin-entangled electron pairs from a suitably prepared two-electron quantum-dot ground state.

  14. Determining Peptide Partitioning Properties via Computer Simulation

    PubMed Central

    Ulmschneider, Jakob P.; Ulmschneider, Martin B.

    2010-01-01

    The transfer of polypeptide segments into lipid bilayers to form transmembrane helices represents the crucial first step in cellular membrane protein folding and assembly. This process is driven by complex and poorly understood atomic interactions of peptides with the lipid bilayer environment. The lack of suitable experimental techniques that can resolve these processes both at atomic resolution and nanosecond timescales has spurred the development of computational techniques. In this review, we summarize the significant progress achieved in the last few years in elucidating the partitioning of peptides into lipid bilayer membranes using atomic detail molecular dynamics simulations. Indeed, partitioning simulations can now provide a wealth of structural and dynamic information. Furthermore, we show that peptide-induced bilayer distortions, insertion pathways, transfer free energies, and kinetic insertion barriers are now accurate enough to complement experiments. Further advances in simulation methods and force field parameter accuracy promise to turn molecular dynamics simulations into a powerful tool for investigating a wide range of membrane active peptide phenomena. PMID:21107546

  15. 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

  16. Life prediction modeling based on strainrange partitioning

    NASA Technical Reports Server (NTRS)

    Halford, Gary R.

    1988-01-01

    Strainrange partitioning (SRP) is an integrated low-cycle-fatigue life predicting system. It was created specifically for calculating cyclic crack initiation life under severe high-temperature fatigue conditions. The key feature of the SRP system is its recognition of the interacting mechanisms of cyclic inelastic deformation that govern cyclic life at high temperatures. The SRP system bridges the gap between the mechanistic level of understanding that breeds new and better materials and the phenomenological level wherein workable engineering life prediction methods are in great demand. The system was recently expanded to address engineering fatigue problems in the low-strain, long-life, nominally elastic regime. This breakthrough, along with other advances in material behavior and testing technology, has permitted the system to also encompass low-strain thermomechanical loading conditions. Other important refinements of the originally proposed method include procedures for dealing with life-reducing effects of multiaxial loading, ratcheting, mean stresses, nonrepetitive (cumulative loading) loading, and environmental and long-time exposure. Procedure were also developed for partitioning creep and plastic strain and for estimating strainrange versus life relations from tensile and creep rupture properties. Each of the important engineering features of the SRP system are discussed and examples shown of how they help toward predicting high-temperature fatigue life under practical, although complex, loading conditions.

  17. [CURRENT OPPORTUNITIES IN THE IDENTIFICATION OF NOVEL MOLECULAR TARGETS FOR PHARMACOLOGICAL CORRECTION OF BLOOD-BRAIN BARRIER PERMEABILITY].

    PubMed

    Morgun, A V; Ruzaeva, V A; Boitsova, E B; Taranushenko, T E; Martynova, G P; Tohidpour, A; Salmina, A B

    2015-01-01

    Review covers current achievements in the methodology of target discovery and validation for the development of drugs restoring structural and functional integrity of the blood-brain barrier (BBB) in cases of brain injury and neuroinflammation. Some new targets (in the context of BBB permeability) are discussed, which are involved in the regulation of signal transduction involving HIF-1, JNK, NF-κB, Rac, 1 etc., expression of tight-junction proteins, and activity of enzymes producing molecules with pro-inflammatory effects in the BBB cells. PMID:27051929

  18. The blood-brain barrier penetration and distribution of PEGylated fluorescein-doped magnetic silica nanoparticles in rat brain

    SciTech Connect

    Ku, Shuting; Yan, Feng; Wang, Ying; Sun, Yilin; Yang, Nan; Ye, Ling

    2010-04-16

    PEGylated PAMAM conjugated fluorescein-doped magnetic silica nanoparticles (PEGylated PFMSNs) have been synthesized for evaluating their ability across the blood-brain barrier (BBB) and distribution in rat brain. The obtained nanoparticles were characterized by transmission electron microscopy (TEM), thermal gravimetry analyses (TGA), zeta potential ({zeta}-potential) titration, and X-ray photoelectron spectroscopy (XPS). The BBB penetration and distribution of PEGylated PFMSNs and FMSNs in rat brain were investigated not only at the cellular level with Confocal laser scanning microscopy (CLSM), but also at the subcellular level with transmission electron microscopy (TEM). The results provide direct evidents that PEGylated PFMSNs could penetrate the BBB and spread into the brain parenchyma.

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

    NASA Astrophysics Data System (ADS)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-05-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. The method presents new opportunities for the use of drugs and for the study of the brain.

  20. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

    PubMed Central

    Saunders, Norman R.; Dreifuss, Jean-Jacques; Dziegielewska, Katarzyna M.; Johansson, Pia A.; Habgood, Mark D.; Møllgård, Kjeld; Bauer, Hans-Christian

    2014-01-01

    Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue) exclusion from the brain when injected systemically, but not when injected directly into it. Rarely cited are earlier experiments of Bouffard and of Franke who showed methylene blue and trypan red stained all tissues except the brain. The term “blood-brain barrier” “Blut-Hirnschranke” is often attributed to Lewandowsky, but it does not appear in his papers. The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern and colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling. As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all the evidence and assessing its quality, rather than selecting papers that supports a preconceived notion or intuitive belief. This review attempts to right the wrongs

  1. 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.

  2. Diffusive isothermal partitioning in a layered medium with geologic applications

    NASA Technical Reports Server (NTRS)

    Hopper, R. W.; Uhlmann, D. R.

    1976-01-01

    The diffusive isothermal partitioning of solute in a layered two-phase material has been analyzed to help elucidate the phenomenon of solute partitioning in multiphase lunar and terrestrial materials and to estimate the cooling history of samples. After reviewing the physical chemistry of partitioning and the case of an infinite one-dimensional diffusion couple, we solve in analytic form the case of a finite one-dimensional couple. The solution can be used to estimate cooling histories or to interpret laboratory experiments on partitioning. A sample calculation is included.

  3. A Framework for Parallel Nonlinear Optimization by Partitioning Localized Constraints

    SciTech Connect

    Xu, You; Chen, Yixin

    2008-06-28

    We present a novel parallel framework for solving large-scale continuous nonlinear optimization problems based on constraint partitioning. The framework distributes constraints and variables to parallel processors and uses an existing solver to handle the partitioned subproblems. In contrast to most previous decomposition methods that require either separability or convexity of constraints, our approach is based on a new constraint partitioning theory and can handle nonconvex problems with inseparable global constraints. We also propose a hypergraph partitioning method to recognize the problem structure. Experimental results show that the proposed parallel algorithm can efficiently solve some difficult test cases.

  4. Molecular partitioning based on the kinetic energy density

    NASA Astrophysics Data System (ADS)

    Noorizadeh, Siamak

    2016-05-01

    Molecular partitioning based on the kinetic energy density is performed to a number of chemical species, which show non-nuclear attractors (NNA) in their gradient maps of the electron density. It is found that NNAs are removed using this molecular partitioning and although the virial theorem is not valid for all of the basins obtained in the being used AIM, all of the atoms obtained using the new approach obey this theorem. A comparison is also made between some atomic topological parameters which are obtained from the new partitioning approach and those calculated based on the electron density partitioning.

  5. 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. PMID:26810802

  6. Brain damage from sup 125 I brachytherapy evaluated by MR imaging, a blood-brain barrier tracer, and light and electron microscopy in a rat model

    SciTech Connect

    Bernstein, M.; Marotta, T.; Stewart, P.; Glen, J.; Resch, L.; Henkelman, M. )

    1990-10-01

    Changes in normal rat brain were studied acutely, and at 3, 6, 9, and 12 months following interstitial brachytherapy with high-activity {sup 125}I seeds. An 80-Gy radiation dose was administered to an area with a 5.5-mm radius. Effects were measured with magnetic resonance (MR) imaging (with and without gadolinium enhancement), leakage of horseradish peroxidase (HRP), electron microscopy, and light microscopy. Significant histological damage was seen at radiation doses above 295 Gy, and breakdown of the blood-brain barrier was observed only in tissue receiving a dose of 165 Gy or greater. Blood-brain barrier breakdown increased up to the 6-month time point, and thereafter appeared to stabilize or decrease. The area of blood-brain barrier disruption indicated by gadolinium-enhanced MR imaging was greater than that indicated by leakage of HRP.

  7. Partition Coefficients at High Pressure and Temperature

    NASA Astrophysics Data System (ADS)

    Righter, K.; Drake, M. J.

    2003-12-01

    Differentiation of terrestrial planets includes separation of a metallic core and possible later fractionation of mineral phases within either a solid or molten mantle (Figure 1). Lithophile and siderophile elements can be used to understand these two different physical processes, and ascertain whether they operated in the early Earth. The distribution of elements in planets can be understood by measuring the partition coefficient, D (ratio of concentrations of an element in different phases (minerals, metals, or melts)). (14K)Figure 1. Schematic cross-section through the Earth, showing: (a) an early magma ocean stage and (b) a later cool and differentiated stage. The siderophile elements (iron-loving) encompass over 30 elements and are defined as those elements for which D(metal/silicate)>1, and are useful for deciphering the details of core formation. This group of elements is commonly broken up into several subclasses, including the slightly siderophile elements (1104). Because these three groups encompass a wide range of partition coefficient values, they can be very useful in trying to determine the conditions under which metal may have equilibrated with the mantle (or a magma ocean). Because metal and silicate may equilibrate by several different mechanisms, such as at the base of a deep magma ocean, or as metal droplets descend through a molten mantle, partition coefficients can potentially shed light on which mechanism may be most important, thus linking the physics and chemistry of core formation. In this chapter, we summarize metal/silicate partitioning of siderophile elements and show how they may be used to understand planetary core formation.Once a planet is differentiated into core and mantle, a mantle will cool during convection, and can start in either a molten or solid state, depending upon the initial thermal conditions. If hot enough, minerals will

  8. 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.

  9. 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. PMID:27137915

  10. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine.

    PubMed

    Schankin, Christoph J; Maniyar, Farooq H; Seo, Youngho; Kori, Shashidar; Eller, Michael; Chou, Denise E; Blecha, Joseph; Murphy, Stephanie T; Hawkins, Randall A; Sprenger, Till; VanBrocklin, Henry F; Goadsby, Peter J

    2016-07-01

    SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks. PMID:27234268

  11. 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

  12. Interspecific resource partitioning in sympatric ursids.

    PubMed

    Belant, Jerrold L; Kielland, Knut; Follmann, Erich H; Adams, Layne G

    2006-12-01

    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 south-central 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

  13. Traceds: An Experimental Trace Element Partitioning Database

    NASA Astrophysics Data System (ADS)

    Nielsen, R. L.; Ghiorso, M. S.

    2014-12-01

    The goal of this project, which is part of the EARTHCHEM initiative, is to compile the existing experimental trace element partitioning data, and to develop a transparent, accessible resource for the community. The primary goal of experimental trace element partitioning studies is to create a database that can be used to develop models of how trace elements behave in natural geochemical systems. The range of approaches as to how this is accomplished and how the data are reported differs dramatically from one system to another and one investigator to another. This provides serious challenges to the creation of a coherent database - and suggests the need for a standard format for data presentation and reporting. The driving force for this compilation is to provide community access to the complete database for trace element experiments. Our new effort includes all the published analytical results from experimental determinations. In compiling the data, we have set a minimum standard for the data to be included. The threshold criteria include: Experimental conditions (temperature, pressure, device, container, time, etc.) Major element composition of the phases Trace element analyses of the phases Data sources that did not report these minimum components were not included. The rationale for not including such data is that the degree of equilibration is unknown, and more important, no rigorous approach to modeling the behavior of trace elements is possible without a knowledge of the actual concentrations or the temperature and pressure of formation. The data are stored using a schema derived from that of the Library of Experimental Phase Relations (LEPR), modified to account for additional metadata, and restructured to permit multiple analytical entries for various element/technique/standard combinations. Our ultimate goal is to produce a database together with a flexible user interface that will be useful for experimentalists to set up their work and to build

  14. Permeability changes in the blood-brain barrier: causes and consequences.

    PubMed

    Pardridge, W M; Connor, J D; Crawford, I L

    1975-01-01

    1. Generalized changes in blood-brain barrier (BBB) permeability are accompanied by extravasation of plasma proteins; thus, they are readily studied with protein markers or protein-dye complexes. Selective changes in permeability involve alterations in BBB transport systems; they are best studied with techniques which detect the qualitative hallmarks of carrier-mediated transport, namely saturation, competition, and stereospecificity. 2. Quantitative assessments of the selective permeability of the BBB can be made from the saturation data expressed in terms of Michaelis-Menten kinetics. The advantages of the latter are twofold: (a) alterations elicited by modified barrier affinity (Km) can be distinguished from alterations in carrier capacity (Vmax); (b) the relative rates of flux of a metabolite across the BBB can be placed in the perspective of cerebral metabolism. Kinetic data on transport processes in the BBB are obtained by either constant infusion or single injection techniques. Results obtained with both methodologies have been comparable. 3. Independent transport systems for glucose, neutral amino acids, basic amino acids, and monocarboxylic acids have been identified in the BBB. The description of these transport systems in kinetic terms provides a background of information on intact mechanisms to which altered transport can be compared. 4. Experimental evidence indicates that the availability of key metabolic substrates, such as glucose or essential amino acids, may be rate-limiting in cerebral metabolism. A working hypothesis was developed that the consequences of a selective change in barrier permeability to one or more of these essential substrates are directly related to altered rates of reaction in substrate-limited pathways, e.g., cerebral protein or neuro-transmitter biosynthesis. 5. Toxicological causes of generalized changes in BBB permeability include hypertonic solutions, organic solvents, surface-active agents, enzymes, and heavy metals. Some

  15. C5a alters blood-brain barrier integrity in experimental lupus.

    PubMed

    Jacob, Alexander; Hack, Bradley; Chiang, Eddie; Garcia, Joe G N; Quigg, Richard J; Alexander, Jessy J

    2010-06-01

    The blood-brain barrier (BBB) is a crucial anatomic location in the brain. Its dysfunction complicates many neurodegenerative diseases, from acute conditions, such as sepsis, to chronic diseases, such as systemic lupus erythematosus (SLE). Several studies suggest an altered BBB in lupus, but the underlying mechanism remains unknown. In the current study, we observed a definite loss of BBB integrity in MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) lupus mice by IgG infiltration into brain parenchyma. In line with this result, we examined the role of complement activation, a key event in this setting, in maintenance of BBB integrity. Complement activation generates C5a, a molecule with multiple functions. Because the expression of the C5a receptor (C5aR) is significantly increased in brain endothelial cells treated with lupus serum, the study focused on the role of C5a signaling through its G-protein-coupled receptor C5aR in brain endothelial cells, in a lupus setting. Reactive oxygen species production increased significantly in endothelial cells, in both primary cells and the bEnd3 cell line treated with lupus serum from MRL/lpr mice, compared with those treated with control serum from MRL(+/+) mice. In addition, increased permeability monitored by changes in transendothelial electrical resistance, cytoskeletal remodeling caused by actin fiber rearrangement, and increased iNOS mRNA expression were observed in bEnd3 cells. These disruptive effects were alleviated by pretreating cells with a C5a receptor antagonist (C5aRant) or a C5a antibody. Furthermore, the structural integrity of the vasculature in MRL/lpr brain was maintained by C5aR inhibition. These results demonstrate the regulation of BBB integrity by the complement system in a neuroinflammatory setting. For the first time, a novel role of C5a in the maintenance of BBB integrity is identified and the potential of C5a/C5aR blockade highlighted as a promising therapeutic strategy in SLE and other neurodegenerative diseases

  16. MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

    NASA Astrophysics Data System (ADS)

    Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

    2011-09-01

    Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain

  17. Blood-Brain Barrier Permeability of Normal Appearing White Matter in Relapsing-Remitting Multiple Sclerosis

    PubMed Central

    Lund, Henrik; Krakauer, Martin; Skimminge, Arnold; Sellebjerg, Finn; Garde, Ellen; Siebner, Hartwig R.; Paulson, Olaf B.; Hesse, Dan; Hanson, Lars G.

    2013-01-01

    Background Multiple sclerosis (MS) affects the integrity of the blood-brain barrier (BBB). Contrast-enhanced T1 weighted magnetic resonance imaging (MRI) is widely used to characterize location and extent of BBB disruptions in focal MS lesions. We employed quantitative T1 measurements before and after the intravenous injection of a paramagnetic contrast agent to assess BBB permeability in the normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS). Methodology/Principal Findings Fifty-nine patients (38 females) with RR-MS undergoing immunomodulatory treatment and nine healthy controls (4 females) underwent quantitative T1 measurements at 3 tesla before and after injection of a paramagnetic contrast agent (0.2 mmol/kg Gd-DTPA). Mean T1 values were calculated for NAWM in patients and total cerebral white matter in healthy subjects for the T1 measurements before and after injection of Gd-DTPA. The pre-injection baseline T1 of NAWM (945±55 [SD] ms) was prolonged in RR-MS relative to healthy controls (903±23 ms, p = 0.028). Gd-DTPA injection shortened T1 to a similar extent in both groups. Mean T1 of NAWM was 866±47 ms in the NAWM of RR-MS patients and 824±13 ms in the white matter of healthy controls. The regional variability of T1 values expressed as the coefficient of variation (CV) was comparable between the two groups at baseline, but not after injection of the contrast agent. After intravenous Gd-DTPA injection, T1 values in NAWM were more variable in RR-MS patients (CV = 0.198±0.046) compared to cerebral white matter of healthy controls (CV = 0.166±0.018, p = 0.046). Conclusions/Significance We found no evidence of a global BBB disruption within the NAWM of RR-MS patients undergoing immunomodulatory treatment. However, the increased variation of T1 values in NAWM after intravenous Gd-DTPA injection points to an increased regional inhomogeneity of BBB function in NAWM in relapsing-remitting MS. PMID:23441184

  18. Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition

    PubMed Central

    Alluri, Himakarnika; Wilson, Rickesha L.; Anasooya Shaji, Chinchusha; Wiggins-Dohlvik, Katie; Patel, Savan; Liu, Yang; Peng, Xu; Beeram, Madhava R.; Davis, Matthew L.; Huang, Jason H.; Tharakan, Binu

    2016-01-01

    Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB) often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI). At a cellular level, tight junction proteins (TJPs) between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1) that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1β (IL-1β) as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1β (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 μg/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 μM; 1 hour), MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour) or MMP-9 siRNA transfection (48 hours) in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1β-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1β treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB

  19. Mouse Adenovirus Type 1 Early Region 1A Effects on the Blood-Brain Barrier

    PubMed Central

    Tirumuru, Nagaraja; Pretto, Carla D.; Castro Jorge, Luiza A.

    2016-01-01

    ABSTRACT Mouse adenovirus type 1 (MAV-1) infects endothelial cells and disrupts the blood-brain barrier (BBB), causing encephalitis in inbred and outbred mice. Using a virus mutant that does not produce the early region 1A protein E1A, we investigated whether the activity of this known viral transcriptional regulator is needed for BBB disruption and other phenotypes associated with encephalitis. The wild-type (wt) virus and E1A mutant virus caused similar levels of permeability of sodium fluorescein in brains of infected mice. In an in vitro assay of BBB integrity, wt and mutant virus caused similar decreases in transendothelial electrical resistance in primary mouse brain endothelial cell monolayers. These results indicate that E1A protein does not contribute to disruption of BBB integrity in animals or cultured cells. Both wt and E1A mutant virus infection of mice led to similar increases in the activity of two matrix metalloproteinases known to correlate with BBB disruption, MMP2 and MMP9, while causing no increase in the steady-state expression of MMP2 or MMP9 mRNA. In contrast, the amount of MMP3 transcripts increased upon infection by both viruses and to a higher level in infections by the mutant virus lacking E1A protein production. There was no difference in the levels of steady-state expression of mRNA for tight junction proteins among mock virus, wt virus, and mutant virus infections. Thus, the MAV-1 E1A protein does not measurably affect BBB integrity in the parameters assayed, although it reduces the amount of MMP3 mRNA steady-state expression induced in brains upon infection. IMPORTANCE Encephalitis can be caused by viruses, and it is potentially life-threatening because of the vital nature of the brain and the lack of treatment options. MAV-1 produces viral encephalitis in its natural host, providing a model for investigating factors involved in development of encephalitis. MAV-1 infection disrupts the BBB and increases activity of matrix

  20. The role of shear stress in Blood-Brain Barrier endothelial physiology

    PubMed Central

    2011-01-01

    Background One of the most important and often neglected physiological stimuli contributing to the differentiation of vascular endothelial cells (ECs) into a blood-brain barrier (BBB) phenotype is shear stress (SS). With the use of a well established humanized dynamic in vitro BBB model and cDNA microarrays, we have profiled the effect of SS in the induction/suppression of ECs genes and related functions. Results Specifically, we found a significant upregulation of tight and adherens junctions proteins and genes. Trans-endothelial electrical resistance (TEER) and permeability measurements to know substances have shown that SS promoted the formation of a tight and highly selective BBB. SS also increased the RNA level of multidrug resistance transporters, ion channels, and several p450 enzymes. The RNA level of a number of specialized carrier-mediated transport systems (e.g., glucose, monocarboxylic acid, etc.) was also upregulated. RNA levels of modulatory enzymes of the glycolytic pathway (e.g., lactate dehydrogenase) were downregulated by SS while those involved in the Krebs cycle (e.g., lactate and other dehydrogenases) were upregulated. Measurements of glucose consumption versus lactate production showed that SS negatively modulated the glycolytic bioenergetic pathways of glucose metabolism in favor of the more efficient aerobic respiration. BBB ECs are responsive to inflammatory stimuli. Our data showed that SS increased the RNA levels of integrins and vascular adhesion molecules. SS also inhibited endothelial cell cycle via regulation of BTG family proteins encoding genes. This was paralleled by significant increase in the cytoskeletal protein content while that of membrane, cytosol, and nuclear sub-cellular fractions decreased. Furthermore, analysis of 2D gel electrophoresis (which allows identifying a large number of proteins per sample) of EC proteins extracted from membrane sub-cellular endothelial fractions showed that SS increased the expression levels