275 research outputs found
Allied Health Regional Workforce Analysis: Bay Area Region
Analyzes the racial/ethnic composition of workers in twenty-two health occupations and graduates of healthcare education programs in the Bay Area. Examines disparities by race/ethnicity in the types of occupations held, educational attainment, and wages
Allied Health Regional Workforce Analysis: Central California
Analyzes the racial/ethnic compositions of workers in twenty-two health occupations and graduates of healthcare education programs in the Central Valley. Examines disparities by race/ethnicity in occupations held, educational attainment, and wages
Modulation des P2X7-Rezeptors durch Tanshinon II A Sulfonat und pathophysiologische Bedeutung des Rezeptors bei zerebraler IschÀmie
Der ATP-getriggerte Ionenkanal P2X7 ist als purinerger OberflĂ€chenrezeptor besonders auf Zellen des Immunsystems und auf Gliazellen im Nervensystem exprimiert. Seine Aktivierung fĂŒhrt zur Freisetzung proinflammatorischer Zytokine, zur Bildung reaktiver Sauerstoffspezies sowie zu einer Beeinflussung des Zellzyklus. Zwar konnte eine Beteiligung des Rezeptors an verschiedenen entzĂŒndlichen und degenerativen Erkrankungen nachgewiesen werden, allerdings bestehen nach wie vor viele Unstimmigkeiten darĂŒber, ob P2X7 im Einzelfall protektiv oder schadend wirkt. Eine therapeutische Modulation des Rezeptors gestaltet sich daher bis heute schwierig. Weiterhin wurde trotz intensiver BemĂŒhungen um selektive, potente P2X7-Modulatoren bisher kein Wirkstoff ĂŒber Phase-II-Studien hinaus entwickelt.
Der erste Teil der Arbeit beschreibt eine Studie zur Identifikation neuer P2X7-Modulatoren und deren Charakterisierung hinsichtlich Potenz, Bindeverhalten und SpeziesspezifitĂ€t. Ziel dieser Studie war es, die Basis fĂŒr die Entwicklung möglicher neuer Therapeutika zu legen, fĂŒr die ein hoher Bedarf besteht.
Im zweiten Teil der Arbeit wurde die Beteiligung des P2X7-Rezeptors an den pathophysiologischen VorgĂ€ngen nach einem Hirninfarkt untersucht. Besondere Aufmerksamkeit lag dabei auf dem Einfluss, den der Rezeptor auf die Bildung eines begleitenden, oftmals fatalen Hirnödems ausĂŒbt.
In einer Wirkstoffbibliothek enthaltene zugelassene Pharmaka und Naturstoffe wurden auf ihre Wirksamkeit am rekombinant exprimierten humanen P2X7-Rezeptor (hP2X7) getestet. Dazu wurde gemessen, inwiefern diese Wirkstoffe den P2X7-vermittelten Ca2+-Einstrom modulieren können. FĂŒr potenziell selektive
Substanzen wurden Konzentrations-Wirkungs-Kurven erstellt. FĂŒr den potenten Inhibitor Tanshinon II A-Sulfonat (TIIAS) und den chemisch verwandten Wirkstoff Tanshinon II A (TIIA) erfolgte diese Untersuchung auch an den rekombinant exprimierten P2X7-Rezeptoren von Maus (mP2X7) und Ratte (rP2X7). Weiterhin
erfolgte eine detaillierte, auf elektrophysiologischen Untersuchungen basierende Darstellung der pharmakodynamischen Eigenschaften von TIIAS. Die SelektivitĂ€t der Wirkung gegenĂŒber P2X2 und P2X4 wurde mithilfe entsprechender Zelllinien geprĂŒft. Die Wirkung modulierender Pharmaka am nativen Rezeptor wurde in humanen, aus peripheren Blutmonozyten gereiften Makrophagen ĂŒberprĂŒft, wozu neben der Darstellung des Ca2+-Einstroms auch ein IL-1ÎČ-ELISA eingesetzt wurde. In allen Experimenten wurde die Beteiligung von P2X7 ĂŒber bekannte Antagonisten verifiziert. Um zu klĂ€ren, inwiefern P2X7 die pathophysiologischen AblĂ€ufe nach Hirninfarkt beeinflusst, wurde bei 20 P2X7-defizienten MĂ€usen (P2X7-/-) und bei 22 zugehörigen Wildtyp-MĂ€usen (WT) eine zerebrale IschĂ€mie
induziert, indem die mittlere Zerebralarterie mit einem dĂŒnnen Faden fĂŒr 60 Minuten transient verschlossen wurde (middle cerebral artery occlusion, MCAO). In den folgenden 72 Stunden wurde ĂŒber klinische Methoden und Magnetresonanzuntersuchungen die Entwicklung neurologischer Defizite, der InfarktgröĂe und des begleitenden Hirnödems evaluiert. Nach schmerzloser Tötung und Hirnentnahme wurden immunhistologisch die Aktivierung und Verteilung von Mikroglia und Astrozyten sowie der Zustand des GefĂ€Ăendothels untersucht. Sham-operierte Tiere dienten in allen Experimenten als Kontrollen.
TIIAS hemmte hP2X7 mit einer IC50 von 4.3 ÎŒM, wĂ€hrend die Potenz an mP2X7 geringer war und rP2X7 kaum geblockt wurde. TIIA modulierte P2X7 nicht. TIIAS hemmte als allosterischer Antagonist die Ăffnung des Ionenkanals und band vermutlich an eine intrazellulĂ€re Bindestelle. Die Wirkung von TIIAS wurde in humanen Makrophagen bestĂ€tigt, in denen der Wirkstoff den Ioneneinstrom und die IL-1ÎČ-Freisetzung hemmte.
Obwohl die neurologische Untersuchung von P2X7-/-- und WT-MÀusen nach MCAO keine signifikanten Unterschiede ergab, zeigte sich in der bildgebenden Diagnostik, dass P2X7-/--MÀuse binnen 24 Stunden nach der OP ein signifikant stÀrkeres Hirnödem entwickelten, welches nicht durch Unterschiede in der
InfarktgröĂe bedingt war. Der Infarkt fĂŒhrte in beiden Gruppen zu einer Gliaaktivierung, die im Fall der Mikroglia in Abwesenheit von P2X7 allerdings reduziert war. Differenzen hinsichtlich der Aktivierung von Astrozyten und der Expression von Laminin im Kapillarendothel wurden nicht festgestellt.
Im Gegensatz zu TIIA, das hĂ€ufig als gleichwertiger Wirkstoff eingesetzt wird, blockt TIIAS hP2X7 speziesspezifisch mit einer hohen Potenz. Maus und Ratte scheiden aufgrund der geringen Wirkung von TIIAS leider als Tiermodelle aus, um die Wirkung von TIIAS in vivo zu prĂŒfen. Weitere Arbeiten sind notwendig, um
die Potenz von TIIAS in anderen Spezies zu evaluieren oder Alternativen zum Tierversuch zu finden und eine mögliche therapeutische Anwendung bei Erkrankungen mit P2X7-Beteiligung zu testen.
P2X7 beeinflusst die pathophysiologischen VorgĂ€nge nach einem Hirninfarkt und begrenzt die Entwicklung eines zytotoxischen Hirnödems, nicht aber die des vasogenen Hirnödems, das sich zeitversetzt einstellt. Eine mögliche ErklĂ€rung fĂŒr diesen Sachverhalt bieten die unterschiedlichen Funktionen, die Gliazellen zu
verschiedenen Zeitpunkten nach zerebraler IschĂ€mie ĂŒbernehmen. Unsere Ergebnisse deuten auch darauf hin, dass verschiedene Tiermodelle des zerebralen Infarkts nicht in allen Punkten vergleichbar sind.:Inhaltsverzeichnis
1 Einleitung........................................................................................................... 1
1.1 Purinerge Signaltransduktion.......................................................................... 1
1.2 P2X-Rezeptoren.............................................................................................. 2
1.3 Pharmakologie des P2X7-Rezeptors............................................................... 3
1.4 Physiologische und pathophysiologische Bedeutung des P2X7-Rezeptor...... 5
1.5 Gegenstand dieser Arbeit............................................................................... 7
2 Veröffentlichungen............................................................................................. 9
2.1 Erste Publikation............................................................................................. 9
2.1.1 Tanshinone II A sulfonate, but not tanshinone II A, acts as potent negative allosteric modulator of the human purinergic receptor P2X7................................. 9
2.1.2 ErgÀnzende Materialien zur ersten Publikation.......................................... 22
2.2 Zweite Publikation......................................................................................... 30
2.2.1 Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery................................................................................. 30
2.2.2 ErgÀnzende Materialien zur zweiten Publikation......................................... 42
2.2.3 Erratum to: Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion............................................ 46
3 Diskussion........................................................................................................ 49
4 Zusammenfassung........................................................................................... 55
5 Summary.......................................................................................................... 57
6 Literaturverzeichnis.......................................................................................... 59
7 Danksagung..................................................................................................... 66ATP-gated ion channel P2X7 is a purinergic cell surface receptor which is mainly expressed on immune and glia cell. Upon activation of P2X7, proinflammatory cytokines are released, reactive oxygen species are generated and the cell cycle may be altered. In this regard, it has been shown that P2X7 plays a role in diseases such as rheumatoid arthritis, Alzheimerâs disease and multiple sclerosis. However, results regarding protective or detrimental effects mediated by P2X7 under particular conditions are often inconsistent. Thus, up to now, any therapeutic modulation of the receptor remains a challenge. Although intensive research has been conducted to find selective, potent P2X7-modulators, no active compound has been developed beyond phase II clinical trials.
The first part of this work describes a study realized to identify new P2X7 modulators and to characterize them in terms of pharmacodynamic properties like potency and species specificity. This study was aimed at providing a basis for the development of new therapeutic agents, which are urgently needed.
During the second part of this work, the involvement of P2X7 in pathophysiological processes after cerebral infarction was examined. Particular attention was paid to the influence of the receptor on the development of an accompanying and often fatal brain edema.
A compound library containing approved drugs and natural compounds was screened for modulators of the recombinantly expressed human P2X7 receptor (hP2X7). Therefor, their effect on P2X7-mediated Ca2+ influx was evaluated. Concentration-response-curves were established for potentially selective compounds. Tanshinone II A sulfonate (TIIAS) turned out to be a potent inhibitor of P2X7. Both TIIAS and tanshinone II A (TIIA), the natural compound TIIAS has been derived from, were also tested on recombinantly expressed mouse and rat P2X7 (mP2X7 and rP2X7, respectively). Furthermore, electrophysiological assays were conducted for a detailed characterization of mechanisms of P2X7 inhibition. Antagonist selectivity was revised using cell lines expressing purinergic receptors P2X2 and P2X4. Human monocyte-derived macrophages were used in fluorometric calcium and dye-uptake assays as well as an IL-1Ă ELISA to evaluate
the effects of modulating compounds on native P2X7. In all experiments, involvement of P2X7 was verified using established P2X7 antagonists.
In order to evaluate whether modulation of P2X7 may affect the outcome after cerebral infarction, cerebral ischemia was induced in 20 P2X7-deficient mice (P2X7-/-) and 22 mice of their corresponding wild type (WT) by transiently occluding their middle cerebral artery for 60 minutes with a thin filament (middle cerebral artery occlusion, MCAO). During 72 hours following surgery, neurological deficits, infarct size and edema development were monitored, applying clinical examinations and magnetic resonance measurements. After humane killing and brain removal, different antibodies were used in order to evaluate the distribution and activation state of microglia and astrocytes as well as the condition of the vascular endothelium. Sham-operated animals were used as negative controls in all experiments.
TIIAS blocked hP2X7 with an IC50 of 4.3 ÎŒM, whereas it proved to be less potent at mP2X7 and poorly modulated rP2X7. TIIA did not modulate P2X7. TIIAS acted as an allosteric antagonist and reduced the opening of the ion channel; it presumably bound to an intracellular binding site. The effect of TIIAS could be
confirmed in human macrophages. In these cells, TIIAS inhibited the ATP-induced Ca2+ entry, dye-uptake and release of IL-1ÎČ.
Although neurological examinations did not reveal significant differences between P2X7-/- and WT mice that underwent MCAO, diagnostic imaging revealed that P2X7-/- mice developed significantly more severe brain edema within 24 hours after surgery, a development that was not due to differences in infarct sizes. Both
groups displayed clear signs of activation of glia cells, but only microglia activation was attenuated in the absence of P2X7. Differences regarding the activation state of astrocytes or the expression of laminin by capillary endothelial cells could not be detected.
TIIAS species specifically blocks hP2X7 with a high potency. TIIA does not convey this effect although both compounds are frequently used interchangeably. Due to the low potency TIIAS displays at mP2X7 and rP2X7, these species unfortunately cannot be used as animal models to evaluate the drugâs effect in vivo. Further
research is necessary to evaluate the potency of TIIAS at other speciesâ P2X7 receptors or to find alternativespurinerge Signaltransduktion, P2X7, Tanshinon II A-Sulfonat, zerebrale IschĂ€mie,
Hirnödem to animal testing in order to study possible therapeutic applications of TIIAS in P2X7-related diseases.
P2X7 does affect pathophysiological events following cerebral ischemia and restricts cytotoxic brain edema development, but does not limit vasogenic cerebral edema formation, which develops at a later stage of the disease. The different functions fulfilled by glia cells at distinct points in time after infarction may provide an explanation for this interesting fact. The results presented also imply that diverse animal models of cerebral ischemia may not be entirely comparable due to differences regarding the pathogenesis of brain edema.:Inhaltsverzeichnis
1 Einleitung........................................................................................................... 1
1.1 Purinerge Signaltransduktion.......................................................................... 1
1.2 P2X-Rezeptoren.............................................................................................. 2
1.3 Pharmakologie des P2X7-Rezeptors............................................................... 3
1.4 Physiologische und pathophysiologische Bedeutung des P2X7-Rezeptor...... 5
1.5 Gegenstand dieser Arbeit............................................................................... 7
2 Veröffentlichungen............................................................................................. 9
2.1 Erste Publikation............................................................................................. 9
2.1.1 Tanshinone II A sulfonate, but not tanshinone II A, acts as potent negative allosteric modulator of the human purinergic receptor P2X7................................. 9
2.1.2 ErgÀnzende Materialien zur ersten Publikation.......................................... 22
2.2 Zweite Publikation......................................................................................... 30
2.2.1 Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery................................................................................. 30
2.2.2 ErgÀnzende Materialien zur zweiten Publikation......................................... 42
2.2.3 Erratum to: Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion............................................ 46
3 Diskussion........................................................................................................ 49
4 Zusammenfassung........................................................................................... 55
5 Summary.......................................................................................................... 57
6 Literaturverzeichnis.......................................................................................... 59
7 Danksagung..................................................................................................... 6
Allied Health Workforce Analysis: Sacramento-Northern California Region
Analyzes the racial/ethnic compositions of workers in twenty-two health occupations and graduates of healthcare education programs in Sacramento and northern California. Examines racial/ethnic disparities in occupations, educational attainment, and wages
Polarity-Specific Cortical Effects of Transcranial Direct Current Stimulation in Primary Somatosensory Cortex of Healthy Humans
Transcranial direct current stimulation (tDCS) is a noninvasive stimulation method that has been shown to modulate the excitability of the motor and visual cortices in human subjects in a polarity dependent manner in previous studies. The aim of our study was to investigate whether anodal and cathodal tDCS can also be used to modulate the excitability of the human primary somatosensory cortex (S1). We measured paired-pulse suppression (PPS) of somatosensory evoked potentials in 36 right-handed volunteers before and after anodal, cathodal or sham stimulation over the right non-dominant S1. Paired-pulse stimulation of the median nerve was performed at the dominant and non-dominant hand. After anodal tDCS, PPS was reduced in the ipsilateral S1 compared to sham stimulation, indicating an excitatory effect of anodal tDCS. In contrast, PPS in the stimulated left hemisphere was increased after cathodal tDCS, indicating an inhibitory effect of cathodal tDCS. Sham stimulation induced no pre-post differences. Thus, tDCS can be used to modulate the excitability of S1 in polarity-dependent manner, which can be assessed by paired-pulse suppression. An interesting topic for further studies could be the investigation of direct correlations between sensory changes and excitability changes induced by tDCS
Interaction of Water with Atomic Layer Deposited Titanium Dioxide on pâSi Photocathode: Modeling of Photoelectrochemical Interfaces in Ultrahigh Vacuum with CryoâPhotoelectron Spectroscopy
This study combines cryoâphotoelectron spectroscopy and electrochemical analysis techniques to investigate the pâSi/SiOâ/TiOâ/HâO system in the context of waterâsplitting. Atomic layer deposition is used for the preparation of a TiOâ thin film coating for a pâSi/SiOâ photocathode. First, an interface experiment is performed to study the contact properties of the interface between pâSi/SiOâ and TiOâ. For the pâSi/TiOâ heterojunction, a downward band bending of 0.3 eV is found for the pâSi toward the interface. Second, a water adsorption experiment is conducted, which allows the investigation of the surface chemistry of the TiOâ coating in contact to water. A direct correlation between the amount of surface hydroxide species, formed due to water dissociation, and TiÂłâș defect state density is found. Furthermore, a surface water species can be identified in addition to the commonly found bulk molecular water. Together with the results from a MottâSchottky analysis, a complete energy level alignment can be constructed
Different cultures, different values: The role of cultural variation in publicâs WTP for marine species conservation
Understanding the cultural variation in public preference for marine species is a necessary pre-requisite if conservation objectives are to include societal preferences in addition to scientific considerations. We report the results of a contingent study undertaken at three case-study sites: Azores islands (Portugal), Gulf of Gdansk (Poland) and Isles of Scilly (UK). The study considered species richness of five specific marine taxa (mammals, birds, fish, invertebrates and algae) as proxies of marine biodiversity and the aim of analysis was to estimate from a multi-site perspective publicâs willingness to pay (WTP) to avoid increased levels of species loss (reduction of species richness) for different marine taxa. Results, based on 1502 face-to-face interviews, showed that income, education and environmental awareness of the respondents were significant predictors of WTP for marine species conservation. Results also indicated that respondents in each of the European locations had different preferences for marine taxa. In the Azores, although mammals and fish were valued highly, small differences occurred in the WTP among different taxa. Respondents in the Isles of Scilly put a relatively low value on fish while algae and marine mammals were highly valued. In Gdansk, respondents defined a clear order of preference for marine mammals>fish>birds>invertebrates and algae. These findings suggested that cultural differences may be important drivers of valuation and undermines the commonly held premise that charismatic/likeable taxa consistently have a disproportionately strong influence on WTP for biodiversity conservation. We conclude that conservation policy must take account of cultural diversity alongside biological diversity
Shipwreck ecology:Understanding the function and processes from microbes to megafauna
An estimated three million shipwrecks exist worldwide and are recognized as cultural resources and foci of archaeological investigations. Shipwrecks also support ecological resources by providing underwater habitats that can be colonized by diverse organisms ranging from microbes to megafauna. In the present article, we review the emerging ecological subdiscipline of shipwreck ecology, which aims to understand ecological functions and processes that occur on shipwrecks. We synthesize how shipwrecks create habitat for biota across multiple trophic levels and then describe how fundamental ecological functions and processes, including succession, zonation, connectivity, energy flow, disturbance, and habitat degradation, manifest on shipwrecks. We highlight future directions in shipwreck ecology that are ripe for exploration, placing a particular emphasis on how shipwrecks may serve as experimental networks to address long-standing ecological questions.</p
Epilepsy in Onchocerciasis Endemic Areas: Systematic Review and Meta-analysis of Population-Based Surveys
Epilepsy is particularly common in tropical areas. One main reason is that many endemic infections have neurological consequences. In addition, the medical, social and demographic burden of epilepsy remains substantial in these countries where it is often seen as a contagious condition and where the aetiology is often undetermined. For several decades, field researchers had reported some overlapping between the geographical distributions of epilepsy and onchocerciasis, a parasitic disease caused by the filarial worm Onchocerca volvulus which afflicts some 40 million persons worldwide. Here, we conducted a statistical analysis of all the data available on the relationship between the two conditions to determine whether the proportion of people suffering from epilepsy in a community could be related to the frequency of onchocerciasis. The combined results of the eight studies carried out in west, central and east Africa indicate a close epidemiological association between the two diseases. Should a causative relationship be demonstrated, onchocerciasis, which is known as âriver blindnessâ because of its most serious sequela and the distribution of its vectors, could thus also be called âriver epilepsyâ. More research is needed to determine the mechanisms explaining this association and to assess the burden of onchocerciasis-associated epilepsy
Taxonomic review of the genus Stenotus Jakovlev (Hemiptera: Heteroptera: Miridae) from the Korean Peninsula
AbstractA genus Stenotus Jakovlev (Hemiptera: Heteroptera: Miridae) is reviewed taxonomically from the Korean Peninsula with a new record Stenotus binotatus (Fabricius 1794). Morphological information, such as descriptions of male and female genitalia, of the Korean species with photographs and illustrations, and a key to the Korean species are provided
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