132,900 research outputs found
De Evangelistarvm Et Apostolorvm Nominibus qui & quot, quales fuerint, quam causam scribendi habuerint, quo loco & quando scripserint, brevis Latino-Germanica Narratio, das ist Kurtze, doch gründliche Meldung Der H. Evangelisten und Aposteln, Nahmen, Zahl, Geschlecht, Gelegenheit zuschreiben, wo und wenn sie geschrieben ... Nebst den Zeugnissen gewisser Autorum ... durch 215. Fragen und Antwort verfasset / von J. F. K. B. T. P. C. [i.e. Johannes Friedrich Kittelmann]
No full textEnth. 2 Gedichte der BeiträgerVerf. ermittelt im Alphabet. Katalog der ULB Sachsen-Anhalt (Halle)Vorlageform des Erscheinungsvermerks: Jena, mit Nisiischen Schrifften druckts Johann Philipp Lindner[. 1707.
Patagiomyia Lindner
No full textGenus Patagiomyia Lindner Patagiomyia Lindner, 1933 c: 331. Type species, Patagiomyia cyphomyioides Lindner, 1933 b (orig. des.).Published as part of Fachin, Diego Aguilar & Assis-Pujol, Cristiane Vieira De, 2016, FAMILY STRATIOMYIDAE, pp. 312-341 in Zootaxa 4122 (1) on page 320, DOI: 10.11646/zootaxa.4122.1.26, http://zenodo.org/record/25492
Toll-like Rezeptor-vermittelte Regulation der Leukotrien-Biosynthese in menschlichen Monozyten
No full textLeukotrienes (LTs) are pro-inflammatory lipid mediators that belong to the group of eicosanoids, which are oxygenated metabolites of one common precursor, the aracidonic acid (AA). This polyunsaturated fatty acid is esterified at the sn-2 position of cellular membrane phospholipids and can be released by cytosolic phospholipase A2 alpha (cPLA2alpha) enzymatic deacylation. AA can be converted into LTs by the catalytic reaction of 5-lipoxygenase (5-LO). Enzymatic activation of cPLA2alpha as well as of 5-LO is regulated by similar determinants. In response to cellular stimuli that elevate the intracellular Ca2+ level and/or activate MAP kinase pathways, cPLA2alpha and 5-LO comigrate from a soluble cell compartment (mainly the cytosol) to the nuclear membrane, where AA is released und converted into LTs. LTs play a significant role in promoting inflammatory reactions and immune processes. They have been shown to be released from leukocytes in response to bacterial and viral infections and substantially contribute to an effective immune reaction for host defense. Innate immune pathogen recognition is mediated to a substantial part by the Toll-like receptor (TLR) family. So far, 10 human TLR subtypes have been identified, all of which detect distinct highly conserved microbial structures and trigger the induction of signaling pathways that lead to the expression of numerous immune and inflammatory genes. TLR signaling culminates in the activation NF-kappaB and/or MAP kinases, which as well are known to be involved in the regulation of cellular LT biosynthesis. In this regard, it seemed conceivable that the release of LTs might be regulated by TLR activation. Present studies were undertaken in order to verify and characterize a possible influence of TLR activation on the LT biosynthesis, and furthermore to identify the involved signaling pathways and underlying mechanisms. First experiments revealed that pre-incubation of differentiated Mono Mac 6 (MM6) cells with a TLR4 ligand, a TLR5 ligand, as well as with different TLR2 ligands led to an about 2-fold enhancement of Ca2+ ionophore induced LT biosynthesis. Ligands of other TLR subtypes did not show any influence. These observations could also be confirmed in primary human monocytes stimulated with ionophore or fMLP. With focus on TLR2 ligands, further studies were carried out to characterize the observed enhancement of LT biosynthesis in MM6 cells. It was demonstrated that the extent of LT formation was dependent on the ligand concentration used, but was also dependent on the duration of pre-incubation. Ligand pre-incubation of 15 minutes was optimal to maximally enhance LT formation and further prolongation of pre-incubation decreased LT formation again. Moreover, simultaneous addition of TLR2 ligands with ionophore did also not enhance LT formation. These results indicated that TLR2 ligands seemed to prime human monocytes for an enhanced response upon ionophore stimulation, but did not act as costimuli, which per se were not capable of directly stimulating the biosynthesis of LTs. To analyze the underlying mechanism, the impact of TLR2 ligands on the two key enzymes of the LT biosynthesis pathway, cPLA2alpha and 5-LO, was investigated. In this regard, 5-LO could not been shown to be positively regulated by TLR ligand priming. Neither a direct stimulation, nor an enhancement of 5-LO activity by TLR ligands was detectable in MM6 cells. Similarly, TLR2 ligands did also not enhance ionophore induced 5-LO translocation to the nuclear membrane. However, it was shown that TLR2 ligands enhanced ionophore induced release of AA in MM6 cells, which occurred with a similar time course as LT formation, displaying a maximum at 10 minutes of pre-incubation. A direct stimulation of AA release, however, could not been detected. Inhibitor studies revealed cPLA2alpha to be essential for AA release in TLR2 ligand primed, ionophore stimulated MM6 cells, but also sPLA2 was found to be involved. However, the priming effect of TLR2 ligands was mediated exclusively by cPLA2alpha. Western Blot analyses revealed that p38 MAP kinase, as well as ERK1/2, are activated in MM6 cells in response to TLR2 ligands, and also Ser-505 phosphorylation of cPLA2alpha was detected, which is known to be mediated by MAP kinases and to increase cPLA2alpha activity in vitro. Maximal cPLA2alpha phosphorylation occurred after 5-10 minutes of TLR2 ligand incubation, slightly preceding maximal AA release at 10 minutes and maximal LT formation at 15 minutes of priming. The combined use of a specific p38 MAPK inhibitor with an inhibitor of the ERK1/2 signaling pathway resulted in a complete prevention of cPLA2alpha phosphorylation and TLR2 ligand mediated enhancement of AA release. Thus, both MAPK pathways seem to play a role for TLR2 ligand mediated priming effects on the release of AA. An impact of other kinases such as Mnk-1 and CamKII, which can also regulate cPLA2alpha by phosphorylation, was excluded. Finally, an anti-hTLR2 antibody significantly reduced enhanced AA release, confirming the priming effects to be dependent on TLR2 activation. In summary, it was concluded that the increase of LT biosynthesis by TLR2 ligand priming is considerably due to an enhanced cellular AA supply, which arises from a MAPK mediated phosphorylation and up-regulation of cPLA2alpha. TLR dependent enhancement of LT biosynthesis represents an interesting link between activation of innate immune receptors and the rapid formation of pro-inflammatory lipid mediators. On the one hand, this support the role of LTs in host defence and infectious diseases, but may also be relevant in pathophysiological processes, which involve TLRs as well as LTs, as it has been shown for the pathogenesis of atherosclerosis or allergic diseases.Leukotriene (LTs) sind Entzündungsmediatoren aus der Gruppe der Eikosanoide, welche sich von der Arachidonsäure (AA) als ihre gemeinsame Vorstufe ableiten. Diese mehrfach ungesättigte Fettsäure ist in der Zelle in Membranphospholipiden verestert, und kann enzymatisch durch die zytosolische PLA2alpha (cPLA2alpha) freigesetzt werden. Weiterhin wird die AA durch die 5-Lipoxygenase (5-LO) zu LTs umgesetzt. 5-LO und cPLA2alpha sind sehr ähnlich reguliert. Zelluläre Stimuli, die zu einer Erhöhung der intrazellulären Ca2+-Konzentration und/oder Aktivierung von Mitogen-aktivierten Proteinkinasen (MAPKs) führen, lösen eine Aktivierung, und die konzertierte Translokation beider Enzyme aus dem Zytosol zur Kernmembran aus, wo die Freisetzung der AA und die LT-Biosynthese erfolgt. LTs spielen eine wichtige Rolle in Entzündungsreaktionen und Immunprozessen. Sie werden von Leukozyten bei bakteriellen und viralen Infektionen gebildet, und tragen zur Aktivierung entsprechender Immunabwehrmechanismen bei. Toll-like Rezeptoren (TLRs) sind Rezeptoren des angeborenen Immunsystems, die eine Schlüsselrolle für die Detektion von Pathogenen im Organismus spielen. Sie erkennen hoch konservierte pathogen-assoziierte molekulare Strukturen und aktivieren Signaltransduktionswege, die zur Expression entzündungsrelevanter Proteine und somit zur Entwicklung einer Immunantwort führen. Die TLR-Aktivierung führt im Allgemeinen zur Aktivierung des Transkriptionsfaktors NF-kappaB, und zur Aktivierung von MAP-Kinasen, deren Rolle in der Regulation der LT-Biosynthese bereits erwähnt wurde. Vor diesem Hintergrund schien es denkbar, dass im Zuge einer TLR-Aktivierung auch eine Regulation der LT-Bildung erfolgen könnte. Ziel dieser Arbeit war es, diesen Zusammenhang zu verifizieren, den Einfluss von TLR-Liganden auf die Biosynthese von LTs zu charakterisieren und die zugrundeliegenden Mechanismen aufzuklären. Erste Versuche zeigten, dass die Vorbehandlung differenzierter Mono Mac 6 (MM6)-Zellen mit einem TLR4-, einem TLR5- und mit verschiedenen TLR2-Liganden zu einer Verdopplung der LT-Biosynthese führte, die durch Ca2+-Ionophor stimuliert worden war. Die Liganden anderer TLR-Subtypen zeigten dagegen keine Wirkung. Der verstärkende Effekt der TLR2-Liganden konnte in primären humanen Monozyten ebenfalls bestätigt werden. In Folgeexperimenten zur Charakterisierung des beobachteten Effektes in MM6-Zellen war die verstärkende Wirkung der TLR2-Liganden abhängig von der eingesetzten Konzentration und der Vorinkubationszeit. Eine 15-minütige Vorbehandlung mit den Liganden erwies sich als optimal, während eine Verlängerung der Inkubationsdauer zum Verschwinden des Effektes führte. Wurden die TLR2-Liganden zusammen mit Ionophor inkubiert, war ebenfalls keine Verstärkung der LT-Bildung messbar. Diese Beobachtungen führten zu der Annahme, dass die TLR2-Liganden zwar als Priming-Agenzien in der Lage sind, die Stimulation der LT-Bildung zu verstärken, selbst jedoch nicht direkt aktivieren können. Zur Aufdeckung des zugrundeliegenden Mechanismus wurde der Einfluss der TLR2-Liganden auf die cPLA2alpha und auf die 5-LO untersucht. Für die 5-LO ließ sich keine positive Regulation durch Priming von MM6-Zellen mit TLR2-Liganden nachweisen: es konnte keine Stimulation, und keine Verstärkung der Ionophor-induzierten 5-LO-Aktivität detektiert werden. Weiterhin bewirkten die TLR2-Liganden keine Verstärkung der 5-LO-Translokation zur nukleären Membran. Dagegen konnte gezeigt werden, dass TLR2-Liganden in MM6-Zellen die Ionophor-induzierte AA-Freisetzung verstärken. Hierbei war, wie für die LT-Bildung, eine Zeitabhängigkeit des Effektes mit einer optimalen Vorinkubationszeit der Liganden von etwa 10 Minuten feststellbar. Eine direkte Stimulation der AA-Freisetzung durch die TLR2-Liganden erfolgte nicht. In Inhibitor-Studien stellte sich heraus, dass sowohl die cPLA2alpha als auch sPLA2 an der AA-Freisetzung in geprimten MM6-Zellen beteiligt sind. Der Verstärkungseffekt der Liganden war jedoch allein durch die cPLA2alpha vermittelt. Weiterhin konnte in MM6-Zellen nach Inkubation mit TLR2-Liganden sowohl die Aktivierung der p38 und der p42/44 MAP-Kinase (ERK1/2), als auch die Phosphorylierung der cPLA2alpha an Ser-505 nachgewiesen werden, welche durch MAP-Kinasen erfolgt, und in vitro zur Aktivitätssteigerung der cPLA2alpha führt. Nach etwa 5-minütiger Behandlung riefen die Liganden maximale Phosphorylierung hervor, die somit einer maximalen AA-Freisetzung bei 10-minütigem Priming und einer maximalen LT-Bildung bei 15-minütigen Priming vorauszugehen schien. Die Kombination von Inhibitoren des p38 und des p42/44 MAP-Kinase Signalweges führte zur vollständigen Aufhebung sowohl der beobachteten cPLA2alpha-Phosphorylierung, als auch der Verstärkung der AA-Freisetzung. Beide MAP-Kinasewege scheinen somit eine Rolle für diesen Verstärkungseffekt der TLR2-Liganden zu spielen. Der Einfluss weiterer für die Regulation der cPLA2alpha relevanter Kinasen (Mnk-1 und CamKII) konnte ausgeschlossen werden. Abschließend wurde gezeigt, dass die beobachtete Steigerung der AA-Freisetzung durch Aktivierung des TLR2 vermittelt wird. Die TLR2-vermittelte Verstärkung der LT-Biosynthese in MM6-Zellen ist somit hauptsächlich auf eine vermehrte AA-Freisetzung zurückzuführen, die wiederum aus der cPLA2alpha-Phosphorylierung durch MAP-Kinasen und der dadurch verstärkten cPLA2alpha-Aktivierung resultiert. Die TLR-abhängige Verstärkung der LT-Bildung stellt einen interessanten Zusammenhang zwischen der Aktivierung von Rezeptoren des angeborenen Immunsystems und der kurzfristigen Freisetzung von Entzündungsmediatoren dar, der die Bedeutung der LTs für die Immunabwehr einmal mehr unterstreicht
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Studies towards the total synthesis of Limnophilaspiroketone and the synthesis of alpha-modified enones of natural product derived model compound Limno-CP
No full textCompounds with an alpha,beta-unsaturated carbonyl moiety and a phenol substituent are reported to exhibit anti-inflammatory and antioxidative activities. NF-kB and Nrf2 are important transcription factors of a complex signaling network, which mediate a multitude of different biological functions. However, they are also implicated in the pathogenesis of many inflammation-associated disorders and can therefore be addressed as molecular targets to alter or prevent undesired malignant events. Reactive cystein residues which are present in the transcription factors act as critical sensors for inducers and are involved in the fine-tuning of cellular homeostasis. Covalent modification or oxidation of the sulfhydryl groups by phenolic Michael acceptors results in an activation of anti-inflammatory Nrf2 and silencing of pro-inflammatory NF-kB respectively. The modulation of the function of the transcription factors can abrogate oxidative and electrophilic stress as well as inflammatory tissue injury.
Herein, studies towards the total synthesis of the natural product limnophilaspiroketone, which belongs to the class of phenolic alpha,beta-unsaturated 3(2H)-furanones, are reported. Important key steps are an enantioselective epoxidation and diastereoselective cyanohydrin reaction which allowed for the formation of two quaternary stereocenters with the correct absolute configuration. A valuable and general strategy for the selective deprotection of a TMS acetylene in presence of a TMS ether was developed.
The synthesis of spirocyclic Limno-CP, a simplified natural product derived model compound, was carried out successfully. Investigations on the formation of the spirocyclic framework revealed deeper insights in the mechanistic details of the cyclization reaction.
In order to gain Michael acceptor specificity by fine tuning the reactivity of the alpha,beta-unsaturated carbonyl unit a library of 16 different, in alpha-position substituted compounds was synthesized from iPr-protected Limno-CP. NMR spectroscopic analysis was used to determine the electrophilicity of the alpha-carbon of the alpha,beta-unsaturated carbonyl subunit.
The altered electronic properties of the enone entity could not be correlated to the observed reactivity towards nucleophiles. A 1,4-addition reaction with thiols or organocuprates was not observed. In contrast, with Limno-CP derivatives bearing chemically inert substituents alkyl lithium reagents effectively added in a 1,2-fashion to the carbonyl group, which lead to the corresponding alkylidene compounds
Pursuit problem with a stochastic prey that sees its chasers
No full textA recent stochastic pursuit model describes a pack of chasers (hounds) that actively move toward a target (hare) that undergoes pure Brownian diffusion (Bernardi and Lindner 2022 Phys. Rev. Lett. 128 040601). Here, this model is extended by introducing a deterministic ‘escape term’, which depends on the hounds’ positions. In other words, the hare can ‘see’ the approaching hounds and run away from them, in addition to the ‘blind’ random diffusion. In the case of a single chaser, the mean capture time (CT) can still be computed analytically. At weak noise, the qualitative behavior of the system depends on whether the hare’s maximum running drift speed is above or below a critical value (the pursuers’ speed), but not on the target’s viewing range, whereas the capture statistics at strong noise is similar to those of the original model without escape term. When multiple hounds are present, the behavior of the system is surprisingly similar to the original model with purely diffusing target, because the escape terms tend to compensate each other if the prey is encircled. At weak noise levels and ‘supracritical’ maximum escape speed, the hare can slip through the chaser pack and lead to a very strong increase of the mean CT with respect to the blind case. This large difference is due to rare events, which are enhanced when the symmetry in the initial conditions is disrupted by some randomness. Comparing the median of the CT probability density (which reflects the typical CT) with the mean CT makes clear the contribution of rare events with exceptionally long CTs
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Receiver operating characteristic curves for a simple stochastic process that carries a static signal
No full textThe detection of a weak signal in the presence of noise is an important problem that is often studied in terms of the receiver operating characteristic (ROC) curve, in which the probability of correct detection is plotted against the probability for a false positive. This kind of analysis is typically applied to the situation in which signal and noise are stochastic variables; the detection problem emerges, however, also often in a context in which both signal and noise are stochastic processes and the (correct or false) detection is said to take place when the process crosses a threshold in a given time window. Here we consider the problem for a combination of a static signal which has to be detected against a dynamic noise process, the well-known Ornstein-Uhlenbeck process. We give exact (but difficult to evaluate) quadrature expressions for the detection rates for false positives and correct detections, investigate systematically a simple sampling approximation suggested earlier, compare to an approximation by Stratonovich for the limit of high threshold, and briefly explore the case of multiplicative signal; all theoretical results are compared to extensive numerical simulations of the corresponding Langevin equation. Our results demonstrate that the sampling approximation provides a reasonable description of the ROC curve for this system, and it clarifies limit cases for the ROC curve
A frequency-resolved mutual information rate and its application to neural systems
No full textThe encoding and processing of time-dependent signals into sequences of action potentials of sensory neurons is still a challenging theoretical problem. Although, with some effort, it is possible to quantify the flow of information in the model-free framework of Shannon’s information theory, this yields just a single number, the mutual information rate. This rate does not indicate which aspects of the stimulus are encoded. Several studies have identified mechanisms at the cellular and network level leading to low- or high-pass filtering of information, i.e., the selective coding of slow or fast stimulus components. However, these findings rely on an approximation, specifically, on the qualitative behavior of the coherence function, an approximate frequency-resolved measure of information flow, whose quality is generally unknown. Here, we develop an assumption-free method to measure a frequency-resolved information rate about a time-dependent Gaussian stimulus. We demonstrate its application for three paradigmatic descriptions of neural firing: an inhomogeneous Poisson process that carries a signal in its instantaneous firing rate; an integrator neuron (stochastic integrate-and-fire model) driven by a time-dependent stimulus; and the synchronous spikes fired by two commonly driven integrator neurons. In agreement with previous coherence-based estimates, we find that Poisson and integrate-and-fire neurons are broadband and low-pass filters of information, respectively. The band-pass information filtering observed in the coherence of synchronous spikes is confirmed by our frequency-resolved information measure in some but not all parameter configurations. Our results also explicitly show how the response-response coherence can fail as an upper bound on the information rate
Detecting single-cell stimulation in a large network of integrate-and-fire neurons
No full textSeveral experiments have shown that the stimulation of a single neuron in the cortex can influence the local network activity and even the behavior of an animal. From the theoretical point of view, it is not clear how stimulating a single cell in a cortical network can evoke a statistically significant change in the activity of a large population. Our previous study considered a random network of integrate-and-fire neurons and proposed a way of detecting the stimulation of a single neuron in the activity of a local network: a threshold detector biased toward a specific subset of neurons. Here, we revisit this model and extend it by introducing a second network acting as a readout. In the simplest scenario, the readout consists of a collection of integrate-and-fire neurons with no recurrent connections. In this case, the ability to detect the stimulus does not improve. However, a readout network with both feed-forward and local recurrent inhibition permits detection with a very small bias, if compared to the readout scheme introduced previously. The crucial role of inhibition is to reduce global input cross correlations, the main factor limiting detectability. Finally, we show that this result is robust if recurrent excitatory connections are included or if a different kind of readout bias (in the synaptic amplitudes instead of connection probability) is used
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