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Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis
(2021)
Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/reperfusion injury. Coordinated interactions between RIPK1, RIPK3 and MLKL lead to the formation of a dedicated death complex called the necrosome that triggers MLKL-mediated membrane rupture and necroptotic cell death. Necroptotic cell death is tightly controlled by post-translational modifications, among which especially phosphorylation has been characterised in great detail. Although selective ubiquitination is relatively well-explored in the early initiation stages of necroptosis, the mechanisms and functional consequences of RIPK3 and MLKL ubiquitination for necrosome function and necroptosis are only starting to emerge. This review provides an overview on how site-specific ubiquitination of RIPK3 and MLKL regulates, fine-tunes and reverses the execution of necroptotic cell death.
Unmotivated and unprepared, an Austrian young man leaves his home town Vienna, only to dive into the unknown Romania. He already has images of this country in his mind. He is on his way towards the magical, dark, sparkling Transdanubien, about which he only knows clichés: that Romanians barely have anything to eat, that it is a country of gypsies, that the official language is Russian, that it is an anachronistic country par excellence. With this perspective, his relationship with local Ilina can only fail. This article follows along the lines of a complicated inter-cultural communication.
Looking back, my memories seem like distant, made-up stories. These words of the main character are to be found all over Jan Koneffkes novel. A foreigner on the run, Felix Kannmacher is forced to tell stories in order to survive. He is at the mercy of a teenager who is avid for constantly new and different bedtime stories. Felix gives in, as he has no other choice but to be a slaveto this child. The following article analyses the fine line between the stories Felix invents for Virginia and two narratological aspects: the actual plot of the novel on the one hand, and the actual course of history, on the other. The entire novel is built on stories-within-stories that twist and turn the course of Story and History alike. Because each one of us writes their own (hi)story.
For intercultural language teaching, coaching students on how to perceive the cultural “other” is of crucial importance in order to avoid culturally based misunderstandings. This paper explores how perceiving the other can offer conclusions for perceiving and becoming aware of the self. Through that, a process of giving and taking ensues in which perceptions of the self and of the other are constantly fluctuating depending on the context in which the communication is taking place. At the crossroads between members of two different cultures, a dialogue emerges in which the points of view of both parties are changed. The paper outlines how perception is a construct in which one’s own origin, education, and emotions are blended in. Intercultural learning is the way to deal with this constructs in a flexible manner so as to create new interpretation patterns. It teaches how to sympathize with the other and how to better understand oneself.
Film is a wonderful means of reflecting upon the identity of the self and the other. A movie like Didi Danquart’s Offset (2006), which deals with intercultural conflicts, even more so. The clash of the Romanian and German cultures depicted in this movie illustrates how the construction of identity – of the self and the other – works.
Using literature in culture and civilization classes enables the contact to foreign culture. Literature does not merely copy reality, but has its own rules of story telling, its own way of changing the perspective on reality, of correcting cliches, in omitting something, so as for the reader to become curious and fill in these „gaps”. In this paper, a fragment from a novel shows how a german businessman arriving in interbellic Romania finds that time is measured differently in those two countries.
Prämissen für die Vermittlung interkultureller Kompetenzen im studienbegleitenden DaF-Unterricht
(2014)
Language teaching alone is not sufficient in order to communicate successfully in the foreign language. Even with the acquisition of one’s native language, one does not learn just vocabulary, grammar, reading, writing, speaking and listening. Apart from all that one learns how to identify and to practice cultural patterns. Here, the learning and teaching process is accompanied by another component: intercultural communication and the acquisition of intercultural competences. These teach the lerner to understand first and foremost their own cultural background in order for them to be able to change perspective and look at and understand the cultural background of the target language. Teaching must be centered on the learner, and the foreign language is not taught „in general“, but with regard to the learners’ culture of origin.
Language teaching through the medium of film may prove very rewarding in that it moves the focus away from language and its general markers (grammar, vocabulary) alone and casts it onto culture, cultural boundaries and rules. Among them, space plays a very important role. It defines who we are, where we come from. Especially the fine line between what is considered public or private space is worth being analyzed. With examples from two movies, students of German as a Foreign Language are meant to discover this fine line, look beyond it and restore an equilibrium between the public and the private in order to be prepared for intercultural experiences.
Cosmin, a twelve-year-old Roma boy from Transylvania, only goes to school for a short while. For his mother, it is more important, that he, the only male of a household with many mouths to feed, help her with work. But Cosmin’s teacher does not give up and proposes a bargain: If Cosmin’s mother lets her children go to school, she will get electricity from the school to be able to watch TV. Due to this arrangement, Cosmin returns to school for a few days, becomes a little thief and embarks on a journey that can become an opportunity for him. A kind of a bildungsroman, a coming of age novel focused on the ups and downs between two worlds on Romanian soil, that could not be more different from one another: the Romanian majority and the Roma minority. This article sets out to document life at the brink of society, with all of its facets.
Background: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes.
Methodology/Principal Findings: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases).
Conclusions/Significance: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71–9.48; P = 0.001) and 4.08 (95% CI 1.79–9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures.
Heterogenous subtypes of breast cancer need to be analyzed separately. Pooling of datasets can provide reasonable sample sizes but dataset bias is an important concern. We assembled a combined dataset of 579 Affymetrix microarrays from triple negative breast cancer (TNBC) in Gene Expression Omnibus (GEO) series GSE31519. We developed a method for selecting comparable datasets and to control for the amount of dataset bias of individual probesets.
Brustkrebs ist die häufigste Krebserkrankung und Todesursache bei Frauen. Die Forschung der letzten Jahrzehnte hat gezeigt, dass es sich dabei nicht um eine einzelne, immer gleich verlaufende Erkrankung handelt. Vielmehr geht man heute davon aus, dass Brustkrebs eine heterogene Erkrankung mit verschiedenen Subtypen darstellt. Sie lassen sich klinisch und molekular deutlich von einander unterscheiden. Wichtiges Ziel der modernen Forschung und ihrer Methoden ist daher die Entwicklung einer individuellen Therapie für jede einzelne Patientin.
Mit Dollys Geburt am 27. Februar 1997 gelingt es Forschern erstmals, die ausdifferenzierte Körperzelle eines erwachsenen Schafes so zurückzuprogrammieren, dass aus ihr ein neuer Embryo und damit ein (fast) identischer Klon des Muttertieres entsteht. Das Ergebnis ist ein kleines Schäfchen und ein Sturm an moralischer Entrüstung. Menschen zu klonen, über lange Zeit als unmöglich postuliert, ist plötzlich in den Bereich des Machbaren gerückt. Auch Habermas lässt sich von diesen Neuigkeiten beunruhigen. In einem kurzen Artikel in der »Süddeutschen Zeitung« vom 17. / 18. Januar 1998 beschreibt er das Klonen von Menschen als eine neue Form der Sklaverei. Der Klon könnte der Möglichkeit beraubt werden, sich als freies und gleiches Mitglied der moralischen Gemeinschaft zu verstehen. »Für den Klon verstetigt sich nämlich in der Definition eines unwiderruflichen Kodes ein Urteil, das eine andere Person vor seiner Geburt über ihn verhängt hat.« (Habermas 1998, 245) Anders als bei der Erziehung könne der Klon, der um seine Herkunft weiß und mit dieser hadert, sich nicht von seiner genetischen Festlegung durch eine andere Person lösen. Vielleicht bliebe es ihm daher für immer versagt, sich als alleiniger Autor seiner Lebensgeschichte zu verstehen und für diese die volle Verantwortung zu übernehmen. Auch die Gleichheit von Klon und demjenigen, der eingreift, sei gefährdet: Anders als in traditionellen Eltern-Kind-Beziehungen lassen sich die sozialen Rollen von Kloner und Geklontem niemals vertauschen. (Habermas 2002, 112)
t is becoming less and less controversial that we ought to aggressively combat climate change. One main reason for doing so is concern for future generations, as it is they who will be the most seriously affected by it. Surprisingly, none of the more prominent deontological theories of intergenerational justice can explain why it is wrong for the present generation to do very little to stop worsening the problem. This paper discusses three such theories, namely indirect reciprocity, common ownership of the earth and human rights. It shows that while indirect reciprocity and common ownership are both too undemanding, the human rights approach misunderstands the nature of our intergenerational relationships, thereby capturing either too much or too little about what is problematic about climate change. The paper finally proposes a way to think about intergenerational justice that avoids the pitfalls of the traditional theories and can explain what is wrong with perpetuating climate change.
Two new species of Psammoecus Latreille, 1829 from Australia are described: Psammoecus australis sp. nov. and P. venustus sp. nov. A taxonomic revision and diagnoses for other Australian species are provided. Psammoecus obesus Grouvelle, 1919 is recorded from Australia for the first time. Two new synonyms are discovered: Psammoecus t-notatus Blackburn, 1908 = P. amoenus Grouvelle, 1912 syn. nov.; Psammoecus vittifer Blackburn, 1903 = P. concolor Grouvelle, 1919 syn. nov. A lectotype is designated for Psammoecus concolor Grouvelle, 1919.
New state records for 33 species of Leiodidae (Coleoptera) are reported from Ohio, with the majority of records from one locality in the southeastern portion of the state. This doubles the known members of
the family in Ohio to 66 species in 20 genera.
ZooBank registration. urn:lsid:zoobank.org:pub:DF3542D6-680B-4F0F-9D93-A30529720879
Naturschutz bedeutet nicht nur Erhaltung und Bewahrung gefährdeter Tiere, Pflanzen und ihrer Lebensräume, Naturschutz bedeutet auch Erhaltung der Vielfalt, Eigenarten und Besonderheiten der unbelebten Natur auf der Erde, besonders der Zeugnisse zur Geschichte der Erde, ihrer Dynamik, ihrer Stoffkreisläufe und zur Evolution.
We present a calculation of the global polarization of Λ hyperons in relativistic Au–Au collisions at RHIC Beam Energy Scan range sNN−−−√=7.7−200 GeV with a 3+1-dimensional cascade+viscous hydro model, UrQMD+vHLLE. Within this model, the mean polarization of Λ in the out-of-plane direction is predicted to decrease rapidly with collision energy from a top value of about 2% at the lowest energy examined. We explore the connection between the polarization signal and thermal vorticity and estimate the feed-down contribution to Λ polarization due to the decay of higher mass hyperons.
Wenn Yvan Goll 1920 programmatisch feststellen konnte, die Basis für alle neue kommende Kunst sei das Kino, um einen ästhetischen Avantgardismus in der Annäherung von Künsten und Film zu begründen, dann beginnt Deleuze mit der Frage: "Was offenbart der Film, was die anderen Künste uns nicht offenbaren?" Anstatt Resonanzen oder Affinitäten im ästhetischen Feld herauszustellen, müssen die "Begriffe, die von der Philosophie für den Film vorgeschlagen werden,[…] spezifisch, das heißt nur dem Film angemessen sein." Der Film als Gegenstand der Untersuchung ist eine Singularität, und dementsprechend haben auch seine Begriffe den Charakter von Singularitäten, die von keinen Universalien, Transzendentalien oder Allgemeinheiten eingeholt werden können. Begriffe, zum Beispiel aus der Psychoanalyse, von außen an den Film heranzutragen, würde die Singularität des Films verfehlen, weil sie nicht mehr vom Film sprechen, sondern etwa vom Imaginären, von Kastrationsangst oder Partialobjekten. Übertragungen dieser Art würden die Bewegung des Denkens auf der Ebene der Immanenz, um die es Deleuze zu tun ist, außer Kraft setzen.
Deleuzes Philosophie des Kinos versteht man besser, wenn man den Abstand sieht, den er von den Filmtheorien der klassischen Moderne nimmt, die für lange Zeit die Diskussionen und Untersuchungen in der Kulturwissenschaft der Medien orientiert haben: Walter Benjamin und Siegfried Kracauer. Beide haben sich durchaus auch auf die Besonderheit des Mediums Film konzentriert, aber sie bewegen sich - wie sich zeigen wird - allein im Horizont des Denkens der Moderne, den Deleuze überschreitet.
Die Neuen Kriege seit dem Epochenbruch von 1989 sind Thema der Gegenwartsliteratur geworden, und sie sucht im Raum der Fiktion eine eigene Anschaulichkeit und spezifische Vorstellungen vom Charakter dieser neuen Konflikte zu erzeugen. Zugleich sind diese Neuen Kriege ein Gegenstand der disziplinär erfaßten Diskurse der Wssenschaften, die nach den kurzen Friedenserwartungen im Anschluß an 1989/90 eine Theorie der Kriege im Zeichen einer neuen Globalisierung verstärkt diskutieren. Wenn das gegenwärtige Denken des Krieges literarisch und außerliterarisch seine Kontur gewinnt, erscheint die Relationierung beider Felder geboten, wie in einem neueren literaturwissenschaftlichen Forschungszweig nach dem Verhältnis von Literatur und Wissen bzw. von literarischen Texten und wissensehaftlichen Diskursen gefragt wird. Das Thema Neue Kriege läßt sich jedoch hier aus zwei Gründen nicht umstandslos einreihen. Der eine Grund ist theoretisch-methodischer Art. Nur die Dualität von disziplinär verfaßten historisch-politischen Diskursen und literarischem Text in den Blick zu nehmen ist zu wenig differenziert. Es ist nötig, sie um eine dritte Dimension zu erweitern: den Komplex der Medien, die als Wissensgeber vom Krieg, als eigene Kriegsmittel und als Gegenspieler der Literatur fungieren.
We found that a true ternary fission with formation of a heavy third fragment (a new kind of radioactivity) is quite possible for superheavy nuclei due to the strong shell effects leading to a three-body clusterization with the two doubly magic tin-like cores. The three-body quasifission process could be even more pronounced for giant nuclear systems formed in collisions of heavy actinide nuclei. In this case a three-body clusterization might be proved experimentally by detection of two coincident lead-like fragments in low-energy U+U collisions.
Background: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF.
Methods: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed.
Results: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized.
Conclusions: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses.
Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476)
Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans.
Wegepläne sind ein wichtiges Instrument der Nationalparkleitung zur Koordinierung vorhandener Nutzungsanforderungen mit den Schutzzielen des Nationalparks. Fast jede Nutzung im Nationalpark geht von Wegen aus. Die Wegedichte und der Ausbaugrad der Wege bestimmen die Intensität der Zerschneidung des Nationalparkgebietes und damit in erheblichem Maße die Möglichkeiten zur Erfüllung seiner Aufgaben als Schutzgebiet und für den ungestörten Ablauf dynamischer ökosystemarer Prozesse in der Natur. Andererseits sind Nationalparke aufgerufen, Ihr Gebiet erlebbar zu machen und geeignete Möglichkeiten für die Erholung und Bildung anzubieten.
Es wird die Entwicklung der Brockenvegetation von 1993 bis 2013 aufgezeigt. Von besonderem Interesse ist dabei die Vegetationsentwicklung auf ehemals versiegelten und später renaturierten Flächen. Aber auch den acidiphilen Zwergstrauchheiden galt ein besonderes Augenmerk, da diese bevorzugte Standorte für die Brockenanemone (Pulsatilla alpina ssp. alba) sind.
Der Brockengarten
(1994)
Die Idee. auf dem höchsten Harzgipfel einen "Alpengarien" einzurichten, hatte Ende des vergangenen Jahrhunderts Prof, Dr. Albert Peter, seinerzeit Direktor des Botanischen Gartens der Universität Göttingen. Sein Ziel war es, der einzigartigen. aber bereits damals gefährdeten Brockenflora eine Überlebenschance zu geben und experimentell nachzuweisen, dass die Brockenkuppe von Natur aus baumfrei ist. Zum anderen wollte er den Brockenbesuchern die Möglichkeit bieten, einen Eindruck von der Formenvielfalt der Hochgebirgsflora zu erhalten. Gleichzeitig sollte u.a. das Wuchsverhalten der "Importpflanzen" aus den Hochgebirgen der Welt unter den ökologischen und klimatischen Bedingungen des Brockens wissenschaftlich begleitet werden.
Die Ausweisung von Nationalparken innerhalb der mitteleuropäischen Kulturlandschaft bietet die einmalige Chance, Strukturveränderungen in anthropogen überprägten aber auch in den Resten naturnaher Lebensräume zu erfassen. Vor allem Pflanzengesellschaften als wichtige Strukturkomponenten der Ökosysteme geben wichtige Hinweise zum Zustand der verschiedenen Lebensraumtypen (ELLENBERG 1996). Regelmäßige pflanzensoziologische Untersuchungen können somit quantitative wie qualitative Veränderungen in den Lebensräumen aufzeigen. Dazu wurden zunächst die Farn- und Blütenpflanzen des Nationalparks Hochharz erfasst (KISON & WERNECKE 2004) und darüber hinaus flächendeckend die Pflanzengesellschaften.
In diesem Beitrag werden an einigen Beispielen die Auswertungsmöglichkeiten aufgezeigt, die die digital vorliegende Vegetationskarte des Nationalparks Harz bietet. Es wird deutlich, dass beim Vergleich der vorliegenden Daten mit Wiederholungsaufnahmen Aussagen zu den ökologischen Veränderungen im Nationalpark Harz gemacht werden können, die das Ergebnis der natürlichen Sukzession bzw. das Ergebnis forstlicher Initialmaßnahmen sind. Die Arbeit zeigt, dass neben den Flächenanteilen der erfassten Pflanzengesellschaften die vorkommenden Arten und ihre Deckungsanteile in der jeweiligen Gesellschaft berechnet werden können. Damit ist es z. B. perspektivisch möglich, flächendeckende Aussagen zu den Ausbreitungstendenzen der Arten z. B. in den Pflanzengesellschaften und in den unterschiedlichen Höhenstufen des Nationalparks Harz zu machen. So zeigt die aktuelle Verbreitung von Picea abies im Nationalpark Harz, dass die Verteilung der Baumart nicht annähernd deckungsgleich mit der Verteilung ihrer natürlichen bzw. naturnahen Waldgesellschaften ist. Diese Diskrepanz tritt bei Fagus sylvatica nicht ganz so extrem auf. Am größten ist die Differenz in Höhenbereichen, in denen Fagus sylvatica ihr natürliches Verbreitungsgebiet hat, aber auch in der Vergangenheit am stärksten zurückgedrängt wurde. Das sind genau die Gebiete, in denen die Rotbuche im Rahmen der forstlichen Initialmaßnahmen des Nationalparks verstärkt eingebracht wurde. Ob Fagus sylvatica dort, wo sie gepflanzt wurde und in höheren Deckungsgraden auftritt, in der Lage ist, das Potenzial für natürliche Buchenwaldgesellschaften zu bilden, wird mit Hilfe der hier dargestellten Erfassungsmethode perspektivisch nachweisbar sein. Dass es sinnvoll ist, zu dem jetzigen Zeitpunkt zwischen naturnahen Waldgesellschaften und Fichtenforsten zu unterscheiden, wird anhand des Vergleichs ausgewählter Parameter aufgezeigt.
Karsten fügt der umfangreichen Lampedusa-Forschung einen wichtigen Aspekt hinzu, indem er die bislang weitgehend unbeachtete geschichtsphilosophische Dimension des Romans beleuchtet. Er zeigt, dass und wie sich Lampedusa der Zeit um 1860/61 sowohl zu erzählerischen Zwecken, zur Handlungsmotivation, Figurengestaltung und -kontextualisierung, bedient als auch dazu, geschichtliche Ereignisse dieser Zeit zu kommentieren und einzuordnen.
Hymenomycetes Fennici
(1881)
Mit dem fast 500 Seiten starken Buch legt der Arbeitskreis Heimische Orchideen Sachsen-Anhalt e. V. (AHO) ein im doppelten Wortsinne schwergewichtiges Werk vor, in dem die über Jahrzehnte gesammelten Kenntnisse des Arbeitskreises für die Öffentlichkeit aufbereitet wurden. Diese immense Arbeitsleistung, die sicher auch eine logistische Herausforderung darstellte, kann gar nicht hoch genug eingeschätzt werden. Das Werk gliedert sich in drei Teile: Orchideen in der Kulturlandschaft, die Orchideenarten Sachsen-Anhalts sowie Orchideen und Vegetation.
The article addresses the question of who reports the dialogue in fictional texts featuring an unreliable narrator. Since no human being can remember and reproduce lengthy conversations accurately, some narrative theorists attribute direct speech representation to the author instead of the character narrator. This means that the speech of other characters may be reported reliably even if the narrator is totally unreliable. The narrator’s version of the events may then be contradicted by others, which allows the reader to perceive his biases. However, Kazuo Ishiguro’s An Artist of the Floating World illustrates the fact that direct speech reports, too, can be distorted by the narrator’s subjectivity, especially his emotions. In Ishiguro’s novel, the narrator’s grief and depression lead him to misremember and invent past conversations. Following Meir Sternberg, the article argues that the reliability of speech reporting in unreliable narration must be determined on a case-by-case basis. The text must signal that the narrator’s speech reporting is unreliable. In the absence of a signal, the reader is supposed to disregard any deviations from verbatim reproduction and to accept the transgression of the limits of human memory.
Understanding the role of short-interfering RNA (siRNA) in diverse biological processes is of current interest and often approached through small RNA sequencing. However, analysis of these datasets is difficult due to the complexity of biological RNA processing pathways, which differ between species. Several properties like strand specificity, length distribution, and distribution of soft-clipped bases are few parameters known to guide researchers in understanding the role of siRNAs. We present RAPID, a generic eukaryotic siRNA analysis pipeline, which captures information inherent in the datasets and automatically produces numerous visualizations as user-friendly HTML reports, covering multiple categories required for siRNA analysis. RAPID also facilitates an automated comparison of multiple datasets, with one of the normalization techniques dedicated for siRNA knockdown analysis, and integrates differential expression analysis using DESeq2.
Hepatitis C virus (HCV) infection leads to the development of hepatic diseases, as well as extrahepatic disorders such as B-cell non-Hodgkin's lymphoma (B-NHL). To reveal the molecular signalling pathways responsible for HCV-associated B-NHL development, we utilised transgenic (Tg) mice that express the full-length HCV genome specifically in B cells and develop non-Hodgkin type B-cell lymphomas (BCLs). The gene expression profiles in B cells from BCL-developing HCV-Tg mice, from BCL-non-developing HCV-Tg mice, and from BCL-non-developing HCV-negative mice were analysed by genome-wide microarray. In BCLs from HCV-Tg mice, the expression of various genes was modified, and for some genes, expression was influenced by the gender of the animals. Markedly modified genes such as Fos, C3, LTβR, A20, NF-κB and miR-26b in BCLs were further characterised using specific assays. We propose that activation of both canonical and alternative NF-κB signalling pathways and down-regulation of miR-26b contribute to the development of HCV-associated B-NHL.
Dry calcareous grasslands in Europe are renowned for their high plant diversity. However, declining habitat areas and highly fragmented distribution threaten the long-term persistence of this valuable habitat type. In Estonia the decline of traditional grassland management and subsequent encroachment of shrubs has resulted in a substantial loss of alvar grasslands – a particularly rare and species-rich type of calcareous grassland. It is known that a shrub cover of more than 70% decreases the alvar grassland species richness. At the same time, a shrub cover of 30% is considered optimal for alvar grasslands and thus a target state for habitat restoration. However, very little is known about the effect of low shrub cover on environmental conditions and species composition of alvar grasslands. Our aim was to detect to what extent the small-scale plant diversity and species composition is influenced by low shrub cover (less than 30%). We hypothesized that even a low shrub cover can have an effect on the environmental conditions of alvar grasslands. We sampled small-scale plant species richness, shrub cover and abiotic environmental conditions such as light, soil moisture, soil pH and soil depth in 10 metre long transects (n = 33) subdivided into 10 cm × 10 cm plots in Estonian alvar grasslands. Structural equation modelling was used to quantify the direct and indirect effects of shrub cover on the richness of characteristic alvar species and on the richness of generalist species. We found that low shrub cover of up to 30% increased total and generalist species richness directly and indirectly by increasing the light heterogeneity. Alvar characteristic species richness was not relat-ed to low shrub cover values. This suggests that when estimating the effects of shrub cover on species richness and on conservation needs of grasslands, habitat specificity of species needs to be taken into account.
In diesem Artikel soll einer der strittigen Vertreter der deutschen Romantik auf zwei verschiedene Weisen analysiert werden, erstens durch Untersuchung des historischen Rahmens seiner antiken Tragödie "Penthesilea", und zweitens, durch den Vergleich des Werkes mit seiner persöhnlichen romantischen Veranlagung, um die traditionellen und historischen Grenzen des Begriffs "Romantik" zu erweitern.
Dieser Artikel behandelt zwei deutsche Schriftstellerinnen – Fanny Lewald und Franziska Gräfin zu Reventlow. Sie sind Repräsentantinnen verschiedener Epochen innerhalb der Deutschen Literatur. Beide hinterließen uns ihre Autobiografien, Anekdoten und wir können heute ihre Entwicklung nachvollziehen und ihr heftiges Ringen um Freiheit, Selbstbestimmung und Selbstverwirklichung gegen geschlechtsspezifische Rollenzuweisungen, Abstammung und sozialen Stand miteinander vergleichen.
Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.
We have analyzed a series of eleven mutations in the 49-kDa protein of mitochondrial complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica to identify functionally important domains in this central subunit. The mutations were selected based on sequence homology with the large subunit of [NiFe] hydrogenases. None of the mutations affected assembly of complex I, all decreased or abolished ubiquinone reductase activity. Several mutants exhibited decreased sensitivities toward ubiquinone-analogous inhibitors. Unexpectedly, seven mutations affected the properties of iron-sulfur cluster N2, a prosthetic group not located in the 49-kDa subunit. In three of these mutants cluster N2 was not detectable by electron-paramagnetic resonance spectroscopy. The fact that the small subunit of hydrogenase is homologous to the PSST subunit of complex I proposed to host cluster N2 offers a straightforward explanation for the observed, unforeseen effects on this iron-sulfur cluster. We propose that the fold around the hydrogen reactive site of [NiFe] hydrogenase is conserved in the 49-kDa subunit of complex I and has become part of the inhibitor and ubiquinone binding region. We discuss that the fourth ligand of iron-sulfur cluster N2 missing in the PSST subunit may be provided by the 49-kDa subunit.
Anti-inflammatory response of Vitamin D on extracranial vessels after subarachnoid hemorrhage
(2023)
Oral e-Poster Presentations - Booth 1: Vascular A (Aneurysms), September 25, 2023, 1:00 PM - 2:30 PM
Background: Vitamin D has been promoted to vascular regeneration in non-cerebral arteries because of its anti-inflammatory properties. Systematic inflammatory reaction as a multifactorial complication after subarachnoid hemorrhage (SAH), correlated with higher mortality and poor outcome, is the result of a multifactorial mechanism with vasoactive inflammation on extracranial vessels. We therefore hypothesized that vitamin D attenuates the systemic vascular inflammatory reaction.
Methods: We investigated the effect of vitamin D pretreatment (100 ng/kg/d; 5 days) in a blood injection SAH model in adult male C57BL6 mice. Vasomotor function (via wire myograph) of carotid and femoral artery and neurological deficits were measured. Different inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM), were also tested.
Results: A significantly enhanced vasorelaxation was identified in Vitamin D pretreated mice (SAH-VitD versus SAH-control: p<0,001; n=10). Missing a relevant difference in vasocontraction of carotid and femoral artery comparing SAH mice with and without vitamin D treatment, there was a significantly higher endothelial related vasorelaxing effect in treated SAH mice (p<0,01, n=5). Neurological deficits in vitamin D pre-treated SAH mice were significantly decreased (p<0,05; n=10). All tested inflammatory factors were down-regulated in vitamin D pre-treated mice (SAH-VitD versus SAH-control: p<0,0001; n=10).
Conclusions: Extracranial vascular Inflammation after SAH, as one of the influencing components in the follow-up after SAH onset, was significantly attenuated by Vitamin D pretreatment. Furthermore, anti-inflammatory effect of vitamin D resulted in a decrease of extracranial vasoconstriction and neurological deficits. Further research should be focused on vitamin D to optimize therapeutic strategies for SAH patients in critical care units.
MRI-detection rate and incidence of lumbar bleeding sources in 190 patients with non-aneurysmal SAH
(2017)
Background: Up to 15% of all spontaneous subarachnoid hemorrhages (SAH) have a non-aneurysmal SAH (NASAH). The evaluation of SAH patients with negative digital subtraction angiography (DSA) is sometimes a diagnostic challenge. Our goal in this study was to reassess the yield of standard MR-imaging of the complete spinal axis to rule out spinal bleeding sources in patients with NASAH.
Methods: We retrospectively analyzed the spinal MRI findings in 190 patients with spontaneous NASAH, containing perimesencephalic (PM) and non-perimesencephalic (NPM) SAH, diagnosed by computer tomography (CT) and/or lumbar puncture (LP), and negative 2nd DSA.
Results: 190 NASAH patients were included in the study, divided into PM-SAH (n = 87; 46%) and NPM-SAH (n = 103; 54%). Overall, 23 (22%) patients had a CT negative SAH, diagnosed by positive LP. MR-imaging of the spinal axis detected two patients with lumbar ependymoma (n = 2; 1,05%). Both patients complained of radicular sciatic pain. The detection rate raised up to 25%, if only patients with radicular sciatic pain received an MRI.
Conclusion: Routine radiological investigation of the complete spinal axis in NASAH patients is expensive and can not be recommended for standard procedure. However, patients with clinical signs of low-back/sciatic pain should be worked up for a spinal pathology.
Background: Previous studies reported decreased volumes of acute stroke admissions during the COVID-19 pandemic. We aimed to examine whether aneurysmal subarachnoid hemorrhage (aSAH) volumes demonstrated similar declines in our department. Furthermore, the impact of the pandemic on disease progression should be analyzed.
Methods: We conducted a retrospective study in the neurosurgical department of the university hospital Frankfurt including patients with the diagnosis of aSAH during the first year of the COVID pandemic. One year cumulative volume for aSAH hospitalization procedures was compared to the year before (03/2020 – 02/2021 vs. 03/2019 – 02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications, and outcome were analyzed.
Results: Compared to the 84 hospital admissions during the pre-pandemic years, the number of aSAH hospitalizations (n = 56) declined during the pandemic without reaching significance. No significant difference in the analyzed patient characteristics including clinical condition at onset, treatment, complications, and outcome, between 56 patients with aSAH admitted during the COVID pandemic and the treated patients in the last 5 years in the pre-COVID period were found. In our multivariable analysis, we detected young age (p < 0.05; OR 4.2) and no existence of early hydrocephalus (p < 0.05; OR 0.13) as important factors for a favorable outcome (mRS ≤ 0–2) after aSAH during the COVID pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age < 50years, p < 0.05; OR 10.5) with an increased rate of cerebral vasospasm after aSAH onset (p < 0.05; OR 26). Nevertheless, past COVID-infection did not reach significance as a high-risk factor for unfavorable outcomes.
Conclusion: There was a relative decrease in the number of patients with aSAH during the COVID-19 pandemic. Despite the extremely different conditions of hospitalization, there was no impairing significant effect on the treatment and outcome of admitted patients with aSAH. A past COVID infection seemed to be an irrelevant limiting factor concerning favorable outcomes.
The efficacy of statin-treatment in aneurysmal subarachnoid hemorrhage (SAH) remains controversial. We aimed to investigate the effects of statin-treatment in non-aneurysmal (na)SAH in accordance with animal research data illustrating the pathophysiology of naSAH. We systematically searched PubMed using PRISMA-guidelines and selected experimental studies assessing the statin-effect on SAH. Detecting the accordance of the applied experimental models with the pathophysiology of naSAH, we analyzed our institutional database of naSAH patients between 1999 and 2018, regarding the effect of statin treatment in these patients and creating a translational concept. Patient characteristics such as statin-treatment (simvastatin 40 mg/d), the occurrence of cerebral vasospasm (CVS), delayed infarction (DI), delayed cerebral ischemia (DCI), and clinical outcome were recorded. In our systematic review of experimental studies, we found 13 studies among 18 titles using blood-injection-animal-models to assess the statin-effect in accordance with the pathophysiology of naSAH. All selected studies differ on study-setting concerning drug-administration, evaluation methods, and neurological tests. Patients from the Back to Bedside project, including 293 naSAH-patients and 51 patients with simvastatin-treatment, were recruited for this analysis. Patients under treatment were affected by a significantly lower risk of CVS (p < 0.01; OR 3.7), DI (p < 0.05; OR 2.6), and DCI (p < 0.05; OR 3). Furthermore, there was a significant association between simvastatin-treatment and favorable-outcome (p < 0.05; OR 3). However, dividing patients with statin-treatment in pre-SAH (n = 31) and post-SAH (n = 20) treatment groups, we only detected a tenuously significant higher chance for a favorable outcome (p < 0.05; OR 0.05) in the small group of 20 patients with statin post-SAH treatment. Using a multivariate-analysis, we detected female gender (55%; p < 0.001; OR 4.9), Hunt&Hess ≤III at admission (p < 0.002; OR 4), no anticoagulant-therapy (p < 0.0001; OR 0.16), and statin-treatment (p < 0.0001; OR 24.2) as the main factors improving the clinical outcome. In conclusion, we detected a significantly lower risk for CVS, DCI, and DI in naSAH patients under statin treatment. Additionally, a significant association between statin treatment and favorable outcome 6 months after naSAH onset could be confirmed. Nevertheless, unified animal experiments should be considered to create the basis for developing new therapeutic schemes.
In the title compound, C15H17ClN2O4S, the atoms in the hydantoin ring are coplanar (r.m.s. deviation = 0.006 Å). The crystal structure is stabilized by intermolecular N-H...O hydrogen bonds which link the molecules into centrosymmetric dimers. The dihedral angle subtended by the 4-chlorophenyl group with the plane passing through the hydantoin unit is 82.98 (4)°. The cyclohexyl ring adopts an ideal chair conformation. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.030; wR factor = 0.081; data-to-parameter ratio = 15.0.
The crystal structure of the title compound, C15H17BrN2O4S, is stabilized by intermolecular N-H...O hydrogen bonds which link the molecules into centrosymmetric dimers. The dihedral angle subtended by the 4-bromophenyl group with the mean plane passing through the hydantoin unit is 83.29 (5)°. The cyclohexyl group adopts an ideal chair conformation with the methyl group in an equatorial position. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; R factor = 0.030; wR factor = 0.070; data-to-parameter ratio = 16.8.
Die Garten-Ringelblume ist aus keinem traditionellem Bauern- und Hausgarten wegzudenken. Sie wird im nördlichen Skandinavien ebenso angepflanzt wie am Mittelmeer und ist auf den Höhen des Pamir in Zentralasien so beliebt wie in den weiten Steppen Russlands. Diese außerordentliche Beliebtheit ist neben den geringen Standortansprüchen auf zwei wesentliche Eigenschaften zurückzuführen. Einerseits besitzt die Art zahlreiche Heilkräfte, die zum Teil schon seit der Antike bekannt sind, andererseits bereichern die attraktiven und vor allem reichlich blühenden Pflanzen von Frühling bis Herbst das Blumenbeet.