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N-Allyltetramethylpiperidine is readily isomerized to the corresponding enamine by treatment with catalytic amounts of B(C6F5)3. It adds HB(C6F5)2 at the nucleophilic enamine carbon atom to form a C/B Lewis adduct. This reacts with two molar equivalents of carbon monoxide by selective head to tail coupling to give a five-membered C2O2B heterocycle. In contrast the enamine/HB(C6F5)2 Lewis pair reacts with two molar equiv. of nitric oxide by head to head coupling. This reaction probably proceeds via equilibrium with the corresponding vicinal N/B Lewis pair. Most products were characterized by X-ray diffraction.
Impact of human mesenchymal stromal cells on antifungal host response against Aspergillus fumigatus
(2017)
Mesenchymal stromal cells (MSCs) are increasingly given as immunotherapy to hematopoietic stem cell transplant (HSCT) recipients with refractory graft-versus-host disease (GvHD). Whereas the immunosuppressive properties of MSCs seem to be beneficial in GvHD, there is, at the same time, major concern that MSCs increase the risk for infection. We therefore investigated the interplay of human MSCs with Aspergillus fumigatus and the impact of MSCs on different arms of the anti-Aspergillus host response in vitro. Although A. fumigatus hyphae increase mRNA levels of IL6 in MSCs, the extracellular availability of IL-6 and other pro-inflammatory cytokines remains unaffected. Human MSCs are able to phagocyte Aspergillus conidia, but phagocytosis of conidia is not associated with an alteration of the cytokine production by MSCs. In addition, human MSCs do not affect activation and function of A. fumigatus specific CD4+ T cells, and MSCs do not negatively impact the oxidative burst activity of phagocytes. Our in vitro data indicate that administration of human MSCs is not associated with a negative impact on the host response against A. fumigatus and that the fungus does not stimulate MSCs to increase the release of those cytokines which play a central role in the pathophysiology of GvHD.
This paper considers the trend towards megaregionalism (TTIP, TPP) that became prominent in the trade domain in the last years of the Obama administration. While megaregionalism has fallen by the wayside since Trump’s inauguration, the underlying rationale for such treaties will most likely reassert itself rather soon. So there are structural issues that need to be discussed from a standpoint of global justice. In all likelihood, megaregionalism is detrimental to global justice. TTIP in particular, or anything like it, might derail any possibility for a trade organization to aid the pursuit of justice at the global level, and any possibility that trade will be used to that end. From the standpoint of global justice one must hope that megaregionalism does not replace WTO multilateralism. The global-justice framework used here is the grounds-of-justice approach offered in the author’s 2012 On Global Justice.
Megaregional trade negotiations have become the subject of heated debate, above all in the context of the Transatlantic Trade and Investment Partnership (TTIP) and the Trans-Pacific Partnership (TPP). In this article, I argue that the justice of the global order suffers from its institutional fragmentation into regime complexes. From a republican perspective, which aspires to non-domination as a guiding principles and idea of global justice, regime complexes raise specific and important challenges in that they open the door to specific forms of domination. I thereby challenge a more optimistic outlook in regime complexes, which paints a positive normative picture of regime complexes, arguing that they enable the enhancement of democracy beyond the state and, consequently, have the potential to reduce the democratic deficit in global governance. By drawing attention to how regime complexes reinforce domination-related injustice, this article contributes an original perspective on megaregionals and to exploring the implications of global justice as non-domination.
Recent trade negotiations such as TTIP include investor protection clauses. Against the background of an analysis of the case for trade, the paper asks whether such clauses can be justified from a normative perspective. More specifically, what is the impact of investor protection on the domestic distribution of the gains from trade between labour and capital, and how should we assess this impact from the perspective of justice? In order to answer this question, the paper develops a series of ideal-type scenarios that reflect the consequences of investor protection on employment on the one hand, and on the distributive conflict between labour and capital on the other. While no claim is made which of these scenarios corresponds to TTIP or other trade agreements, they provide a useful normative framework to analyse such agreements.
nvestor-state-dispute-settlement (ISDS) is an arbitration mechanism to settle disputes between foreign investors and host-states. Seemingly a technical issue in private international law, ISDS procedures have recently become a matter of public concern and the target of political resistance, due to the power they grant to foreign investors in matters of public policies in the countries they invest in. This article examines the practice of ISDS through the lenses of liberal-statist theories of international justice, which value self-determination. It argues that the investor-state arbitration system illustrates how liberal-statist theories of international distributive justice ought to care about relative socioeconomic disadvantage, contra the sufficiency principle that they typically defend. The sufficiency principle draws on a questionable conception of the freedom that self-determination consists in.
Readers of Hannah Arendt’s now classic formulation of the statelessness problem in her 1951 book The Origins of Totalitarianism abound at a moment when the number of stateless peoples worldwide continues to rise exponentially. Along with statelessness, few concepts in Arendt scholarship have spawned such a volume of literature, and perhaps none have provoked as much interest outside of the field of philosophy, as ‘the right to have rights.’ Interpreting this enigmatic term exposes the heart of our beliefs about the nature of the political and has important consequences for how we practice politics on a global scale because it implicitly takes plural human beings, and not the citizen, as its subjects. Arendt’s conceptualization of this problem remains unsurpassed in its diagnosis of the political situation of statelessness, as well as its intimate description of the human cost of what she refers to as ‘world loss,’ a phenomenon that the prevailing human rights and global justice discourse does not take into account. And yet, as an alternative framework for thinking about global politics, the right to have rights resists easy interpretation, let alone practical application.
The CLOUD (Cosmics Leaving OUtdoor Droplets) experiment at CERN is studying the nucleation and growth of aerosol particles under atmospheric conditions, and their activation into cloud droplets. A key feature of the CLOUD experiment is precise control of the experimental parameters. Temperature uniformity and stability in the chamber are important since many of the processes under study are sensitive to temperature and also to contaminants that can be released from the stainless steel walls by upward temperature fluctuations. The air enclosed within the 3 m CLOUD chamber is equipped with several arrays (strings) of high precision, fast-response thermometers to measure its temperature. Here we present a study of the air temperature uniformity inside the CLOUD chamber under various experimental conditions. Measurements were performed under calibration conditions and run conditions, which are distinguished by the flow rate of fresh air and trace gases entering the chamber: 20 l/min and up to 210 l/min, respectively. During steady-state calibration runs between −70 °C and +20 °C, the air temperature uniformity is better than +/−0.06 °C in the radial direction and +/−0.1 °C in the vertical direction. Larger non-uniformities are present during experimental runs, depending on the temperature control of the make-up air and trace gases (since some trace gases require elevated temperatures until injection into the chamber). The temperature stability is a few times 0.01 °C over periods of several hours during either calibration or steady-state run conditions. During rapid adiabatic expansions to activate cloud droplets and ice particles, the chamber walls are up to 10 °C warmer than the enclosed air. This results in larger non-uniformities while the air returns to its equilibrium temperature with time constant of about 200 s.
Information theory provides a formal framework within which information processing and its disorders can be described. However, information theory has rarely been applied to modeling aspects of the cognitive neuroscience of schizophrenia. The goal of this article is to highlight the benefits of an approach based on information theory, including its recent extensions, for understanding several disrupted neural goal functions as well as related cognitive and symptomatic phenomena in schizophrenia. We begin by demonstrating that foundational concepts from information theory—such as Shannon information, entropy, data compression, block coding, and strategies to increase the signal-to-noise ratio—can be used to provide novel understandings of cognitive impairments in schizophrenia and metrics to evaluate their integrity. We then describe more recent developments in information theory, including the concepts of infomax, coherent infomax, and coding with synergy, to demonstrate how these can be used to develop computational models of schizophrenia-related failures in the tuning of sensory neurons, gain control, perceptual organization, thought organization, selective attention, context processing, predictive coding, and cognitive control. Throughout, we demonstrate how disordered mechanisms may explain both perceptual/cognitive changes and symptom emergence in schizophrenia. Finally, we demonstrate that there is consistency between some information-theoretic concepts and recent discoveries in neurobiology, especially involving the existence of distinct sites for the accumulation of driving input and contextual information prior to their interaction. This convergence can be used to guide future theory, experiment, and treatment development.
Auf Grundlage einer interviewbasierten Studie zu heterosexuellen Paaren, in denen die Frau das Haupteinkommen verdient, beschäftigt sich der Beitrag mit milieuspezifischen Bewältigungsmustern prekärer Beschäftigungsverhältnisse. Vor dem Hintergrund der Erosion des Ernährermodells werden dabei Transformationen von Männlichkeit in den Blick genommen. Es wird die These entwickelt, dass sich mit dem Selbstverständnis als "Künstler" im hochqualifizierten individualisierten Milieu des urbanen Raums ein spezifisches Bewältigungsmuster von Prekarität herausgebildet hat.
The inner boundary and the cristae membrane are connected by pore-like structures termed crista junctions (CJs). The MICOS complex is required for CJ formation and enriched at CJs. Here, we address the roles of the MICOS subunits Mic27 and Mic10. We observe a positive genetic interaction between Mic27 and Mic60 and deletion of Mic27 results in impaired formation of CJs and altered cristae membrane curvature. Mic27 acts in an antagonistic manner to Mic60 as it promotes oligomerization of the F1FO-ATP synthase and partially restores CJ formation in cells lacking Mic60. Mic10 impairs oligomerization of the F1FO-ATP synthase similar to Mic60. Applying complexome profiling, we observed that deletion of Mic27 destabilizes the MICOS complex but does not impair formation of a high molecular weight Mic10 subcomplex. Moreover, this Mic10 subcomplex comigrates with the dimeric F1FO-ATP synthase in a Mic27-independent manner. Further, we observed a chemical crosslink of Mic10 to Mic27 and of Mic10 to the F1FO-ATP synthase subunit e. We corroborate the physical interaction of the MICOS complex and the F1FO-ATP synthase. We propose a model in which part of the F1FO-ATP synthase is linked to the MICOS complex via Mic10 and Mic27 and by that is regulating CJ formation.
Background: Computed-tomography-guided interventions are attractive for tissue sampling of paediatric tumor lesions; however, it comes with exposure to ionizing radiation. The aim of this study was to analyse the radiation dose, accuracy and speed of CT-guided interventions in paediatric patient cohort.
Methods: We retrospectively reviewed CT-guided interventions over a 10 -year period in 65 children. The intervention site consisted of bones in 38, chest (lung) in 15 and abdomen (liver, lymph nodes) in 12 cases. Radiation dose and duration of the procedures were analysed. The statistical analysis was performed using dedicated statistical software (BiAS 8.3.6 software, Epsilon Verlag, North Hasted).
Results: All interventions were performed successfully. Mean target access path to lesion within the patients was 6.0 cm (min 3.5 cm, max 11.2 cm). Time duration to complete intervention was 25:15 min (min 17:03 min, max 43:00 min). The dose-length product (DLP) of intervention scan was 29.5 mGy · cm (min 6 mGy · cm, max 85 mGy · cm) with the lowest dose for biopsies in the region of the chest (p = 0.04).
Conclusions: With justified indications, CT-guided paediatric interventions are safe, effective and can be performed both, with short intervention times and low radiation exposure.
Background: To meet the requirements imposed by the time-dependency of acute stroke therapies, it is necessary 1) to initiate structural and cultural changes in the breadth of stroke-ready hospitals and 2) to find new ways to train the personnel treating patients with acute stroke. We aimed to implement and validate a composite intervention of a stroke team algorithm and simulation-based stroke team training as an effective quality initiative in our regional interdisciplinary neurovascular network consisting of 7 stroke units.
Methods: We recorded door-to-needle times of all consecutive stroke patients receiving thrombolysis at seven stroke units for 3 months before and after a 2 month intervention which included setting up a team-based stroke workflow at each stroke unit, a train-the-trainer seminar for stroke team simulation training and a stroke team simulation training session at each hospital as well as a recommendation to take up regular stroke team trainings.
Results: The intervention reduced the network-wide median door-to-needle time by 12 minutes from 43,0 (IQR 29,8–60,0, n = 122) to 31,0 (IQR 24,0–42,0, n = 112) minutes (p < 0.001) and substantially increased the share of patients receiving thrombolysis within 30 minutes of hospital arrival from 41.5% to 59.6% (p < 0.001). Stroke team training participants stated a significant increase in knowledge on the topic of acute stroke care and in the perception of patient safety. The overall course concept was regarded as highly useful by most participants from different professional backgrounds.
Conclusions: The composite intervention of a binding team-based algorithm and stroke team simulation training showed to be well-transferable in our regional stroke network. We provide suggestions and materials for similar campaigns in other stroke networks.
"Ihr sollt euch nicht zu den Götzen wenden, und gegossene Götter sollt ihr euch nicht machen [...](Lev 19,4) [...] sollen wir nicht meinen, daß das Göttliche dem Gold und Silber oder Stein, einem Gebilde der Kunst und der Erfindung des Menschen gleich sei. (Acta 17,29) Pfui über euch und über das, was ihr an Gottes Statt verehrt! [...] (Q 21,67)"
Diese drei Sätze stammen nacheinander aus der hebräischen Bibel, dem Neuen Testament und dem Koran. Man kann sie beinahe wie einen Text lesen, an dem sich die These des Ägyptologen Jan Assmann belegen ließe, dass mit der Herausbildung monotheistischer Religionen wie Judentum, Christentum und Islam im Allgemeinen und dem Bilderverbot im Besonderen die Unterscheidung zwischen wahr und falsch in die Götterwelt gekommen sei (Assmann 1998, S. 17). ...
Es wäre eine bessere Welt, würde es diese Bilder nicht geben: Die Rede ist von Darstellungen, die sexuellen Missbrauch von und sexualisierte Gewalt an Kindern und Jugendlichen zeigen. Die physischen und psychischen Verletzungen, die durch den Missbrauch, aber auch durch dessen Perpetuierung in Bildern verursacht werden, sind unermesslich. Daher greift die Gesellschaft zu einem ihrer schärfsten Schwerter – dem Strafrecht.
Mit flexiblen Video-Endoskopen gelingen heute hochaufgelöste Bilder des Magen-Darm-Traktes. Bösartige Tumoren werden früher erkannt und oft auch entfernt, ohne die Bauchdecke aufzuschneiden. Sogar Verengungen der Gallenwege lassen sich mit hochpräziser Endoskopietechnik darstellen und behandeln. Die Medizinische Klinik 1 der Universitätsklinik unter der Leitung von Prof. Dr. Stefan Zeuzem gehört zu den Pionieren auf diesem Gebiet.
Lieblingsbild
(2017)
In lebende Körper zu sehen, ohne das Messer anzusetzen, das war lange ein Traum von Wissenschaftlern und Ärzten. Was vor mehr als 120 Jahren mit Conrad Röntgens Entdeckung der X-Strahlen begann, hat sich mit Magnetenzephalographie und Magnetresonanztomographie zu gängigen Instrumenten der Hightech-Medizin entwickelt.
Lieblingsbild
(2017)
Dieses Bild ist wichtig, weil wir daran verstanden haben, wie in der Zelle fehlerhaftes Spleißen verhindert wird. Dazu muss man wissen, dass unsere Gene sich aus Exons und dazwischenliegenden Introns zusammensetzen. Während des Spleißens werden die Introns entfernt und die Exons in ein reifes Transkript zusammengefügt, das dann für ein Protein kodiert. Allerdings gibt es innerhalb der Introns viele Bereiche, die einem Exon sehr ähnlich sehen. Werden diese sogenannten "PseudoExons" fälschlicherweise während des Spleißprozesses erkannt und in das reife Transkript eingebaut, kann das fatale Folgen für das kodierte Protein und oft die gesamte Zelle haben. ...
Gleichungen mit mehreren Unbekannten zu lösen, üben Schüler schon in der Mittelstufe. Für die einen ist es eine spannende mathematische Knobelei, für die anderen eher Quälerei. Doch den wenigsten ist bewusst, wie viele Leben dadurch jeden Tag gerettet werden. Die moderne medizinische Bildgebung beruht darauf, sehr viele Gleichungen nach sehr vielen Unbekannten aufzulösen.
Comics sind ein überaus beliebtes Genre, vielleicht mehr denn je. Manga, aber auch Graphic Novels haben heute in jedem Buchladen ihre eigenen Regale. Aber worum handelt es sich eigentlich: um Bilder, die mit Text ergänzt werden, oder vice versa? Lesen wir oder schauen wir Comics, und warum lohnt es sich, dieses Misch-Genre zu erforschen? Darüber hat Dirk Frank mit Bernd Dolle-Weinkauff, Literaturwissenschaftler und Comic-Experte am Institut für Jugendbuchforschung, gesprochen.
Im Frankfurter Städel Museum ist ein Papst-Porträt zu sehen, das viele Geschichten erzählt: von Julius II., der als ebenso kriegerisch wie kunstsinnig galt, von einem Bildmotiv, das bis heute Standards setzt, und von technischen Methoden, die zeigen, dass hier wohl mehr Raffael drinsteckt, als manche wahrhaben wollen – wodurch das Bild rund 500 Jahre nach seiner Entstehung vielleicht selbst Geschichte schreibt.
Lieblingsbild
(2017)
Für Spezialisten historischer Epochen, aus denen kaum schriftliche Zeugnisse vorliegen, spielten Bilder schon immer eine zentrale Rolle. Doch wie steht es um ihre Bedeutung in der Geschichtswissenschaft allgemein? Welche Relevanz hatte bzw. hat für sie der "iconic turn"? Darüber sprach der Philosoph und Publizist Rolf Wiggershaus mit Historikern der Goethe-Universität.
In der Lichtmikroskopie gibt es heute viele fortgeschrittene Techniken, mit denen man beispielsweise das Wachstum lebender Organismen, kleinste Zellstrukturen oder das Eindringen von Bakterien in Zellen untersuchen kann. Die dafür benötigten Mikroskope sind teure Hightech-Geräte, deren Bedienung Übung erfordert. Damit die vorhandenen Geräte möglichst effizient genutzt werden können, hat die Goethe-Universität ihre Mikroskopie-Einrichtungen in verschiedenen Instituten auf dem Campus Riedberg im "Frankfurt Center for Advanced Light Microscopy" (FCAM) zusammengelegt. ...
Durchblicke im Rückblick : Prof. Jürgen Bereiter-Hahn über 40 Jahre Erfahrungen mit Lichtmikroskopie
(2017)
Ich bin Biologe. Das ist eine Wissenschaft, die sich mit Strukturen beschäftigt und diese sind besonders gut in Bildern darstellbar. Ich achte auch auf den ästhetischen Wert von Bildern, er trägt oft wesentlich zur Verständlichkeit der Aussage bei, besonders in Publikationen. Aber ich bin auch Wort-affin. Es ist mir sehr wichtig, gut zu formulieren. Ich habe auch Philosophie studiert und jetzt arbeite ich mehr in dieser Richtung. Derzeit beschäftige ich mich mit dem Verhältnis von Biologie und Normen. ...
Lieblingsbild
(2017)
Das Bild zeigt die Kryo-EM-Elektronendichtekarte des bakteriellen Kalium-Aufnahmesystems KtrAB mit ADP gebunden mit einer Auflösung von 6.6 Å. Das Bild ist mein Lieblingsbild, weil man bereits auf den ersten Blick eine dramatische Konformationsänderung im Vergleich zu einer früheren ATPgebundenen Struktur erkennen konnte, nämlich die Ausbildung langgestreckter α-Helices (hier gelb markiert), die die regulatorischen A-Untereinheiten (blau) mit den Kaliumionen-translozierenden B-Untereinheiten (grau) verbinden. ...
"Ästhetisch ist, was hilft"
(2017)
Lieblingsbild
(2017)
Das rechte Bild stellt die Elektronendichte eines menschlichen Proteins dar, gewonnen durch die Röntgenstrahl-Beugung an Kristallen dieses Proteins. Die Struktur hat Sagar Bhogaraju 2016 aufgeklärt. Das linke Bild stellt ein erstes Strukturmodell auf der Basis der gemessenen Elektronendichte dar. ...
Schönheit liegt auch in der Wissenschaft im Auge des Betrachters. So wie Eltern ihre Sprösslinge schön finden, schwärmen auch Forscher wie Mike Heilemann und Ivan Dikic von ihren Bildern fluoreszierender Bakterien. Doch wenn sie es auf das Cover einer Fachzeitschrift schaffen wollen, nehmen sie die Hilfe wissenschaftlicher Illustratorinnen wie Ella Marushchenko in Anspruch.
Lieblingsbild
(2017)
Was ist ein geographisches Bild? Darauf hat sicher jeder eine Antwort: Beim einen poppen im Kopf zunächst die Urlaubsfotos von der finnischen Schären-Küste oder aus Paris auf, die andere denkt an Satellitenaufnahmen des schwindenden Eisrandes der Arktis im GEO-Magazin oder an Claudia Kleinerts Wetterkarte in den Tagesthemen. Auf den ersten Blick scheint klar: alles Bilder, alles irgendwie geographisch.
Das Recht – abstrakt und bilderfeindlich? Ein Fehlurteil. Denn schon immer hat das Recht zu sinnlichen Hilfsmitteln gegriffen, um sich den Menschen verständlich zu machen, teils auf realer, besonders gern aber auf sprachlicher Ebene. Die heutige Bilderflut ist jedoch auch für die Rechtswissenschaft ein neues Phänomen.
Der Aufbau unserer Umwelt folgt bestimmten Regelmäßigkeiten, die für uns so selbstverständlich sind, dass wir ihrer kaum bewusst sind. Doch würden Sie die Milch unter dem Bett suchen oder das Kissen in der Badewanne? Wohl kaum. Die Psychologin Prof. Melissa Lê-Hoa Võ untersucht das erlernte Regelwerk, die Entwicklung von sogenanntem Szenenwissen, mithilfe psychophysischer Verfahren, Blickbewegungsund Hirnpotenzialmessungen.
Der Mensch besteht aus vielen Körperteilen, und doch ist es fast ausschließlich das Gesicht, an dem wir ein Individuum erkennen. Aber erkennen wir es wirklich? In Zeiten des Selfie-Kults und der biometrischen Verfahren ist diese Frage aktueller denn je. Wir leben in einer »fazialen« Gesellschaft: Das Gesicht ist Medium für alle erdenklichen Arten, sich mitzuteilen.
AKTIVA-MCI is a program for patients with mild cognitive impairment (MCI) that aims to enhance participation in cognitively stimulating leisure activities. Participation in cognitively stimulating activities seems to be a potential strategy for people with MCI delaying cognitive decline for a while. In total, 35 MCI patients were enrolled in the pilot study of whom 29 completed the whole program (16 female, 71.1±7.5 years; Mini Mental Status Examination score: 28±2.2). Daily activity protocols were used to measure the frequency of participation in cognitively stimulating activities during the program (12 sessions). Additional standardized psychometric tests and questionnaires were used to assess cognition, mood, and subjective memory decline. Analyses of the daily activity protocols showed that during the intervention participants increased the frequency of several cognitively stimulating leisure activities. Comparison of pre-post data indicates no changes in cognitive status, mood, and subjective memory decline. These findings indicate that the program is suitable for patients with MCI.
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
Mutations are the ultimate basis of evolution, yet their occurrence rate is known only for few species. We directly estimated the spontaneous mutation rate and the mutational spectrum in the nonbiting midge C. riparius with a new approach. Individuals from ten mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing parental genotypes. We identified 51 new single site mutations of which 25 were insertions or deletions and 26 single nucleotide mutations. This shift in the mutational spectrum compared to other organisms was explained by the high A/T content of the species. We estimated a haploid mutation rate of 2.1 × 10−9 (95% confidence interval: 1.4 × 10−9 – 3.1 × 10-9) that is in the range of recent estimates for other insects and supports the drift barrier hypothesis. We show that accurate mutation rate estimation from a high number of observed mutations is feasible with moderate effort even for nonmodel species.
The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome. A crucial element of MHC I antigen presentation is the peptide-loading complex (PLC), a multisubunit machinery, which contains as key constituents the transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). While TAP recognizes and shuttles the cytosolic antigenic peptides into the endoplasmic reticulum (ER), Tsn samples peptides in the ER for their ability to form stable complexes with MHC I, a process called peptide proofreading or peptide editing. Through its selection of peptides that improve MHC I stability, Tsn contributes to the hierarchy of immunodominant peptide epitopes. Despite the fact that it concerns a key event in adaptive immunity, insights into the catalytic mechanism of peptide proofreading carried out by Tsn have only lately been gained via biochemical, biophysical, and structural studies. Furthermore, a Tsn homolog called TAP-binding protein-related (TAPBPR) has only recently been demonstrated to function as a second MHC I-specific chaperone and peptide proofreader. Although TAPBPR is PLC-independent and has a distinct allomorph specificity, it is likely to share a common catalytic mechanism with Tsn. This review focuses on the current knowledge of the multivalent protein–protein interactions and the concomitant dynamic molecular processes underlying peptide-proofreading catalysis. We do not only derive a model that highlights the common mechanistic principles shared by the MHC I editors Tsn and TAPBPR, and the MHC II editor HLA-DM, but also illustrate the distinct quality control strategies employed by these chaperones to sample epitopes. Unraveling the mechanistic underpinnings of catalyzed peptide proofreading will be crucial for a thorough understanding of many aspects of immune recognition, from infection control and tumor immunity to autoimmune diseases and transplant rejection.
Viewing of ambiguous stimuli can lead to bistable perception alternating between the possible percepts. During continuous presentation of ambiguous stimuli, percept changes occur as single events, whereas during intermittent presentation of ambiguous stimuli, percept changes occur at more or less regular intervals either as single events or bursts. Response patterns can be highly variable and have been reported to show systematic differences between patients with schizophrenia and healthy controls. Existing models of bistable perception often use detailed assumptions and large parameter sets which make parameter estimation challenging. Here we propose a parsimonious stochastic model that provides a link between empirical data analysis of the observed response patterns and detailed models of underlying neuronal processes. Firstly, we use a Hidden Markov Model (HMM) for the times between percept changes, which assumes one single state in continuous presentation and a stable and an unstable state in intermittent presentation. The HMM captures the observed differences between patients with schizophrenia and healthy controls, but remains descriptive. Therefore, we secondly propose a hierarchical Brownian model (HBM), which produces similar response patterns but also provides a relation to potential underlying mechanisms. The main idea is that neuronal activity is described as an activity difference between two competing neuronal populations reflected in Brownian motions with drift. This differential activity generates switching between the two conflicting percepts and between stable and unstable states with similar mechanisms on different neuronal levels. With only a small number of parameters, the HBM can be fitted closely to a high variety of response patterns and captures group differences between healthy controls and patients with schizophrenia. At the same time, it provides a link to mechanistic models of bistable perception, linking the group differences to potential underlying mechanisms.
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto major histocompatibility complex class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders. The development of therapies or drugs therefore requires a detailed comprehension of structure and function of this ABC transporter, but our knowledge about various aspects is still insufficient. This review highlights recent achievements on the structure and dynamics of antigenic peptides in complex with TAP. Understanding the binding mode of antigenic peptides in the TAP complex will crucially impact rational design of inhibitors, drug development, or vaccination strategies.
Perfectionism nowadays is frequently understood as a multidimensional personality trait with two higher-order dimensions of perfectionistic strivings and perfectionistic concerns. While perfectionistic concerns are robustly found to correlate with negative outcomes and psychological malfunctioning, findings concerning the outcomes of perfectionistic strivings are inconsistent. There is evidence that perfectionistic strivings relate to psychological maladjustment on the one hand but to positive outcomes on the other hand as well. Moreover, perfectionistic strivings and perfectionistic concerns frequently showed substantial overlap. These inconsistencies of differential relations and the substantial overlap of perfectionistic strivings and perfectionistic concerns raise questions concerning the factorial structure of perfectionism and the meaning of its dimensions. In this study, several bifactor models were applied to disentangle the common variance of perfectionistic strivings and perfectionistic concerns at the item level using Hill et al.’s (2004) Perfectionism Inventory (PI). The PI measures a broad range of perfectionism dimensions by four perfectionistic strivings and four perfectionistic concerns subscales. The bifactor-(S – 1) model with one general factor defined by concern over mistakes as the reference facet, four specific perfectionistic strivings factors, and three specific perfectionistic concerns factors showed acceptable fit. The results revealed a clear separation between perfectionistic strivings and perfectionistic concerns, as the general factor represented concern over mistakes, while the perfectionistic strivings factors each explained a substantial amount of reliable variance independent of the general factor. As a result, factor scores of the specific perfectionistic strivings factors and the general factor had differential relationships with achievement motivation, neuroticism, conscientiousness, and self-efficacy that met with theoretical expectations, while results for manifest subscale scores were ambiguous. Our results question the existence of reliable sub-constructs of perfectionistic concerns independent of the general factor when defined by concern over mistakes.
Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.
Although existing research has established that aesthetic pleasure and aesthetic interest are two distinct positive aesthetic responses, empirical research on aesthetic preferences usually considers only aesthetic liking to capture participants’ aesthetic response. This causes some fundamental contradictions in the literature; some studies find a positive relationship between easy-to-process stimulus characteristics and aesthetic liking, while others suggest a negative relationship. The present research addresses these empirical contradictions by investigating the dual character of aesthetic liking as manifested in both the pleasure and interest components. Based on the Pleasure-Interest Model of Aesthetic Liking (PIA Model; Graf and Landwehr, 2015), two studies investigated the formation of pleasure and interest and their relationship with aesthetic liking responses. Using abstract art as the stimuli, Study 1 employed a 3 (stimulus fluency: low, medium, high) × 2 (processing style: automatic, controlled) × 2 (aesthetic response: pleasure, interest) experimental design to examine the processing dynamics responsible for experiencing aesthetic pleasure versus aesthetic interest. We find that the effect of stimulus fluency on pleasure is mediated by a gut-level fluency experience. Stimulus fluency and interest, by contrast, are related through a process of disfluency reduction, such that disfluent stimuli that grow more fluent due to processing efforts become interesting. The second study employed product designs (bikes, chairs, and lamps) as stimuli and a 2 (fluency: low, high) × 2 (processing style: automatic, controlled) × 3 (product type: bike, chair, lamp) experimental design to examine pleasure and interest as mediators of the relationship between stimulus fluency and design attractiveness. With respect to lamps and chairs, the results suggest that the effect of stimulus fluency on attractiveness is fully mediated by aesthetic pleasure, especially in the automatic processing style. Conversely, disfluent product designs can enhance design attractiveness judgments due to interest when a controlled processing style is adopted.
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.