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Seit der Entdeckung des HI-Virus in 1983, wurden diverse Beobachtungen zu neurologischen Komplikationen bei infizierten Patienten publiziert. Dabei standen initial lebensbedrohliche Komplikationen wie opportunistische Infektionen oder cerebrale Lymphome im Vordergrund. In Zeiten der antiretroviralen Therapie rücken jedoch vermehrt andere, chronisch verlaufende Folgen der Erkrankung in den Fokus. Neurokognitive Störungen bei HIV-infizierten wurden bereits erstmals im Jahre 1986 beschrieben. Seitdem wurden neben der manifesten HIV-assoziierten Demenz auch mildere Einbußen im kongitiven Bereich - sogenannte HIV-assoziierte neurokognitive Störungen (HAND) - klassifiziert, deren Diagnostik mittels diverser neuropsychologischer Testungen erfolgen kann. Hierfür sind geeignete Screening-Tools notwendig, die entsprechenden Anforderungen entsprechen sollten. Einheitliche Empfehlungen für einen bestimmten Test finden sich jedoch in aktuellen Leitlinien und Publikationen nicht. Die vorliegende Arbeit wurde zur Evaluation des MoCA-Tests (Montreal Cognitive Assessment) zur Detektion HIV-1-assoziierter neurokognitiver Störungen angefertigt.
Hierfür wurde der MoCA-Test an 89 HIV-infizierten Männern und Frauen zwischen 21 und 64 Jahren des HIV-Centers Frankfurt am Main durchgeführt und die Ergebnisse mit der gut validierten HIV-Demenz-Skala verglichen. Zudem wurde der Einfluss verschiedener Faktoren wie Geschlecht, Alter, CDC-Stadium, antiretrovirale Therapie, Dauer der HIV-Infektion, CD4-Zellzahl, Viruslast, HCV-Koinfektion, Bildung, Risikogruppenzugehörigkeit, Alkoholkonsum und CPE-Score untersucht.
Der Vergleich zwischen den absoluten Ergebnissen der HDS und des MoCA ergab einen hochsignifikanten statistischen Zusammenhang. Ein statistischer Zusammenhang konnte auch für die Parameter Alter, medikamentöse HIV-Therapie, Dauer der HIV-Infektion zum Untersuchungszeitpunkt sowie Bildung errechnet werden. Die relativen MoCA-Testergebnisse wurden sowohl mit einem Cut-off-Wert von 10 als auch einem Cut-off-Wert von 14 der HDS verglichen.
In Zusammenschau der Ergebnisse korreliert der MoCA-Test auf Grundlage der erhobenen Daten mit der HDS, wobei die Sensitivität in Bezug auf mildere kognitive Störungen niedriger als wünschenswert ist. Eine manifeste HIV-Demenz kann zuverlässig diagnostiziert werden, bei der Diagnostik von milderen Funktionseinschränkungen bestehen jedoch Limitationen. Auf Grund der einfachen Durchführung stellt er ein akzeptables alternatives Screening-Tool dar, wobei Personen mit auffälligen Testergebnissen einer weiteren neuropsychologischen Testung zugeführt werden sollten.
Dieser Band versammelt die Vorträge einer Tagung der Johannes- Althusius-Gesellschaft e. V., die vom 26.–29.5.2016 in Wittenberg stattfand.
Die umfassende Thematik wurde auf vier Aspekte konzentriert: 1) Religion und Konstitutionalisierung 2) die Bedeutung der Reformation für Rechts- und Staatslehren der frühen Neuzeit, 3) Völkerrecht, 4) Recht, Gehorsam und Religion. Dem folgt auch die Gliederung des Buches. Leider ist die Einleitung des Herausgebers sehr formal. Angesichts einiger sehr anregender neuer Forschungsthesen bzw. -ergebnisse wäre der inhaltliche Schwung der Tagung gleich als Eröffnung gut vermittelbar gewesen. ...
La creación de audio-podcasts ofrece una excelente oportunidad para representar de forma oral los contenidos de matemáticas usando medios digitales tanto en la formación docente, como en la educación primaria. Sin embargo, en el proceso de creación de los audio- -podcasts hay fases gráficas-escritas y otras orales que están estrechamente vinculadas entre sí. Este artículo trata sobre la creación y utilización de podcast en la educación primaria (PriMaPodcast) y en la formación docente (MathePodcast) tanto para la enseñanza como para la investigación.Mathematics audio-podcasts: communication and representation with ICTLa creación de audio-podcasts ofrece una excelente oportunidad para representar de forma oral los contenidos de matemáticas usando medios digitales tanto en la formación docente, como en la educación primaria. Sin embargo, en el proceso de creación de los audio- -podcasts hay fases gráficas-escritas y otras orales que están estrechamente vinculadas entre sí. Este artículo trata sobre la creación y utilización de podcast en la educación primaria (PriMaPodcast) y en la formación docente (MathePodcast) tanto para la enseñanza como para la investigación.
Abstract
Divergence is mostly viewed as a progressive process often initiated by selection targeting individual loci, ultimately resulting in ever increasing genomic isolation due to linkage. However, recent studies show that this process may stall at intermediate stable equilibrium states without achieving complete genomic isolation. We tested the extent of genomic isolation between two recurrently hybridizing nonbiting midge sister taxa, Chironomus riparius and Chironomus piger, by analyzing the divergence landscape. Using a principal component‐based method, we estimated that only about 28.44% of the genomes were mutually isolated, whereas the rest was still exchanged. The divergence landscape was fragmented into isolated regions of on average 30 kb, distributed throughout the genome. Selection and divergence time strongly influenced lengths of isolated regions, whereas local recombination rate only had minor impact. Comparison of divergence time distributions obtained from several coalescence‐simulated divergence scenarios with the observed divergence time estimates in an approximate Bayesian computation framework favored a short and concluded divergence event in the past. Most divergence happened during a short time span about 4.5 million generations ago, followed by a stable equilibrium between mutual gene flow through ongoing hybridization for the larger part of the genome and isolation in some regions due to rapid purifying selection of introgression, supported by high effective population sizes and recombination rates.
Impact Summary
The process of speciation has fascinated biologists from early on. Prevailing theory suggested that gene flow among populations is the main obstacle for their divergence. Recently, it became clear that speciation with gene flow is possible under certain circumstances. However, it remains unclear how the divergence process proceeds in time, how widespread the phenomenon is, and whether it always and inevitably leads to complete isolation. Comparing the genomes of individuals of two regularly hybridizing sister taxa of nonbiting midges, we could show that they diverged during a short period millions of generations ago. Their divergence process apparently ceased before the entire genome was mutually isolated. The taxa remain distinct since, even though they share most of their genome. Our findings thus extend our view of the nature of species and the temporal dynamics of their divergence and describe novel approaches to analyze both current and past divergence processes.
Ice-nucleating particle concentrations of the past: insights from a 600-year-old Greenland ice core
(2020)
Ice-nucleating particles (INPs) affect the microphysics in cloud and precipitation processes. Hence, they modulate the radiative properties of clouds. However, atmospheric INP concentrations of the past are basically unknown. Here, we present INP measurements from an ice core in Greenland, which dates back to the year 1370. In total 135 samples were analyzed with the FRIDGE droplet freezing assay in the temperature range from −14 to −35 ∘C. The sampling frequency was set to 1 in 10 years from 1370 to 1960. From 1960 to 1990 the frequency was increased to one sample per year. Additionally, a few special events were probed, including volcanic episodes. The typical time coverage of a sample was on the order of a few months. Historical atmospheric INP concentrations were estimated with a conversion factor, which depends on the snow accumulation rate of the ice core, particle dry deposition velocity, and wet scavenging ratio. Typical atmospheric INP concentrations were on the order of 0.1 L−1 at −25 ∘C. The INP variability was found to be about 1–2 orders of magnitude. Yet, the short-term variability from samples over a seasonal cycle was considerably lower. INP concentrations were significantly correlated to some chemical tracers derived from continuous-flow analysis (CFA) and ion chromatography (IC) over a broad range of nucleation temperatures. The highest correlation coefficients were found for the particle concentration (spherical diameter dp > 1.2 µm). The correlation is higher for a time period of seasonal samples, where INP concentrations follow a clear annual pattern, highlighting the importance of the annual dust input in Greenland from East Asian deserts during spring. Scanning electron microscopy (SEM) analysis of selected samples found mineral dust to be the dominant particle fraction, verifying their significance as INPs. Overall, the concentrations compare reasonably well to present-day INP concentrations, albeit they are on the lower side. However, we found that the INP concentration at medium supercooled temperatures differed before and after 1960. Average INP concentrations at −23, −24, −25, −26, and −28 ∘C were significantly higher (and more variable) in the modern-day period, which could indicate a potential anthropogenic impact, e.g., from land-use change.
Ice nucleating particle concentrations of the past: insights from a
600 year old Greenland ice core
(2020)
Ice nucleating particles (INPs) affect the microphysics in cloud and precipitation processes. Hence, they modulate the radiative properties of clouds. However, atmospheric INP concentrations of the past are basically unknown. Here, we present INP measurements from an ice core in Greenland, which dates back to the year 1370. In total 135 samples were analyzed with the FRIDGE droplet freezing assay in the temperature range from −14 ◦C to −35 ◦C. The sampling frequency was set to 1 in 10 years from 1370 to 1960. From 1960 to 1990 the frequency was increased to 1 sample per year. Additionally, a number of special events were probed, including volcanic episodes. The typical time coverage of a sample was on the order of a few months. Historical atmospheric INP concentrations were estimated with a conversion factor, which depends on the snow accumulation rate of the ice core, particle dry deposition velocity and the wet scavenging ratio. Typical atmospheric INP concentrations were on the order of 0.1 L -1 at −25 ◦C. The INP variability was found to be about 1 – 2 orders of magnitude. Yet, the short-term variability from samples over a seasonal cycle was considerably lower. INP concentrations were significantly correlated to chemical tracers derived from continuous flow analysis (CFA) and ion chromatography (IC) over a broad range of nucleation temperatures. The highest correlation coefficients were found for the particle concentration (dp > 1.2 µm). The correlation is higher for the seasonal samples, where INP concentrations follow a clear annual pattern, highlighting the importance of the annual dust input in Greenland from East Asian deserts during spring. Scanning electron microscopy (SEM) of single particles retrieved from selected samples found particles of soil origin to be the dominant fraction, verifying the significance of mineral dust particles as INPs. Overall, the concentrations compare reasonably well to present day INP concentrations, albeit they are on the lower side. However, we found that the INP concentration at medium supercooled temperatures differed before and after 1960. Average INP concentrations at −23 ◦C, −24 ◦C, −25 ◦C, −26 ◦C and −28 ◦C were significantly higher (and more variable) in the modern day period, which could indicate a potential anthropogenic impact or some post-coring contamination of the topmost, very porous firn.
Ice particle activation and evolution have important atmospheric implications for cloud formation, initiation of precipitation and radiative interactions. The initial formation of atmospheric ice by heterogeneous ice nucleation requires the presence of a nucleating seed, an ice-nucleating particle (INP), to facilitate its first emergence. Unfortunately, only a few long-term measurements of INPs exist, and as a result, knowledge about geographic and seasonal variations of INP concentrations is sparse. Here we present data from nearly 2 years of INP measurements from four stations in different regions of the world: the Amazon (Brazil), the Caribbean (Martinique), central Europe (Germany) and the Arctic (Svalbard). The sites feature diverse geographical climates and ecosystems that are associated with dissimilar transport patterns, aerosol characteristics and levels of anthropogenic impact (ranging from near pristine to mostly rural). Interestingly, observed INP concentrations, which represent measurements in the deposition and condensation freezing modes, do not differ greatly from site to site but usually fall well within the same order of magnitude. Moreover, short-term variability overwhelms all long-term trends and/or seasonality in the INP concentration at all locations. An analysis of the frequency distributions of INP concentrations suggests that INPs tend to be well mixed and reflective of large-scale air mass movements. No universal physical or chemical parameter could be identified to be a causal link driving INP climatology, highlighting the complex nature of the ice nucleation process. Amazonian INP concentrations were mostly unaffected by the biomass burning season, even though aerosol concentrations increase by a factor of 10 from the wet to dry season. Caribbean INPs were positively correlated to parameters related to transported mineral dust, which is known to increase during the Northern Hemisphere summer. A wind sector analysis revealed the absence of an anthropogenic impact on average INP concentrations at the site in central Europe. Likewise, no Arctic haze influence was observed on INPs at the Arctic site, where low concentrations were generally measured. We consider the collected data to be a unique resource for the community that illustrates some of the challenges and knowledge gaps of the field in general, while specifically highlighting the need for more long-term observations of INPs worldwide.
Reactive oxygen species (ROS) have been shown or at least suggested to play an essential role for cellular signaling as second messengers. NADPH oxidases represent a source of controlled ROS formation. Accordingly, understanding the role of individual NADPH oxidases bears potential to interfere with intracellular signaling cascades without disturbing the signaling itself. Many tools have been developed to study or inhibit the functions and roles of the NADPH oxidases. This short review summarizes diseases, potentially associated with NADPH oxidases, genetically modified animals, and inhibitors.
Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, non-canonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK and CLK. Using the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a non-canonical binding mode in CLK1, providing a rational for selectivity over the closely-related CLK3 which harbors a smaller DFG-1 alanine. Our data suggests that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.
Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, noncanonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK, and CLK. By use of the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a noncanonical binding mode in CLK1, providing a rationale for selectivity over the closely related CLK3 which harbors a smaller DFG-1 alanine. Our data suggest that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.
Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase.
MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.
Mit dem Klimawandel könnte das Grundwasser künftig weltweit in vielen Regionen knapp werden. Das zeigt eine große internationale Studie, die vom Doktoranden Robert Reinecke und der Geographin Prof. Petra Döll initiiert wurde. Vielerorts könnte das zu Wassermangel führen oder einen bestehenden Wassermangel verschärfen. Gleichzeitig werden andere Regionen unter steigenden Grundwasserständen zu leiden haben. Ackerflächen könnten durch Vernässung verloren gehen.
Recurrent cortical network dynamics plays a crucial role for sequential information processing in the brain. While the theoretical framework of reservoir computing provides a conceptual basis for the understanding of recurrent neural computation, it often requires manual adjustments of global network parameters, in particular of the spectral radius of the recurrent synaptic weight matrix. Being a mathematical and relatively complex quantity, the spectral radius is not readily accessible to biological neural networks, which generally adhere to the principle that information about the network state should either be encoded in local intrinsic dynamical quantities (e.g. membrane potentials), or transmitted via synaptic connectivity. We present two synaptic scaling rules for echo state networks that solely rely on locally accessible variables. Both rules work online, in the presence of a continuous stream of input signals. The first rule, termed flow control, is based on a local comparison between the mean squared recurrent membrane potential and the mean squared activity of the neuron itself. It is derived from a global scaling condition on the dynamic flow of neural activities and requires the separability of external and recurrent input currents. We gained further insight into the adaptation dynamics of flow control by using a mean field approximation on the variances of neural activities that allowed us to describe the interplay between network activity and adaptation as a two-dimensional dynamical system. The second rule that we considered, variance control, directly regulates the variance of neural activities by locally scaling the recurrent synaptic weights. The target set point of this homeostatic mechanism is dynamically determined as a function of the variance of the locally measured external input. This functional relation was derived from the same mean-field approach that was used to describe the approximate dynamics of flow control.
The effectiveness of the presented mechanisms was tested numerically using different external input protocols. The network performance after adaptation was evaluated by training the network to perform a time delayed XOR operation on binary sequences. As our main result, we found that flow control can reliably regulate the spectral radius under different input statistics, but precise tuning is negatively affected by interneural correlations. Furthermore, flow control showed a consistent task performance over a wide range of input strengths/variances. Variance control, on the other side, did not yield the desired spectral radii with the same precision. Moreover, task performance was less consistent across different input strengths.
Given the better performance and simpler mathematical form of flow control, we concluded that a local control of the spectral radius via an implicit adaptation scheme is a realistic alternative to approaches using classical “set point” homeostatic feedback controls of neural firing.
Author summary How can a neural network control its recurrent synaptic strengths such that network dynamics are optimal for sequential information processing? An important quantity in this respect, the spectral radius of the recurrent synaptic weight matrix, is a non-local quantity. Therefore, a direct calculation of the spectral radius is not feasible for biological networks. However, we show that there exist a local and biologically plausible adaptation mechanism, flow control, which allows to control the recurrent weight spectral radius while the network is operating under the influence of external inputs. Flow control is based on a theorem of random matrix theory, which is applicable if inter-synaptic correlations are weak. We apply the new adaption rule to echo-state networks having the task to perform a time-delayed XOR operation on random binary input sequences. We find that flow-controlled networks can adapt to a wide range of input strengths while retaining essentially constant task performance.
Recurrent cortical network dynamics plays a crucial role for sequential information processing in the brain. While the theoretical framework of reservoir computing provides a conceptual basis for the understanding of recurrent neural computation, it often requires manual adjustments of global network parameters, in particular of the spectral radius of the recurrent synaptic weight matrix. Being a mathematical and relatively complex quantity, the spectral radius is not readily accessible to biological neural networks, which generally adhere to the principle that information about the network state should either be encoded in local intrinsic dynamical quantities (e.g. membrane potentials), or transmitted via synaptic connectivity. We present two synaptic scaling rules for echo state networks that solely rely on locally accessible variables. Both rules work online, in the presence of a continuous stream of input signals. The first rule, termed flow control, is based on a local comparison between the mean squared recurrent membrane potential and the mean squared activity of the neuron itself. It is derived from a global scaling condition on the dynamic flow of neural activities and requires the separability of external and recurrent input currents. We gained further insight into the adaptation dynamics of flow control by using a mean field approximation on the variances of neural activities that allowed us to describe the interplay between network activity and adaptation as a two-dimensional dynamical system. The second rule that we considered, variance control, directly regulates the variance of neural activities by locally scaling the recurrent synaptic weights. The target set point of this homeostatic mechanism is dynamically determined as a function of the variance of the locally measured external input. This functional relation was derived from the same mean-field approach that was used to describe the approximate dynamics of flow control.
The effectiveness of the presented mechanisms was tested numerically using different external input protocols. The network performance after adaptation was evaluated by training the network to perform a time delayed XOR operation on binary sequences. As our main result, we found that flow control can reliably regulate the spectral radius under different input statistics, but precise tuning is negatively affected by interneural correlations. Furthermore, flow control showed a consistent task performance over a wide range of input strengths/variances. Variance control, on the other side, did not yield the desired spectral radii with the same precision. Moreover, task performance was less consistent across different input strengths.
Given the better performance and simpler mathematical form of flow control, we concluded that a local control of the spectral radius via an implicit adaptation scheme is a realistic alternative to approaches using classical “set point” homeostatic feedback controls of neural firing.
Author summary How can a neural network control its recurrent synaptic strengths such that network dynamics are optimal for sequential information processing? An important quantity in this respect, the spectral radius of the recurrent synaptic weight matrix, is a non-local quantity. Therefore, a direct calculation of the spectral radius is not feasible for biological networks. However, we show that there exist a local and biologically plausible adaptation mechanism, flow control, which allows to control the recurrent weight spectral radius while the network is operating under the influence of external inputs. Flow control is based on a theorem of random matrix theory, which is applicable if inter-synaptic correlations are weak. We apply the new adaption rule to echo-state networks having the task to perform a time-delayed XOR operation on random binary input sequences. We find that flow-controlled networks can adapt to a wide range of input strengths while retaining essentially constant task performance.
Measurements of halogenated trace gases in ambient air frequently rely on canister sampling followed by offline laboratory analysis. This allows for a large number of compounds to be analysed under stable conditions, maximizing measurement precision. However, individual compounds might be affected during the sampling and storage of canister samples. In order to assess halocarbon stability in whole-air samples from the upper troposphere and lowermost stratosphere, we performed stability tests using the high-resolution sampler (HIRES) air sampling unit, which is part of the Civil Aircraft for the Regular Investigation of the atmosphere Based on an Instrument Container (CARIBIC) instrument package. The HIRES unit holds 88 lightweight stainless-steel cylinders that are pressurized in flight to 4.5 bar using metal bellows pumps. The HIRES unit was first deployed in 2010 but has up to now not been used for regular halocarbon analysis with the exception of chloromethane analysis. The sample collection unit was tested for the sampling and storage effects of 28 halogenated compounds. The focus was on compound stability in the stainless-steel canisters during storage of up to 5 weeks and on the influence of ozone, since flights take place in the upper troposphere and lowermost stratosphere with ozone mixing ratios of up to several hundred parts per billion by volume (ppbv). Most of the investigated (hydro)chlorofluorocarbons and long-lived hydrofluorocarbons were found to be stable over a storage time of up to 5 weeks and were unaltered by ozone being present during pressurization. Some compounds such as dichloromethane, trichloromethane, and tetrachloroethene started to decrease in the canisters after a storage time of more than 2 weeks or exhibited lowered mixing ratios in samples pressurized with ozone present. A few compounds such as tetrachloromethane and tribromomethane were found to be unstable in the HIRES stainless-steel canisters independent of ozone levels. Furthermore, growth was observed during storage for some species, namely for HFC-152a, HFC-23, and Halon 1301.
Stanley Cavell is one of very few philosophers who systematically reflect on the impact and influence of autobiographical detail, experience, and preferences on their philosophical work. The aim of this essay is to show how Cavell’s use of autobiographical exploration is rooted in his early aesthetic theory, in particular his view of the similarities between philosophy and aesthetic criticism. Cavell argues that criticism starts by exploiting and incorporating a subjective vantage point, eventually bringing the reader to test the significance of a work on herself. In his ‘Aesthetic Problems of Modern Philosophy’, Cavell states exactly this form of appeal to the ‘We’ of author and reader as the basic move of his own version of ‘ordinary language philosophy’. It is because of the connections Cavell sees between criticism and philosophy that his aesthetic diagnosis harks back on his overall critical style of thinking.
Do current levels of bank capital in Europe suffice to support a swift recovery from the COVID-19 crisis? Recent research shows that a well-capitalized banking sector is a major factor driving the speed and breadth of recoveries from economic downturns. In particular, loan supply is negatively affected by low levels of capital. We estimate a capital shortfall in European banks of up to 600 billion euro in a severe scenario, and around 143 billion euro in a moderate scenario. We propose a precautionary recapitalization on the European level that puts the European Stability Mechanism (ESM) center stage. This proposal would cut through the sovereign-bank nexus, safeguard financial stability, and position the Eurozone for a quick recovery from the pandemic.
Investigation of co-translational protein folding using cryo-EM and solid-state NMR enhanced by DNP
(2020)
Die zelluläre Proteinbiosynthese findet am Peptidyltransferase-Zentrum innerhalb der großen ribosomalen Untereinheit statt. Die neu synthetisierte Polypeptidkette passiert den ribosomalen Exit-Tunnel, der 80-100 Å lang und 10-20 Å breit ist. Proteinfaltung findet kotranslational statt, während die Peptidkette durch den ribosomalen Tunnel geschleust wird. Zu welchem Ausmaß die Proteine ihre native Struktur noch am Ribosom gebunden annehmen, steht im Fokus aktueller Studien. Verschiedene Methoden, die naszierende Proteinkette am Ribosom zu arretieren und die Faltung des Proteins untersuchen zu können, wurden entwickelt. Zur Herstellung von Ribosom naszierenden Proteinkomplexen (RNCs) in vivo werden Arrestierungspeptide (APs) verwendet. Ein oft genutztes AP ist die 17 Aminosäuren lange SecM Sequenz des E. coli Sekretionsmonitors, das C-Terminal an das zu untersuchende Protein kloniert werden kann und dadurch die Peptidkette am Ribosom behält. RNCs wurden mittels verschiedener Methoden untersucht, einschließlich Proteolyse-Experimenten, enzymatischen Aktivitätsmessungen, FRET, Cryo-EM und NMR-Spektroskopie. Alle Methoden zeigten auf, dass sich die Proteine kotranslational falten und auch am Ribosom eine funktionale Struktur annehmen können. Außerdem konnte eine Peptidkette eine α-Helix innerhalb des Ribosoms ausbilden. Ebenso wurden nicht-native kompakte Strukturen innerhalb der Vestibule detektiert.
Die Translation ist ein nicht-uniformer Prozess und der genetische Code degeneriert mit bis zu sechs Codons, die eine einzelne Aminosäure kodieren. Die Verteilung dieser synonymen Codons ist nicht zufällig und sie werden mit verschiedenen Frequenzen innerhalb eines ORFs verwendet. Codons mit einer höheren tRNA Häufigkeit werden schneller eingebaut als Codons, die seltener verwendet werden. Diese seltenen Codons sind häufig zwischen Proteindomänen oder Sekundärstrukturelementen platziert und könnten daher zur Separierung von Faltungsevents dienen. Dass der Austausch von synonymen Codons nicht ohne Folgen ist, zeigten verschiedene Studien. Buhr et al. (2016) zeigte, dass der synonyme Austausch die Translationsgeschwindigkeit, aber auch die Proteinkonformation des bovinen Augenlinsenproteins γB crystallin (GBC) beeinflusst. Während die unmodifizierte Gensequenz aus B. taurus in E. coli langsamer translatiert wurde und zu einem vollständig reduzierten GBC Protein (U) führte, wurde die harmonisierte Genvariante, die der Codon-Verwendung in E. coli angepasst war, schneller exprimiert und resultierte in einem teilweise oxidierten GBC Protein (H). Dieser Befund war der Ausgangspunkt für diese Doktorarbeit.
Die gemessenen Oxidationsunterschiede basieren auf der unterschiedlichen Translationsgeschwindigkeit der beiden Gensequenzen. Die N-terminale Domäne (NTD) des Zweidomänen-Proteins GBC enthält sechs der insgesamt sieben Cysteinreste. Nur in dieser Domäne wurde Oxidation detektiert und die drei Cysteine Cys18, Cys22 und Cys78 bilden eine Ansammlung mit einem Abstand von 5.4-6.4 Å. Um zu untersuchen, ob die Unterschiede bereits nach der Translation der NTD ausgebildet werden, wurde ein Ein-Domänen-Konstrukt hergestellt. Dieses Konstrukt beinhaltete die Aminosäuren 1-82, aber nicht den Peptidlinker, der beide Domänen verbindet. Allerdings wurden bei der Translation der ersten 70 Aminosäuren die meisten Translationspausen detektiert. Das 2D 1H-15N HSQC wies anhand der unterschiedlichen chemischen Verschiebung der Signale auf eine gefaltete Proteinstruktur hin. Daher konnte sich die NTD ohne Beteiligung der CTD eigenständig falten. Zugabe von DTT zu beiden Proteinvarianten U und H führte zu keinem messbaren Effekt. Im Gegensatz zu dem Volllängen-Protein, in dem die Variante H teilweise oxidiert war, war die NTD der Variante H vollständig reduziert.
Zusätzlich sollte geklärt werden, ob auch mögliche Disulfidbrücken im Inneren des Ribosoms ausgebildet werden können. Dann könnte in beiden Genvarianten eine anfängliche Disulfidbrücke ausgebildet werden und durch die unterschiedliche Translationsgeschwindigkeit die Disulfidbrücke in der langsamen Genvariante im E. coli Zytosol reduziert werden, während diese in der schneller translatierten Variante von der CTD geschützt wird. Um zu untersuchen, ob in der Tat Disulfidbrücken im ribosomalen Tunnel ausgebildet werden können, wurden GBC-Fragmente mittels der SecM Sequenz an das Ribosom arretiert und diese RNCs mittels theoretischer Simulation, Festkörper-NMR, Massenspektrometrie und Cryo-EM gemessen.
Theoretische Simulation mittels flexible-mecanno zeigten, dass der ribosomale Tunnel groß genug für die Ausbildung verschiedenster Disulfidbrücken ist. In einem U32SecM Konstrukt, das vier Cysteine und die SecM Sequenz beinhaltet, konnten alle theoretisch möglichen Disulfidbrücken gebildet werden.
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