Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Proteostasis is critical for cells to maintain the balance between protein synthesis, quality control, and degradation. This is particularly important for myeloid cells of the central nervous system as their immunological function relies on proper intracellular protein turnover by the ubiquitin-proteasome system. Accordingly, disruption of proteasome activity due to, e.g., loss-of-function mutations within genes encoding proteasome subunits, results in systemic autoinflammation. On the molecular level, pharmacological inhibition of proteasome results in endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) as well as an induction of type I interferons (IFN). Nevertheless, our understanding as to whether and to which extent UPR signaling regulates type I IFN response is limited. To address this issue, we have tested the effects of proteasome dysfunction upon treatment with proteasome inhibitors in primary murine microglia and microglia-like cell line BV-2. Our data show that proteasome impairment by bortezomib is a stimulus that activates all three intracellular ER-stress transducers activation transcription factor 6, protein kinase R-like endoplasmic reticulum kinase and inositol-requiring protein 1 alpha (IRE1α), causing a full activation of the UPR. We further demonstrate that impaired proteasome activity in microglia cells triggers an induction of IFNβ1 in an IRE1-dependent manner. An inhibition of the IRE1 endoribonuclease activity significantly attenuates TANK-binding kinase 1-mediated activation of type I IFN. Moreover, interfering with TANK-binding kinase 1 activity also compromised the expression of C/EBP homologous protein 10, thereby emphasizing a multilayered interplay between UPR and type IFN response pathway. Interestingly, the induced protein kinase R-like endoplasmic reticulum kinase-activation transcription factor 4-C/EBP homologous protein 10 and IRE1-X-box-binding protein 1 axes caused a significant upregulation of proinflammatory cytokine interleukin 6 expression that exacerbates STAT1/STAT3 signaling in cells with dysfunctional proteasomes. Altogether, these findings indicate that proteasome impairment disrupts ER homeostasis and triggers a complex interchange between ER-stress sensors and type I IFN signaling, thus inducing in myeloid cells a state of chronic inflammation

Ökonomisches Konzept zur Parkraumbewirtschaftung in Berlin-Wilmersdorf

Die Überlastung der vorhandenen Verkehrsinfrastruktur in Ballungsgebieten zu den Hauptverkehrszeiten stellt ein zunehmendes wirtschaftliches und verkehrliches Problem dar. In diesem Beitrag werden Lösungsmöglichkeiten für eine effiziente Verteilung bzw. Allokation des knappen Gutes Freie Fahrt untersucht, wobei die Betrachtung aus ökonomischer Sicht erfolgt. Die erstbeste Lösung besteht in der Internalisierung von externen Kosten über verursachungsgerechte Straßennutzungspreise. Aufgrund eines erheblichen Aufwands dieser Internalisierungsmethode wird eine zweitbeste Lösung über Parkraummanagement gewählt. Für ein abgegrenztes Gebiet in Berlin-Wilmersdorf, in dem bislang keine Gebühren erhoben werden, wird eine mögliche Ausgestaltung einer Parkplatzgebühr pro 30 Minuten unter ökonomischen Aspekten vorgestellt. Berücksichtigt werden dabei die durchschnittlichen Stau-, Opportunitäts- und Bereitstellungskosten pro Stellplatz. Zusätzlich wurden über eine repräsentative Stichprobe Daten zur Zahlungsbereitschaft erhoben. Abschließend erfolgt eine Analyse der möglichen verkehrlichen und wirtschaftlichen Folgen dieser Maßnahme. -- The existing traffic infrastructure in agglomerate areas is surcharged in rush hours. This paper discusses some possible solutions of efficient allocation of the scarce good road capacity. It focuses on the economic view. An internalisation of external costs by road pricing would be the first best method. Because it is very complicated to install such a system of internalisation, a second best method is examined: regulatory parking policies. Since there is no existing system of parking policies in this specific area in place, a possible scenario of parking taxes under economic aspects is developed for a defined area in Berlin-Wilmersdorf. We examined the average congestion costs, the opportunity costs of use and the cost of supply per parking space. In addition a representative survey has been conducted to reveal the commuter's willingness to pay, for a free parking space. Finally an analysis of possible economic and infrastructural effects of parking policies on traffic is made.Straßennutzungspreise,Staukosten,Internalisierung,Parkraumbewirtschaftung,öffentliche Güter,Marktversagen,road-pricing,congestion costs,internalisation,parking management,public goods,market failure

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

Background: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA

Re-structuring of marine communities exposed to environmental change

Species richness is the most commonly used but controversial biodiversity metric in studies on aspects of community stability such as structural composition or productivity. The apparent ambiguity of theoretical and experimental findings may in part be due to experimental shortcomings and/or heterogeneity of scales and methods in earlier studies. This has led to an urgent call for improved and more realistic experiments. In a series of experiments replicated at a global scale we translocated several hundred marine hard bottom communities to new environments simulating a rapid but moderate environmental change. Subsequently, we measured their rate of compositional change (re-structuring) which in the great majority of cases represented a compositional convergence towards local communities. Re-structuring is driven by mortality of community components (original species) and establishment of new species in the changed environmental context. The rate of this re-structuring was then related to various system properties. We show that availability of free substratum relates negatively while taxon richness relates positively to structural persistence (i.e., no or slow re-structuring). Thus, when faced with environmental change, taxon-rich communities retain their original composition longer than taxon-poor communities. The effect of taxon richness, however, interacts with another aspect of diversity, functional richness. Indeed, taxon richness relates positively to persistence in functionally depauperate communities, but not in functionally diverse communities. The interaction between taxonomic and functional diversity with regard to the behaviour of communities exposed to environmental stress may help understand some of the seemingly contrasting findings of past research

SARS-CoV-2 Variant of Concern B.1.1.7: Diagnostic Sensitivity of Three Antigen-Detecting Rapid Tests.

Funder: Foundation for Innovative New DiagnosticsFunder: World Health OrganizationFunder: Ministry of Science, Research and Culture, State of Baden Wuerttemberg, German

Anisotropic topographies restore endothelial monolayer integrity and promote the proliferation of senescent endothelial cells

Thrombogenicity remains a major issue in cardiovascular implants (CVIs). Complete surficial coverage of CVIs by a monolayer of endothelial cells (ECs) prior to implantation represents a promising strategy but is hampered by the overall logistical complexity and the high number of cells required. Consequently, extensive cell expansion is necessary, which may eventually lead to replicative senescence. Considering that micro-structured surfaces with anisotropic topography may promote endothelialization, we investigated the impact of gratings on the biomechanical properties and the replicative capacity of senescent ECs. After cultivation on gridded surfaces, the cells showed significant improvements in terms of adherens junction integrity, cell elongation, and orientation of the actin filaments, as well as enhanced yes-associated protein nuclear translocation and cell proliferation. Our data therefore suggest that micro-structured surfaces with anisotropic topographies may improve long-term endothelialization of CVIs. Keywords: aging; anisotropy; endothelial cells; monolayer integrity; proliferation; senescence; telomere; topograph

Zum Zusammenhang von Geschlechterungleichheiten in Bildung, Beruf und Karriere : ein Ausblick

Ziel der folgenden Ausführungen im abschliessenden Teil dieses Sammelbands zur Entwicklung und Genese von geschlechtsspezifischen Bildungsungleichheiten ist es, den Blick zu öffnen in Richtung Berufsleben. Wie sind die verbesserten Bildungsmöglichkeiten von Frauen zu interpretieren? Ist es in den letzten Jahrzehnten gelungen, eines der grundlegendsten gesellschaftlichen Ungleichheitsverhältnisse zu beseitigen? Oder beginnt sich dieses sogar zu verkehren in eine gesellschaftliche Benachteiligung der Männer? Wir gehen bei unseren Überlegungen von der These aus, dass ein Abbau von Benachteiligungen der Frauen im Bildungssystem für sich genommen noch wenig aussagekräftig ist, wenn wir uns mit der klassischen soziologischen Frage der Persistenz bzw. des Wandels von gesellschaftlichen Ungleichheiten befassen wollen. Erst wenn die ganze Verknüpfung von Bildung und gesellschaftlicher Ungleichheit in den Blick genommen wird und sich dabei zeigt, dass Frauen ihre Bildungsgewinne auch in entsprechende Chancen im Beschäftigungssystem umsetzen können, sind ihre verbesserten Bildungschancen ein Gewinn für die Individuen und ein Fortschritt für die Gesellschaft – und erst dann könnten mögliche Bildungsvorteile von Frauen, wie sie in den vorliegenden Aufsätzen z.T. diagnostiziert werden, gar als neue gesellschaftliche Benachteiligungen von Männern skandalisiert werden

Применение технологий клиентоориентированного маркетинга для поддержания и развития имиджа компании

Актуальность проблем, освещенных в данной работе, заключается в необходимости изучения потребителя, при условии постоянного изменения поведения клиентов компании ввиду высокой конкуренции на розничном рынке электроники. Проблема. С помощью каких нововведений можно повысить клиентоориентированность компании ООО «М.видео Менеджмент» и её имидж? Объектом исследования ВКР являются маркетинговые коммуникации ООО «М.видео Менеджмент». Предмет исследования – технологии коммуникационных стратегий организации. Цель работы – разработка программы лояльности для поддержания и развития имиджа компании (на примере ООО «М.видео Менеджмент» г. Томск). Методологической основой исследования являются абстрактно- логические, экономико-статистические методы, а также использование системного подхода, применение методов сравнения, группировок, графического отображения исследуемой информации. Практическая значимость исследования заключается в том, что предложенная и разработанная программа лояльности может быть использована в других компаниях для поддержки и развития имиджа компании.The relevance of the issues discussed in this paper is to study the consumer, the subject of constant change of customer behavior due to high competition in the retail market of electronics. Problem. What innovations can enhance the customer focus of the company "M. video Management" and its image? The object of research WRC is the marketing communications LLC "M. video Management". Subject of research – technology communication strategies of the organization. The work purpose – development of loyalty programs for the maintenance and development of the company's image (on the example of OOO "M. video Management" Tomsk). The methodological basis of the research is abstract - logic, economic-statistical methods, and the use of a systematic approach, applying the methods of comparison of groups graphical display of researched information. Practical significance of the research lies in the fact that the proposed and developed loyalty program can be used in other companies for the support and development of the company's image

Onset of pain to surgery time in acute aortic dissections type A: a mandatory factor for evaluating surgical results?

ObjectiveAn acute aortic dissection type A (AADA) is a rare but life-threatening event. The mortality rate ranges between 18% to 28% and mortality is often within the first 24 h and up to 1%–2% per hour. Although the onset of pain to surgery time has not been a relevant factor in terms of research in the field of AADA, we hypothesize that a patient's preoperative conditions depend on the length of this time.MethodsBetween January 2000 and January 2018, 430 patients received surgical treatment for acute aortic dissection DeBakey type I at our tertiary referral hospital. In 11 patients, the exact time point of initial onset of pain was retrospectively not detectable. Accordingly, a total of 419 patients were included in the study. The cohort was categorized into two groups: Group A with an onset of pain to surgery time < 6 h (n = 211) and Group B > 6 h (n = 208), respectively.ResultsMedian age was 63.5 years (y) ((IQR: 53.3–71.4 y); (67.5% male)). Preoperative conditions differed significantly between the cohorts. Differences were detected in terms of malperfusion (A: 39.3%; B: 23.6%; P: 0.001), neurological symptoms (A: 24.2%; B: 15.4%; P: 0.024), and the dissection of supra-aortic arteries (A: 25.1%; B: 16.8%; P: 0.037). In particular, cerebral malperfusion (A 15.2%: B: 8.2%; P: 0.026) and limb malperfusion (A: 18%, B: 10.1%; P: 0.020) were significantly increased in Group A. Furthermore, Group A showed a decreased median survival time (A: 1,359.0 d; B: 2,247.5 d; P: 0.001), extended ventilation time (A: 53.0 h; B: 44.0 h; P: 0.249) and higher 30-day mortality rate (A: 25.1%; B: 17.3%; P: 0.051).ConclusionsPatients with a short onset of pain to surgery time in cases of AADA present themselves not only with more severe preoperative symptoms but are also the more compromised cohort. Despite early presentation and emergency aortic repair, these patients show increased chances of early mortality. The “onset of pain to surgery time” should become a mandatory factor when making comparable surgical evaluations in the field of AADA