Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitorinduced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases

Coulomb dissociation of N 20,21

Neutron-rich light nuclei and their reactions play an important role in the creation of chemical elements. Here, data from a Coulomb dissociation experiment on N20,21 are reported. Relativistic N20,21 ions impinged on a lead target and the Coulomb dissociation cross section was determined in a kinematically complete experiment. Using the detailed balance theorem, the N19(n,γ)N20 and N20(n,γ)N21 excitation functions and thermonuclear reaction rates have been determined. The N19(n,γ)N20 rate is up to a factor of 5 higher at

Raf-1 and B-Raf in vascular development and tumor angiogenesis

Angiogenese wird durch Endothelzellen induziert und ist notwendig für die Entstehung neuer Blutgefäße. Dafür wird die komplexe Koordination von multiplen biologischen Prozessen erfordert: Endothelzell Proliferation, kollektive Zellmigration, Zell-Zell Kommunikation und die Formung eines Lumens. Die korrekte Anordnung eines Vaskulären Netzwerkes ist für einen gesunden Organismus notwendig, da eine Dysfunktion zu einer Vielfalt von Krankheiten führt. Das Verstehen der molekularen Maschinerie welche die Angiogenese kontrolliert wird neue therapeutische Behandlungen für viele menschliche Krankheiten, wie Entzündungskrankheiten oder Krebs ermöglichen. Wir identifizieren Raf-1 als eine essentielle Komponente der molekularen „Sprouting“ Maschinerie. Die Deletion von Raf-1 beeinträchtigt die Endothelzell Kohäsion, das “Sprouting” und die Angiogenese in vivo, was zu einer verminderten Vaskularisierung der Retina (Entwicklungsangiogenese) als auch zu einer reduzierten Tumor Vaskularisierung und Wachstum führt (pathologische Angiogenese). Mechanistisch wird Raf-1 durch das kleine G Protein Rap1 zu VE-Cadherin Komplexen rekrutiert. Dort wird es für die Assoziation des Rho Effektor Rok-α an entstehenden Zell-Zell Kontakten benötigt. Diese Raf-1 vermittelte Feinregulierung von Rok-α ermöglicht die Aktivierung von Myosin an Zell-Zell Kontakten und die zeitgemäße Reifung von Zell-Zell Adhäsionen um die Zell Kohäsion während der „Sprouting“ Angiogenese aufrechtzuerhalten. Im Gegenzug dazu führt die Ablation von B-Raf im Endothelzell/Hämatopoetischem Zellkompartment zu einem vermehrten Wachstum von Tumoren. Wir finden weniger nekrotisches Gewebe dass mit einer geringeren intratumoralen vaskulären Permeabilität korreliert. Die Barriere Funktion von B-Raf KO Endothelzellen wird nicht durch VEGF abgeschwächt, was dafür spricht dass B-Raf für VEGF induzierte Permeabilität benötigt wird. Wir nehmen an dass die Ablation von B-Raf zu einer Blutgefäß Normalisierung führt durch Umkehrung der Hyper-Permeabilität welche typisch für Tumor-assoziierte Gefäße ist. Das würde zu einer erhöhten Funktionalität der Blutgefäße führen und zu einem beschleunigten Tumorwachstum. Die Ablation von 3 Raf Allelen in Endothelzellen (3AD = B-Raf f/f;Raf-1 f/+ or B-Raf f/+;Raf-1 f/f) führt zum frühen postnatalen Tod der Tiere aufgrund eines Respiratorischen Defektes. Die Lungen der Mäuse sind mit Blut gefüllt und eine Ruptur der pulmonalen Blutgefäße konnte festgestellt werden. In vitro zeigen Endothelzellen von 3AD Mäusen eine reduzierte Resistenz gegenüber angelegtem Scherstress, dass sich durch Desintegration von VE-Cadherin vermittelten Zell-Zell Adhäsionen offenlegt. Die induzierte Deletion von B-Raf und Raf-1 im vaskulären/hämatopoetischen System blockiert fast komplett die Einwanderung neuer Blutgefässe in den Matrigel Plug. Wir schliessen daraus dass die gleichzeitige Inhibition von Raf-1 und B-Raf am effektivsten das Wachstum von Blutgefässen hemmt aber die vaskuläre Homöostase beinträchtigt.Angiogenesis is initiated by endothelial cells and indispensable for the development of new blood vessels. It requires the complex coordination of multiple biological processes: endothelial cell proliferation, collective cell migration, cell-to-cell communication and lumen formation. The correct alignment of the vascular networks is a requirement for a healthy organism since dysfunction leads to a variety of disorders. Understanding the molecular machinery controlling angiogenesis will give rise to novel therapeutic treatments for many human diseases such as inflammatory disorders or cancer. Here we identify Raf-1 as an essential component of the molecular sprouting machinery. Raf-1 dele tion impairs endothelial cell cohesion, sprouting and in vivo angiogenesis, leading to a decreased vascularization of the retina (developmental angiogenesis) and reduced tumor angiogenesis and growth (pathological angiogenesis). Mechanistically, Raf-1 is recruited to VE-Cadherin complexes by the small G Protein Rap1, and is required for the association of the Rho effector Rok-α with nascent adherens junctions (AJ). This Raf-1-mediated fine tuning of Rok-α signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis. In contrast, B-Raf ablation in the endothelial/hematopoietic cell compartment increases tumor xenograft growth. We find decreased necrotic areas correlating with lower levels of intratumoral vascular permeability. The barrier function of B-Raf KO endothelial cells is not weakened by VEGF treatment, suggesting that B-Raf is needed to control VEGF-induced vascular permeability. We suggest that B-Raf ablation results in vessel “normalization” by reversing the hyper-permeability typical of tumor-associated vessels; this would increase the functionality of the vasculature and accelerate tumor growth. Finally, ablation of 3 Raf alleles in endothelial cells (3AD = B-Raf f/f;Raf-1 f/+ or B-Raf f/+;Raf-1 f/f) leads to early postnatal death of the animals because of a respiratory defect. The lungs of these animals are filled with blood and rupture of pulmonary blood vessels could be observed. In vitro, endothelial cells from 3AD mice show reduced resistance to applied shear stress characterized by disintegration of VE-Cadherin mediated junctions. The induced deletion of B-Raf and Raf-1 in the vascular/haematopoietic compartment almost completely abrogates blood vessel invasion in the Matrigel plug assay. We conclude that simultaneous targeting Raf-1 and B-Raf most effectively inhibits blood vessel growth but affects vascular homeostasis

Gutachten und Diskussionsbeiträge zu René Buchholz, Gegendiskurse. Jüdische Antworten auf das Christentum in der frühen Moderne

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Sidonie Kellerer, Zerrissene Moderne. Descartes bei den Neukantianern, Husserl und Heidegger

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Capacitive Near-field Communication for Ubiquitous Interaction and Perception

Smart objects within instrumented environments offer an always available and intuitive way of interacting with a system. Connecting these objects to other objects in range or even to smartphones and computers, enables substantially innovative interaction and sensing approaches. In this paper, we investigate the concept of Capacitive Near-Field Communication to enable ubiquitous interaction with everyday objects in a short-range spatial context. Our central contribution is a generic framework describing and evaluating this communication method in Ubiquitous Computing. We prove the relevance of our approach by an open-source implementation of a low-cost object tag and a transceiver offering a high-quality communication link at typical distances up to 15 cm. Moreover, we present three case studies considering tangible interaction for the visually impaired, natural interaction with everyday objects, and sleeping behavior analysis