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

Fate and state transitions during human blood vessel organoid development

Blood vessel organoids (BVOs) derived from human pluripotent stem cells have emerged as a novel system to understand human vascular development, model disorders, and develop regenerative therapies. However, it is unclear which molecular states constitute BVOs and how cells differentiate and self-organize within BVOs in vitro and after transplantation. Here we reconstruct BVO development over a time course using single-cell transcriptomics. We observe progenitor states that bifurcate into endothelial and mural fates, and find that BVOs do not acquire definitive arterio-venous endothelial identities in vitro. Chromatin accessibility profiling identifies gene regulatory network (GRN) features associated with endothelial and mural fate decisions, and transcriptome-coupled lineage recording reveals multipotent progenitor states within BVOs. We perform single-cell genetic perturbations within mosaic BVOs to dissect the impact of transcription factor (TF) and receptor depletion on cell differentiation, and highlight multiple TFs including MECOM and ETV2 as strong-effect regulators of human BVO development. We show that manipulation of VEGF and Notch signaling pathways alters BVO morphogenesis and endothelial GRNs, and induces arteriovenous-like state differentiation. We analyze matured BVOs after transplantation using scRNA-seq, and observe matured endothelium with clear arteriovenous specification. We also observe off-target cell fates with bone and adipocyte features, suggesting multipotent states reside within the BVOs in vitro that expand and diversify in less restrictive conditions. Finally, we map vascular disease associated genes to BVO cell states to highlight the potential of BVOs for disease modeling. Altogether, our data and analyses provide the first comprehensive cell state atlas of BVO development and illuminate both the power and limitation of BVOs for translational research

Profilin 1 is required for abscission during late cytokinesis of chondrocytes

Profilins are key factors for dynamic rearrangements of the actin cytoskeleton. However, the functions of profilins in differentiated mammalian cells are uncertain because profilin deficiency is early embryonic lethal for higher eukaryotes. To examine profilin function in chondrocytes, we disrupted the profilin 1 gene in cartilage (Col2pfn1). Homozygous Col2pfn1 mice develop progressive chondrodysplasia caused by disorganization of the growth plate and defective chondrocyte cytokinesis, indicated by the appearance of binucleated cells. Surprisingly, Col2pfn1 chondrocytes assemble and contract actomyosin rings normally during cell division; however, they display defects during late cytokinesis as they frequently fail to complete abscission due to their inability to develop strong traction forces. This reduced force generation results from an impaired formation of lamellipodia, focal adhesions and stress fibres, which in part could be linked to an impaired mDia1-mediated actin filament elongation. Neither an actin nor a poly-proline binding-deficient profilin 1 is able to rescue the defects. Taken together, our results demonstrate that profilin 1 is not required for actomyosin ring formation in dividing chondrocytes but necessary to generate sufficient force for abscission during late cytokinesis

The anomalous polymict ordinary chondrite breccia of Elmshorn (H3‐6)—Late reaccretion after collision between two ordinary chondrite parent bodies, complete disruption, and mixing possibly about 2.8 Gyr ago

Elmshorn fell April 25, 2023, about 30 km northwest of the city of Hamburg (Germany). Shortly after the fall, 21 pieces were recovered totaling a mass of 4277 g. Elmshorn is a polymict and anomalous H3‐6 chondritic, fragmental breccia. The rock is a mixture of typical H chondrite lithologies and clasts of intermediate H/L (or L, based on magnetic properties) chondrite origin. In some of the 21 pieces, the H chondrite lithologies dominate, while in others the H/L (or L) chondrite components are prevalent. The H/L chondrite assignment of these components is based on the mean composition of their olivines in equilibrated type 4 fragments (~Fa21–22). The physical properties like density (3.34 g cm−3) and magnetic susceptibility (logχ <5.0, with χ in 10−9 m3 kg−1) are typical for L chondrites, which is inconsistent with the oxygen isotope compositions: all eight O isotope analyses from two different fragments clearly fall into the H chondrite field. Thus, the fragments found in the strewn field vary in mineralogy, mineral chemistry, and physical properties but not in O isotope characteristics. The sample most intensively studied belongs to the stones dominated by H chondrite lithologies. The chemical composition and nucleosynthetic Cr and Ti isotope data are typical for ordinary chondrites. The noble gases in Elmshorn represent a mixture between cosmogenic, radiogenic, and primordially trapped noble gases, while a solar wind component can be excluded. Because the chondritic rock of Elmshorn contains (a) H chondrite parent body interior materials (of types 5 and 6), (b) chondrite parent body near‐surface materials (of types 3 and 4), (c) fragments of an H/L chondrite (dominant in many stones), (d) shock‐darkened fragments, and (e) clasts of various types of impact melts but no solar wind‐implanted noble gases, the different components cannot have been part of a parent body regolith. The most straightforward explanation is that the fragmental breccia of Elmshorn represents a reaccreted rock after a catastrophic collision between an H chondrite parent body and another body with H/L (or L) chondrite characteristics but with deviating O isotope values (i.e. that of H chondrites), complete disruption of the bodies, mixing, and reassembly. This is the only straightforward way that the implantation of solar wind gases could have been avoided in this kind of complex breccia. The gas retention ages of about 2.8 Gyr possibly indicate the closure time after the catastrophic collision between H and H/L (or L) chondrite parent bodies, while the cosmic ray exposure age for Elmshorn, which had a preatmospheric radius of 25–40 cm, is ~17–20 Myr

The \u3csup\u3e33\u3c/sup\u3eS(p,γ)\u3csup\u3e34\u3c/sup\u3eCl reaction in classical nova explosions

The analysis of microscopic grains within primitive meteorites has revealed isotopic ratios largely characteristic of the conditions thought to prevail in various astrophysical environments. Recently, several grains have been identified with isotopic signatures similar to those predicted within the ejecta of nova explosions on oxygen-neon white dwarfs. A possible smoking gun for a grain of nova origin is a large 33S abundance: nucleosynthesis calculations predict as much as 150 times the solar abundance of 33S in the ejecta of oxygen-neon novae. This overproduction factor may, however, vary by factors of at least 0.01 - 3 because of uncertainties in the 33S(p,γ)34Cl reaction rate over nova temperatures. In addition, better knowledge of this rate would help with the interpretation of nova observations over the S-Ca mass region, and contribute towards the firm establishment of a nucleosynthetic endpoint in these phenomena. Finally, constraining this rate may help to finally confirm or rule out the decay of an isomeric state of 34Cl (Ex = 146 keV, t1/2 =32 min) as a source for observable gamma-rays from novae. Direct examinations of the 33S(p,γ)34Cl reaction in the past have only identified resonances down to Er = 434 keV. At nova temperatures, lower-lying resonances could certainly play a dominant role. Several recent, complementary studies dedicated to improving our knowledge of the 33S(p,γ)34Cl rate, using both indirect methods (measurement of the 34S( 3He,t)34Cl and 33S(3He,d) 34Cl reactions with the Munich Q3D spectrograph) and direct methods (in normal kinematics at CENPA, University of Washington, and in inverse kinematics with the DRAGON recoil mass separator at TRIUMF) are presented here. Our results affect predictions of sulphur isotopic ratios in nova ejecta (e.g. 32S/33S) that may be used as diagnostic tools for the nova paternity of grains. © ?Copyright owned by the author(s)

Theoretical Modeling for the STEREO Mission

International audienceWe summarize the theory and modeling efforts for the STEREO mission, which will be used to interpret the data of both the remote-sensing (SECCHI, SWAVES) and in-situ instruments (IMPACT, PLASTIC). The modeling includes the coronal plasma, in both open and closed magnetic structures, and the solar wind and its expansion outwards from the Sun, which defines the heliosphere. Particular emphasis is given to modeling of dynamic phenomena associated with the initiation and propagation of coronal mass ejections (CMEs). The modeling of the CME initiation includes magnetic shearing, kink instability, filament eruption, and magnetic reconnection in the flaring lower corona. The modeling of CME propagation entails interplanetary shocks, interplanetary particle beams, solar energetic particles (SEPs), geoeffective connections, and space weather. This review describes mostly existing models of groups that have committed their work to the STEREO mission, but is by no means exhaustive or comprehensive regarding alternative theoretical approaches