Constraining the initial mass function of stars in the Galactic Centre

(abridged) Here we discuss the question whether the extreme circumstances in the centre of the Milky Way may be the reason for a significant variation of the IMF. By means of stellar evolution models using different codes we show that the observed luminosity in the central parsec is too high to be explained by a long-standing top-heavy IMF, considering the limited amount of mass inferred from stellar kinematics in this region. In contrast, continuous star formation over the Galaxy's lifetime following a canonical IMF results in a mass-to-light ratio and a total mass of stellar black holes (SBHs) consistent with the observations. Furthermore, these SBHs migrate towards the centre due to dynamical friction, turning the cusp of visible stars into a core as observed in the Galactic Centre. For the first time here we explain the luminosity and dynamical mass of the central cluster and both the presence and extent of the observed core, since the number of SBHs expected from a canonical IMF is just enough to make up for the missing luminous mass. We conclude that the Galactic Centre is consistent with the canonical IMF and do not suggest a systematic variation as a result of the region's properties such as high density, metallicity, strong tidal field etc.Comment: MNRAS, accepted, 8 pages, 4 figure

A Critical Study on Acylating and Covalent Reversible Fragment Inhibitors of SARS-CoV-2 Main Protease Targeting the S1 Site with Pyridine

SARS coronavirus main proteases (3CL proteases) have been validated as pharmacological targets for the treatment of coronavirus infections. Current inhibitors of SARS main protease, including the clinically admitted drug nirmatrelvir are peptidomimetics with the downsides of this class of drugs including limited oral bioavailability, cellular permeability, and rapid metabolic degradation. Here, we investigate covalent fragment inhibitors of SARS Mpro as potential alternatives to peptidomimetic inhibitors in use today. Starting from inhibitors acylating the enzyme's active site, a set of reactive fragments was synthesized, and the inhibitory potency was correlated with the chemical stability of the inhibitors and the kinetic stability of the covalent enzyme-inhibitor complex. We found that all tested acylating carboxylates, several of them published prominently, were hydrolyzed in assay buffer and the inhibitory acyl-enzyme complexes were rapidly degraded leading to the irreversible inactivation of these drugs. Acylating carbonates were found to be more stable than acylating carboxylates, however, were inactive in infected cells. Finally, reversibly covalent fragments were investigated as chemically stable SARS CoV-2 inhibitors. Best was a pyridine-aldehyde fragment with an IC50 of 1.8 μM at a molecular weight of 211 g/mol, showing that pyridine fragments indeed are able to block the active site of SARS-CoV-2 main protease

On the dissolution of star clusters in the Galactic centre. I. Circular orbits

We present N-body simulations of dissolving star clusters close to galactic centres. For this purpose, we developed a new N-body program called nbody6gc based on Aarseth's series of N-body codes. We describe the algorithm in detail. We report about the density wave phenomenon in the tidal arms which has been recently explained by Kuepper et al. (2008). Standing waves develop in the tidal arms. The wave knots or clumps develop at the position, where the emerging tidal arm hits the potential wall of the effective potential and is reflected. The escaping stars move through the wave knots further into the tidal arms. We show the consistency of the positions of the wave knots with the theory in Just et al. (2009). We also demonstrate a simple method to study the properties of tidal arms. By solving many eigenvalue problems along the tidal arms, we construct numerically a 1D coordinate system whose direction is always along a principal axis of the local tensor of inertia. Along this coordinate system, physical quantities can be evaluated. The half-mass or dissolution times of our models are almost independent of the particle number which indicates that two-body relaxation is not the dominant mechanism leading to the dissolution. This may be a typical situation for many young star clusters. We propose a classification scheme which sheds light on the dissolution mechanism.Comment: 18 pages, 20 figures; accepted by MNRA

Protective role of the HSP90 inhibitor, STA-9090, in lungs of SARS-CoV-2-infected Syrian golden hamsters

Introduction The emergence of new SARS-CoV-2 variants, capable of escaping the humoral immunity acquired by the available vaccines, together with waning immunity and vaccine hesitancy, challenges the efficacy of the vaccination strategy in fighting COVID-19. Improved therapeutic strategies are urgently needed to better intervene particularly in severe cases of the disease. They should aim at controlling the hyperinflammatory state generated on infection, reducing lung tissue pathology and inhibiting viral replication. Previous research has pointed to a possible role for the chaperone HSP90 in SARS-CoV-2 replication and COVID-19 pathogenesis. Pharmacological intervention through HSP90 inhibitors was shown to be beneficial in the treatment of inflammatory diseases, infections and reducing replication of diverse viruses. Methods In this study, we investigated the effects of the potent HSP90 inhibitor Ganetespib (STA-9090) in vitro on alveolar epithelial cells and alveolar macrophages to characterise its effects on cell activation and viral replication. Additionally, the Syrian hamster animal model was used to evaluate its efficacy in controlling systemic inflammation and viral burden after infection. Results In vitro, STA-9090 reduced viral replication on alveolar epithelial cells in a dose-dependent manner and lowered significantly the expression of proinflammatory genes, in both alveolar epithelial cells and alveolar macrophages. In vivo, although no reduction in viral load was observed, administration of STA-9090 led to an overall improvement of the clinical condition of infected animals, with reduced oedema formation and lung tissue pathology. Conclusion Altogether, we show that HSP90 inhibition could serve as a potential treatment option for moderate and severe cases of COVID-19

Protective role of the HSP90 inhibitor, STA-9090, in lungs of SARS-CoV-2-infected Syrian golden hamsters

Introduction The emergence of new SARS-CoV-2 variants, capable of escaping the humoral immunity acquired by the available vaccines, together with waning immunity and vaccine hesitancy, challenges the efficacy of the vaccination strategy in fighting COVID-19. Improved therapeutic strategies are urgently needed to better intervene particularly in severe cases of the disease. They should aim at controlling the hyperinflammatory state generated on infection, reducing lung tissue pathology and inhibiting viral replication. Previous research has pointed to a possible role for the chaperone HSP90 in SARS-CoV-2 replication and COVID-19 pathogenesis. Pharmacological intervention through HSP90 inhibitors was shown to be beneficial in the treatment of inflammatory diseases, infections and reducing replication of diverse viruses. Methods In this study, we investigated the effects of the potent HSP90 inhibitor Ganetespib (STA-9090) in vitro on alveolar epithelial cells and alveolar macrophages to characterise its effects on cell activation and viral replication. Additionally, the Syrian hamster animal model was used to evaluate its efficacy in controlling systemic inflammation and viral burden after infection. Results In vitro, STA-9090 reduced viral replication on alveolar epithelial cells in a dose-dependent manner and lowered significantly the expression of proinflammatory genes, in both alveolar epithelial cells and alveolar macrophages. In vivo, although no reduction in viral load was observed, administration of STA-9090 led to an overall improvement of the clinical condition of infected animals, with reduced oedema formation and lung tissue pathology. Conclusion Altogether, we show that HSP90 inhibition could serve as a potential treatment option for moderate and severe cases of COVID-19.http://dx.doi.org/10.13039/501100002347Bundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100013865Stiftung Charitéhttp://dx.doi.org/10.13039/501100006188Einstein Stiftung Berlinhttp://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001656Helmholtz-GemeinschaftPeer Reviewe

Weighing the cusp at the Galactic Centre

This paper has been withdrawn temporarily by the authors. As stars close to the galactic centre have short orbital periods it has been possible to trace large fractions of their orbits in the recent years. Previously the data of the orbit of the star S2 have been fitted with Keplerian orbits corresponding to a massive black hole (MBH) with a mass of M$_{BH}$=3-4$\times10^6$M_sun implying an insignificant cusp mass.However, it has also been shown that the central black hole resides in a ~1'' diameter stellar cluster of a priori unknown mass. In a spherical potential which is neither Keplerian nor harmonic, orbits will precess resulting in inclined rosetta shaped trajectories on the sky. In this case, the assumption of non-Keplerian orbits is a more physical approach. It is also the only approach through which cusp mass information can be obtained via stellar dynamics of the cusp members. This paper presents the first exemplary modelling efforts in this direction. Using positional and radial data of star S2, we find that there could exist an unobserved extended mass component of several 10$^5$M$_{\odot}$ forming a so-called 'cusp' centred on the black hole position. Considering only the fraction of the cusp mass M$_{S2_{apo}}$ within the apocenter of the S2 orbit we find as an upper limit that M$_{S2_{apo}}$/(M$_{BH}$ + M$_{S2_{apo}}$) $\le$ 0.05. A large extended cusp mass, if present, is unlikely to be composed of sub-solar mass constituents, but could be explained rather well by a cluster of high M/L stellar remnants, which we find to form a stable configuration.Comment: Accepted by Astronomische Nachrichten, 13 pages, 6 figures. Some modifications were applied to the previous version of this pape

Stellar Processes Near the Massive Black Hole in the Galactic Center

A massive black hole resides in the center of most, perhaps all galaxies. The one in the center of our home galaxy, the Milky Way, provides a uniquely accessible laboratory for studying in detail the connections and interactions between a massive black hole and the stellar system in which it grows; for investigating the effects of extreme density, velocity and tidal fields on stars; and for using stars to probe the central dark mass and probe post-Newtonian gravity in the weak- and strong-field limits. Recent results, open questions and future prospects are reviewed in the wider context of the theoretical framework and physical processes that underlie them. Contents: [1] Introduction (1.1) Astrophysical context (1.2) Science questions (1.3) Scope and connections to related topics [2] Observational overview: Stars in the Galactic center (2.1) The central 100 parsecs (2.2) The central parsec [3] Stellar dynamics at extreme densities (3.1) Physical processes and scales (3.2) The stellar cusp in the Galactic center (3.3) Mass segregation (3.4) Stellar Collisions [4] Probing the dark mass with stellar dynamics (4.1) Weighing and pinpointing the dark mass (4.2) Constraints on non-BH dark mass alternatives (4.3) Limits on MBH binarity (4.4) High-velocity runaway stars [5] Probing post-Newtonian gravity near the MBH (5.1) Relativistic orbital effects (5.2) Gravitational lensing [6] Strong star-MBH interactions (6.1) Tidal disruption (6.2) Dissipative interactions with the MBH [7] The riddle of the young stars (7.1) The difficulties of forming or importing stars near a MBH (7.2) Proposed solutions (7.3) Feeding the MBH with stellar winds [8] Outlook (8.1) Progress report (8.2) Future directionsComment: Invited review article, to appear in Physics Reports. 101 p

Human alveolar progenitors generate dual lineage bronchioalveolar organoids

Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280+/EpCAM+ population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3β inhibitor, CHIR99021. By RNA-seq profiling of GSK-3β knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction

Star Formation and Dynamics in the Galactic Centre

The centre of our Galaxy is one of the most studied and yet enigmatic places in the Universe. At a distance of about 8 kpc from our Sun, the Galactic centre (GC) is the ideal environment to study the extreme processes that take place in the vicinity of a supermassive black hole (SMBH). Despite the hostile environment, several tens of early-type stars populate the central parsec of our Galaxy. A fraction of them lie in a thin ring with mild eccentricity and inner radius ~0.04 pc, while the S-stars, i.e. the ~30 stars closest to the SMBH (<0.04 pc), have randomly oriented and highly eccentric orbits. The formation of such early-type stars has been a puzzle for a long time: molecular clouds should be tidally disrupted by the SMBH before they can fragment into stars. We review the main scenarios proposed to explain the formation and the dynamical evolution of the early-type stars in the GC. In particular, we discuss the most popular in situ scenarios (accretion disc fragmentation and molecular cloud disruption) and migration scenarios (star cluster inspiral and Hills mechanism). We focus on the most pressing challenges that must be faced to shed light on the process of star formation in the vicinity of a SMBH.Comment: 68 pages, 35 figures; invited review chapter, to be published in expanded form in Haardt, F., Gorini, V., Moschella, U. and Treves, A., 'Astrophysical Black Holes'. Lecture Notes in Physics. Springer 201

SARS-CoV-2 variant Alpha has a spike-dependent replication advantage over the ancestral B.1 strain in human cells with low ACE2 expression

Epidemiological data demonstrate that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) Alpha and Delta are more transmissible, infectious, and pathogenic than previous variants. Phenotypic properties of VOC remain understudied. Here, we provide an extensive functional study of VOC Alpha replication and cell entry phenotypes assisted by reverse genetics, mutational mapping of spike in lentiviral pseudotypes, viral and cellular gene expression studies, and infectivity stability assays in an enhanced range of cell and epithelial culture models. In almost all models, VOC Alpha spread less or equally efficiently as ancestral (B.1) SARS-CoV-2. B.1. and VOC Alpha shared similar susceptibility to serum neutralization. Despite increased relative abundance of specific sgRNAs in the context of VOC Alpha infection, immune gene expression in infected cells did not differ between VOC Alpha and B.1. However, inferior spreading and entry efficiencies of VOC Alpha corresponded to lower abundance of proteolytically cleaved spike products presumably linked to the T716I mutation. In addition, we identified a bronchial cell line, NCI-H1299, which supported 24-fold increased growth of VOC Alpha and is to our knowledge the only cell line to recapitulate the fitness advantage of VOC Alpha compared to B.1. Interestingly, also VOC Delta showed a strong (595-fold) fitness advantage over B.1 in these cells. Comparative analysis of chimeric viruses expressing VOC Alpha spike in the backbone of B.1, and vice versa, showed that the specific replication phenotype of VOC Alpha in NCI-H1299 cells is largely determined by its spike protein. Despite undetectable ACE2 protein expression in NCI-H1299 cells, CRISPR/Cas9 knock-out and antibody-mediated blocking experiments revealed that multicycle spread of B.1 and VOC Alpha required ACE2 expression. Interestingly, entry of VOC Alpha, as opposed to B.1 virions, was largely unaffected by treatment with exogenous trypsin or saliva prior to infection, suggesting enhanced resistance of VOC Alpha spike to premature proteolytic cleavage in the extracellular environment of the human respiratory tract. This property may result in delayed degradation of VOC Alpha particle infectivity in conditions typical of mucosal fluids of the upper respiratory tract that may be recapitulated in NCI-H1299 cells closer than in highly ACE2-expressing cell lines and models. Our study highlights the importance of cell model evaluation and comparison for in-depth characterization of virus variant-specific phenotypes and uncovers a fine-tuned interrelationship between VOC Alpha- and host cell-specific determinants that may underlie the increased and prolonged virus shedding detected in patients infected with VOC Alpha