Chronic inflammation is widely recognized as a significant factor that promotes and worsens the development of malignancies, including hepatocellular carcinoma. This study aimed to explore the potential role of microRNAs in inflammation-associated nonresolving hepatocarcinogenesis. By conducting a comprehensive analysis of altered microRNAs in animal models with liver cancer of various etiologies, we identified miR-122 as the most significantly downregulated microRNA in the liver of animals with inflammation-associated liver cancer. Although previous research has indicated the importance of miR-122 in maintaining hepatocyte function, its specific role as either the trigger or the consequence of underlying diseases remains unclear. Through extensive analysis of animals and in vitro models, we have successfully demonstrated that miR-122 transcription is differentially regulated by the immunoregulatory cytokines, by the transforming growth factor-beta 1 (TGFβ1), and the bone morphogenetic protein-6 (BMP6). Furthermore, we presented convincing evidence directly linking reduced miR-122 transcription to inflammation and in chronic liver diseases. The results of this study strongly suggest that prolonged activation of pro-inflammatory signaling pathways, leading to disruption of cytokine-mediated regulation of miR-122, may significantly contribute to the onset and exacerbation of chronic liver disease.

The relative distribution of molecular gas and star formation in galaxies gives insight into the physical processes and timescales of the cycle between gas and stars. In this work, we track the relative spatial configuration of CO and Hα emission at high resolution in each of our galaxy targets and use these measurements to quantify the distributions of regions in different evolutionary stages of star formation: from molecular gas without star formation traced by Hα to star-forming gas, and to H ii regions. The large sample, drawn from the Physics at High Angular resolution in Nearby GalaxieS ALMA and narrowband Hα (PHANGS-ALMA and PHANGS-Hα) surveys, spans a wide range of stellar masses and morphological types, allowing us to investigate the dependencies of the gas‒star formation cycle on global galaxy properties. At a resolution of 150 pc, the incidence of regions in different stages shows a dependence on stellar mass and Hubble type of galaxies over the radial range probed. Massive and/or earlier-type galaxies in our sample exhibit a significant reservoir of molecular gas without star formation traced by Hα, while lower-mass galaxies harbor substantial H ii regions that may have dispersed their birth clouds or formed from low-mass, more isolated clouds. Galactic structures add a further layer of complexity to the relative distribution of CO and Hα emission. Trends between galaxy properties and distributions of gas traced by CO and Hα are visible only when the observed spatial scale is ≪500 pc, reflecting the critical resolution requirement to distinguish stages of the star formation process.

Background: Exploiting the immune system, particularly CD8+ T cells to eliminate tumors has revolutionized the treatment landscape. However, despite the evident successes of CD8+ T cell-targeting immunotherapies such as anti-PD1 checkpoint inhibitors, many patients fail to respond especially those with poorly immunogenic tumors. Additional obstacles to successful immunotherapy responses include therapy-induced toxicity, lack of bio-markers of response, an immunosuppressive environment leading to T cell dysfunction and exhaustion and poor immune infiltration highlighting a need for novel combinatorial approaches to augment immunotherapeutic activity. Aims: We aimed to uncover novel therapeutic agents capable of augmenting the anti-tumoral responses of CD8+ T cells in ex vivo systems and in vivo syngenetic poorly immunogenic tumor models. Methods: To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen, using Lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells that were combined tumor cells expressing the LCMV gp33 (B16) peptide CTL epitope and incubated with an NIH 770 compound library. Hits that increased tumor-cell killing when combined with LCMV-primed splenic T cells were further validated ex vivo. The key candidate was assessed in vivo in C57BL/6J syngeneic tumor models. Immunocompromised NSG mice as well as antibody depletion were used validate CD8+ T cell dependence. In vitro and in vivo immunomodulatory effects were deciphered using flow cytometry, immunoblot, CRISPR/Cas9 and histological analyses. Results: We identified 5-Nonyloxytryptamine (5-NL), a serotonin receptor (HTR) agonist, as increasing the ability of T cells to target tumor cells. In vitro, 5-NL induced apoptosis in melanoma and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) at low micromolar levels. 5-NL delayed tumor growth in vivo and the phenotype was dependent on the hosts’ immune system, specifically CD8+ T cells as their depletion abrogated the phenotype (Figure 1A-B). 5-NL’s pro-immune effects were attributed to the upregulation of antigen presenting machinery in melanoma, BCP-ALL and other poorly immunogenic tumors with low MHC-I/HLAA-C expression (Figure 1C). Importantly, the upregulation of MHC-I/HLAA-C occurred without concomitant increases in PD-L1 expression and was linked to upregulation of cAMP Response Element-Binding Protein (CREB) in vitro and in vivo. As demonstrated through CRISPR/Cas9 HTR1D knockout, the immunomodulatory and pro-apoptotic effects of 5-NL occurred independently of receptor target signaling. 5-NL was successfully combined with an anti-PD1 antibody in vivo for maximal tumor growth inhibition. Figure 1: The serotonin agonist 5-Nonyloxytryptamine (5-NL) was identified as potentiating T cell mediated anti-tumor immunity. (A) C57BL/6J or (B) CD8 depleted C57BL/6J mice were subcutaneously injected with 5 x 105 gp33 expressing tumor cells. 7 days post-tumor injection, mice were randomized and treated daily 6.25 mg/kg of 5-NL or vehicle for five consecutive days and tumor volume was measured (n = 9-12). H2-Db (MHC-I, murine cell lines) and HLAA-C (human cells lines) were assessed by FACS analysis following treatment with 5-NL for 24 hours (n = 3-9). Error bars in all experiments indicate SEM; *P < 0.05 as determined by a Student´s t-test (unpaired, 2 tailed). Image:Summary/Conclusion: This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors and increasing their responsiveness to immunotherapies.

Introduction Rapid sequence induction of anaesthesia is indicated in patients with an increased risk of pulmonary aspiration. The main objective of the technique is to reduce the critical time period between loss of airway protective reflexes and rapid inflation of the cuff of the endotracheal tube to minimise the chance of aspiration of gastric contents. The COVID-19 pandemic has reinforced the importance of first-pass intubation success to ensure patient and healthcare worker safety. The aim of this study is to compare the first-pass intubation success rate (FPS) using the videolaryngoscopy compared with conventional direct laryngoscopy in surgical patients with a high risk of pulmonary aspiration.Methods and analysis The LARA trial is a multicentre, patient-blinded, randomised controlled trial. Consecutive patients requiring tracheal intubation are randomly allocated to either the McGrath MAC videolaryngoscope or direct laryngoscopy using the Macintosh laryngoscope. The expected rate of FPS is 92% in the McGrath group and 82% in the Macintosh group. Each group must include a total of 500 patients to achieve 90% power for detecting a difference at the 5% significance level. Successful intubation with the FPS is the primary endpoint. The secondary endpoints are the time to intubation, the number of intubation attempts, the necessity of airway management alternatives, the visualisation of the glottis using the Cormack and Lehane Score and the Percentage Of Glottic Opening Score and definite adverse events.Ethics and dissemination The project is approved by the local ethics committee of the Medical Association of the Rhineland Palatine state (registration number: 2020–15502) and medical ethics committee of the University of Freiburg (registration number: 21–1303). The results of this study will be made available in form of manuscripts for publication and presentations at national and international meetings.Trial registration NCT04794764.

We have noticed an error in the radial metallicity gradient fits provided in Table 3 (Appendix C) of the published article. The columns that list the metallicity gradients have units of dex arcmin-1, rather than the noted dex kpc-1. In the following we provide a corrected version of the table. All figures in the published article are shown in units of R25, and are unchanged from the published version. The results and conclusions of the paper are not affected by this error.

We contrast the gas kinematics and dark matter contents of z = 2 star-forming galaxies (SFGs) from state-of-the-art cosmological simulations within the Lambda CDM framework to observations. To this end, we create realistic mock observations of massive SFGs (M-* > 4 x 10(10) M-circle dot, SFR >50 M-circle dot yr(-1)) from the TNG50 simulation of the IllustrisTNG suite, resembling near-infrared, adaptive-optics assisted integral-field observations from the ground. Using observational line fitting and modelling techniques, we analyse in detail the kinematics of seven TNG50 galaxies from five different projections per galaxy, and compare them to observations of twelve massive SFGs by Genzel et al. (2020). The simulated galaxies show clear signs of disc rotation but mostly exhibit more asymmetric rotation curves, partly due to large intrinsic radial and vertical velocity components. At identical inclination angle, their 1D velocity profiles can vary along different lines of sight by up to Delta v = 200 km s(-1). From dynamical modelling we infer rotation speeds and velocity dispersions that are broadly consistent with observational results. We find low central dark matter fractions compatible with observations (f(DM)(v) (< R e ) = v(DM)(2)(R-e)/v(circ)(2)(R-e) similar to 0.32 +/- 0.10), however for disc effective radii R-e that are mostly too small: at fixed R-e the TNG50 dark matter fractions are too high by a factor of similar to 2. We speculate that the differences in gas kinematics and dark matter content compared to the observations may be due to physical processes that are not resolved in sufficient detail with the numerical resolution available in current cosmological simulations.

The distribution of metals within a galaxy traces the baryon cycle and the buildup of galactic disks, but the detailed gas phase metallicity distribution remains poorly sampled. We have determined the gas phase oxygen abundances for 7138 H ii regions across the disks of eight nearby galaxies using Very Large Telescope/Multi Unit Spectroscopic Explorer (MUSE) optical integral field spectroscopy as part of the PHANGS–MUSE survey. After removing the first-order radial gradients present in each galaxy, we look at the statistics of the metallicity offset (ΔO/H) and explore azimuthal variations. Across each galaxy, we find low ( σ = 0.03–0.05 dex) scatter at any given radius, indicative of efficient mixing. We compare physical parameters for those H ii regions that are 1 σ outliers toward both enhanced and reduced abundances. Regions with enhanced abundances have high ionization parameter, higher H α luminosity, lower H α velocity dispersion, younger star clusters, and associated molecular gas clouds showing higher molecular gas densities. This indicates recent star formation has locally enriched the material. Regions with reduced abundances show increased H α velocity dispersions, suggestive of mixing introducing more pristine material. We observe subtle azimuthal variations in half of the sample, but cannot always cleanly associate this with the spiral pattern. Regions with enhanced and reduced abundances are found distributed throughout the disk, and in half of our galaxies we can identify subsections of spiral arms with clearly associated metallicity gradients. This suggests spiral arms play a role in organizing and mixing the interstellar medium.

We present half-light sizes measured from emission tracing star formation in 281 star-forming galaxies from the survey at . Sizes are derived by fitting 2D exponential disk models, with bootstrap errors averaging 20%. sizes are a median (mean) of 1.19 (1.26) times larger than those of the stellar continuum—which, due to radial dust gradients, places an upper limit on the growth in stellar size via star formation—with just intrinsic scatter. At fixed continuum size the size shows no residual trend with stellar mass, star formation rate, redshift, or morphology. The only significant residual trend is with the excess obscuration of by dust, at fixed continuum obscuration. The scatter in continuum size at fixed stellar mass is likely driven by the scatter in halo spin parameters. The stability of the ratio of size to continuum size demonstrates a high degree of stability in halo spin and in the transfer of angular momentum to the disk over a wide range of physical conditions and cosmic time. This may require local regulation by feedback processes. The implication of our results, as we demonstrate using a toy model, is that our upper limit on star-formation-driven growth is sufficient only to evolve star-forming galaxies approximately along the observed size–mass relation, consistent with the size growth of galaxies at constant cumulative comoving number density. To explain the observed evolution of the size–mass relation of star-forming disk galaxies, other processes, such as the preferential quenching of compact galaxies or galaxy mergers, may be required.

We present kinematic orientations and high-resolution (150 pc) rotation curves for 67 main-sequence star-forming galaxies surveyed in CO (2–1) emission by PHANGS–ALMA. Our measurements are based on the application of a new fitting method tailored to CO velocity fields. Our approach identifies an optimal global orientation as a way to reduce the impact of nonaxisymmetric (bar and spiral) features and the uneven spatial sampling characteristic of CO emission in the inner regions of nearby galaxies. The method performs especially well when applied to the large number of independent lines of sight contained in the PHANGS CO velocity fields mapped at 1″ resolution. The high-resolution rotation curves fitted to these data are sensitive probes of mass distribution in the inner regions of these galaxies. We use the inner slope as well as the amplitude of our fitted rotation curves to demonstrate that CO is a reliable global dynamical mass tracer. From the consistency between photometric orientations from the literature and kinematic orientations determined with our method, we infer that the shapes of stellar disks in the mass range of log( ) = 9.0–10.9 probed by our sample are very close to circular and have uniform thickness.

We have previously shown that the acid sphingomyelinase/ceramide system plays an important role in bacterial and viral infections. Pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram or maprotiline or genetic down-regulation of the enzyme prevents infection with authentic SARS-CoV-2 or pseudoviral particles expressing pp-VSV-SARS-CoV-2 spike that served as a bona fide system mimicking SARS-CoV-2 infection. Mechanistically, acid sphingomyelinase mediates the formation of ceramide-enriched membrane platforms that serve the infection with pp-VSV-SARS-CoV-2 spike. Neutralization or consumption of surface ceramide reduces infection with pp-VSV-SARS-CoV-2 spike. Treatment of volunteers with a low dose of amitriptyline prevents infection of freshly isolated nasal epithelial cells with pp-VSV-SARS-CoV-2 spike, indicating that amitriptyline can be repurposed to prevent SARS-CoV-2 infection. Our data suggest the use of amitriptyline, a safe drug clinically used for almost 60 years, other antidepressants blocking the acid sphingomyelinase, anti-ceramide antibodies and neutral ceramidase for prophylaxis and treatment of coronavirus disease-19. Funding: The study was supported by DFG grant Gu-335-35/1 and BMBF, RAPID Consortium, grant 01KI1723D to SP. Conflict of Interest: The authors declare no competing financial interests. Ethical Approval: The experiments were approved by the local ethics committee under the number 20-9348-BO.

We present half-light sizes measured from Hα emission tracing star-formation in 281 star-forming galaxies from the KMOS survey at 0.7 . z . 2.7. Sizes are derived by fitting 2D exponential disk models, with bootstrap errors averaging 20%. Hα sizes are a median (mean) of 1.19 (1.26) times larger than those of the stellar continuum – which due to radial dust gradients places an upper limit on the growth in stellar size via star formation – with just ∼ 43% intrinsic scatter. At fixed continuum size the Hα size shows no residual trend with stellar mass, star formation rate, redshift or morphology. The only significant residual trend is with the excess obscuration of Hα by dust, at fixed continuum obscuration. The scatter in continuum size at fixed stellar mass is likely driven by the scatter in halo spin parameters. The stability of the ratio of Hα size to continuum size demonstrates a high degree of stability in halo spin and in the transfer of angular momentum to the disk over a wide range of physical conditions and cosmic time. This may require local regulation by feedback processes. The implication of our results, as we demonstrate using a toy model, is that our upper limit on star-formation driven growth is sufficient only to evolve star-forming galaxies approximately along the observed size-mass relation, consistent with the size growth of galaxies at constant cumulative co-moving number density. To explain the observed evolution of the size-mass relation of star-forming disk galaxies other processes, such as the preferential quenching of compact galaxies or galaxy mergers, may be required.

Context. Cloud-scale surveys of molecular gas reveal the link between giant molecular cloud properties and star formation across a range of galactic environments. Cloud populations in galaxy disks are considered to be representative of the normal star formation process, while galaxy centers tend to harbor denser gas that exhibits more extreme star formation. At high resolution, however, molecular clouds with exceptional gas properties and star formation activity may also be observed in normal disk environments. In this paper we study the brightest cloud traced in CO(2-1) emission in the disk of nearby spiral galaxy NGC 628.Aims. We characterize the properties of the molecular and ionized gas that is spatially coincident with an extremely bright HII region in the context of the NGC 628 galactic environment. We investigate how feedback and large-scale processes influence the properties of the molecular gas in this region.Methods. High-resolution ALMA observations of CO(2-1) and CO(1-0) emission were used to characterize the mass and dynamical state of the "headlight" molecular cloud. The characteristics of this cloud are compared to the typical properties of molecular clouds in NGC 628. A simple large velocity gradient (LVG) analysis incorporating additional ALMA observations of (CO)-C-13(1-0), HCO+(1-0), and HCN(1-0) emission was used to constrain the beam-diluted density and temperature of the molecular gas. We analyzed the MUSE spectrum using Starburst99 to characterize the young stellar population associated with the HII region.Results. The unusually bright headlight cloud is massive (1-2x10(7) M-circle dot), with a beam-diluted density of n(H2)=5x10(4) cm(-3) based on LVG modeling. It has a low virial parameter, suggesting that the CO emission associated with this cloud may be overluminous due to heating by the HII region. A young (2-4 Myr) stellar population with mass 3x10(5) M-circle dot is associated.Conclusions. We argue that the headlight cloud is currently being destroyed by feedback from young massive stars. Due to the large mass of the cloud, this phase of the its evolution is long enough for the impact of feedback on the excitation of the gas to be observed. The high mass of the headlight cloud may be related to its location at a spiral co-rotation radius, where gas experiences reduced galactic shear compared to other regions of the disk and receives a sustained inflow of gas that can promote the mass growth of the cloud.

We provide a coherent, uniform measurement of the evolution of the logarithmic star formation rate (SFR)–stellar mass (M*) relation, called the main sequence (MS) of star-forming galaxies , for star-forming and all galaxies out to . We measure the MS using mean stacks of 3 GHz radio-continuum images to derive average SFRs for ∼ 200,000 mass-selected galaxies at z > 0.3 in the COSMOS field. We describe the MS relation by adopting a new model that incorporates a linear relation at low stellar mass (log(M*/M⊙) < 10) and a flattening at high stellar mass that becomes more prominent at low redshift (z < 1.5). We find that the SFR density peaks at 1.5 < z < 2, and at each epoch there is a characteristic stellar mass (M* = 1–4 × 1010M⊙) that contributes the most to the overall SFR density. This characteristic mass increases with redshift, at least to z ∼ 2.5. We find no significant evidence for variations in the MS relation for galaxies in different environments traced by the galaxy number density at 0.3 < z < 3, nor for galaxies in X-ray groups at z ∼ 0.75. We confirm that massive bulge-dominated galaxies have lower SFRs than disk-dominated galaxies at a fixed stellar mass at z < 1.2. As a consequence, the increase in bulge-dominated galaxies in the local star-forming population leads to a flattening of the MS at high stellar masses. This indicates that “mass quenching” is linked with changes in the morphological composition of galaxies at a fixed stellar mass.