Super star cluster feedback driving ionization, shocks and outflows in the halo of the nearby starburst ESO 338-IG04

Stellar feedback strongly affects the interstellar medium (ISM) of galaxies. Stellar feedback in the first galaxies likely plays a major role in enabling the escape of LyC photons, which contribute to the re-ionization of the Universe. Nearby starburst galaxies serve as local analogues allowing for a spatially resolved assessment of the feedback processes in these galaxies. We characterize the feedback effects from the star clusters in the local high-redshift analogue ESO 338-IG04 on the ISM and compare the results with the properties of the most massive clusters. We use high quality VLT/MUSE optical integral field data to derive the physical properties of the ISM such as ionization, density, shocks, and perform new fitting of the spectral energy distributions of the brightest clusters in ESO 338-IG04 from HST imaging. ESO 338-IG04 has a large ionized halo which we detect to a distance of 9 kpc. We identify 4 Wolf-Rayet (WR) clusters based on the blue and red WR bump. We follow previously identified ionization cones and find that the ionization of the halo increases with distance. Analysis of the galaxy kinematics shows two complex outflows driven by the numerous young clusters in the galaxy. We find a ring of shocked emission traced by an enhanced [OI]/H$\alpha$ ratio surrounding the starburst and at the end of the outflow. Finally we detect nitrogen enriched gas associated with the outflow, likely caused by the WR stars in the massive star clusters. Photo-ionization dominates the central starburst and sets the ionization structure of the entire halo, resulting in a density bounded halo, facilitating the escape of LyC photons. Outside the central starburst, shocks triggered by an expanding super bubble become important. The shocks at the end of the outflow suggest interaction between the hot outflowing material and the more quiescent halo gas.Comment: Accepted for publication in Astronomy and Astrophysics, 22 pages, 15 figure

Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients

Aims: To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results: One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion: Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix

Vav proteins are key regulators of Card9 signaling for innate antifungal immunity

Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adaptor Card9. Although Card9 is essential for antifungal defense, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, we identify Vav proteins as key activators of the Card9 pathway. Vav1, Vav2, and Vav3 cooperate downstream of Dectin-1, Dectin-2, and Mincle to engage Card9 for NF-κB control and proinflammatory gene transcription. Although Vav family members show functional redundancy, Vav1/2/3(-/-) mice phenocopy Card9(-/-) animals with extreme susceptibility to fungi. In this context, Vav3 is the single most important Vav in mice, and a polymorphism in human VAV3 is associated with susceptibility to candidemia in patients. Our results reveal a molecular mechanism for CLR-mediated Card9 regulation that controls innate immunity to fungal infections

Immunosuppression-independent role of regulatory T cells against hypertension-driven renal dysfunctions

Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39+ regulatory T (TREG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in TREG/TH cell ratios have a direct impact on tissue-resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that TREG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases.This work has been supported by grants from the Castilla-León Autonomous Government (CSI101U13), the Spanish Ministry of Economy and Competitiveness (SAF2012-31371, RD12/0036/0002), Worldwide Cancer Research, the Solórzano Foundation, and the Ramón Areces Foundation to X.R.B. P.M. is funded by the Spanish Ministry of Economy and Competitiveness (SAF2011-27330). S.F., M.M.-M., J.R.-V., and A.M.-M. were supported by the Spanish Ministry of Economy and Competitiveness through BES-2010-031386, CSIC JAE-Doc, Juan de la Cierva, and BES-2009-016103 contracts, respectively. Spanish government-sponsored funding to X.R.B. is partially supported by the European Regional Development Fund.Peer Reviewe

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection

BACKGROUND: The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration. METHODS: We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms. FINDINGS: Within this cohort (median age 39 years, interquartile range 30-47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590. INTERPRETATION: Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection. FUNDING INFORMATION: The COVIDsortium is supported by funding donated by individuals, charitable Trusts, and corporations including Goldman Sachs, Citadel and Citadel Securities, The Guy Foundation, GW Pharmaceuticals, Kusuma Trust, and Jagclif Charitable Trust, and enabled by Barts Charity with support from University College London Hospitals (UCLH) Charity. This work was additionally supported by the Translational Mass Spectrometry Research Group and the Biomedical Research Center (BRC) at Great Ormond Street Hospital

Prospective Case-Control Study of Cardiovascular Abnormalities 6 Months Following Mild COVID-19 in Healthcare Workers

OBJECTIVES: The purpose of this study was to detect cardiovascular changes after mild severe acute respiratory syndrome coronavirus 2 infection. BACKGROUND: Concern exists that mild coronavirus disease 2019 may cause myocardial and vascular disease. METHODS: Participants were recruited from COVIDsortium, a 3-hospital prospective study of 731 health care workers who underwent first-wave weekly symptom, polymerase chain reaction, and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post-infection, 74 seropositive and 75 age-, sex-, and ethnicity-matched seronegative control subjects were recruited for cardiovascular phenotyping (comprehensive phantom-calibrated cardiovascular magnetic resonance and blood biomarkers). Analysis was blinded, using objective artificial intelligence analytics where available. RESULTS: A total of 149 subjects (mean age 37 years, range 18 to 63 years, 58% women) were recruited. Seropositive infections had been mild with case definition, noncase definition, and asymptomatic disease in 45 (61%), 18 (24%), and 11 (15%), respectively, with 1 person hospitalized (for 2 days). Between seropositive and seronegative groups, there were no differences in cardiac structure (left ventricular volumes, mass, atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterization (T1, T2, extracellular volume fraction mapping, late gadolinium enhancement) or biomarkers (troponin, N-terminal pro-B-type natriuretic peptide). With abnormal defined by the 75 seronegatives (2 SDs from mean, e.g., ejection fraction 1,072 ms, septal T2 >52.4 ms), individuals had abnormalities including reduced ejection fraction (n = 2, minimum 50%), T1 elevation (n = 6), T2 elevation (n = 9), late gadolinium enhancement (n = 13, median 1%, max 5% of myocardium), biomarker elevation (borderline troponin elevation in 4; all N-terminal pro-B-type natriuretic peptide normal). These were distributed equally between seropositive and seronegative individuals. CONCLUSIONS: Cardiovascular abnormalities are no more common in seropositive versus seronegative otherwise healthy, workforce representative individuals 6 months post-mild severe acute respiratory syndrome coronavirus 2 infection

Lupinus mutabilis oil obtained by expeller press: Yield, physicochemical characterization, antioxidant capacity, fatty acids and oxidative stability analyses

The oil of debittered and dehulled grains from two Andean lupins (Lupinus mutabilis) from Peru, Andenes and Común, was extracted by expellerpress. The extraction yield and the proximal composition of both varieties were assessed. The oil and the cake, as well as the defatted flour from thevariety with the highest extraction yield, werecharacterised for physico-chemical properties, total polyphenol content andantioxidant capacity. Theoil shelf-life at 25 °C was extrapolated by Rancimat test. Andenes presented an oil yield of 22.1% (vs. 18.4% of Común), CIELAB colour coordinates ofL* = 36.5, a* = 2.2, b* = 20, refractive index and density at 25 ºC of 1.469 and 0.903 g/mL, acid number of 3.2 mg KOH/g, free fatty acids content of1.6%, peroxide number of 2.7 meqO2/kg, p-anisidine number of 1.3, unsaponificable content of 58%, total antioxidant capacity 21.4 μmol TE/g and total polyphenol content of 7.0 mg AGE/100 g. The predominant fatty acid, tocopherol and phytosterol in the oil were oleic acid (56.2%), γ-tocopherol (555 mg/kg) and β-sitosterol (41900 mg/100 g), respectively. The oil shelf-life at 25 ºC was 2.7 years. The Lupinus mutabilis oil extracted by expeller presented an acceptable quality with a lower environmental negative impact than the oils obtained by solvent extraction