The iron-regulated surface determinant B (IsdB) protein from Staphylococcus aureus acts as a receptor for the host protein vitronectin.

Staphylococcus aureus is an important bacterial pathogen that can cause a wide spectrum of diseases in humans and other animals. S. aureus expresses a variety of virulence factors that promote infection with this pathogen. These include cell-surface proteins that mediate adherence of the bacterial cells to host extracellular matrix components, such as fibronectin and fibrinogen. Here, using immunoblotting, ELISA, and surface plasmon resonance analysis, we report that the iron-regulated surface determinant B (IsdB) protein, besides being involved in heme transport, plays a novel role as a receptor for the plasma and extracellular matrix protein vitronectin (Vn). Vn-binding activity was expressed by staphylococcal strains grown under iron starvation conditions when Isd proteins are expressed. Recombinant IsdB bound Vn dose dependently and specifically. Both near-iron transporter motifs NEAT1 and NEAT2 of IsdB individually bound Vn in a saturable manner, with KD values in the range of 16-18 nm Binding of Vn to IsdB was specifically blocked by heparin and reduced at high ionic strength. Furthermore, IsdB-expressing bacterial cells bound significantly higher amounts of Vn from human plasma than did an isdB mutant. Adherence to and invasion of epithelial and endothelial cells by IsdB-expressing S. aureus cells was promoted by Vn, and an αvβ3 integrin-blocking mAb or cilengitide inhibited adherence and invasion by staphylococci, suggesting that Vn acts as a bridge between IsdB and host αvβ3 integrin

Sickle cell disease: embedding patient participation into an international conference can transform the role of lived experience

Educación terapéutica del paciente; Taller de pacientes; Enfermedad de células falciformesEducació terapèutica del pacient; Taller de pacients; Malaltia de cèl·lules falciformesPatient therapeutic education; Patients workshop; Sickle cell diseaseBackground Sickle cell disease (SCD) is an inherited chronic life-threatening disorder with increasing prevalence in Europe. People living with SCD in Europe mainly belong to vulnerable minorities, have a lower level of health education and suffer from isolation compared to those living with other chronic conditions. As a result, SCD patients are much less likely to partner in the design of research related to their condition and are limited in their ability to influence the research agenda. Aiming to increase the influence of patient voice in the development of SCD-related research, we set out to develop patient centered actions in the frame of International Scientific Conferences in collaboration with the ERN-EuroBloodNet, Oxford Blood Group, Annual Sickle Cell Disease and Thalassaemia Conference (ASCAT), the European Hematology Association and the British Society of Hematology. Results Two events were organized: a one-day research prioritization workshop and a series of education sessions based on topics chosen by SCD patients and their families. Methodology and outcomes were analyzed in terms of influence on scientific, medical and patient communities. Conclusion The ERN-EuroBloodNet workshops with patients at annual ASCAT conferences have provided an opportunity to enhance patient experience and empowerment in SCD in Europe, producing benefits for patients, caregivers, patient associations and health professionals. Future work should focus on delivering the research questions identified at this workshop and the opportunities to share information for patient education

Comparison of the ENEAR Peculiar Velocities with the PSCz Gravity Field

We present a comparison between the peculiar velocity field measured from the ENEAR all-sky $D_n-\sigma$ catalog and that derived from the galaxy distribution of the IRAS PSCz redshift survey. The analysis is based on a modal expansion of these data in redshift space by means of spherical harmonics and Bessel functions. The effective smoothing scale of the expansion is almost linear with redshift reaching 1500km/s at 3000km/s. The general flow patterns in the filtered ENEAR and PSCz velocity fields agree well within 6000km/s, assuming a linear biasing relation between the mass and the PSCz galaxies. The comparison allows us to determine the parameter $\beta=\Omega^{0.6}/b$, where $\Omega$ is the cosmological density parameter and $b$ is the linear biasing factor. A likelihood analysis of the ENEAR and PSCz modes yields $\beta=0.5 +- 0.1$, in good agreement with values obtained from Tully-Fisher surveys.Comment: Submitted to MNRA

Morphology demonstrates similar autophagy alterations in neurodegeneration and brain tumors

Malignant glioma are the most malignant brain tumors. Frequent genetic alterations involve PTEN (Phosphatase homolog deleted on chromosome Tensin and Ten), a lipid phosphatase that after mutation is not able to convert phosphatidylinositol (3,4,5)-triphosphate (PIP3) into phosphatidylinositol (4,5)-bisphosphate (PIP2) and thereby inhibiting AKT, which in turn activates the apoptotic factors, mutations of p53 and retinoblastoma, both responsible of controlling the phase transition G1 / S of cell cycle under physiological conditions and prevent the replication of DNA when the cell is altered. Recently a dramatic uptake of the amino acid glutamine was reported in malignant glioma. This amino acid produces a marked inhibition of the autophagy pathway. Consistently, autophagy is defective in human glioblastoma similar to neurodegeneration. Autophagy is the main clearing system to remove damaged or potentially harmful organelles and misfolded proteins. Autophagy progresses through several stages: (i) the phagophore (ii) the autophagosome (iii) the amphisomes; (iv) the autophagolysosome and (v) the autophagoproteasome. The last stages involves the fusion of amphisome with lysosome which originates autophagolysosome that contains the elements to be removed and lytic enzymes necessary for this degradation process, while the autophagoproteasome derives from the fusion with component of the proteasome. The autophagy machinery can be measured by several specific markers such as beclin1 and LC3, the occurrence of stagnant autophagy vacuoles. In the present study we characterized the consistency and relevance of autophagy failure in glioblastoma by using human cell lines, primary human cell cultures and in vivo human glioblastoma cells implanted in the brain of nude mice. In baseline conditions we observed in cells obtained from surgery of human patients a marked inhibition of the autophagy pathway. This was associated with an increase in autophagy substrates overlapping with neurodegenerative disorders. In keeping with the ongoing autophagy inhibition we found that activation of the autophagy pathway reduced cell proliferation and promoted cell differentiation dose-dependently in vitro while the systemic administration of a powerful autophagy activator reduced the volume of brain tumor in vivo by 96.6%. These data indicate a relevant role of autophagy failure in glioblastoma and suggest potential approaches to contrast tumor growth

Cluster vs. Field Elliptical Galaxies and Clues on their Formation

Using new observations for a sample of 931 early-type galaxies we investigate whether the \mg2--\so relation shows any dependence on the local environment. The galaxies have been assigned to three different environments depending on the local overdensity: clusters, groups, and field, having used our completeredshift database to guide the assignment of galaxies. It is found that cluster, group and field early-type galaxies follow almost identical \mg2--\so\ relations, with the largest \mg2 zero-point difference (clusters minus field) being only $0.007\pm 0.002$ mag. No correlation of the residuals is found with the morphological type or the bulge to disk ratio. Using stellar population models in a differential fashion, this small zero-point difference implies a luminosity-weighted age difference of only $\sim 1$ Gyr between the corresponding stellar populations, with field galaxies being younger. The mass-weighted age difference could be significantly smaller, if minor events of late star formation took place preferentially in field galaxies. We combine these results with the existing evidence for the bulk of stars in cluster early-type galaxies having formed at very high redshift, and conclude that the bulk of stars in galactic spheroids had to form at high redshifts (z\gsim 3), no matter whether such spheroids now reside in low or high density regions. The cosmological implications of these findings are briefly discussed.Comment: 16 pages, 2 figures, accepted for publication in the ApJ.

International variation in the management of severe COVID-19 patients

Background: There is little evidence to support the management of severe COVID-19 patients. Methods: To document this variation in practices, we performed an online survey (April 30-May 25, 2020) on behalf of the European Society of Intensive Care Medicine (ESICM). A case vignette was sent to ESICM members. Questions investigated practices for a previously healthy 39-year-old patient presenting with severe hypoxemia from COVID-19 infection. Results: A total of 1132 ICU specialists (response rate 20%) from 85 countries (12 regions) responded to the survey. The survey provides information on the heterogeneity in patient's management, more particularly regarding the timing of ICU admission, the first line oxygenation strategy, optimization of management, and ventilatory settings in case of refractory hypoxemia. Practices related to antibacterial, antiviral, and anti-inflammatory therapies are also investigated. Conclusions: There are important practice variations in the management of severe COVID-19 patients, including differences at regional and individual levels. Large outcome studies based on multinational registries are warranted.publishersversionpublishe

Symptoms of burnout in intensive care unit specialists facing the COVID-19 outbreak

Background: The COVID-19 pandemic has resulted in an unprecedented healthcare crisis with a high prevalence of psychological distress in healthcare providers. We sought to document the prevalence of burnout syndrome amongst intensivists facing the COVID-19 outbreak. Methods: Cross-sectional survey among intensivists part of the European Society of Intensive Care Medicine. Symptoms of severe burnout, anxiety and depression were collected. Factors independently associated with severe burnout were assessed using Cox model. Results: Response rate was 20% (1001 completed questionnaires were returned, 45 years [39–53], 34% women, from 85 countries, 12 regions, 50% university-affiliated hospitals). The prevalence of symptoms of anxiety and depression or severe burnout was 46.5%, 30.2%, and 51%, respectively, and varied significantly across regions. Rating of the relationship between intensivists and other ICU stakeholders differed significantly according to the presence of anxiety, depression, or burnout. Similar figures were reported for their rating of the ethical climate or the quality of the decision-making. Factors independently associated with anxiety were female gender (HR 1.85 [1.33–2.55]), working in a university-affiliated hospital (HR 0.58 [0.42–0.80]), living in a city of > 1 million inhabitants (HR 1.40 [1.01–1.94]), and clinician’s rating of the ethical climate (HR 0.83 [0.77–0.90]). Independent determinants of depression included female gender (HR 1.63 [1.15–2.31]) and clinician’s rating of the ethical climate (HR 0.84 [0.78–0.92]). Factors independently associated with symptoms of severe burnout included age (HR 0.98/year [0.97–0.99]) and clinician’s rating of the ethical climate (HR 0.76 [0.69–0.82]). Conclusions: The COVID-19 pandemic has had an overwhelming psychological impact on intensivists. Follow-up, and management are warranted to assess long-term psychological outcomes and alleviate the psychological burden of the pandemic on frontline personnel.publishersversionpublishe

ENEAR Redshift-Distance Survey: Cosmological Constraints

We present an analysis of the ENEAR sample of peculiar velocities of elliptical galaxies, obtained with D_n-\sigma distances. We use the velocity correlation function to analyze the statistics of the field-object's velocities, while the analysis of the cluster data is based on the estimate of their rms peculiar velocity, Vrms. The statistics of the model velocity field is parameterized by the amplitude, \eta_8=\sigma_8 \Omega_m^{0.6}, and by the shape parameter, \Gamma. From the velocity correlation statistics we obtain \eta_8=0.51{-0.09}{+0.24} for \Gamma=0.25 at the 2\sigma level. Even though less constraining, a consistent result is obtained by comparing the measured Vrms of clusters to linear theory predictions. For \Gamma=0.25 we find \eta_8=0.63{-0.19}{+0.22}$ at 1\sigma. Overall, our results point toward a statistical concordance of the cosmic flows traced by spirals and early-type galaxies, with galaxy distances estimated using TF and D_n-\sigma distance indicators, respectively.Comment: 5 pages, 2 figures, accepted for publication in ApJ Letter

Dynamic Mechanical Interactions Between Neighboring Airspaces Determine Cyclic Opening and Closure in Injured Lung

OBJECTIVES:: Positive pressure ventilation exposes the lung to mechanical stresses that can exacerbate injury. The exact mechanism of this pathologic process remains elusive. The goal of this study was to describe recruitment/derecruitment at acinar length scales over short-time frames and test the hypothesis that mechanical interdependence between neighboring lung units determines the spatial and temporal distributions of recruitment/derecruitment, using a computational model. DESIGN:: Experimental animal study. SETTING:: International synchrotron radiation laboratory. SUBJECTS:: Four anesthetized rabbits, ventilated in pressure controlled mode. INTERVENTIONS:: The lung was consecutively imaged at ~ 1.5-minute intervals using phase-contrast synchrotron imaging, at positive end-expiratory pressures of 12, 9, 6, 3, and 0 cm H2O before and after lavage and mechanical ventilation induced injury. The extent and spatial distribution of recruitment/derecruitment was analyzed by subtracting subsequent images. In a realistic lung structure, we implemented a mechanistic model in which each unit has individual pressures and speeds of opening and closing. Derecruited and recruited lung fractions (Fderecruited, Frecruited) were computed based on the comparison of the aerated volumes at successive time points. MEASUREMENTS AND MAIN RESULTS:: Alternative recruitment/derecruitment occurred in neighboring alveoli over short-time scales in all tested positive end-expiratory pressure levels and despite stable pressure controlled mode. The computational model reproduced this behavior only when parenchymal interdependence between neighboring acini was accounted for. Simulations closely mimicked the experimental magnitude of Fderecruited and Frecruited when mechanical interdependence was included, while its exclusion gave Frecruited values of zero at positive end-expiratory pressure greater than or equal to 3 cm H2O. CONCLUSIONS:: These findings give further insight into the microscopic behavior of the injured lung and provide a means of testing protective-ventilation strategies to prevent recruitment/derecruitment and subsequent lung damage