252 research outputs found
Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo
Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis. The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods: In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro. In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain. This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest
A new approach for the limit to tree height using a liquid nanolayer model
Liquids in contact with solids are submitted to intermolecular forces
inferring density gradients at the walls. The van der Waals forces make liquid
heterogeneous, the stress tensor is not any more spherical as in homogeneous
bulks and it is possible to obtain stable thin liquid films wetting vertical
walls up to altitudes that incompressible fluid models are not forecasting.
Application to micro tubes of xylem enables to understand why the ascent of sap
is possible for very high trees like sequoias or giant eucalyptus.Comment: In the conclusion is a complementary comment to the Continuum
Mechanics and Thermodynamics paper. 21 pages, 4 figures. Continuum Mechanics
and Thermodynamics 20, 5 (2008) to appea
Sustained VWF‐ADAMTS‐13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction
Background
Prolonged recovery is common after acute SARS-CoV-2 infection; however, the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF/ADAMTS-13 imbalance, dysregulated angiogenesis, and immunothrombosis are hallmarks of acute COVID-19. We hypothesized that VWF/ADAMTS-13 imbalance persists in convalescence together with endothelial cell (EC) activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation.
Patients and methods
Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS-13, Weibel Palade Body (WPB) proteins, and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n = 20) and acute COVID-19 patients (n = 36).
Results
ADAMTS-13 levels were reduced (p = 0.009) and the VWF-ADAMTS-13 ratio was increased in convalescence (p = 0.0004). Levels of platelet factor 4 (PF4), a putative protector of VWF, were also elevated (p = 0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively.
Conclusion
Our data provide insights into sustained EC activation, dysregulated angiogenesis, and VWF/ADAMTS-13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immunothrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence
ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19
Background
Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID-19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS-13)--mediated proteolysis.
Objectives
This study investigated the hypothesis that ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the observed microvascular thrombosis.
Patients and Methods
Patients with COVID-19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS-13 activity, and known inhibitors thereof were assessed.
Results
We observed markedly increased VWF collagen-binding activity in patients with severe COVID-19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS-13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS-13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID-19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS-13 and other proteases. We observed that both N- and O-linked sialylation were altered in severe COVID-19. Furthermore, plasma levels of the ADAMTS-13 inhibitors interleukin-6, thrombospondin-1, and platelet factor 4 were significantly elevated.
Conclusions
These findings support the hypothesis that SARS-CoV-2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down-regulation in ADAMTS-13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS-13-VWF multimer dysfunction may be useful in COVID-microvascular thrombosis and angiopathy
Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy
We review HB stars in a broad astrophysical context, including both variable
and non-variable stars. A reassessment of the Oosterhoff dichotomy is
presented, which provides unprecedented detail regarding its origin and
systematics. We show that the Oosterhoff dichotomy and the distribution of
globular clusters (GCs) in the HB morphology-metallicity plane both exclude,
with high statistical significance, the possibility that the Galactic halo may
have formed from the accretion of dwarf galaxies resembling present-day Milky
Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the
second-parameter problem is presented. A technique is proposed to estimate the
HB types of extragalactic GCs on the basis of integrated far-UV photometry. The
relationship between the absolute V magnitude of the HB at the RR Lyrae level
and metallicity, as obtained on the basis of trigonometric parallax
measurements for the star RR Lyrae, is also revisited, giving a distance
modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are
studied. Finally, the conductive opacities used in evolutionary calculations of
low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and
Space Scienc
Extent and Causes of Chesapeake Bay Warming
Coastal environments such as the Chesapeake Bay have long been impacted by eutrophication stressors resulting from human activities, and these impacts are now being compounded by global warming trends. However, there are few studies documenting long-term estuarine temperature change and the relative contributions of rivers, the atmosphere, and the ocean. In this study, Chesapeake Bay warming, since 1985, is quantified using a combination of cruise observations and model outputs, and the relative contributions to that warming are estimated via numerical sensitivity experiments with a watershed–estuarine modeling system. Throughout the Bay’s main stem, similar warming rates are found at the surface and bottom between the late 1980s and late 2010s (0.02 +/- 0.02C/year, mean +/- 1 standard error), with elevated summer rates (0.04 +/- 0.01C/year) and lower rates of winter warming (0.01 +/- 0.01C/year). Most (~85%) of this estuarine warming is driven by atmospheric effects. The secondary influence of ocean warming increases with proximity to the Bay mouth, where it accounts for more than half of summer warming in bottom waters. Sea level rise has slightly reduced summer warming, and the influence of riverine warming has been limited to the heads of tidal tributaries. Future rates of warming in Chesapeake Bay will depend not only on global atmospheric trends, but also on regional circulation patterns in mid-Atlantic waters, which are currently warming faster than the atmosphere.
Supporting model data available at: https://doi.org/10.25773/c774-a36
A multi-center study on the attitudes of Malaysian emergency health care staff towards allowing family presence during resuscitation of adult patients
BACKGROUND
The practice of allowing family members to witness on-going active resuscitation has been gaining ground in many developed countries since it was first introduced in the early 1990s. In many Asian countries, the acceptability of this practice has not been well studied.
AIM
We conducted a multi-center questionnaire study to determine the attitudes of health care professionals in Malaysia towards family presence to witness ongoing medical procedures during resuscitation.
METHODS
Using a bilingual questionnaire (in Malay and English language), we asked our respondents about their attitudes towards allowing family presence (FP) as well as their actual experience of requests from families to be allowed to witness resuscitations. Multiple logistic regression was used to analyze the association between the many variables and a positive attitude towards FP.
RESULTS
Out of 300 health care professionals who received forms, 270 responded (a 90% response rate). Generally only 15.8% of our respondents agreed to allow relatives to witness resuscitations, although more than twice the number (38.5%) agreed that relatives do have a right to be around during resuscitation. Health care providers are significantly more likely to allow FP if the procedures are perceived as likely to be successful (e.g., intravenous cannulation and blood taking as compared to chest tube insertion). Doctors were more than twice as likely as paramedics to agree to FP (p-value = 0.002). This is probably due to the Malaysian work culture in our health care systems in which paramedics usually adopt a 'follow-the-leader' attitude in their daily practice.
CONCLUSION
The concept of allowing FP is not well accepted among our Malaysian health care providers
Feasibility studies for the measurement of time-like proton electromagnetic form factors from p¯ p→ μ+μ- at P ¯ ANDA at FAIR
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, | GE| and | GM| , using the p¯ p→ μ+μ- reaction at P ¯ ANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at P ¯ ANDA , using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is p¯ p→ π+π-, due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distributions of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented
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