Decoding Functional High-Density Lipoprotein Particle Surfaceome Interactions

High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol transport (RCT) and several cytoprotective activities. Despite its relevance for human health, many aspects of HDL-mediated lipid trafficking and cellular signaling remain elusive at the molecular level. During HDL's journey throughout the body, its functions are mediated through interactions with cell surface receptors on different cell types. To characterize and better understand the functional interplay between HDL particles and tissue, we analyzed the surfaceome-residing receptor neighborhoods with which HDL potentially interacts. We applied a combination of chemoproteomic technologies including automated cell surface capturing (auto-CSC) and HATRIC-based ligand-receptor capturing (HATRIC-LRC) on four different cellular model systems mimicking tissues relevant for RCT. The surfaceome analysis of EA.hy926, HEPG2, foam cells, and human aortic endothelial cells (HAECs) revealed the main currently known HDL receptor scavenger receptor B1 (SCRB1), as well as 155 shared cell surface receptors representing potential HDL interaction candidates. Since vascular endothelial growth factor A (VEGF-A) was recently found as a regulatory factor of transendothelial transport of HDL, we next analyzed the VEGF-modulated surfaceome of HAEC using the auto-CSC technology. VEGF-A treatment led to the remodeling of the surfaceome of HAEC cells, including the previously reported higher surfaceome abundance of SCRB1. In total, 165 additional receptors were found on HAEC upon VEGF-A treatment representing SCRB1 co-regulated receptors potentially involved in HDL function. Using the HATRIC-LRC technology on human endothelial cells, we specifically aimed for the identification of other bona fide (co-)receptors of HDL beyond SCRB1. HATRIC-LRC enabled, next to SCRB1, the identification of the receptor tyrosine-protein kinase Mer (MERTK). Through RNA interference, we revealed its contribution to endothelial HDL binding and uptake. Furthermore, subsequent proximity ligation assays (PLAs) demonstrated the spatial vicinity of MERTK and SCRB1 on the endothelial cell surface. The data shown provide direct evidence for a complex and dynamic HDL receptome and that receptor nanoscale organization may influence binding and uptake of HDL

Dynamic correlation functions and Boltzmann Langevin approach for driven one dimensional lattice gas

We study the dynamics of the totally asymmetric exclusion process with open boundaries by phenomenological theories complemented by extensive Monte-Carlo simulations. Upon combining domain wall theory with a kinetic approach known as Boltzmann-Langevin theory we are able to give a complete qualitative picture of the dynamics in the low and high density regime and at the corresponding phase boundary. At the coexistence line between high and low density phases we observe a time scale separation between local density fluctuations and collective domain wall motion, which are well accounted for by the Boltzmann-Langevin and domain wall theory, respectively. We present Monte-Carlo data for the correlation functions and power spectra in the full parameter range of the model.Comment: 10 pages, 9 figure

Der Kohlensäuregehalt der Luft in und bei Dorpat : bestimmt in den Monaten September 1888 bis Januar 1889 : Inaugural-Dissertation zur Erlangung des Grades eines Doctors der Medicin

http://tartu.ester.ee/record=b2171222~S1*es

Glucocorticoid sensitivity of circulating monocytes in essential hypertension

Background: Essential hypertension ranks among the strongest cardiovascular risk factors. Cytokine production by monocytes plays a key role in atherosclerosis development and acute coronary syndromes. We investigated whether stimulated monocyte cytokine release and its inhibition by glucocorticoids would differ between hypertensive and normotensive subjects. Methods: Study participants were 222 middle-aged male employees with industrial jobs. Following the criteria of the World Health Organization/International Society for Hypertension, 76 subjects were classified as being hypertensive (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). In vitro monocyte tumor necrosis factor (TNF)-α release after lipopolysaccharide (LPS) stimulation was assessed with and without coincubation with incremental doses of dexamethasone. Monocyte glucocorticoid sensitivity was defined as the dexamethasone concentration inhibiting TNF-α release by 50%. Results: Hypertensive subjects showed 11% higher LPS-stimulated TNF-α release than normotensive subjects (F1,181= 5.21, P = .024). In hypertensive subjects, monocyte glucocorticoid sensitivity was 21% lower than in normotensive subjects (F1,178= 4.94, P = .027), indicating that dexamethasone inhibited relatively less TNF-α release in hypertensive subjects. Results held significance when a set of classic cardiovascular risk factors was controlled for. Conclusion: The findings suggest that proinflammatory activity of circulating monocytes is higher in hypertensive than in normotensive men, providing one potential pathway to explain the increased atherosclerotic risk with essential hypertension. Am J Hypertens 2004;17:489-494 © 2004 American Journal of Hypertension, Lt

CsrA and its regulators control the time-point of ColicinE2 release in Escherichia coli

The bacterial SOS response is a cellular reaction to DNA damage, that, among other actions, triggers the expression of colicin - toxic bacteriocins in Escherichia coli that are released to kill close relatives competing for resources. However, it is largely unknown, how the complex network regulating toxin expression controls the time-point of toxin release to prevent premature release of inefficient protein concentrations. Here, we study how different regulatory mechanisms affect production and release of the bacteriocin ColicinE2 in Escherichia coli. Combining experimental and theoretical approaches, we demonstrate that the global carbon storage regulator CsrA controls the duration of the delay between toxin production and release and emphasize the importance of CsrA sequestering elements for the timing of ColicinE2 release. In particular, we show that ssDNA originating from rolling-circle replication of the toxin-producing plasmid represents a yet unknown additional CsrA sequestering element, which is essential in the ColicinE2-producing strain to enable toxin release by reducing the amount of free CsrA molecules in the bacterial cell. Taken together, our findings show that CsrA times ColicinE2 release and reveal a dual function for CsrA as an ssDNA and mRNA-binding protein, introducing ssDNA as an important post-transcriptional gene regulatory element

Generalisability of deep learning-based early warning in the intensive care unit: a retrospective empirical evaluation

Deep learning (DL) can aid doctors in detecting worsening patient states early, affording them time to react and prevent bad outcomes. While DL-based early warning models usually work well in the hospitals they were trained for, they tend to be less reliable when applied at new hospitals. This makes it difficult to deploy them at scale. Using carefully harmonised intensive care data from four data sources across Europe and the US (totalling 334,812 stays), we systematically assessed the reliability of DL models for three common adverse events: death, acute kidney injury (AKI), and sepsis. We tested whether using more than one data source and/or explicitly optimising for generalisability during training improves model performance at new hospitals. We found that models achieved high AUROC for mortality (0.838-0.869), AKI (0.823-0.866), and sepsis (0.749-0.824) at the training hospital. As expected, performance dropped at new hospitals, sometimes by as much as -0.200. Using more than one data source for training mitigated the performance drop, with multi-source models performing roughly on par with the best single-source model. This suggests that as data from more hospitals become available for training, model robustness is likely to increase, lower-bounding robustness with the performance of the most applicable data source in the training data. Dedicated methods promoting generalisability did not noticeably improve performance in our experiments

Device for lengthening of a musculotendinous unit by direct continuous traction in the sheep

Background Retraction, atrophy and fatty infiltration are signs subsequent to chronic rotator cuff tendon tears. They are associated with an increased pennation angle and a shortening of the muscle fibers in series. These deleterious changes of the muscular architecture are not reversible with current repair techniques and are the main factors for failed rotator cuff tendon repair. Whereas fast stretching of the retracted musculotendinous unit results in proliferation of non-contractile fibrous tissue, slow stretching may lead to muscle regeneration in terms of sarcomerogenesis. To slowly stretch the retracted musculotendinous unit in a sheep model, two here described tensioning devices have been developed and mounted on the scapular spine of the sheep using an expandable threaded rod, which has been interposed between the retracted tendon end and the original insertion site at the humeral head. Traction is transmitted in line with the musculotendinous unit by sutures knotted on the expandable threaded rod. The threaded rod of the tensioner is driven within the body through a rotating axis, which enters the body on the opposite side. The tendon end, which was previously released (16 weeks prior) from its insertion site with a bone chip, was elongated with a velocity of 1 mm/day. Results After several steps of technical improvements, the tensioner proved to be capable of actively stretching the retracted and degenerated muscle back to the original length and to withstand the external forces acting on it. Conclusion This technical report describes the experimental technique for continuous elongation of the musculotendinous unit and reversion of the length of chronically shortened muscle

Persistent memory for a Brownian walker in a random array of obstacles

We show that for particles performing Brownian motion in a frozen array of scatterers long-time correlations emerge in the mean-square displacement. Defining the velocity autocorrelation function (VACF) via the second time-derivative of the mean-square displacement, power-law tails govern the long-time dynamics similar to the case of ballistic motion. The physical origin of the persistent memory is due to repeated encounters with the same obstacle which occurs naturally in Brownian dynamics without involving other scattering centers. This observation suggests that in this case the VACF exhibits these anomalies already at first order in the scattering density. Here we provide an analytic solution for the dynamics of a tracer for a dilute planar Lorentz gas and compare our results to computer simulations. Our result support the idea that quenched disorder provides a generic mechanism for persistent correlations irrespective of the microdynamics of the tracer particle.Comment: 11 pages, 4 figures, accepted in Chemical Physic