Heparin Interaction with the Primed Polymorphonuclear Leukocyte CD11b Induces Apoptosis and Prevents Cell Activation

Heparin is known to have anti-inflammatory effects, yet the mechanisms are not completely understood. In this study, we tested the hypothesis that heparin has a direct effect on activated polymorphonuclear leukocytes (PMNLs), changing their activation state, and can explain its anti-inflammatory effect. To test our hypothesis, we designed both in vitro and ex vivo studies to elucidate the mechanism by which heparin modulates PMNL functions and therefore the inflammatory response. We specifically tested the hypothesis that priming of PMNLs renders them more susceptible to heparin. Amplified levels of CD11b and increased rate of superoxide release manifested PMNL priming. Increase in cell priming resulted in a dose-dependent increase in heparin binding to PMNLs followed by augmented apoptosis. Blocking antibodies to CD11b inhibited heparin binding and abolished the apoptotic response. Moreover, heparin caused a significant dose-dependent decrease in the rate of superoxide release from PMNLs, which was blunted by blocking antibodies to CD11b. Altogether, this study shows that the interaction of heparin with the PMNL CD11b results in cell apoptosis and explains heparin’s anti-inflammatory effects

Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages

After retinal injury in mice, infiltrating monocyte-derived macrophages preserve retinal ganglion cells and promote retinal progenitor cell renewal

Fault Rerupture during the July 2019 Ridgecrest Earthquake Pair from Joint Slip Inversion of InSAR, Optical Imagery, and GPS

International audienceThe Ridgecrest earthquake pair ruptured a previously unknown orthogonal fault system in the eastern California shear zone. The stronger of the two, an Mw 7.1 earthquake that occurred on 6 July 2019, was preceded by an Mw 6.4 foreshock that occurred 34 hr earlier. In this study, distinct final slip distributions for the two earthquakes are obtained via joint inversion of Interferometric Synthetic Aperture Radar (InSAR), optical imagery, and Global Positioning System (GPS) measurements. Special attention is paid to the merging of dense (e.g., InSAR and optical imagery) and sparse geodetic (e.g., GPS) datasets. In addition, a new approach is introduced for data and model discretization through intermittent model‐ and data‐space reconditioning that stabilizes the inversion, thus ensuring that small changes in the data space do not cause disproportionate large changes to the model space. Although the coseismic slip of the Mw 6.4 earthquake was complex, involving three distinct asperities distributed among an intersecting orthogonal set of faults, the coseismic slip of the Mw 7.1 earthquake was limited to the main northwest‐striking fault. In addition to the Mw 7.1 earthquake, that northwest‐striking fault plane also hosted one of the Mw 6.4 asperities. Slip on this coplanar foreshock asperity increased the shear stress at the future site of the Mw 7.1 hypocenter, and triggered a vigorous aftershock activity on the main northwest fault that culminated in its rupture. This, in turn, reactivated the coplanar foreshock asperity. In addition to failing twice within 34 hr, we find that the reruptured asperity slipped about six times more durin

Non‐Triggering and Then Triggering of a Repeating Aftershock Sequence in the Dead Sea by the 2023 Kahramanmaraş Earthquake Pair: Implications for the Physics of Remote Delayed Aftershocks

Abstract Most aftershocks occur in areas experiencing large co‐seismic stress changes, yet some occur long after the mainshock in remote lightly stressed regions. The triggering mechanism of these remote delayed aftershocks is not well understood. Here, we study aftershocks occurring in the Dead Sea (DS) area following the 2023 Mw7.8 and Mw7.6 Kahramanmaraş earthquakes. Most aftershocks cluster along previously quiescent structures off‐ the main DS fault strand. Visual inspection disclosed three aftershocks instantaneously triggered by the Mw7.6 in the northern DS basin, and match‐filtering revealed a delayed aftershock. Waveform similarity and temporal clustering suggest the northern DS aftershocks re‐rupture a stick‐slip patch loaded by surrounding creep. Velocity‐gradient seismograms show the Mw7.6 exerted larger transient stresses than the Mw7.8, which may explain triggering by the Mw7.6, but not by the Mw7.8. This account of instantaneously triggered repeaters underscores the role of interactions between aseismic and seismic slip in remote triggering

Heparin Interaction with the Primed Polymorphonuclear Leukocyte CD11b Induces Apoptosis and Prevents Cell Activation.

Heparin is known to have anti-inflammatory effects, yet the mechanisms are not completely understood. In this study, we tested the hypothesis that heparin has a direct effect on activated polymorphonuclear leukocytes (PMNLs), changing their activation state, and can explain its anti-inflammatory effect. To test our hypothesis, we designed both in vitro and ex vivo studies to elucidate the mechanism by which heparin modulates PMNL functions and therefore the inflammatory response. We specifically tested the hypothesis that priming of PMNLs renders them more susceptible to heparin. Amplified levels of CD11b and increased rate of superoxide release manifested PMNL priming. Increase in cell priming resulted in a dose-dependent increase in heparin binding to PMNLs followed by augmented apoptosis. Blocking antibodies to CD11b inhibited heparin binding and abolished the apoptotic response. Moreover, heparin caused a significant dose-dependent decrease in the rate of superoxide release from PMNLs, which was blunted by blocking antibodies to CD11b. Altogether, this study shows that the interaction of heparin with the PMNL CD11b results in cell apoptosis and explains heparin's anti-inflammatory effects

SNG100, a novel topical treatment for moderate atopic dermatitis, in patients aged 6 years or older: A randomised, double‐blind, active‐controlled trial

Abstract Background Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. It is associated with significant itch and impaired quality of life. Systemic treatments are efficient but associated with side effects. Novel topical treatments with a favourable safety profile are needed. SNG100 is a novel composition of hydrocortisone 1% in a cream base comprising sulphated polysaccharide (SPS; extracted from in‐house cultivated Porphyridium Cruentum unicellular algae), a well‐known hydrating, moisturising and a skin barrier repairing agent. Objectives To assess the safety, usability and efficacy of SNG100 cream in patients aged ≥6 years with moderate AD. Methods In this proof of concept phase I, double‐blind, randomised trial, participants received one of three treatments for 14 days: SNG100 twice daily (BID), hydrocortisone 1% BID or mometasone furoate once daily (QD). The primary endpoint was the safety and tolerability of SNG100 cream compared to hydrocortisone 1% and mometasone furoate. The secondary endpoint was the subject's usability of SNG100. Exploratory efficacy endpoints included percent change from baseline in SCOring AD (SCORAD), Eczema Area and Severity Index, Patient‐Oriented Eczema Measure, Dermatology Life Quality Index, pruritus Numerical Rating Score (NRS), peak pruritus‐NRS and Investigator's Global Assessment. Subjects were also followed up without any treatment for additional 14 days. Results Overall, 66 participants were screened, and 60 patients were randomised. SNG100 demonstrated a high safety profile, similar to marketed products hydrocortisone 1% and mometasone furoate 0.1%, with no unanticipated drug safety related events. SNG100 and mometasone furoate 0.1% cream achieved almost similar and statistically significant greater percentage reductions from baseline in SCORAD as compared to hydrocortisone 1% cream. SNG100 demonstrated significant improvement in NRS as compared to hydrocortisone 1% cream. Remarkably, SNG100 led to a lasting effect with only 29.4% of subjects returning to IGA3 during the follow‐up period compared to 50% and 38.9% in the hydrocortisone 1% and in mometasone furoate treatment arms, respectively. Conclusions Topical SNG100 is an effective, safe, and well‐tolerated innovative treatment for moderate AD. Trial registration number: NCT04615962 (Topical Cream SNG100 for Treatment in Moderate AD Subjects)