Heparan sulfate (HS) proteoglycans at the cell surface and in the extracellular matrix of most animal tissues are essential in development and homeostasis, and are implicated in disease processes. ...Emerging evidence demonstrates the important roles of HS in inflammatory reactions, particularly in the regulation of leukocyte extravasation. Heparin, a classical anticoagulant, exhibits anti-inflammatory effects in animal models and in the clinic, presumably through interference with the functions of HS, as both polysaccharides share a high similarity in molecular structure. Apart of regulation during biosynthesis, the structures of HS and heparin are significantly modulated by heparanase, an endoglycosidase that is upregulated in a number of inflammatory conditions. Exploring the physiological roles of HS and heparin and the mode of heparanase action in modulating their functions during inflammation responses is of importance for future studies.
Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to ...coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9:LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL. Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation. Pharmacological inhibition of this binding can be exploited as therapeutic intervention to lower LDL levels.
When the magnetosphere of a magnetar is perturbed by crustal deformation, an electric field E parallel to the magnetic field line would appear via Alfvén waves in the charge starvation region. The ...electron-positron pair bunches will be generated via two-stream instability in the magnetosphere, and these pairs will undergo charge separation in the E and in the meantime emit coherent curvature radiation. Following the approach of Yang & Zhang, we find that the superposed curvature radiation becomes narrower due to charge separation, with the width of spectrum depending on the separation between the electron and positron clumps. This mechanism can interpret the narrow spectra of fast radio bursts (FRBs), in particular, the spectrum of Galactic FRB 200428 recently detected in association with a hard X-ray burst from the Galactic magnetar SGR J1935+2154.
Microplastics, as emerging contaminants in the global environment, have become a cause for concern for both academics and the public. The present understanding of microplastic pollution is primarily ...focused on marine environments, and less attention has been given to freshwater environments, in particular, to urban rivers. In this study, microplastics were sampled from surface water and sediments in 14 sites located in the lower course of the Pearl River. These sampling sites are located along Guangzhou of South China, with built-up areas being the dominant land use. The abundances of microplastics in surface water and sediments ranged from 379 to 7924 items·m−3 and 80 to 9597 items·kg−1, respectively. Polyethylene and polypropylene were the common types of microplastics, together accounting for 64.3% and 73.8% of surface water and sediment samples, respectively. Fibers were the dominant microplastic shapes in both water and sediment samples. The abundances of microplastics varied in surface water and sediments with each site, which might be affected by multiple factors. Our results indicated that wastewater treatment plants (WWTP) could reduce microplastics from municipal sewage which was finally discharged into the Pearl River along Guangzhou.
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•Microplastics in the Pearl River along Guangzhou were investigated for the first time.•Fibers were detected in both surface water and sediment samples.•PE and PP were the dominant polymer types in surface water and sediments.•WWTP in Guangzhou could reduce microplastic pollution in the municipal sewage.
Abstract The second brightest gamma-ray burst, GRB 230307A (with a duration T 90 ∼ 40 s), exhibited characteristics indicative of a magnetar engine during the prompt emission phase. Notably, a ...suspected kilonova was identified in its follow-up optical and infrared observations. Here we propose that the origin of GRB 230307A is a neutron star–white dwarf (NS–WD) merger as this could naturally explain the long duration and the large physical offset from the center of its host galaxy. In the framework of such an NS–WD merger event, the late-time kilonova-like emission is very likely to be powered by the spin-down of the magnetar and the radioactive decay of 56 Ni, rather than by the decay of r -process elements as these heavy elements may not easily be synthesized in an NS-WD merger. It is demonstrated that the above scenario can be supported by our fit to the late-time observational data, where a mass of ∼10 −3 M ⊙ 56 Ni is involved in the ejecta of a mass of ∼0.1 M ⊙ . Particularly, the magnetar parameters required by the fit are consistent with those derived from the early X-ray observation.
Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, ...we aimed to investigate their safety when used during pregnancy within a unique population source.
Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998-2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations.
Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11-3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31-1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01-4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41-2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25-4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00-1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51-4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02-2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02-1.19; 747 exposed cases) exposures were associated with MCM.
Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.
Liquid-liquid phase separation (LLPS) plays important roles in various cellular processes, facilitating membrane-less organelles construction, chromatin condensation, signal transduction on inner ...membrane and many other processes. Current perception is that LLPS relies on weak multivalent interactions and crowded environments intracellularly. In this study, we demonstrate that heparan sulfate can serve as a platform to induce the phase separation of basic fibroblast growth factor on cell surface. The phase separation model provides an alternative mechanism how bFGF is enriched to its receptors, therefore triggering the signaling transduction. The research provides insights on the mechanism how growth factors can be recruited to cell surface by heparan sulfate and execute their functions, extending people's view on phase separation from intracellular to extracellular proteins at cellular level.
GaN Schottky barrier diode (SBD) temperature sensors with TiN, Ni, and NiN anodes were fabricated in this study to evaluate the effect of anode material and inhomogeneous interface on the ...sensitivity. The temperature-dependent current-voltage curves negatively shift with the increasing temperature, presenting a slight inhomogeneous barrier behavior. Compared with the Ni anode, the TiN and NiN anodes suppress the inhomogeneity. The sensitivity obtained from the sub-threshold region follows the same tendency for all the SBDs, which increases with the decreasing current level. Furthermore, the NiN anode temperature sensor shows slightly higher sensitivity and better linearity compared with the Ni and TiN anodes, with the highest sensitivity of 2.54 mV/K. The discrepancy between the measured sensitivity and the theoretical value is ascribed to the inhomogeneous interface barrier.
Abstract
Some catastrophic stellar explosions, such as supernovae (SNe), compact binary coalescences, and microtidal disruption events, are believed to be embedded in the accretion disks of active ...galactic nuclei (AGNs). We show high-energy neutrinos can be produced efficiently through
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interactions between shock-accelerated cosmic rays and AGN disk materials shortly after the explosion ejecta shock breaks out of the disk. AGN stellar explosions are ideal targets for joint neutrino and electromagnetic (EM) multimessenger observations. Future EM follow-up observations of neutrino bursts can help us search for yet-discovered AGN stellar explosions. We suggest that AGN stellar explosions could potentially be important astrophysical neutrino sources. The contribution from AGN stellar explosions to the observed diffuse neutrino background depends on the uncertain local event rate densities of these events in AGN disks. By considering thermonuclear SNe, core-collapse SNe, gamma-ray burst associated SNe, kilonovae, and choked GRBs in AGN disks with known theoretical local event rate densities, we show that these events may contribute to ≲10% of the observed diffuse neutrino background.
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