Heparan sulfate proteoglycans (HSPGs) are an important constituent of the macrophage glycocalyx and extracellular microenvironment. To examine their role in atherogenesis, we inactivated the ...biosynthetic gene N-acetylglucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) in macrophages and crossbred the strain to Ldlr−/− mice. When placed on an atherogenic diet, Ldlr−/−Ndst1f/fLysMCre+ mice had increased atherosclerotic plaque area and volume compared to Ldlr−/− mice. Diminished sulfation of heparan sulfate resulted in enhanced chemokine expression; increased macrophages in plaques; increased expression of ACAT2, a key enzyme in cholesterol ester storage; and increased foam cell conversion. Motif analysis of promoters of upregulated genes suggested increased type I interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-β. The proinflammatory macrophages derived from Ndst1f/fLysMCre+ mice also sensitized the animals to diet-induced obesity. We propose that macrophage HSPGs control basal activation of macrophages by maintaining type I interferon reception in a quiescent state through sequestration of IFN-β.
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•Reducing macrophage HSPG sulfation increases atherosclerosis and obesity•Altered HSPG sulfation increases expression of inflammatory genes•Increased inflammation promotes macrophage infiltration and foam cell conversion•Macrophage HSPGs sequester IFN-β and modulate activation of the cells
Heparan sulfate proteoglycans (HSPGs) are important constituents of the macrophage glycocalyx and extracellular microenvironment. Gordts et al. show that HSPGs control basal activation of macrophages by sequestering IFN-β to maintain type I interferon signaling in a quiescent state. Decreased macrophage HSPG sulfation results in autocrine activation, obesity, T2DM, and atherosclerosis.
Objectives. For rehabilitation professionals to adequately address meaningful participation in social activities with their patients after a stroke, there must be a better understanding of ...neurobehavior, that is, how neurological impairment and its sequelae and environmental factors support or limit social participation. The current study examines how stroke severity (NIH Stroke Scale), its impact on perceived mobility (Stroke Impact Scale mobility domain), and the environment (MOS Social Support–Positive Social Interactions scale and Measure of Stroke Environment receptivity and built environment domains) influence social participation (Activity Card Sort: ACS). Methods. A correlational, cross-sectional design examined the relationships among neurological impairment, perceived limitations in activity, environmental factors, and social participation. Participants included 48 individuals who were at least 6 months post-stroke both with aphasia (N=22) and without aphasia (N=26) living in the community for whom all measures were available for analysis. Results. No differences in social participation were found between those with and without aphasia, though both groups reported a large (25-30%) decline in participating in their prestroke social activities. For the ACS Social Domain activities and ACS Partner to Do With activities (percent retained), 37% and 35% of the variance, respectively, was accounted for by the predictor variables, with only MOS Social Support making an independent contribution to social participation. In this sample, neurological impairment was not a significant correlate of social participation. Additionally, perceived mobility and the built environment were not found to independently predict participation in social activities. Conclusions. Perceived social support was found to predict social participation in individuals living in the community 6 months or greater post-stroke. Focusing on social support during post-stroke rehabilitation may provide an avenue for increased social participation and more successful community reintegration.
Elevated plasma triglyceride levels represent a risk factor for premature atherosclerosis. In mice, accumulation of triglyceride-rich lipoproteins can occur if sulfation of heparan sulfate in ...hepatocytes is diminished, as this alters hepatic lipoprotein clearance via heparan sulfate proteoglycans (HSPGs). However, the relevant HSPG has not been determined. In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycan-deficient mice showed that only syndecan-1 mutants (Sdc1-/- mice) accumulated plasma triglycerides. Sdc1-/- mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HSPG mediating hepatic triglyceride clearance. Immunoelectron microscopy showed that syndecan-1 was expressed specifically on the microvilli of hepatocyte basal membranes, facing the space of Disse, where lipoprotein uptake occurs. Abundant syndecan-1 on wild-type murine hepatocytes exhibited saturable binding of VLDL and inhibition by heparin and facilitated degradation of VLDL. Furthermore, adenovirus-encoded syndecan-1 restored binding, uptake, and degradation of VLDL in isolated Sdc1-/- hepatocytes and the lipoprotein clearance defect in Sdc1-/- mice. These findings provide the first in vivo genetic evidence that syndecan-1 is the primary hepatocyte HSPG receptor mediating the clearance of both hepatic and intestinally derived triglyceride-rich lipoproteins.
Globins play a key role in regulating nitric oxide (NO) levels in all forms of life. Five key reactions of NO with mammalian muscle myoglobin (Mb) and red blood cell hemoglobin (Hb) have been ...examined: (1) reversible NO binding to Fe(II) forms; (2) reversible NO binding to Fe(III) forms; (3) NO dioxygenation by Fe(II)O2 complexes; (4) autoxidation of Fe(II)NO complexes in the presence of O2; and (5) autoreduction of Fe(III)NO complexes. NO reacts rapidly and almost irreversibly with deoxyMb(FeII) in the absence of O2, whereas it reacts much more slowly and weakly with metMb(FeIII). The reaction of NO with Mb(FeII)O2 is very rapid and results in oxidation of the iron atom and dioxygenation of NO to nitrate. Autoxidation of Mb(FeII)NO in air is determined by the slow rate of NO dissociation from the Fe(II)NO complex, which is followed by rapid O2 binding to the newly formed deoxyMb(FeII) and dioxygenation of the displaced NO to generate NO3− and metMb(FeIII). MetMb(FeIII)NO autoreduces slowly by addition of a hydroxide ion to bound NO to generate nitrous acid and reduced deoxyMb(FeII), which immediately binds another NO to generate Mb(FeII)NO as the final product. The reverse of this process involves nitrite reduction to NO by deoxyMb(FeII), which can occur on physiological time scales when the globin concentration is in the millimolar range. The relevance of these processes to the regulation of NO metabolism by hemoglobins and myoglobins in humans and other organisms is discussed.
Mammalian myoglobin (Mb) and hemoglobin (Hb) scavenge and detoxify nitric oxide (NO). DeoxyMb(FeII) rapidly captures NO in the distal pocket (gray cavity, transition state) and then forms an ultra-stable Mb(FeII)NO complex, whereas Mb(FeII)O2 rapidly dioxygenates NO to nitrate. When exposed to O2, Mb(FeII)NO slowly oxidizes to nitrate and metMb(FeIII). Display omitted
•A key physiological function of mammalian myoglobin and hemoglobin is to scavenge NO.•NO binds avidly and rapidly to reduced myoglobin and hemoglobin.•NO is rapidly dioxygenated to nitrate by oxygenated myoglobin and hemoglobin.•NO bound to reduced myoglobin and hemoglobin is oxidized to nitrate upon exposure to O2.•The oxidized forms of myoglobin and hemoglobin autoreduce slowly when NO is bound.
OBJECTIVE—Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density ...lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear.
APPROACH AND RESULTS—Triglyceride-rich lipoprotein clearance was measured in AlbCreNdst1, Ldlr, and AlbCreLrp1 mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors (AlbCreNdst1 Lrp1 Ldlr) displayed dramatic hyperlipidemia (870±270 mg triglyceride/dL; 1300±350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈20–40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈40–60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet.
CONCLUSIONS—These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.
The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins ...on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (Ndst1f/fAlbCre⁺ mice), decreased binding of ApoE-deficient TRLs to HSPGs on human hepatoma cells, and decreased clearance of ApoE-deficient ³HTRLs in vivo. Evidence for a second ligand was suggested by the faster clearance of ApoE-deficient TRLs after injection into WT Ndst1f/fAlbCre⁻ versus mutant Ndst1f/fAlbCre⁺ mice and elevated fasting and postprandial plasma triglycerides in compound Apoe⁻/⁻Ndst1f/fAlbCre⁺ mice compared with either single mutant. ApoAV emerged as a candidate based on 6-fold enrichment of ApoAV in TRLs accumulating in Ndst1f/fAlbCre⁺ mice, decreased binding of TRLs to proteoglycans after depletion of ApoAV or addition of anti-ApoAV mAb, and decreased heparan sulfate-dependent binding of ApoAV-deficient particles to hepatocytes. Importantly, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
Background:
The Early Career Publishers Committee (ECPC) of the STM Association (the International Association of Scientific, Technical, and Medical Publishers)'s Early Career Publishers Committee ...(ECPC) aims to engage, and provide tools and resources for, early-career publishers (ECPs) and professionals. The committee believes it is important to survey the community regularly to understand the background, needs, and concerns of its members to better achieve the committee's goals.
Objectives:
Early-career professionals were surveyed in 2014 and 2020: the first survey was undertaken to get a baseline understanding of the community and to guide the newly formed ECPC whereas the second not only sought to review some aspects of the first survey but also to identify and explore ways to improve engagement and support through new or revised survey questions.
Methods:
The two surveys were conducted online through the ECPC mailing list and social networks. The surveys were voluntary, with the option to skip some questions, and responses - some in the form of a rating scale - were collected anonymously. Each survey remained open for over a month to maximize responses, but neither was pretested. Some questions in the first survey were revised in the second in the light of learnings from the first survey.
Results:
Most of respondents were women, 25-54 years old, from the UK or the US, with higher degrees, and working in editorial roles. In the second survey, many respondents were interested in developing their career either in their current
role or in a different one, and nearly half were actively seeking a new role. Over half said that finding the right role was a challenge. Many had never participated in a publishing-related mentoring scheme, and most had not heard of the STM mentoring scheme before.
Conclusions:
More tools, resources, and outreach for entry-level and younger industry members, for those from countries outside the UK and US, and for those seeking to develop their careers may be useful in the future. The mentoring scheme could be publicized more prominently to drive engagement. A new survey will be needed in the next 2-3 years, given the potential impact of the COVID-19 global pandemic on the number of respondents in the second (2020) survey and their motivation.
Electronic cigarettes are essentially electronic nicotine delivery systems (ENDS). Use of ENDS has increased sharply in the United States in recent years, particularly among youth. We reviewed the ...literature on ENDS use, based on a PubMed search, with a focus on effects that could influence anesthetic and surgical outcomes. We also included a meta-analysis of articles published between 2016 and 2018 reporting injuries from exploding ENDS. These devices deliver nicotine, which is addictive and a cardiac stimulant. The nicotine in ENDS has been linked to increased risk of heart disease and myocardial infarction. Also, ENDS deliver vapors of solvents, flavorings, and other chemicals that can cause chronic and acute respiratory diseases. Furthermore, ENDS use may pose a cancer risk. However, ENDS are somewhat less dangerous than cigarettes and are used as smoking cessation devices. From the literature review, we identified 15 articles reporting injuries from ENDS fires and explosions to 93 patients. Most of these patients were young (mean age = 31.6 years) and male (91%). The most common injury sites were the thigh (62%) and hand (33%). Because the anesthetist will likely encounter increasing numbers of ENDS users in the future, it is important to identify these patients and to understand the risks of ENDS use.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface ...heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. Ext1(HEP) mutant mice exhibit an 8-fold reduction of heparan sulfate in primary hepatocytes and a 5-fold reduction of heparan sulfate in whole liver tissue. Conditional hepatocyte Ext1 gene deletion greatly reduced AAV2 liver transduction following intravenous injection. Ad5 transduction requires blood coagulation factor X (FX); FX binds to the Ad5 capsid hexon protein and bridges the virus to HSPGs on the cell surface. Ad5.FX transduction was abrogated in primary hepatocytes from Ext1(HEP) mice. However, in contrast to the case with AAV2, Ad5 transduction was not significantly reduced in the livers of Ext1(HEP) mice. FX remained essential for Ad5 transduction in vivo in Ext1(HEP) mice. We conclude that while AAV2 requires HSPGs for entry into mouse hepatocytes, HSPGs are dispensable for Ad5 hepatocyte transduction in vivo. This study reopens the question of how adenovirus enters cells in vivo.
Our understanding of how viruses enter cells, and how they can be used as therapeutic vectors to manage disease, begins with identification of the cell surface receptors to which viruses bind and which mediate viral entry. Both adeno-associated virus 2 and adenovirus 5 are currently thought to enter hepatocytes in vivo through heparan sulfate proteoglycans (HSPGs). However, direct evidence for these conclusions is lacking. Experiments presented herein, in which hepatic heparan sulfate synthesis was genetically abolished, demonstrated that HSPGs are not likely to function as hepatocyte Ad5 receptors in vivo. The data also demonstrate that HSPGs are required for hepatocyte transduction by AAV2. These results reopen the question of the identity of the Ad5 receptor in vivo and emphasize the necessity of demonstrating the nature of the receptor by genetic means, both for understanding Ad5 entry into cells in vivo and for optimization of Ad5 vectors as therapeutic agents.
The major pathway for nitric oxide scavenging in red cells involves the direct reaction of the gas with HbO
2 to form nitrate and the ferric form of the protein, metHb. Because both atoms of O
2 are ...incorporated into nitrate, this process is called NO dioxygenation (NOD). The NOD reaction involves an initial, very rapid bimolecular addition of NO to bound O
2 to form a transient Fe(III)–peroxynitrite complex, which can be observed spectrally at alkaline pH. This intermediate rapidly isomerizes at pH 7 (
t
1/2 ≤ 1 ms) to metHb and NO
3
−, which is nontoxic and readily transported out of red cells and excreted. The rate of NO consumption by intracellular HbO
2 during normal blood flow is limited by diffusion up to and into the red cells and is too slow to interfere significantly with vasoregulation. In contrast, extracellular HbO
2 is highly vasoconstrictive, and the resultant hypertension is a significant side effect of most hemoglobin-based blood substitutes. The major cause of this blood pressure effect seems to be the high rate of NO dioxygenation by cell-free HbO
2, which can extravasate into the vessel walls and interfere directly with NO signaling between endothelial and smooth muscle cells. This interpretation is supported by a strong linear correlation between the magnitude of the blood pressure effect caused by infusion of cross-linked recombinant hemoglobin tetramers in vivo and the rate of NO dioxygenation by these proteins measured in vitro.
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