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Background: We have aimed at exposing left ventricular diastolic functions and the presence of known genetic mutations for familial erythrocytosis, in patients who exhibit idiopathic erythrocytosis. Methods: Sixty-four patients with idiopathic erythrocytosis (mean age, 46.4 +/- 2.7 years) and 30 age-matched healthy subjects were prospectively evaluated. The regions of interest of the erythropoietin receptor, hemoglobin beta-globin, von Hippel-Lindau, hypoxia-inducible factor 2 alpha, and Egl-9 family hypoxia-inducible factor genes were amplified by PCR. Left ventricular (LV) mass was measured by M-mode and 2-dimensional echocardiography. LV diastolic functions were assessed by conventional echocardiography and tissue Doppler imaging. Results: As a result of genetic analyses, genetic mutations for familial erythrocytosis were detected in 5 patients. It has been observed in our study that the risk of cardiovascular disorders is higher in patients. Interventricular septum thickness, left atrial diameter, and some diastolic function parameters such as deceleration time and isovolumetric relaxation time have been found to be significantly higher in idiopathic erythrocytosis group than in the controls. Conclusion: This study has shown that LV diastolic functions were impaired in patients with idiopathic erythrocytosis. In this patient group with increased risk of cardiovascular disorders, the frequent genetic mutations have been detected in 5 patients only. Therefore, further clinical investigations are needed as novel genetic mutations may be discovered in patients with idiopathic erythrocytosis because of cardiovascular risk. scientific and technological research council of Turkey [Tubitak-215S524] This research was funded by scientific and technological research council of Turkey (Tubitak-215S524).

Americans are more worried about misinformation than about sexism, racism, terrorism, and climate change. Fears over misinformation on social media are overblown. Misinformation represents a minute proportion of the news that people consume online (~ 1%), and a small minority of people account for most of the misinformation consumed and shared online. People, on average, are good at detecting fake news and identifying reliable sources of information. People do not believe everything they see and read on the internet. Instead, they are active consumers of information who domesticate technologies in unexcepted ways. It’s very unlikely that social media exacerbates the misinformation problem, that fake news contributes to important political events or that falsehoods spread faster than the truth. Yet, some fake news stories do go viral, and understanding why, despite their inaccuracy, they go viral is important. In a series of experiments, we identified a factor that, alongside accuracy, drives the sharing of true and fake news: the ‘interestingness-if-true’ of a piece of news, e.g. if alcohol was a cure against COVID-19, the pandemic would end in an unprecedented international booze-up. In three experiments (N = 904), participants were more willing to share news they found more interesting-if-true, as well as news they deemed more accurate. They rated fake news less accurate but more interesting-if-true than true news. People may not share news of questionable accuracy by mistake, but instead because the news has qualities that compensate for its potential inaccuracy, such as being interesting-if-true. Despite these qualities, why are most people are reluctant to share fake news? To benefit from communication, receivers should trust less people sharing fake news. And the costs of sharing fake news should be higher than the reputational benefits of sharing true news. Otherwise we would end up trusting people misleading us half of the time. Four experiments (N = 3,656) support this hypothesis: sharing fake news hurts one’s reputation in a way that is difficult to fix, even for politically congruent fake news. Most participants asked to be paid to share fake news (even when politically congruent), and asked for more when their reputation was at stake. During the second part of my PhD, I tested solutions to inform people efficiently. I found that discussing in small groups the scientific evidence on Genetically Modified (GM) food safety and the usefulness of vaccines changed people’s minds in the direction of the scientific consensus. To scale up the power of discussion, we created a chatbot that emulated the most important traits of discussion. We found that rebutting the most common counterarguments against GMOs with a chatbot led to more positive attitudes towards GMOs than a non-persuasive control text and a paragraph highlighting the scientific consensus. However, the dialogical structure of the chatbot seemed to have mattered more than its interactivity. During the pandemic, we deployed a chatbot to inform the French population about COVID- 19 vaccines. Interacting a few minutes with this chatbot, which answered the most common questions about COVID-19 vaccines, increased people’s intention to get vaccinated and had a positive impact on their attitudes towards the vaccines. In the end, people are not stupid. When provided with good arguments, they change their mind in the direction of good arguments. Most people avoid sharing misinformation because they care about their reputation. We do not live in a post-truth society in which people disregard the truth. Overall, we should probably be more concerned about the large portion of people who do not trust reliable sources and are uninformed because they do not follow the news, rather than the minority of people who trust unreliable sources and are misinformed., Les fausses nouvelles affolent. Les Américains sont plus préoccupés par la désinformation que par le sexisme, le racisme, et le changement climatique. Ces craintes sont très largement exagérées. La désinformation ne représente qu'une infime portion des nouvelles consommées en ligne (~ 1 %) et une petite minorité de gens est à l'origine de la majorité des fausses informations consommées et partagées en ligne. En moyenne, les gens sont capables de reconnaître les fausses nouvelles et d'identifier les sources d'information fiables. Les gens ne croient pas tout ce qu'ils voient et lisent sur l'internet. Il est peu probable que les réseaux sociaux exacerbent le problème de la désinformation, que les fausses nouvelles aient contribué à des événements politiques importants ou que les fausses nouvelles se répandent plus vite que la vérité. Cependant, certaines fausses nouvelles sont virales, et il est intéressant de comprendre pourquoi, malgré leur manque de fiabilité, ces fausses nouvelles deviennent virales. Au cours d'une série d'expériences, nous avons identifié un facteur qui motive le partage des vraies et des fausses nouvelles : "l'intérêt-si-vrai" d'une nouvelle, e.g. si l’alcool était un remède contre la COVID-19 il suffirait de faire la fête pour se protéger du virus. Au cours de trois expériences en ligne (N = 904), les participants étaient plus disposés à partager des nouvelles qu'ils trouvaient plus intéressantes-si-vraies, ainsi que des nouvelles qu'ils jugeaient plus fiables. Ils considéraient les fausses nouvelles comme moins fiables mais plus intéressantes-si-vraies que les vraies nouvelles. Les gens pourraient partager des fausses nouvelles non pas par erreur, mais plutôt parce que ces nouvelles possèdent des qualités qui compensent pour leur manque de fiabilité, comme le fait d'être intéressantessi- vraies. Malgré ces qualités, pourquoi la plupart des gens sont-ils réticents à partager des fausses nouvelles ? Quatre expériences (N = 3 656) montrent que le partage de fausse nouvelle nuit à la réputation de son transmetteur d'une manière difficile à compenser par le partage de vraies nouvelles. La plupart des participants demandèrent à être payés pour partager des fausses nouvelles, et ce montant était d’autant plus important que leur réputation était en jeu. Durant le deuxième parti de mon doctorat j’ai mesuré l’efficacité d’interventions pour informer efficacement les gens. J’ai montré que discuter en petits groupes des preuves scientifiques portant sur la sûreté des organismes génétiquement modifiés (OGM) et de l'utilité des vaccins, influençait l’opinion des gens en direction du consensus scientifique. Pour étendre le pouvoir persuasif de la discussion, nous avons développé un chatbot simulant les caractéristiques les plus importantes d’une discussion. Interagir avec ce chatbot réfutant les contre-arguments les plus courants contre les OGMs entraîna des attitudes plus positives à l'égard des OGMs que plusieurs conditions de contrôle (N = 1306). Pendant la pandémie, nous avons déployé un chatbot répondant aux questions les plus courantes sur les vaccins COVID-19. Interagir quelques minutes avec ce chatbot augmenta l'intention des gens de se faire vacciner et eu un impact positif sur leurs attitudes envers les vaccins. Au final, les gens ne sont pas stupides. Lorsqu'on leur présente de bons arguments, ils changent d'avis en direction de ces bons arguments. La plupart des gens évitent de partager des fausses nouvelles par souci pour leur réputation. L’ère de la « post-vérité » n’existe pas, la fiabilité de l’information est aussi importante aujourd’hui que par le passé. Dans l'ensemble, il est probablement plus important de se préoccuper du grand nombre de gens qui ne font pas confiance aux sources fiables et ne sont pas informés parce qu'ils ne suivent pas l'actualité, plutôt que de la minorité de gens qui font trop confiance aux sources douteuses et sont mal informées.

The HDL receptor SR-BI mediates the transfer of cholesteryl esters from HDL to cells and controls HDL abundance and structure. Depending on the genetic background, loss of SR-BI causes hypercholesterolemia, anemia, reticulocytosis, splenomegaly, thrombocytopenia, female infertility, and fatal coronary heart disease (CHD). The carboxy terminus of SR-BI (⁵⁰⁵QEAKL⁵⁰⁹) must bind to the cytoplasmic adaptor PDZK1 for normal hepatic—but not steroidogenic cell—expression of SR-BI protein. To determine whether SR-BI's carboxy terminus is also required for normal protein levels in steroidogenic cells, we introduced into SR-BI's gene a ⁵⁰⁷Ala/STOP mutation that produces a truncated receptor (SR-BIΔCT). As expected, the dramatic reduction of hepatic receptor protein in SR-BIΔCT mice was similar to that in PDZK1 knockout (KO) mice. Unlike SR-BI KO females, SR-BIΔCT females were fertile. The severity of SR-BIΔCT mice's hypercholesterolemia was intermediate between those of SR-BI KO and PDZK1 KO mice. Substantially reduced levels of the receptor in adrenal cortical cells, ovarian cells, and testicular Leydig cells in SR-BIΔCT mice suggested that steroidogenic cells have an adaptor(s) functionally analogous to hepatic PDZK1. When SR-BIΔCT mice were crossed with apolipoprotein E KO mice (SR-BIΔCT/apoE KO), pathologies including hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, and rapid-onset and fatal occlusive coronary arterial atherosclerosis and CHD (median age of death: 9 wk) were observed. These results provide new insights into the control of SR-BI in steroidogenic cells and establish SR-BIΔCT/apoE KO mice as a new animal model for the study of CHD., National Institutes of Health (U.S.) (Grant HL127174), National Institutes of Health (U.S.) (Grant T32GM007287)

Objective— Deep vein thrombosis (DVT) and pulmonary embolism are frequent causes of morbidity and mortality. The goal of our study was to determine whether plasma high-density lipoprotein (HDL), which inversely correlates with the risk of cardiovascular events, affects DVT. Methods and Results— Using a murine DVT model of inferior vena cava stenosis, we demonstrated that deficiency of the HDL receptor, scavenger receptor class B type I (SR-BI), promotes venous thrombosis. As SR-BI −/− mice have increased plasma cholesterol levels and abnormal HDL particles, we tested SR-BI −/− mice with an SR-BI liver transgene that normalizes both parameters. These mice also exhibited increased susceptibility to DVT, indicating a protective role of extrahepatic SR-BI. Mice lacking the major HDL apolipoprotein apoA-I or endothelial nitric oxide synthase (eNOS) (a downstream target of endothelial SR-BI signaling) also had a prothrombotic phenotype. Intravenous infusion of human apoA-I, an HDL component and SR-BI ligend, prevented DVT in wild-type but not SR-BI −/− or eNOS −/− mice, suggesting that its effect is mediated by SR-BI and eNOS. Intravenous apoA-I infusion abolished histamine-induced platelet–endothelial interactions, which are important for DVT initiation. Conclusion— An apoA-I (HDL)–SR-BI–eNOS axis is highly protective in DVT and may provide new targets for prophylaxis and treatment of venous thrombosis.

The HDL receptor, scavenger receptor, class B, type I (SR-BI), is a homooligomeric cell surface glycoprotein that controls HDL structure and metabolism by mediating the cellular selective uptake of lipids, mainly cholesteryl esters, from HDL. The mechanism underlying SR-BI-mediated lipid transfer, which differs from classic receptor-mediated endocytosis, involves a two-step process (binding followed by lipid transport) that is poorly understood. Our previous structure/activity analysis of the small-molecule inhibitor blocker of lipid transport 1 (BLT-1), which potently (IC 50 ∼ 50 nM) blocks SR-BI-mediated lipid transport, established that the sulfur in BLT-1’s thiosemicarbazone moiety was essential for activity. Here we show that BLT-1 is an irreversible inhibitor of SR-BI, raising the possibility that cysteine(s) in SR-BI interact with BLT-1. Mass spectrometric analysis of purified SR-BI showed two of its six exoplasmic cysteines have free thiol groups (Cys251 and Cys384). Converting Cys384 (but not Cys251) to serine resulted in complete BLT-1 insensitivity, establishing that the unique molecular target of BLT-1 inhibition of cellular SR-BI dependent lipid transport is SR-BI itself. The C384S substitution reduced the receptor’s intrinsic lipid uptake activity by approximately 60% without dramatically altering its surface expression, homooligomerization, or HDL binding. Thus, a small-molecule screening approach identified a key residue in SR-BI involved in lipid transport, providing a powerful springboard into the analyses of the structure and mechanism of SR-BI, and highlighting the power of this approach for such analyses.

The etiology of human female infertility is often uncertain. The sterility of high-density lipoprotein (HDL) receptor-negative (SR-BI−/−) female mice suggests a link between female infertility and abnormal lipoprotein metabolism. SR-BI−/− mice exhibit elevated plasma total cholesterol [with normal-sized and abnormally large HDL and high unesterified to total plasma cholesterol (UC:TC) ratio]. We explored the influence of hepatic SR-BI on female fertility by inducing hepatic SR-BI expression in SR-BI−/− animals by adenovirus transduction or stable transgenesis. For transgenes, we used both wild-type SR-BI and a double-point mutant, Q402R/Q418R (SR-BI-RR), which is unable to bind to and mediate lipid transfer from wild-type HDL normally, but retains virtually normal lipid transport activities with low-density lipoprotein. Essentially wild-type levels of hepatic SR-BI expression in SR-BI−/− mice restored to nearly normal the HDL size distribution and plasma UC:TC ratio, whereas approximately 7- to 40-fold overexpression dramatically lowered plasma TC and increased biliary cholesterol secretion. In contrast, SR-BI-RR overexpression had little effect on SR-BI+/+ mice, but in SR-BI−/− mice, it substantially reduced levels of abnormally large HDL and normalized the UC:TC ratio. In all cases, hepatic transgenic expression restored female fertility. Overexpression in SR-BI−/− mice of lecithin:cholesterol acyl transferase, which esterifies plasma HDL cholesterol, did not normalize the UC:TC ratio, probably because the abnormal HDL was a poor substrate, and did not restore fertility. Thus, hepatic SR-BI-mediated lipoprotein metabolism influences murine female fertility, raising the possibility that dyslipidemia might contribute to human female infertility and that targeting lipoprotein metabolism might complement current assisted reproductive technologies.

The HDL receptor scavenger receptor, class B type I (SR-BI) controls the structure and fate of plasma HDL. Female SR-BI KO mice are infertile, apparently because of their abnormal cholesterol-enriched HDL particles. We examined the growth and meiotic progression of SR-BI KO oocytes and found that they underwent normal germinal vesicle breakdown; however, SR-BI KO eggs, which had accumulated excess cholesterol in vivo, spontaneously activated, and they escaped metaphase II (MII) arrest and progressed to pronuclear, MIII, and anaphase/telophase III stages. Eggs from fertile WT mice were activated when loaded in vitro with excess cholesterol by a cholesterol/methyl-β-cyclodextrin complex, phenocopying SR-BI KO oocytes. In vitro cholesterol loading of eggs induced reduction in maturation promoting factor and MAPK activities, elevation of intracellular calcium, extrusion of a second polar body, and progression to meiotic stages beyond MII. These results suggest that the infertility of SR-BI KO females is caused, at least in part, by excess cholesterol in eggs inducing premature activation and that cholesterol can activate WT mouse eggs to escape from MII arrest. Analysis of SR-BI KO female infertility raises the possibility that abnormalities in cholesterol metabolism might underlie some cases of human female infertility of unknown etiology.

α-Factor receptors from Saccharomyces cerevisiae are G-protein-coupled receptors containing seven transmembrane segments. Receptors solubilized with the detergent n-dodecyl β-d-maltoside were found to sediment as a single 8S species in glycerol density gradients. When the membranes from cells coexpressing two differentially tagged receptors were solubilized with detergent and subjected to immunoprecipitation, we found that the antibodies specific for either epitope tag resulted in precipitation of both tagged species. Coprecipitation was not a consequence of incomplete detergent extraction because the abundant plasma membrane protein Pma1 did not coprecipitate with the receptors. Moreover, the receptor complexes were present prior to detergent extraction because coimmunoprecipitation was not observed when cells expressing the single tagged species were mixed prior to membrane preparation. Treatment of cultures with α-factor had little effect on the extent of oligomerization as judged by the sedimentation behavior of the receptor complexes and by the efficiency of coimmunoprecipitation. The ability of receptor complexes to undergo ligand-mediated endocytosis was evaluated by using membrane fractionation and fluorescence microscopy. Mutant receptors that fail to bind α-factor (Ste2-S184R) or lack the endocytosis signal (Ste2-T326) became competent for ligand-mediated endocytosis when they were expressed in cells containing wild-type receptors. Coimmunoprecipitation experiments indicated that the C-terminal cytoplasmic domain and intermolecular disulfide bonds were unnecessary for oligomer formation. We conclude that α-factor receptors form homo-oligomers and that these complexes are subject to ligand-mediated endocytosis. Furthermore, we show for the first time that unoccupied receptors participate in these endocytosis-competent complexes.

Deep vein thrombosis (DVT) and pulmonary embolism are frequent causes of morbidity and mortality. The goal of our study was to determine whether plasma high-density lipoprotein (HDL), which inversely correlates with the risk of cardiovascular events, affects DVT.Using a murine DVT model of inferior vena cava stenosis, we demonstrated that deficiency of the HDL receptor, scavenger receptor class B type I (SR-BI), promotes venous thrombosis. As SR-BI(-/-) mice have increased plasma cholesterol levels and abnormal HDL particles, we tested SR-BI(-/-) mice with an SR-BI liver transgene that normalizes both parameters. These mice also exhibited increased susceptibility to DVT, indicating a protective role of extrahepatic SR-BI. Mice lacking the major HDL apolipoprotein apoA-I or endothelial nitric oxide synthase (eNOS) (a downstream target of endothelial SR-BI signaling) also had a prothrombotic phenotype. Intravenous infusion of human apoA-I, an HDL component and SR-BI ligend, prevented DVT in wild-type but not SR-BI(-/-) or eNOS(-/-) mice, suggesting that its effect is mediated by SR-BI and eNOS. Intravenous apoA-I infusion abolished histamine-induced platelet-endothelial interactions, which are important for DVT initiation.An apoA-I (HDL)-SR-BI-eNOS axis is highly protective in DVT and may provide new targets for prophylaxis and treatment of venous thrombosis.

The normal expression, cell surface localization, and function of the murine high density lipoprotein receptor scavenger receptor class B type I (SR-BI) in hepatocytes in vivo, and thus normal lipoprotein metabolism, depend on its four PDZ domain (PDZ1-PDZ4) containing cytoplasmic adaptor protein PDZK1. Previous studies showed that the C terminus of SR-BI ("target peptide") binds directly to PDZ1 and influences hepatic SR-BI protein expression. Unexpectedly an inactivating mutation in PDZ1 (Tyr(20) → Ala) only partially, rather than completely, suppresses the ability of PDZK1 to control hepatic SR-BI. We used isothermal titration calorimetry to show that PDZ3, but not PDZ2 or PDZ4, can also bind the target peptide (K(d) = 37.0 μm), albeit with ∼10-fold lower affinity than PDZ1. This binding is abrogated by a Tyr(253) → Ala substitution. Comparison of the 1.5-Å resolution crystal structure of PDZ3 with its bound target peptide ((505)QEAKL(509)) to that of peptide-bound PDZ1 indicated fewer target peptide stabilizing atomic interactions (hydrogen bonds and hydrophobic interactions) in PDZ3. A double (Tyr(20) → Ala (PDZ1) + Tyr(253) → Ala (PDZ3)) substitution abrogated all target peptide binding to PDZK1. In vivo hepatic expression of a singly substituted (Tyr(253) → Ala (PDZ3)) PDZK1 transgene (Tg) was able to correct all of the SR-BI-related defects in PDZK1 knock-out mice, whereas the doubly substituted [Tyr(20) → Ala (PDZ1) + Tyr(253) → Ala (PDZ3)]Tg was unable to correct these defects. Thus, we conclude that PDZK1-mediated control of hepatic SR-BI requires direct binding of the SR-BI C terminus to either the PDZ1 or PDZ3 domains, and that binding to both domains simultaneously is not required for PDZK1 control of hepatic SR-BI.

The PDZ1 domain of the four PDZ domain-containing protein PDZK1 has been reported to bind the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), and to control hepatic SR-BI expression and function. We generated wild-type (WT) and mutant murine PDZ1 domains, the mutants bearing single amino acid substitutions in their carboxylate binding loop (Lys(14)-Xaa(4)-Asn(19)-Tyr-Gly-Phe-Phe-Leu(24)), and measured their binding affinity for a 7-residue peptide corresponding to the C terminus of SR-BI ((503)VLQEAKL(509)). The Y20A and G21Y substitutions abrogated all binding activity. Surprisingly, binding affinities (K(d)) of the K14A and F22A mutants were 3.2 and 4.0 μM, respectively, similar to 2.6 μM measured for the WT PDZ1. To understand these findings, we determined the high resolution structure of WT PDZ1 bound to a 5-residue sequence from the C-terminal SR-BI ((505)QEAKL(509)) using x-ray crystallography. In addition, we incorporated the K14A and Y20A substitutions into full-length PDZK1 liver-specific transgenes and expressed them in WT and PDZK1 knock-out mice. In WT mice, the transgenes did not alter endogenous hepatic SR-BI protein expression (intracellular distribution or amount) or lipoprotein metabolism (total plasma cholesterol, lipoprotein size distribution). In PDZK1 knock-out mice, as expected, the K14A mutant behaved like wild-type PDZK1 and completely corrected their hepatic SR-BI and plasma lipoprotein abnormalities. Unexpectedly, the 10-20-fold overexpressed Y20A mutant also substantially, but not completely, corrected these abnormalities. The results suggest that there may be an additional site(s) within PDZK1 that bind(s) SR-BI and mediate(s) productive SR-BI-PDZK1 interaction previously attributed exclusively to the canonical binding of the C-terminal SR-BI to PDZ1.

Cerebrovascular and cardiovascular diseases are a major cause of morbidity and mortality. Soluble P-selectin (sP-selectin) is a biomarker for platelet/endothelial activation and is considered a risk factor for vascular disease. sP-selectin enhances procoagulant activity by inducing leukocyte-derived microparticle production and promotes activation of leukocyte integrins. However, it is not known whether it directly contributes to vascular complications. We investigated the effect of increased levels of sP-selectin on blood-brain barrier (BBB) function, stroke outcome, and atherosclerosis by comparing wild-type mice with P-selΔCT/ΔCT mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-selΔCT/ΔCT mice presented several abnormalities, including (1) higher BBB permeability, with 25% of the animals showing differential permeability between the right and left hemispheres; (2) altered social behavior with increased aggression; (3) larger infarcts in the middle cerebral artery occlusion ischemic stroke model; and (4) increased susceptibility to atherosclerotic, macrophage-rich lesion development in both male and female mice on the apoE−/− genetic background. Thus, elevated sP-selectin is not only a biomarker for vascular disease, but also may contribute directly to atherosclerosis and cerebrovascular complications.

The peroxiredoxin (Prdx) family of antioxidant enzymes uses redox-active cysteines to reduce peroxides, lipid hydroperoxides, and peroxynitrites. Prdx1 is known to be important to protect red blood cells against reactive oxygen species and in tumor prevention. In this study, the role of Prdx1 in inflammation, thrombosis, and atherosclerosis was investigated. Using intravital microscopy, we showed that the number of leukocytes rolling per minute in unstimulated veins was increased by 2.5-fold in Prdx 1 −/− compared to Prdx 1 +/+ mice. In Prdx 1 −/− mice, 50% of leukocytes rolled at a velocity Prdx 1 +/+ mice, suggesting that adhesion molecule density on the endothelium may have been increased by Prdx1 deficiency. Indeed, endothelial P-selectin, soluble P-selectin, and von Willebrand factor in plasma were increased in Prdx 1 −/− mice compared to Prdx 1 +/+ mice, indicating elevated Weibel–Palade body release. In contrast to this excessive endothelial activation, Prdx 1 −/− platelets showed no sign of hyperreactivity, and their aggregation both in vitro and in vivo was normal. We also examined the role of Prdx1 in the apoE −/− murine spontaneous model of atherosclerosis. Prdx 1 −/− / apoE −/− mice fed normal chow developed larger, more macrophage-rich aortic sinus lesions than Prdx 1 +/+ / apoE −/− mice, despite similar amounts and size distributions of cholesterol in their plasma lipoproteins. Thus, Prdx1 protects against excessive endothelial activation and atherosclerosis, and the Prdx 1 −/− mice could serve as an animal model susceptible to chronic inflammation.

Objective— High-density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediated cellular uptake of lipoprotein cholesterol controls HDL structure and plasma HDL and biliary cholesterol levels. In SR-BI knockout (KO) mice, an unusually high plasma unesterified-to-total cholesterol ratio (UC:TC) and abnormally large HDL particles apparently contribute to pathology, including female infertility, susceptibility to atherosclerosis and coronary heart disease, and anemia. Here we examined the influence of SR-BI deficiency on platelets. Methods and Results— The high plasma UC:TC ratio in SR-BI KO mice was correlated with platelet abnormalities, including high cholesterol content, abnormal morphologies, high clearance rates, and thrombocytopenia. One day after platelets from wild-type mice were infused into SR-BI KO mice, they exhibited abnormally high cholesterol content and clearance rates similar to those of endogenous platelets. Platelets from SR-BI KO mice exhibited in vitro a blunted aggregation response to the agonist ADP but a normal response to PAR4. Conclusions— In SR-BI KO mice abnormal circulating lipoproteins, particularly their high UC:TC ratio—rather than the absence of SR-BI in platelets themselves—induce defects in platelet structure and clearance, together with a mild defect in function.

Tissue-restricted transcription factors (TFs), which confer specialized cellular properties, are usually identified through sequence homology or cis-element analysis of lineage-specific genes; conventional modes of mRNA profiling often fail to report non-abundant TF transcripts. We evaluated the dynamic expression during mouse gut organogenesis of 1381 transcripts,covering nearly every known and predicted TF, and documented the expression of approximately 1000 TF genes in gastrointestinal development. Despite distinctive structures and functions, the stomach and intestine exhibit limited differences in TF genes. Among differentially expressed transcripts, a few are virtually restricted to the digestive tract, including Nr2e3,previously regarded as a photoreceptor-specific product. TFs that are enriched in digestive organs commonly serve essential tissue-specific functions, hence justifying a search for other tissue-restricted TFs. Computational data mining and experimental investigation focused interest on a novel homeobox TF, Isx,which appears selectively in gut epithelium and mirrors expression of the intestinal TF Cdx2. Isx-deficient mice carry a specific defect in intestinal gene expression: dysregulation of the high density lipoprotein (HDL) receptor and cholesterol transporter scavenger receptor class B, type I (Scarb1). Thus,integration of developmental gene expression with biological assessment, as described here for TFs, represents a powerful tool to investigate control of tissue differentiation.

Purpose of review A novel mechanism for the regulation of lipoprotein receptor activity is providing new insights into the control of lipid metabolism. The tissue-specific adaptors ARH (autosomal recessive hypercholesterolemia) and PDZK1 [where PDZ derives from postsynaptic density protein (PSD-95)/Drosophila discs-large (dlg)/tight-junction protein (ZO1)] have been shown to control the activities of distinct types of lipoprotein receptors in a posttranscriptional fashion, significantly affecting overall lipoprotein metabolism. This review will focus on one of these lipoprotein receptor-adaptor pairs, the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and its adaptor PDZK1. Recent findings The PDZ domain-containing adaptor protein PDZK1 has been shown to bind to and control the activity of the high-density lipoprotein receptor SR-BI via a tissue-specific posttranscriptional mechanism. Mice deficient in PDZK1 have elevated plasma cholesterol levels due to the virtually complete hepatic ablation of SR-BI, implicating PDZK1 as a novel regulator of high-density lipoprotein metabolism. Summary The functions of ARH and PDZK1 suggest that other adaptor proteins may be found to control the activities of other cell-surface receptors in a similar tissue-specific fashion. Manipulation of the expression and/or activities of such adaptors might provide new insights into receptor physiology and these adaptors may prove to be attractive targets for pharmaceutical intervention in cholesterol metabolism-related disease processes.