SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Atherosclerosis, which underlies life-threatening cardiovascular disorders such as myocardial infarction and stroke1, is initiated by passage of low-density lipoprotein (LDL) cholesterol into the artery wall and its engulfment by macrophages, which leads to foam cell formation and lesion development2,3. It is unclear how circulating LDL enters the artery wall to instigate atherosclerosis. Here we show in mice that scavenger receptor class B type 1 (SR-B1) in endothelial cells mediates the delivery of LDL into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and transcytosis of LDL across endothelial monolayers requires its direct binding to SR-B1 and an eight-amino-acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)4. DOCK4 promotes internalization of SR-B1 and transport of LDL by coupling the binding of LDL to SR-B1 with activation of RAC1. The expression of SR-B1 and DOCK4 is increased in atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries. These findings challenge the long-held concept that atherogenesis involves passive movement of LDL across a compromised endothelial barrier. Interventions that inhibit the endothelial delivery of LDL into artery walls may represent a new therapeutic category in the battle against cardiovascular disease

Widespread reforestation before European influence on Amazonia

An estimated 90-95% of indigenous people in Amazonia died following European Contact. This population collapse is postulated to have caused decreases in atmospheric CO2 concentrations at c. 1610 CE, as a result of a wave of land abandonment in the wake of disease, slavery and warfare, whereby the attendant reversion to forest significantly increased terrestrial carbon sequestration. Based on 39 Amazonian fossil pollen records, we show that there was no synchronous reforestation event associated with such an atmospheric CO2 response following European arrival in Amazonia. Instead, we find that, at most sites, land abandonment and forest regrowth began c. 300 - 600 years before European arrival. Pre-European pandemics, social strife or environmental change may have contributed to these early site abandonments and ecological shifts

Evaluation of a point-of-care calcium device in bovine plasma and serum

Hypocalcemia is a common metabolic disease in dairy cows, and it is defined as total calcium (tCa) blood concentration <2.0 mmol/L. The alternatives for the gold standard test to measure tCa in bovine blood are limited. Therefore, our objective was to compare the performance of the calcium (Ca) point-of-care compact analyzer (POC; ARKRAY Inc.) device with the gold standard method to measure bovine blood tCa concentration. Blood samples (n = 151) from dairy cows were collected within 24 h postpartum from multiparous and primiparous dairy cows for serum and plasma. Then, serum and plasma were stored at −80°C until further analyses with the gold standard method on an automatic analyzer (Cobas C501 analyzer; Roche Diagnostics) and the POC device. The tCa blood concentration was measured in the laboratory in plasma and serum samples using both methods within 10 mo of sample collection. Correlation coefficients (Spearman), coefficients of variation (CV, %), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, Passing and Bablok regression, and Bland-Altman agreement test were performed between the gold standard and the POC device. The range and median tCa plasma concentrations measured with the POC device were 1.1 to 2.8 mmol/L and 2.4 mmol/L, respectively. The range and median tCa serum concentrations measured with the POC device were 1.1 to 2.7 mmol/L and 2.3 mmol/L, respectively. The tCa blood concentrations range and median with the gold standard were 1.1 to 2.6 mmol/L and 2.3 mmol/L. The hypocalcemia prevalence of our study population was 11.2%. The CV were 1.89% and 0.55% for low and high tCa in plasma samples measured with the POC, respectively. The CV were 2.57% and 1.58% for low and high tCa in serum, respectively. The Spearman correlation coefficient showed a strong correlation between the gold standard and the POC device for both serum and plasma tCa concentration. The sensitivity of the POC device for both plasma (41.1%) and serum (64.7%) Ca was poor. However, the specificity of the POC device was perfect in plasma (99.2%) and serum (99.2%). The PPV in plasma and serum were 87.5% and 91.6%, respectively. Negative predicted values were 93.0% and 95.6% in plasma and serum. The mean (95% CI) difference between the gold standard and the POC device in plasma and serum were 0.35 (−0.52, 1.23) mmol/L and 0.19 (−0.53, 0.92) mmol/L, respectively. Finally, we observed a strong correlation between the POC device and the gold standard method for tCa plasma and serum. However, the clinical application of the POC device should be carefully considered because its ability to detect cows with hypocalcemia in serum or plasma samples was poor. However, the device performed better than previously analyzed POC devices and needs further improvement to be a valuable tool for the dairy industry

Roles of Cellular Activation and Sulfated Glycans in Haemophilus somnus Adherence to Bovine Brain Microvascular Endothelial Cells

Haemophilus somnus can cause a devastating fibrinopurulent meningitis with thrombotic vasculitis and encephalitis in cattle. The mechanisms used by H. somnus to migrate from the bloodstream into the central nervous system (CNS) are unknown. In this study, we demonstrate that H. somnus adheres to, but does not invade, bovine brain endothelial cells (BBEC) in vitro. The number of adherent H. somnus was significantly increased by prior activation of the BBEC with tumor necrosis factor alpha (TNF-α). Addition of exogenous glycosaminoglycans significantly reduced H. somnus adherence to resting and TNF-α-activated BBEC. Heparinase digestion of the endothelial cell's glycocalyx or sodium chlorate inhibition of endothelial cell sulfated glycan synthesis significantly reduced the number of adherent H. somnus. In contrast, addition of hyaluronic acid, a nonsulfated glycosaminoglycan, had no inhibitory effect. These findings suggest a critical role for both cellular activation and sulfated glycosaminoglycans in adherence of H. somnus to BBEC. Using heparin-labeled agarose beads, we demonstrated a high-molecular-weight heparin-binding protein expressed by H. somnus. Heparin was also shown to bind H. somnus in a 4°C binding assay. These data suggest that heparin-binding proteins on H. somnus could serve as initial adhesins to sulfated proteoglycans on the endothelial cell surface, thus contributing to the ability of H. somnus to infect the bovine CNS

Widespread reforestation before European influence on Amazonia

An estimated 90 to 95% of Indigenous people in Amazonia died after European contact. This population collapse is postulated to have caused decreases in atmospheric carbon dioxide concentrations at around 1610 CE, as a result of a wave of land abandonment in the wake of disease, slavery, and warfare, whereby the attendant reversion to forest substantially increased terrestrial carbon sequestration. On the basis of 39 Amazonian fossil pollen records, we show that there was no synchronous reforestation event associated with such an atmospheric carbon dioxide response after European arrival in Amazonia. Instead, we find that, at most sites, land abandonment and forest regrowth began about 300 to 600 years before European arrival. Pre-European pandemics, social strife, or environmental change may have contributed to these early site abandonments and ecological shifts

Smectite in mangrove soils of the State of São Paulo, Brazil Esmectitas em solos de mangue no Estado de São Paulo

Smectitic clay minerals are frequently identified in mangrove soils, but there is little information about their types and origins. Besides their importance in the agronomical and geotechnical areas, smectites play an important environmental role by adsorbing nutrients, organic pollutants and heavy metals. Smectites found in mangrove soils can be of marine or continental detrital origin, or of neoformation origin. Thus, the objective of this study was to identify the types of smectites present in the State of São Paulo mangrove soils (Brazil), and to relate them to their possible origins. Soil samples were taken in five mangroves along the State of Sao Paulo State coast line. The mineral composition of the clay fraction was identified by X-ray Diffractometry (XRD) applying the Greene-Kelly test and by Fourier transform infrared spectroscopy (FTIR). Highlighting the peaks in the 3,560 cm-1 band and in the region near 798 and 820 cm-1, there was a predominance of nontronite in the soil at the Sítio Grande River, Pai Matos Island, Caranguejo Island and Itapanhaú River mangroves, and possibly a lower concentration of ferric montmorillonite in the Escuro River mangrove. Since the continental sediments in these environments are very poor in smectite, the origin of these minerals in the mangrove soils studied is related to sedimentation left by past marine transgressions, to neoformation processes, or yet to a combination of both origins.<br>Minerais de argila esmectíticos são freqüentemente identificados em solos de manguezais, mas são escassas as informações sobre os tipos encontrados e suas origens. A despeito da importância para a agronomia e geotecnia, as esmectitas desempenham também importante papel no âmbito ambiental, atuando na adsorção de nutrientes, poluentes orgânicos e metais pesados. Esmectitas em solos de manguezais podem ser de origem detrítica, marinha ou continental, e também de neoformação. Assim, este estudo objetivou identificar os tipos de esmectitas presentes em solos de manguezais do Estado de São Paulo e relacioná-los com suas possíveis origens. Para tanto, foram amostrados solos de cinco manguezais distribuídos ao longo do litoral paulista, cuja identificação dos constituintes mineralógicos da fração argila foi realizada por difratometria de raios X (DRX) com aplicação do teste de Greene-Kelly e por espectroscopia no infravermelho com transformada de Fourier (FTIR). Destacando os picos na banda de 3.560 cm-1 e na região próxima a 798 e 820 cm-1, verificou-se o predomínio de nontronita nos solos dos manguezais do Rio Sítio Grande, Ilha de Pai Matos, Ilha do Caranguejo e Rio Itapanhaú e, possivelmente menor participação de montmorilonita férrica no manguezal do Rio Escuro. Como os sedimentos continentais destes ambientes são muito pobres em esmectitas, a origem destes minerais nos solos dos manguezais estudados está relacionada à sedimentação deixada pelas transgressões marinhas pretéritas ou aos processos de neoformação ou, ainda, com uma combinação de ambas origens