Atherosclerotic plaque destabilization in Mice: A comparative study

Atherosclerosis-Associated diseases are the main cause ofmortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions thatmay become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-Threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animalmodelsmimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models

Planetary Defense Ground Zero: MASCOT's View on the Rocks - an Update between First Images and Sample Return

At 01:57:20 UTC on October 3rd, 2018, after 3½ years of cruise aboard the JAXA spacecraft HAYABUSA2 and about 3 months in the vicinity of its target, the MASCOT lander was separated successfully by from an altitude of 41 m. After a free-fall of only ~5m51s MASCOT made first contact with C-type near-Earth and potentially hazardous asteroid (162173) Ryugu, by hitting a big boulder. MASCOT then bounced for ~11m3s, in the process already gathering valuable information on mechanical properties of the surface before it came to rest. It was able to perform science measurements at 3 different locations on the surface of Ryugu and took many images of its spectacular pitch-black landscape. MASCOT’s payload suite was designed to investigate the fine-scale structure, multispectral reflectance, thermal characteristics and magnetic properties of the surface. Somewhat unexpectedly, MASCOT encountered very rugged terrain littered with large surface boulders. Observing in-situ, it confirmed the absence of fine particles and dust as already implied by the remote sensing instruments aboard the HAYABUSA2 spacecraft. After some 17h of operations, MASCOT‘s mission ended with the last communication contact as it followed Ryugu’s rotation beyond the horizon as seen from HAYABUSA2. Soon after, its primary battery was depleted. We present a broad overview of the recent scientific results of the MASCOT mission from separation through descent, landing and in-situ investigations on Ryugu until the end of its operation and relate them to the needs of planetary defense interactions with asteroids. We also recall the agile, responsive and sometimes serendipitous creation of MASCOT, the two-year rush of building and delivering it to JAXA’s HAYABUSA2 spacecraft in time for launch, and the four years of in-flight operations and on-ground testing to make the most of the brief on-surface mission

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Higher Leukocyte Count Is Associated with Lower Presence of Carotid Lipid-Rich Necrotic Core: A Sub-Study in the Plaque at RISK (PARISK) Study

Background: Increasing evidence suggests that inflammation inside the vessel wall has a prominent role in atherosclerosis. In carotid atherosclerosis in particular, vulnerable plaque characteristics are strongly linked to an increased stroke risk. An association between leukocytes and plaque characteristics has not been investigated before and could help with gaining knowledge on the role of inflammation in plaque vulnerability, which could contribute to a new target for intervention. In this study, we investigated the association of the leukocyte count with carotid vulnerable plaque characteristics. Methods: All patients from the Plaque At RISK (PARISK) study whom had complete data on their leukocyte count and CTA- and MRI-based plaque characteristics were included. Univariable logistic regression was used to detect associations of the leukocyte count with the separate plaque characteristics (intra-plaque haemorrhage (IPH), lipid-rich-necrotic core (LRNC), thin or ruptured fibrous cap (TRFC), plaque ulceration and plaque calcifications). Subsequently, other known risk factors for stroke were included as covariates in a multivariable logistic regression model. Results: 161 patients were eligible for inclusion in this study. Forty-six (28.6%) of these patients were female with a mean age of 70 [IQR 64–74]. An association was found between a higher leukocyte count and lower prevalence of LRNC (OR 0.818 (95% CI 0.687–0.975)) while adjusting for covariates. No associations were found between the leucocyte count and the presence of IPH, TRFC, plaque ulceration or calcifications. Conclusions: The leukocyte count is inversely associated with the presence of LRNC in the atherosclerotic carotid plaque in patients with a recently symptomatic carotid stenosis. The exact role of leukocytes and inflammation in plaque vulnerability deserves further attention

Higher Leukocyte Count Is Associated with Lower Presence of Carotid Lipid-Rich Necrotic Core: A Sub-Study in the Plaque at RISK (PARISK) Study

Background: Increasing evidence suggests that inflammation inside the vessel wall has a prominent role in atherosclerosis. In carotid atherosclerosis in particular, vulnerable plaque characteristics are strongly linked to an increased stroke risk. An association between leukocytes and plaque characteristics has not been investigated before and could help with gaining knowledge on the role of inflammation in plaque vulnerability, which could contribute to a new target for intervention. In this study, we investigated the association of the leukocyte count with carotid vulnerable plaque characteristics. Methods: All patients from the Plaque At RISK (PARISK) study whom had complete data on their leukocyte count and CTA- and MRI-based plaque characteristics were included. Univariable logistic regression was used to detect associations of the leukocyte count with the separate plaque characteristics (intra-plaque haemorrhage (IPH), lipid-rich-necrotic core (LRNC), thin or ruptured fibrous cap (TRFC), plaque ulceration and plaque calcifications). Subsequently, other known risk factors for stroke were included as covariates in a multivariable logistic regression model. Results: 161 patients were eligible for inclusion in this study. Forty-six (28.6%) of these patients were female with a mean age of 70 [IQR 64–74]. An association was found between a higher leukocyte count and lower prevalence of LRNC (OR 0.818 (95% CI 0.687–0.975)) while adjusting for covariates. No associations were found between the leucocyte count and the presence of IPH, TRFC, plaque ulceration or calcifications. Conclusions: The leukocyte count is inversely associated with the presence of LRNC in the atherosclerotic carotid plaque in patients with a recently symptomatic carotid stenosis. The exact role of leukocytes and inflammation in plaque vulnerability deserves further attention

Representative carotid cross-sections of studied specimens for the mouse models of atherosclerotic plaque destabilization.

<p>Mice were fed chow diet (CD) or high fat diet (HFD) as indicated. From left to right: LCCA LRA, model based on the combination of partial ligation of LCCA and LRA; LRA Cast, model based on the combined cast placement around LCCA and partial ligation of LRA; LCCA Cast, model based on the partial ligation of LCCA in combination with the cast placement around the LCCA; Cast, model based on cast placement around the LCCA. Red, yellow and green bars represent thrombus, no lesion or atherosclerotic lesion, respectively. Scale bar = 100μm. LCCA: left common carotid artery; LRA: left renal artery; CD: chow diet; HFD: high fat diet.</p

Structural features of the atherosclerotic lesions.

<p>Quantification of (<b>A</b>) intimal area, (<b>B</b>) intima to media ratio, (<b>C</b>) necrotic core size and (<b>D</b>) fibrous cap thickness. Fibrous cap thickness was only measured when necrotic core was present. NC: necrotic core; FC: fibrous cap; CD: chow diet; HFD: high fat diet; LCCA: left common coronary artery; LRA: left renal artery.</p

Schematic diagrams and experimental setups of the mouse models of atherosclerotic plaque destabilization.

<p>(<b>A</b>) Model based on the combined partial ligation of LCCA (left) and LRA (right). (<b>B</b>) Model based on the combination of cast placement around LCCA (left) and partial ligation of LRA (right). (<b>C</b>) Model based on the partial ligation of LCCA in combination with the cast placement around the LCCA. (<b>D</b>) Model based on cast placement around the LCCA. LCCA: left common carotid artery; LRA: left renal artery; LECA: left external carotid artery; LICA: left internal carotid artery; LSTA: left superior thyroid artery; CD: chow diet; HFD: high fat diet; Lig.: ligation.</p

Vulnerability-Index of the lesions in the mouse models of atherosclerotic plaque destabilization.

<p>Vulnerability-Index (VI) was calculated by the relation between analyzed unstable (<i>U</i>) and stable (<i>S</i>) features of the plaque and corrected by the incidence of lesion formation (p, VI_c). Lesions not representing the type II phenotype were scored as zero. SD was not indicated for models with incidence of n = 1 of type II lesions. LCCA: left common coronary artery; LRA: left renal artery; CD: chow diet; HFD: high fat diet. (n = 3–8; p < 0.05, p < 0.01, p < 0.001 with 1-way ANOVA with Bonferroni’s Multiple Comparison test)</p><p>Vulnerability-Index of the lesions in the mouse models of atherosclerotic plaque destabilization.</p

Compositional features of the atherosclerotic lesions.

<p>Quantification of (<b>A</b>) macrophage (CD68+ area), (<b>B</b>) vascular smooth muscle cell (SMA+ area) and (<b>C</b>) total collagen (picrosirius red+ area) content. (<b>D</b>) Quantification of the incidence of intraplaque hemorrhage in Pearls’ Prussian blue stained sections. CD: chow diet; HFD: high fat diet; LCCA: left common coronary artery; LRA: left renal artery; IPH: intraplaque hemorrhages.</p