bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipokine omentin-1 enhances atherosclerotic plaque stability by binding to macrophage integrin receptor
Authors: Wang Z.J , Lin X.Z , Zhou Y.J 
Published: November 2020

Abstract

Background
Omentin-1 is a novel cytokine which is primarily released by epicardial adipose tissues, and the molecule structure analysis revealed that it contained a fibrinogen-like domain. Clinical studies considered that the expression of omentin-1 is tightly associated with the development of cardiovascular diseases. In this research, we sought to investigate the effect of omentin-1 on already-established atherosclerotic lesion in ApoE−/− mouse and find out the cellular receptor of omentin-1 in macrophages.

Methods
We investigated the effect of omentin-1 on the plaque phenotype by implanting the ALZET minipump (which can continuously inject omentin-1 solution into mice's jugular vein) in western diet-treated ApoE−/− mice. To validate the conjugation of omentin-1 to integrin receptor αvβ3 and αvβ5, we performed immunoprecipitation experiment. Confocal microscopy was used to verify the spatial co-localization of omentin-1 and integrin receptors.

Results
In vivo studies showed that the administration of omentin-1 increased the collagen content and the average fibrous cap thickness of atherosclerotic plaque in ApoE−/− mice. Omentin-1 mitigated the formation of necrotic cores within the plaque, and reduced the foam cell infiltration concomitantly. Immunohistochemistry analysis of the atherosclerotic lesion from the aorta of mice revealed that the intravenous infusion of omentin-1 can suppress expression of inflammatory cytokines in vivo. Immunoprecipitation experiment and confocal microscopy analysis confirmed the binding of omentin-1 to integrin receptor αvβ3 and αvβ5. To further study the mechanism by which omentin-1 had exerted its protective function, we used human myeloid leukemia mononuclear cell line (THP1) and oxidized low density lipoprotein (ox-LDL) to establish macrophage-derived foam cell model in vitro. Cell studies demonstrated that omentin-1 can attenuated the apoptosis and inflammatory cytokines secretion in ox-LDL-induced macrophages. Besides, omentin-1 can promote the phosphorylation of integrin-relevant signaling pathway in macrophage. After adding the cilengitide (inhibitor of integrin receptor αvβ3 and αvβ5) or intervening the expression of integrin subunit αv, the phenomenon induced by omentin-1 were potently suppressed. Moreover, flowcytometry analysis provided the evidence that omentin-1 had a negative effect on macrophage efferocytosis ability.

Conclusions
The administration of adipokine omentin-1 can inhibit the necrotic cores formation and pro-inflammatory cytokines expression within the atherosclerotic lesion. The mechanism might be the inhibition of apoptosis and the secretion of pro-inflammatory cytokines in macrophage by binding to integrin receptor αvβ3 and αvβ5.
Effect of omentin-1 on AS plaques.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): National natural science foundation of China
Alarmin-activated B cells accelerate atherosclerosis after myocardial infarction via plasma cell-immunoglobulin dependent mechanisms
Authors: Kyaw T , Loveland P , Kanellakis P , Cao A , Huang A , Peter K , Toh B.H , Bobik A 
Published: November 2020

Abstract

Introduction
Myocardial infarction (MI) accelerates atherosclerosis and for years greatly increases the risk of recurrent cardiovascular events, such as stroke and MI. B cell-derived autoantibodies produced in response to MI also persist for years.

Purpose
We investigated the role of B cells in adaptive immune responses to MI.

Methods
We used an apolipoprotein-E-deficient (ApoE−/−) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells using loss and gain of function approaches. In loss of function experiment, after inducing an MI we depleted B cells using an anti-CD20 antibody. Gain of function experiments involve transfers of purified MI-B cells from different donor mice, isolated one week after MI, into atherosclerotic ApoE−/− mice.

Results
Depletion of B cells in MI mice prevented immunoglobulin G accumulation in plaques and MI-induced acceleration of atherosclerosis. Adoptive transfer of wildtype MI-B cells into atherosclerotic ApoE−/− mice greatly increased IgG accumulation in plaque and accelerated atherosclerosis in recipient mice. Cytokines that promote humoral immunity were also greatly increased in B cells activated by MI. These cells formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Transfer of MI-B cells deficient in Blimp-1, the transcriptional repressor that drives their terminal differentiation to antibody-producing plasma cells failed to accelerate atherosclerosis in recipient mice. Alarmins released from infarcted heart were responsible for activation of B cells via toll-like receptors; transfer of MI-B cells deficient in MyD88, the canonical adaptor protein for inflammatory signaling downstream of toll-like receptors, prevented acceleration of atherosclerosis in recipient mice.

Conclusion
Our data implicate early B cell activation and autoantibodies as a central cause for accelerated atherosclerosis post MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Health and Medical Research Council of Australia
Selective inhibition of Histone deacetylases reverses vascular remodelling and improves right ventricle function in pulmonary hypertension
Authors: Kurakula K.B , Sun X.Q , Van Der Feen D.E , Hagdorn Q.A.J , Bogaard H.J , Berger R.M , Goumans M.J 
Published: November 2020

Abstract

Introduction
Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle (RV) failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation, and disturbed transforming growth factor beta (TGF-β) signalling. Histone deacetylases (HDACs) have been shown to promote proliferation and inflammation in vascular cells. Although inhibition of HDACs using small molecule inhibitors attenuated vascular remodeling, these inhibitors worsened RV function in animal models of PAH. Therefore, we aim to validate Quisinostat, a selective inhibitor of HDACs whether it could reverse vascular remodeling in the lungs and improves RV function.

Objective
To determine the effect of Quisinostat on vascular remodelling and RV function in PAH.

Methods and results
We found that HDAC1 expression is increased in lungs of PAH patients. Inhibition of HDACs activity by Quisinostat significantly decreased TGF-β signaling and strongly decreased proliferation and inflammation in microvascular endothelial cells (MVECs). In addition, conditioned medium from Quisinostat treated PAH MVECs inhibited the growth of healthy smooth muscle cells. Quisinostat reversed abnormal vascular remodelling in the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, and improved RV function. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding. Importantly, Quisinostat exhibited no systemic and cardio toxic effects in vivo.

Conclusions
Our data demonstrate that selective inhibition of HDACs reverses vascular remodeling in the lungs and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Dutch Lung Foundation
Lower plasma melatonin levels predict worse long-term survival in pulmonary arterial hypertension
Authors: Cai Z , Klein T , Geenen L.W , Tu L , Tian S , Van Den Bosch A.E , De Rijke Y.B , Reiss I.K.M , Boersma E , Duncker D.J , Boomars K.A , Guignabert C , Merkus D 
Published: November 2020

Abstract

Background
Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms may be involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve pulmonary arterial hypertension (PAH) patients and their clinical significance are still unknown.

Methods and results
Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in treatment-naïve PAH patients (n=43) and healthy controls (n=111). Melatonin levels were higher in PAH patients when compared with controls (Median 118.9 [IQR 109.3–147.7] versus 108.0 [102.3–115.2] pM, P&lt;0.001) (Figure 1A). The overall mortality was 26% (11/43) during a median long-term follow-up of 42 [IQR: 32–58] months. When PAH patients were stratified into 4 groups according to the quartiles of melatonin levels, the mortality from below 1st quartile to above 4th quartile was 55% (6/11), 10% (1/10), 0% (0/12), and 40% (4/10), respectively (Figure 1B). Kaplan-Meier analysis further showed that patients with melatonin levels below the 1st quartile (&lt;109.3 pM) had a worse long-term survival than patients with melatonin levels above the 1st quartile (Mean survival times were 46 [95% CI: 30–65] versus 68 [58–77] months, Log-rank, p=0.026) (Figure 1C).

Conclusion
Endogenous melatonin levels were increased in treatment-naïve PAH patients, and lower levels of melatonin were associated with worse long-term survival in patient with PAH, however, whether exogenous melatonin supplements may be effective as a therapeutic strategy in human PAH remains to be established.
Figure 1

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.
Impact of the gut microbiome on the atorvastatin-dependent modulation of the serum lipidome
Authors: Roessler J , Zimmermann F , Schmidt D , Escher U , Jasina A , Heimesaat M.M , Gast M , Poller W , Giral-Arnal H , Schumann P , Leistner D.M , Landmesser U , Haghikia A 
Published: November 2020

Abstract

Background and aims
The modulation of serum lipids, in particular of the low-density lipoprotein cholesterol (LDL-C), by statins varies between individuals. The mechanisms regulating this interindividual variation are only poorly understood. Here, we investigated the relation between the gut microbiome and the regulatory properties of atorvastatin on the serum lipidome using mice with depleted gut microbiome.

Methods
Over a period of 6 weeks, mice (C57BL/6) with either an intact (conventional mice, CONV, n=24) or antibiotic-based depleted gut microbiome (antibiotic treated mice, ABS, n=16) were put on standard chow diet (SCD) or high fat diet (HFD), respectively. During the last 4 weeks of treatment atorvastatin (Ator, 10mg/kg body weight/day) or control vehicle was administered via daily oral gavage. Blood lipids (total cholesterol, VLDL, LDL-C, HDL-C) and serum sphingolipids were compared among the groups. The expressions of hepatic and intestinal genes involved in cholesterol metabolism were analyzed by qRT-PCR. Alterations in the gut microbiota profile of mice with intact gut microbiome were examined using 16S RNA qRT-PCR.

Results
In CONV mice, HFD led to significantly increased blood LDL-C levels as compared with SCD (HFD: 36.8±1.4 mg/dl vs. SCD: 22.0±1.8 mg/dl; P&lt;0.01). In CONV mice atorvastatin treatment significantly reduced blood LDL-C levels after HFD, whereas in ABS mice the LDL-C lowering effect of atorvastatin was markedly attenuated (CONV+HFD+Ator: 31.0±1.8 mg/dl vs. ABS+HFD+Ator: 46.4±3 mg/dl; P&lt;0.01). A significant reduction in the abundance of several plasma lipids, in particular sphingolipids and glycerophospholipids upon atorvastatin treatment was observed in CONV mice, but not in ABS mice. The expressions of distinct hepatic and intestinal cholesterol-regulating genes (ldlr, srebp2, pcsk9 and npc1l1) upon atorvastatin treatment were significantly altered in gut microbiota depleted mice. In response to HFD a decrease in the relative abundance of the bacterial phyla Bacteroides and an increase in the relative abundance of Firmicutes was observed. The altered ratio between Bacteroides and Firmicutes in HFD fed mice was partly reversed upon atorvastatin treatment.

Conclusions
Our findings indicate a crucial role of the gut microbiome for the regulatory properties of atorvastatin on the serum lipidome and, in turn, support a critical impact of atorvastatin on the gut microbial composition. The results provide novel insights into potential microbiota related mechanisms underlying interindividual variation in modulation of the serum lipidome by statins, given interindividual differences in microbiome composition and function.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): German Heart Research Foundation
Effect of testosterone on lipid metabolism and endothelium in men with type 2 diabetes mellitus and hypogonadism
Authors: Khripun I , Vorobyev S , Khripun A , Kogan M , Demidova A , Belousov I 
Published: November 2020

Abstract

Background
To date, knowledge about the effects of testosterone (T) on the cardiovascular system of men remains controversial and requires additional research. Especially the putative impact of T replacement therapy (TRT) on lipid metabolism and endothelial dysfunction as a starting mechanism for the development of cardiovascular pathology in men with type 2 diabetes mellitus (T2DM) presenting with T deficiency has to be elucidated.
The aim of this work was to evaluate the effect of T replacement therapy on lipid metabolism and function of endothelium in men with T2DM and hypogonadism.

Methods
The study included 95 men (mean age 55,3±2,4 years) with T2DM and late onset hypogonadism, established according to EAU 2015 criteria. Parameters of carbohydrate and lipid metabolism, as well as ultrasound assessment of flow-mediated dilatation of the brachial artery (FMD-BA) and intima-media thickness (IMT) of brachial arteries were performed at baseline and after 9 months. Patients were randomized into 2 groups: 1 - 45 men receiving TRT, using 1% transdermal T-gel and 2 (control group) - 50 men, who were not assigned to TRT. Statistical analysis was carried out using the Wilcoxon - test for repeated measurements (STATISTICA 10 software package).

Results
During the treatment period no serious adverse events were registered. The study revealed a significant decrease in HbA1c (p&lt;0.001), total cholesterol (p=0.009), triglycerides (p=0.004) and LDL (p=0.01) levels as well as an increase in HDL level (p=0.001) in the 1st group vs baseline and compared to the 2nd one. There was a decrease in IMT (from 1.0 [0.8; 1.1] to 0.7 [0.6; 0.9] mm, p=0.002) in the 1st group compared to the 2nd (p&lt;0.001). The endothelium-dependent FMD-BA increased 1.5 - fold in men applying T-Gel vs baseline as well as compared to the control group at the time point of follow- up (p&lt;0.001). At the same time TRT leaded to acceleration of the time until maximal vasodilation – it became twice faster (from 120 [90; 120] to 60 [60; 90] sec, p&lt;0.001) compared to baseline and the 2nd group (p&lt;0.001). Linear blood flow velocity increased markedly in the 1st group compared to the 2nd at the time point of follow-up (p=0.03).

Conclusion
TRT in men with T2DM and T deficiency leads to an improvement in carbohydrate and lipid metabolism together with a significant decrease in IMT and enhancement of endothelium vasomotor function, seems to facilitate a reduction in cardiovascular risk.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Russian Science Foundation
The de Winter’s pattern revisited: a case series
Authors: John Thadathilankal-Jess , Pecoraro Alfonso , Weich Hellmuth , Joubert Lloyd , Griffiths Bradley , Herbst Philip 
Published: November 2020

Abstract

Background
The de Winter’s electrocardiogram (ECG) pattern signifying proximal left anterior descending (LAD) artery occlusion was first described in 2008. The ECG changes were thought to be static and mechanisms for this were suggested. In addition, the optimal management of these patients was reported to be via a primary percutaneous coronary intervention (PCI) strategy.

Case summary
Case 1: A 48-year-old gentleman presented with a 2-h history of ischaemic chest pain with initial de Winter’s pattern on ECG. This progressed to anterior ST-elevation myocardial infarction (STEMI) complicated by ventricular fibrillation. Emergency angiography revealed a mid-vessel LAD occlusion which was successfully reperfused. Case 2: A 34-year-old female presented with a 2-h history of ischaemic chest pain with initial ECG showing a de Winter’s pattern. Due to concerns of performing PCI timeously, a pharmacoinvasive strategy of reperfusion was adopted with resolution of the de Winter’s pattern. Urgent angiography revealed a proximal LAD lesion which was successfully stented.

Discussion
The two cases highlight that the de Winter’s pattern may in fact not be static, but rather lie along the continuum of ischaemia and may evolve into STEMI. In addition, we provide further evidence that if primary PCI cannot be offered in a timeous manner, thrombolytic therapy may be considered in such patients. The de Winter’s pattern remains a high-risk ECG pattern that requires early recognition and intervention.
Methods for estimating tuberculosis incidence and mortality by age and sex
Authors: Dodd Peter J , Sismanidis Charalambos , Glaziou Philippe 
Published: November 2020

Abstract

Aims
To develop methods to disaggregate World Health Orgagnization estimates of tuberculosis (TB) incidence and mortality for each country by sex and age.

Methods
For countries where incidence estimates derived from a factor adjustment of notifications and case detection ratio over 0.85, or with &lt;1000 reported TB cases, we disaggregated incidence proportional to notifications. For each other country, a prior was constructed using a hierarchical model of age-stratified prevalence survey data, meta-analysis of sex ratios, and mathematical modelling for children under 15 years. Samples from this prior were used to disaggregate incidence and accepted if incidence exceeded notifications in each age/sex category. Results were inspected and, if implausible, incidence was disaggregated proportional to notifications. Mortality was disaggregated proportional to patterns in vital registration (VR) data in countries with VR data. Where VR data were lacking, a case-fatality ratio (CFR) approach was applied to estimated incidence, with separate CFRs by HIV/ART status, child/adult age groups, and anti-TB treatment status. Uncertainty in all disaggregated country estimates was constructed to be consistent with corresponding overall uncertainty.

Results
We generated disaggregated results for 216 countries. For 125 countries, incidence disaggregation was based on notifications. Of the rest, accepted samples from the prior were considered implausible in 4 countries. For 72 countries, mortality disaggregation was based on VR data; the rest were based on the CFR approach.

Conclusions
While multi-stage, this approach is comparatively simple in overall logic. Disaggregated estimates have relatively larger uncertainty and should be used with caution.
A ΔSOC-based equalization strategy applied to industry
Authors: Wang Maonan , Chang Chun , Ji Feng 
Published: November 2020

Abstract
The voltage-based equalization strategy is widely used in the industry because the voltage (U) of the battery cell is very easy to obtain, but it is difficult to provide an accurate parameter for the battery management system (BMS). This study proposes a new equalization strategy, which is based on the difference between the state of charge (SOC) of any two battery cells in the battery pack, that is, a ΔSOC-based equalization strategy. The new strategy is not only as simple as the voltage-based equalization strategy, but it can also provide an accurate parameter for the BMS. Simply put, using the relationship between the open circuit voltage and the SOC of the battery pack, the proposed strategy can convert the difference between the voltage of the battery cells into ΔSOC, which renders a good performance. Additionally, the required parameters are all from the BMS, and no additional calculation is required, which makes the strategy as simple as the voltage-based balancing strategy. The four experiments show that the relative errors of ΔSOC estimated by the ΔSOC-based equalization strategy are 0.37%, 0.39%, 0.1% and 0.17%, and thereby demonstrate that the ΔSOC-based equalization strategy proposed in this study shows promise in replacing the voltage-based equalization strategy within the industry to obtain better performance.
Not All Terror Is Alike: How Right-Wing Extremist and Islamist Terror Threat Affect Anti-immigration Party Support
Authors: Jacobs Laura , van Spanje Joost 
Published: November 2020

AbstractTerror threat has been theorized to affect political attitudes. Most prior studies have focused exclusively on Islamist terror threat, while effects of right-wing extremist terrorism on voting behavior have been understudied. We argue that effects on the propensity to vote (PTV) for an anti-immigration party (AIP) depend on the type of threat and is moderated by right-wing authoritarianism (RWA) and internal motivation to control prejudice (IMCP). Using a cross-country experiment in Germany, the Netherlands, and Sweden (N = 1,187), we find that Islamist terror threat increases PTV for AIPs amongst voters high in RWA; similarly, right-wing extremist terror threat reduces PTV for AIPs amongst participants high in RWA. IMCP did not moderate the relationship between terror threat and PTV for an AIP.
A nonconforming pressure-robust finite element method for the Stokes equations on anisotropic meshes
Authors: Apel Thomas , Kempf Volker , Linke Alexander , Merdon Christian 
Published: November 2020

Abstract
Most classical finite element schemes for the (Navier–)Stokes equations are neither pressure-robust, nor are they inf-sup stable on general anisotropic triangulations. A lack of pressure-robustness may lead to large velocity errors, whenever the Stokes momentum balance is dominated by a strong and complicated pressure gradient. It is a consequence of a method, which does not exactly satisfy the divergence constraint. However, inf-sup stable schemes can often be made pressure-robust just by a recent, modified discretization of the exterior force term, using ${\boldsymbol{H}}(\operatorname{div})$-conforming velocity reconstruction operators. This approach has so far only been analyzed on shape-regular triangulations. The novelty of the present contribution is that the reconstruction approach for the Crouzeix–Raviart method, which has a stable Fortin operator on arbitrary meshes, is combined with results on the interpolation error on anisotropic elements for reconstruction operators of Raviart–Thomas and Brezzi–Douglas–Marini type, generalizing the method to a large class of anisotropic triangulations. Numerical examples confirm the theoretical results in a two- and a three-dimensional test case.