bluuebunny/crossref_metadata_2025 huggingface dataset:
A computationally efficient non-coherent technique for wireless relay networks
Authors: Alabed Samer , Zreikat Aymen I. , Al-Abed Mohammad
Published: May 2022

This article introduces a full-rate differential distributed orthogonal space-time coding technique using the amplify-and-forward protocol. The proposed technique has a markedly low encoding and decoding complexity at all transmitting and receiving terminals. Furthermore, the method does not need either differential encoding or channel state information at any transmitting or receiving terminal where the information symbols are directly transmitted. Instead, the differential detection scheme is performed at the destination terminal. In our simulations, the performance of the suggested technique is performed by computer simulations in Rayleigh fading channel, using the amplify-and-forward protocol, to show that our proposed differential technique outperforms the corresponding reference techniques
Absorption performance of biomass hollow pyramidal microwave absorber using multi-slot array technique
Authors: Izzati Fazin Mas , Rashidy Razali Ahmad , Nasir Taib Mohd , Mohamad Noor Norhayati , Mohd Kasim Linda , Mohamat Kasim Nazirah , Abdullah Idris Hasnain
Published: May 2022

Electromagnetic interference (EMI) is an undesired electromagnetic (EM) wave by nearby electronic devices, process equipment, and measuring instruments. In this work, a novel multi-slot technique is applied to the hollow biomass pyramidal microwave absorber to study its absorption properties thoroughly. Two different slot arrangements in horizontal and vertical configuration are designed for the proposed microwave absorbers. Both slot design concepts have identical shape and size. This work aims to study, compare and analyze the absorption performance of the proposed designs at L, S, C and X frequency bands. The biomass material is used to form as absorbent material. The characteristics performance of the multi-slot design on biomass hollow pyramidal microwave absorbers are measured by using naval research laboratory (NRL) Arch space-free method. The frequency range set up for the measurement is in between 1 GHz to 12 GHz. The multi-vertical slots design exhibits better absorption performance at
 C-band and X-band which is -63.67 dB and -46.78 dB respectively while the multi-horizontal slots design provides better absorption performance at
 S-band which is -16.92 dB. The results shows that both design performances are frequency-dependent since horizontal slots design improve maximum absorption performance at low frequency while vertical slots design delivers better performance at high frequency. 
Convolution neural network model for fundus photograph quality assessment
Authors: Sheet Sinan S. Mohammed , Tan Tian-Swee , Bin As'ari Muhammad Amir , Wan Hitam Wan Hazabbah , Ngoo Qi Zhe , Sia Joyce S.Y. , Hiik Kelvin Ling Chia
Published: May 2022

The excellent quality of color fundus photograph is crucial for the ophthalmologist to process the correct diagnosis and for convolutional neural network (CNN) models to optimize output classification. As a result of main causes as acquire devises efficiency and experience of a physician most fundus photographs can have uneven illuminance, blur, and bad contrast, in addition to micro-features of retinal diseases, which need to force their contrast. Fundus photograph quality assessment method is proposed to find out the perfect enhanced color fundus Technique in fundoscopy photographs-based CNN model. Five photograph quality measurements, in addition to five CNN metrics, were used as standard in this study. In this research innovative approach combining photograph quality measurement and CNN metrics analysis is proposed to find out the best enhance method that is set for the multiclass CNN model. The contrast enhancement techniques are evaluated using 267 color fundus photographs divided into three retina diseases cases were downloaded from the open-source database “FIGSHARE”. The study outcome showed that the presented system (single-CNN) can determine well the contrast enhancement method, as well as the low-quality fundus photograph then it can boost CNN metrics to achieve superior.
Flow incorporated neural network based lightweight video compression architecture
Authors: Sangeeta Sangeeta , Gulia Preeti , Gill Nasib Singh
Published: May 2022

The sudden surge in the video transmission over internet motivated the exploration of more promising and potent video compression architectures. Though the frame prediction based hand designed techniques are performing well and widely used but the recent deep learning based researches in this domain provided further directions of pure deep learning based next generation codecs. As the bandwidth over the internet is varying, adaptive bit rate representation is more suitable for video quality adjustment in tune with bandwidth variation. The proposed architecture comprises of end to end trainable video compression network consisting of majorly three modules namely-motion extension network, flow autoencoder and frame autoencoder. Frame autoencoder generates the individual compressed frames, flow autoencoder is used for optical flow based motion compensation chore and next frame is predicted by the motion extension network. The network is designed and evaluated in incremental manner. The analysis of the outcomes demonstrates the promising performance of the network quantitatively and qualitatively. Moreover, the results reveal that inclusion of optical flow based motion compensation network to the MotionNet architecture has enhanced the performance.
An improved approach for managing energy efficiency in mobile networks
Authors: Abdullah Radhwan M. , Abdulqader Ayad H. , Ali Dia M. , Alwan Ali A. , Abualkishik Abedallah Z.
Published: May 2022

It is highly expected that soon there will be environmental and economic negative implications from the amount of energy consumed by wireless network devices. Therefore, many researchers have paid attention toward addressing these challenges to investigate the impact of these wireless networks on both environment and the economy. This paper proposes an approach for alternating work among the fifth generation (5G) with Long-Term Evolution (LTE) wireless networks. The idea of the proposed approach relies on turning off specific base stations (BSs) and antennas for the users based on the required quality of service (QoS). Some BSs like 5G networks aim to provide high-speed communications with significant savings in energy consumption during high traffic periods. On the other hand, there is a slow speed with the high consumption of energy in other BSs like LTE networks. Our proposed solution employs the idea of activating some of the BSs networks and changing the number of active antennas that achieves optimal results for the entire area. Doing so lead to a significant reduction in energy consumption when the traffic load is low. The experimental results illustrate that our proposed solution outperforms the most recent approaches by saving a significant amount in power consumption while maintaining a stable service awareness during switching situations.
COVID-19 detection based on combined domain features
Authors: Al Okashi Omar Munthir , Ahmed Ismail Taha , Abed Leith Hamid
Published: May 2022

The computed tomography (CT) scan delivers more detailed information and higher judgment accuracy than a chest X-ray, which has a wide range of uses in diagnosing and decision-making to aid medical professionals. This paper proposed a method to detect COVID-19 from CT scan images using the combination of spatial domain and transform domain features. Using the lung segmentation step, the CT image is first processed and segmented, and then various domain features are extracted. From these domain features, the highest combined domain features (CDF) are obtained. Finally, the detection task is completed using random forest (RF) and Naive Bayesian (NB) classifiers. The proposed method is tested using a dataset of CT scan images, and the results are compared to several current techniques. The results showed that our method based on CDF outperforms previous methods, with an overall accuracy of nearly 98%. As can be shown, CDF is the best domain feature to apply for detecting COVID-19.
Employing light fidelity technology in health monitoring system
Authors: Al-Dabbagh Marwan , Ali Awos Kh.
Published: May 2022

Light Fidelity (Li-Fi) is an emerging technology that has been in transferring data packets in Internet of Things (IoT) applications. During the COVID-19 pandemic, healthcare institutes try to manage the rapid increase of patients’ numbers. The healthcare team may not have the ability to monitor patients’ stats around the clock with the conventional techniques. In this paper, a healthcare monitoring framework to exchange health data between biosensors and terminals employing Li-Fi technology is proposed. It exploits Li-Fi to transmit data towards a terminal then to a cloud platform. It is intended for use in highly dense healthcare institutes where the number of patients is high. Exploiting Li-Fi to establish connection to cut high cost of other transmission technologies including Wi-Fi and provides less complexity and shorter latency. We evaluate the framework in a real-life environment using biosensors and Li-Fi communication model (for network infrastructure), these two components are connected to a computing terminal to help health staff monitor patients. The computing terminal is connected to a cloud platform to provide remote monitoring and computing resilience. The framework shows superior performance in real-world scenarios compared to Wi-Fi. A comprehensive analysis has been conducted to show the differences between Li-Fi and Wi-Fi.
Blockchain integrated multi-agent system for breast cancer diagnosis
Authors: Ramanath Thirumalaimuthu Thirumalaiappan , Hossen Md. Jakir , Sayeed Md. Shohel
Published: May 2022

The integration of multi-agent system and blockchain technology can be beneficial to healthcare applications by providing intelligent data analysis with security. This paper presents an architecture that integrates multi-agent learning system and blockchain technology to support breast cancer diagnosis in a secured manner. The proposed system is based on a parallel hybrid fuzzy logic approach for supporting the prediction of breast cancer disease. The proposed system showed a classification accuracy of 96.49% in breast cancer diagnosis when testing with the Wisconsin Diagnostic Breast Cancer dataset. The blockchain is used to provide agent security in the proposed system to ensure that the only trusted and reputed agents are participated in the decision-making process.
Celso Furtado, o Golpe de 1964 e a Ditadura Militar
Authors: Rosa Lilian da
Published: May 2022

O artigo discute a interpretação de Celso Furtado sobre o Golpe Civil-militar de 1964 e os reflexos dos governos militares para a sociedade brasileira. Por meio de recursos filológicos, o trabalho analisa um conjunto de textos produzidos entre 1962 e 2004, a partir de três perspectivas: (a) a ruptura política como um desdobramento do subdesenvolvimento; (b) as implicações do processo de globalização e a influência da hegemonia externa na política do Brasil e seus desdobramentos; e (c) os desajustes estruturais entre o Centro-Sul e o Nordeste. Por fim, o artigo insere Furtado como um autor importante para o debate historiográfico relacionado à Ditadura Civil-militar.
Abstract 100: Mitochondrial Dynamics Directs Macrophage Polarization During Atherosclerosis: Implications For Disease Regression
Authors: Susser Leah I , Nguyen My Anh , Geoffrion Michele , Khacho Mireille , Rayner Katey J
Published: May 2022

Coronary heart disease is caused by atherosclerosis, a cholesterol-driven inflammatory disease of the vessel wall. A hallmark of atherogenesis is the accumulation of pro-inflammatory (M1) macrophages within the vessel wall, which sustains the inflammatory environment of the atherosclerotic plaque. In contrast, during disease regression, macrophages adopt a pro-resolving, anti-inflammatory phenotype (M2). Macrophage subtypes also exhibit different metabolic programs, where M1 macrophages' preferentiality use glycolytic metabolism and are associated with high levels of reactive oxygen species (ROS), while M2 macrophages primarily use oxidative metabolism. Macrophages adapt to these different metabolic needs and protect from mitochondrial DNA damage by ROS by undergoing cycles of fission (fragmentation) & fusion (elongation), which have been demonstrated to direct differentiation and function in other cell types, including T-cells. We
hypothesize
that the balance of mitochondrial fusion & fission directs macrophage polarization and may influence macrophage plasticity during atherosclerosis progression and regression. We found that mouse bone marrow-derived macrophages polarized to an M1 phenotype have a more elongated mitochondrial network, whereas both resting (M0) and M2 macrophages have a more fragmented mitochondrial phenotype. We find that M1 macrophages are more active with a higher number of mitochondria undergoing either a fission or fusion event compared to both M0 and M2 cells. The M1-like elongated mitochondrial phenotype can also be seen under atherogenic lipid-loading conditions. Exciting preliminary data suggests inhibiting mitochondrial fission (i.e. by knocking down three critical proteins, Drp1, Mff & Fis1) or inhibiting mitochondrial fusion (i.e. by knocking down fusion proteins Opa1, Mfn1 & Mfn2) impacts macrophages ability to polarizing into M1 or M2 phenotypes. Together these data suggest that the changes in mitochondrial dynamics direct the polarization of these macrophages and thus could be targeted to promote regression. Regression is an untapped area of atherosclerosis research, and mitochondria dynamics may be a new target to direction macrophage polarization within a lesion.
Abstract 101: B1b Cell Homeostasis Is Maintained By Cd40 In Atherosclerosis
Authors: Reiche Myrthe E , Pattarabajinard Oom , Upadhye Aditi , Poels Kikkie , van Tiel Claudia , Malin Stephen G , Binder Christoph J , Gerdes Norbert , Weber Christian , Atzler Dorothee , McNamara Coleen A , Lutgens Esther
Published: May 2022

Background:
The co-stimulatory CD40-CD40L dyad is an important driver of atherosclerosis. CD40 exerts divergent, cell-specific roles, which differentially impacts atherogenesis.

Objectives:
We here investigate the role of the most prominent CD40-expressing cell type, the CD40
+
B cell, in atherosclerosis.

Methods:
B cell subset specific CD40-expression of patients with mild and severe coronary artery disease (CAD) was determined by mass-cytometry and correlated to CAD severity. Underlying mechanisms were revealed using CD19-CD40
flfl
-ApoE
-/-
(CD40
BKO
) and CD40
flfl
-ApoE
-/-
(CD40
BWT
) mice.

Results:
Patients with severe CAD had similar CD40 expression levels on most B cell subsets but showed a profound decrease in CD40 on B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40
BKO
mice exhibited an increased plaque area and a more advanced stage of atherosclerosis. Absence of B cell CD40 caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgM and (anti-ox/MDA-LDL) IgG. Interestingly, transcriptomics analysis revealed that the absence of CD40 on B1b cells in particular, caused altered gene expression pathways related to lipid uptake (
Cd36, Ldlr
), cellular stress and metabolism (
Nr4a1, Hif1a
), and cell death (
Naip5/6, Top1
).

Indeed,
in vitro
analysis showed that B1b
CD40KO
cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions.

Finally, transfer of wild-type B1b cells into CD40
BKO
mice prevented the increase in atherosclerosis.

Conclusions:
We here show that CD40 is a critical modulator of B1 cell protective function in hypercholesterolemia and atherosclerosis.
Abstract 102: Apolipoprotein E Receptor 2 In Endothelium Affords Protection From Both Atherosclerosis And Insulin Resistance
Authors: Sacharidou Anastasia , Huang Linzhang , Tanigaki Keiji , Mineo Chieko , Shaul Philip W
Published: May 2022

Introduction:
Apolipoprotein E Receptor 2 (ApoER2) is an LDL receptor family member that mediates the actions of apolipoprotein E (apoE) and other ligands. The LRP8 gene that encodes ApoER2 is a major gene locus for premature atherosclerosis and myocardial infarction. Studies were designed to determine how ApoER2 in endothelial cells impacts cardiovascular and metabolic health.

Hypothesis:
Based on prior cell culture studies, the hypothesis was that endothelial ApoER2 is atheroprotective. How endothelial ApoER2 impacts adiposity or glucose homeostasis is more difficult to predict.

Methods:
In vivo studies were done in control ApoER2 floxed mice (ApoER2
fl/fl
) and mice deficient in ApoER2 in endothelial cells (ApoER2
ΔEC
). Studies of endothelial cell insulin uptake and transcytosis were performed in human aortic and skeletal muscle endothelial cells (HAEC and HSMEC).

Results:
Atherosclerotic lesion severity on LDLR
-/-
background was increased in ApoER2
ΔEC
mice compared to ApoER2
fl/fl
, and this was not related to differences in circulating lipids. Intravital microscopy revealed that leukocyte-endothelial cell adhesion is increased in ApoER2
ΔEC
, and vascular TNFα and IL-1β expression was exaggerated. There was no impact of endothelial ApoER2 silencing on adiposity. However, standard chow-fed ApoER2
ΔEC
mice displayed marked glucose intolerance and insulin resistance. Both pancreatic insulin secretion and hepatic insulin sensitivity were normal. Alternatively, in ApoER2
ΔEC
mice skeletal muscle glucose disposal was decreased by 41%, and this was due to a 55% fall in insulin delivery to muscle. Using human apoE3 ex vivo, apoE stimulated a 279% increase in insulin uptake in HAEC, and the finding was confirmed in HSMEC. Insulin transcytosis rose 209% with apoE, and apoE enhancement of insulin transport was fully ApoER2-dependent.

Conclusions:
Endothelial ApoER2 affords atheroprotection by decreasing leukocyte-endothelial cell adhesion and inflammatory gene expression in the vessel wall. Endothelial ApoER2 also has antidiabetic action, and this is due to the promotion of endothelial insulin transport to skeletal muscle. Targeting of the related mechanisms may provide protection from both cardiovascular and metabolic disease.
Abstract 104: Massively Parallel Validation Of Genetic Variants With Inflammatory-specific Effects In Human Endothelial Cells
Authors: Stolze Lindsey K , Toropainen Anu , Ord Tiit , Whalen Michael B , Kaikkonen Minna , Romanoski Casey E
Published: May 2022

Genome-wide association studies have linked thousands of genetic variants with complex diseases and traits. However, most genetic variants identified reside in non-coding regions of the genome, including variants associated with a myriad of vascular phenotypes, including coronary artery disease, pulse pressure, and stroke. In a prior study, we performed Quantitative Trait Locus (QTL) analysis for expression, transcription factor binding, chromatin accessibility, and histone H3 acetylation on the 27
th
residue (H3K27ac) across 53 primary Human Aortic Endothelial Cell (HAEC) samples. This analysis was performed in untreated and pro-inflammatory cytokine Interleukin 1 Beta (IL1B) treated conditions. This resource allowed us to fine-map non-coding functional variants within HAECs in both simulated healthy and diseased conditions. To this, we now add results from massively parallel reporter assay for >16,000 regions that were prioritized from our QTL study. Using Self-Transcribing Active Regulatory Region sequencing (STARR-seq) for these regions in the immortalized HAEC cell line (teloHAECs), we identified 5,592 common variants with allele specific effects. These variants are enriched for endothelial cell specific transcription factor ERG binding QTLs as well as HAEC chromatin accessible sites, but not enriched for accessible regions from other cell types. This suggests cell-type specificity of the allele specific signals detected. We performed STARR-seq in untreated and two time points of IL1B-treated conditions. We found that the variants with significant allelic effects were enriched for inflammatory master regulator NF-kB binding QTLs regardless of the treatment condition in which STARR-seq was performed, highlighting the importance of the healthy cell regulatory landscape in determining inflammation response. Additionally, of the 3,459 loci with allele specific signals and QTL evidence, 219 were associated with a complex disease or trait via the GWAS catalog. These data together allow us to elucidate the functional variants within disease associated loci and link them to epigenetic traits and gene expression providing potential pathways through with genetic variation modifies endothelial cell biology and vascular health.
Abstract 105: Chronic Stress Primes Innate Immune Responses In Mice And Humans
Authors: Barrett Tessa J , Corr Emma , Solingen Coen , Schlamp Florencia , Brown Emily J , KOELWYN Graeme J , Lee Angela , Shanley Lianne , Spruill Tanya , Bozal Fazli , De Jong Annika , Newman Alexandra , Drenkova Kamelia , Silvestro Michele , Rhamkhelawon Bhama , Reynolds Harmony , Hochman Judith S , Nahrendorf Matthias , Swirski Filip K , A Fisher Edward A , Berger Jeffrey S , Moore Kathryn J
Published: May 2022

Psychological stress is associated with elevated circulating markers of inflammation, including inflammatory cytokines and acute phase reactants that accelerate progression of chronic inflammatory diseases (e.g., atherosclerosis, metabolic syndrome, autoimmune diseases and cancer). However, the mechanisms underlying inflammatory reactivity to stress and how it confers future health risk are poorly understood. Monocyte-derived macrophages play key roles in sustaining tissue inflammation, and recent studies show that they can maintain epigenetic memory of pathogen or sterile inflammatory insults, leading to a heightened inflammatory state upon secondary stimulation. We show herein that psychological stress induces transcriptomic and epigenomic reprogramming of monocytes which primes them for a heightened inflammatory immune response following challenge. Monocytes isolated from stressed mice or humans with high reported levels of psychological stress exhibit a common signature of heightened inflammatory gene expression and produce increased levels of proinflammatory cytokines upon ex vivo stimulation with Toll-like receptor ligands. RNA and ATAC sequencing studies revealed that monocytes from stressed mice and humans exhibit activation of cellular metabolic pathways, including mTOR and PI3Kinase pathways, and reduced chromatin accessibility at loci associated with mitochondrial respiration. Taken together, our findings suggest that psychological stress primes the reprogramming of innate immune cells resulting in a hyperresponsive inflammatory state, which may explain its deleterious association with inflammatory disease risk.
Abstract 108: Quantitative Phosphoproteomics And Causal Analysis Reveal Distinct And Combinatorial Signaling Mechanisms In Protease-Activated Receptor PAR1 And PAR4 Platelet Activation Programs
Authors: Reitsma Stephanie , Klimek John , Parra-Izquierdo Iván , Babur Ozgun , Melrose Alexander , Zheng Tony , pang jiaqing , McCarty Owen J , Minnier Jessica , Wilmarth Phillip , Demir Emek , Reddy Ashok , David Larry , Aslan Joseph
Published: May 2022

Intracellular signaling pathways downstream of platelet protease-activated receptors (PARs) mediate hemostasis - and, also contribute to thrombosis in vascular diseases - through mechanisms that remain unspecified. Here, we assess the hypothesis that platelet PAR1 and PAR4 each activate specific, as well as overlapping signaling systems to drive platelet responses underlying hemostasis and thrombosis. Our systems biology approach incorporates state-of-the-art mass spectrometry, computational and cell physiological tools to measure and map phosphorylation events in platelet PAR responses. Following isolation from n=4 healthy human donors, washed platelets were treated with PAR1 agonist (TRAP6), PAR4 agonist (AYPGFK), thrombin, or vehicle, prior to lysis, digestion, phosphopeptide enrichment and 16plex tandem mass tag (TMT) labeling. Relative to resting platelets, we measured >1,000 significant phosphorylation events in response to PAR agonists (fold-change >1.5; false discovery rate <0.01), including >600 phosphorylation events common to TRAP6, AYPGFK and thrombin stimulation. These included phosphorylation of well-established mediators (GSK3α, PAK2) and more novel and emerging effectors in platelet activation pathways (BIN2, NKX3-2). Specific PAR1 and PAR4 agonist responses of mechanistic and translational interest were also noted, including phosphorylation of PAR1 T410 or PAR4 S369; thrombin uniquely activated tyrosine kinase Fer Y714 phosphorylation, in a manner that may integrate PAR1 and PAR4 signaling. CausalPath analysis identified >100 signaling relations among site-specific phosphorylation changes downstream of PARs, around MAPK, PI3K/Akt, mTOR/S6K and other pathways. Finally, physiological assays of platelet adhesion, secretion and aggregation, as well as biochemical assays of platelet signaling validated roles for several effectors and pathways in platelet PAR responses. In conclusion, we provide a quantitative omics study and causal analysis of platelet PAR signaling, including specific PAR1 and PAR4 agonist responses. Ultimately, this work will help to specify essential effectors, as well as biomarkers and therapeutic targets in platelet dysregulation, hyperactivity and thrombotic diseases.
Abstract 109: Platelets Amplify Endotheliopathy In Covid-19
Authors: Barrett Tessa J , Cornwell MacIntosh , Myndzar Khrystyna , Rolling Christina , Xia Yuhe , Drenkova Kamelia , Biebuyck Antoine , Fields Alexander , Tawil Michael , Luttrell-Williams Elliot , Yuriditsky Eugene , Smith Grace , Cotzia Paolo , Neal Matthew D , Kornblith Lucy , Pittaluga Stefania , Rapkiewicz Amy , Burgess Hannah , Mohr Ian , Stapleford Kenneth , Voora Deepak , Ruggles Kelly , Hochman Judith , Berger Jeffrey S
Published: May 2022

In addition to their pivotal role in thrombosis and hemostasis, platelets participate in inflammatory responses and endothelial cell activation - hallmarks in the pathogenesis of coronavirus disease 2019 (COVID-19). Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). To explore this interaction, ECs were treated with platelet releasate from patients with and without COVID-19, and EC mRNA sequencing performed. We demonstrate that platelet released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. Investigation of the COVID-19 platelet transcriptome identified pathways related to organelle/granule release, metabolism, and immune effector function in addition to upregulation of
S100A8
and
S100A9
mRNA. Incubation of primary megakaryocytes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also induced upregulation of
S100A8
and
S100A9
mRNA. Consistent with increased gene expression, the heterodimer protein product of
S100A8
/
A9
, myeloid-related protein (MRP)8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls. We demonstrate that platelet-derived MRP8/14 activates microvascular endothelial cells, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to thromboinflammation and poor clinical outcomes in COVID-19 patients. Finally, we present evidence that therapeutic targeting of platelet P2Y
12
represents a promising candidate to reduce proinflammatory and prothrombotic platelet-endothelial interactions. Altogether, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.
Abstract 110: C1 Esterase Inhibitor Functions As An Anticoagulant In Human And Murine Venous Thrombosis
Authors: Grover Steven P , Hindberg Kristian , Wolberg Alisa S , Braekkan Sigrid , Mackman Nigel , Hansen John-bjarne
Published: May 2022

Factor (F) XII and FXI play a central role in venous thrombus formation in preclinical disease models and contributes to venous thromboembolism (VTE) in humans. Agents targeting FXIa have been developed and effectively prevent VTE in humans. C1 esterase inhibitor (C1INH) is a serine protease inhibitor that inhibits several proteases, including FXII and FXI. In this study, we investigated the anticoagulant activity of C1INH in humans and mice. First, plasma C1INH levels were determined in a population-based nested case-control study consisting of 405 VTE patients and 829 age- and sex-matched controls derived from the Tromsø Study. Participants with plasma C1INH levels in the highest quartile had a significantly lower risk of VTE (odds ratio [OR] of 0.68, confidence interval 0.49-0.96, P<0.05), unprovoked VTE (OR 0.59, confidence interval 0.39-0.89) and pulmonary embolism (OR 0.57, confidence interval 0.34-0.92) compared to participants with C1INH levels in the lowest quartile after adjustment for age and sex. Secondly, plasma-based thrombin generation studies were conducted to assess the anticoagulant function of C1INH. Supplementation of normal human pooled plasma with exogenous human purified C1INH (0.2 and 0.4mg/ml) significantly inhibited thrombin generation initiated with silica (P<0.05) and significantly prolonged the activated partial thromboplastin assay clotting time (P<0.001). Thirdly, administration of a clinically approved human purified C1INH product to mice significantly reduced thrombus weight (P<0.05) in the murine inferior vena cava stenosis model of venous thrombosis. Studies with C1 inhibitor deficient mice and substrate selective C1INH variants are currently ongoing. Our results indicate that C1INH serves as an endogenous anticoagulant with higher plasma levels of C1INH associated with a decreased future risk of VTE. Further, exogenous C1INH effectively inhibits thrombin generation in vitro and venous thrombus formation in a mouse model. Our findings suggest that C1INH may prevent thrombosis caused by activation of the intrinsic coagulation pathway.
Abstract 111: Vein-Chip Is A New Experimental Model To Predict Pathophysiology Of SARS-CoV-2 Induced Thrombosis
Authors: Rajeeva Pandian Navaneeth Krishna , Connor John H , Cooke John P , Jain Abhishek
Published: May 2022

There is a serious limitation of experimental models that can improve our limited knowledge of the mechanisms that regulate endotheliopathy and venous thrombosis (VT) clinically observed frequently amongst the most severe COVID-19 patients. Also, while observation and study of VT in humans are difficult due to the deep-lying nature of the deep veins in which VT develops, lab animal models do not include the venous valves, which are the sites for thrombus development in humans. We develop a Vein-chip microfluidic platform that includes venous valve architecture, endothelial cells (ECs), and whole blood flow, which can include the three factors of Virchow’s triad - endothelial inflammation, stasis of blood flow, and coagulable nature of blood. Our
in silico
and
in vitro
observations with Vein-Chip reveal that incompetent valves and thrombosis changes the blood flow pattern in and around the venous valves. We show that healthy endothelium at the venous valve cusps adapt to the complex flow patterns and have an anti-thrombotic phenotype compared to the venous lumen. But exposure of the lumen to living and replicating SARS-CoV-2 virus and inflammatory cytokines found in COVID-19 patient samples inflames the lumen and the valve endothelium becomes pro-thrombotic. Interestingly, when we directed our investigation to analyze the ACE2 expression on these cells, as ACE2 is the functional receptor of the SARS-CoV-2 virus, we found that ACE2 expression was poor under a static culture, but increased dramatically when venous ECs were exposed to shear stress within the vein-chip. This data supports our hypothesis that ACE2 expression (and therefore, SARS-CoV-2 entry into the endothelium) is dependent on venous hemodynamics and the Vein-Chip model is a highly dissectible platform that will help us to unravel the molecular mechanisms that lead to VT and its treatment strategies for COVID-19 and beyond.
Abstract 114: Single-cell and Spatial Transcriptomics Reveal An IL-1β Mediated VSMC Phenotypic Switch During Vasculitis and Cardiovascular Inflammation
Authors: Porritt Rebecca A , Zemmour David , Abe Masanori , Lee Youngho , Gomez Angela , Chen Shuang , Crother Timothy R , Shimada Kenichi , Arditi Moshe , Noval Rivas Magali
Published: May 2022

NLRP3 activation and IL-1β production are implicated in Kawasaki Disease (KD) pathogenesis, however a detailed description of the molecular networks and cellular subsets involved in this process is lacking. Here, we used single-cell RNA sequencing and spatial transcriptomics to characterize the cellular landscape of vascular tissues in a murine model of KD vasculitis. We observed infiltrations of innate and adaptive immune cells associated with increased expression of
Nlrp3
,
Il1b and Il18
. Monocytes, macrophages and dendritic cells were the main sources of IL-1β. Fibroblasts and vascular smooth muscle cells (VSMCs) expressed high levels of IL-1 receptor, while lymphocytes expressed high levels of IL-18 receptor. VSMCs in vasculitis lesions underwent a phenotypic switch, with upregulation of inflammatory mediators and fibroblast markers, and a downregulation of genes involved in contractile functions. Genetic inhibition of IL-1β signalling on VSMCs efficiently attenuated the phenotypic switch of VSMCs and the development of cardiovascular lesions during murine KD. In addition, pharmacological inhibition of NLRP3 prevented the development of cardiovascular inflammation. Our results unravel the cellular diversity involved in IL-1β production and signalling in KD cardiovascular lesions and demonstrate that therapeutic strategies targeting NLRP3 might be beneficial for human KD.
Abstract 118: Methamphetamine Causes Endothelial Dysfunction Via Reduction Of Cystathionine Gamma Lyase And Hydrogen Sulfide Bioavailability
Authors: Kolluru Gopi Krishna K , Glawe John D , Pardue Sibile , Kasabali Ahmad , RAJENDRAN Saranya , Cannon Allison L , Abdullah Chowdhury S , Traylor James G , Shackelford Rodney , Woolard Matthew D , Dominic Paari , Bhuiyan Shenuarin , Orr Wayne W , Goeders Nicholas E , Kevil Chris
Published: May 2022

Background:
Methamphetamine (METH) is an addictive illicit drug used worldwide that can elicit significant damage on blood vessels resulting in increased inflammation and cardiovascular dysfunction. Recent studies highlight increased prevalence of cardiovascular disease (CVD) and associated complications including hypertension, vasospasm, left ventricular hypertrophy, and coronary artery disease in younger populations due to METH use making cardiovascular complications the second leading cause of death in METH substance users. The purpose of this study is to understand the underlying molecular mechanisms of METH-related cardiovascular injury.

Methods and Results:
Here we report that METH administration in a mouse model of ‘binge and crash’ decreases vascular function through a CSE/H
2
S/NO-dependent pathway. METH significantly reduced H
2
S and NO bioavailability in plasma and skeletal muscle tissues co-incident with a significant reduction in flow-mediated vasodilation (FMD) and blood flow velocity highlighting endothelial dysfunction. METH administration also reduced cardiac ejection fraction (EF) and fractional shortening (FS) indicating pump dysfunction. Interestingly, METH treatment selectively decreased CSE expression co-incident with reduced eNOS phosphorylation. Importantly, either exogenous H
2
S therapy or endothelial CSE transgenic overexpression corrected endothelial dysfunction and associated pathological responses due to METH toxicity.

Conclusions:
Our results uniquely demonstrate that METH mediates reduction of CSE expression and activity in endothelial cells, and subsequent attenuation of H
2
S/NO bioavailability directly leading to impaired cardiac and vascular function. Exogenous sulfide therapy or endothelial CSE transgenic overexpression rescues METH-induced vascular dysfunction.
Abstract 119: Mitochondrial Redox Mechanisms Leading To Sustained Radiation-induced Endothelial Injury
Authors: Ait-Aissa Karima , Koval Olha , Lindsey Nathanial R , Broadhurst Kimberly , Grumbach Isabella M
Published: May 2022

Rationale:
Radiation therapy strongly increases the risk of developing atherosclerotic vascular disease, such as coronary and carotid artery disease. Recently, we found that
in vitro
inhibition of the mitochondrial Ca
2+
uniporter (MCU) protects from endothelial barrier breakdown following irradiation.

Objective:
To determine the mechanisms by which irradiation initiates vascular wall injury and test potential mitigators.

Methods and Results:
At 24 and 240 h After head and neck irradiation with 12 Gy x-ray, decreased endothelium-dependent vasodilation was seen in carotid arteries of C57Bl/6 mice. This was prevented by pre-infusion of the mitochondrial superoxide scavenger mitoTEMPO. Altered dilation correlated with increased mitochondrial ROS, loss of NO production and mitochondrial, but not nuclear DNA damage in human coronary endothelial cells
in vitro.
Enhancing mitochondrial in contrast to nuclear base excision repair by overexpression of subcellular targeted 8-Oxoguanine glycosylase blocked mitochondrial ROS and maintained NO production at all time points. Similarly, treatment with pravastatin, knockdown of MCU or its pharmacologic inhibition blocked irradiation-induced mitochondrial DNA damage and excess oxidative stress while maintaining NO production. These findings were recapitulated in vivo in a transgenic model of endothelial MCU knockout and in mice pretreated with pravastatin at 24 and 240 h after irradiation. Irradiation hyperpolarized the mitochondrial membrane potential (αψ
mito
) and increased baseline matrix Ca
2+
levels ([Ca
2+
]
m
) as well as Ca
2+
transients. MCU knockdown decreased αψ
mito
,

[Ca
2+
]
m
and Ca
2+
transients as did mitoTEMPO, whereas pravastatin pretreatment hyperpolarized αψ
mito
despite lowering [Ca
2+
]
m
.

Conclusion:
These findings demonstrate that mitochondrial DNA damage after irradiation drives a feed-forward circuit with ROS production and is sufficient to maintain endothelial dysfunction. Irradiation hyperpolarizes αψ
mito
and blocking this or its sequela, increased [Ca
2+
]
m
, prevents irradiation-induced endothelial injury. These findings also suggest additional mechanisms of statins in mitochondria and MCU as a new approach to mitigate irradiation-induced vascular disease.
Abstract 120: Genetic And Physiological Role For Hepatic C/EBPα In Plasma Lipid Metabolism
Authors: Hu Krista Y , Jadhav Kavita , Walsh Noel M , Ha Elizabeth E , Quartuccia Gabriella , Bauer Robert C
Published: May 2022

CCAAT/enhancer-binding protein alpha (C/EBPa) is a transcription factor known to mediate glucose and lipid metabolism. Hepatic protein levels of C/EBPa are controlled by the pseudokinase Tribbles-1 (
TRIB1
), a gene which has repeatedly been linked to plasma lipids and coronary artery disease by human genome-wide association studies. Previous work has shown that genetic perturbation of hepatic Trib1 in mice alters plasma lipids. However, it is unknown if C/EBPa governs the relationship between Trib1 and plasma lipids. To investigate this, we first reasoned that if C/EBPa does govern this relationship, then human
CEBPA
should also be a GWAS hit for plasma lipids in existing data. Indeed, there is a GWAS locus for HDL cholesterol and triglycerides (TGs) at Chr19q13.11, with the lead SNP located 80kb downstream of
CEBPA
in an intron of the annotated gene
PEPD
. To see if this GWAS locus is identifying C/EBPa, we performed CRISPR deletion and CRISPR interference (CRISPRi) of the SNP locus in human hepatocytes and found that doing so reduced
CEBPA
gene expression (CRISPR: -85.5%, p<0.01; CRISPRi: -29.7%, p<0.005), confirming that the 19q13 GWAS locus regulates
CEBPA
gene expression. We next sought to determine how hepatic C/EBPa regulates lipids by performing hepatic knockout of Cebpa via AAV-Cre treatment in adult mice. Hepatic knockout of C/EBPa significantly reduced plasma lipids (-21%, p<0.005). RNA-seq analysis of livers from these mice identified changes in expression of known regulators of plasma lipids, including reduced Pcsk9 expression (-60.5%, p<0.005). Subsequent ELISA analysis confirmed that mice lacking hepatic C/EBPa have reduced circulating PCSK9 (-54%, p<0.005). Crossing these mice to a transgenic mouse expressing human apoB confirmed that these mice have reduced non-HDL cholesterol (-49.7%, p<0.01). Ongoing studies seek to confirm the PCSK9 phenotype in human hepatoma cells, while also investigating how C/EBPa may regulate plasma TGs and HDL cholesterol. In summary, we demonstrate here that human
CEBPA
is likely a causal gene at the 19q13 plasma lipid GWAS locus, and that in mice, Cebpa is a novel regulator of plasma PCSK9 and non-HDL cholesterol. These data illustrate the translational relevance of targeting hepatic C/EBPa in adult animals.
Abstract 122: The Anti-Oxidant Function Of Apolipoprotein A-I Rescues Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Dysfunction
Authors: Manandhar Bikash , Pandzic Elvis , Deshpande Nandan , Chen Sing-Young , Wasinger Valerie C , Kockx Maaike , Glaros Elias , Ong Kwok Leung , Thomas Shane , Wilkins Marc , Whan Renee , Cochran Blake J , Rye Kerry Anne
Published: May 2022

Introduction:
Apolipoprotein (apo) A-I, the main apolipoprotein constituent of high-density lipoproteins, increases glucose-stimulated insulin secretion (GSIS) and is internalised by β-cells. Cholesterol accumulation in β-cells causes oxidative stress, reduces islet mass and decreases GSIS. ApoA-I increases GSIS in β-cells with high cholesterol levels, but it is not known if this is dependent on apoA-I internalisation.

Hypothesis:
Internalised apoA-I increases GSIS in β-cells with high cholesterol levels by lowering oxidative stress.

Methods:
Cholesterol-loaded Ins-1E insulinoma cells were incubated with unlabelled and/or Alexa Fluor488-labelled apoA-I. Alexa488-labelled apoA-I internalisation was quantified by flow cytometry and its intracellular location was determined by confocal microscopy and western blotting. ApoA-I binding partners on the Ins-1E surface were identified by mass spectroscopy. Generation of reactive oxygen species (ROS) in mitochondria was measured using MitoSOX.

Results:
ApoA-I was internalised by 43.4±3.6% of the Ins-1E cells (apoA-I
+
cells) in a dose-, time-, temperature- and cholesterol-dependent manner. ApoA-I internalisation was comparable under basal (2.8 mM) and high (25 mM) glucose conditions and mediated by an F
1
-ATPase β-subunit on the Ins-1E cell surface. Cell surface F
1
-ATPase β-subunit and cholesterol levels in apoA-I
+
Ins-1E cells were 1.7±0.3- and 1.3±0.1-fold higher, respectively, than in Ins-1E cells without internalised apoA-I (apoA-I
-
cells). Differentially expressed genes in the apoA-I
+
and apoA-I
-
Ins-1E cells were related to protein synthesis, the ER stress-related unfolded protein response, insulin secretion and mitochondrial function. Internalised apoA-I localised to mitochondria, lowered the cholesterol-mediated increase in ROS levels, and improved insulin secretion in cholesterol-loaded Ins-1E cells. The ATPase inhibitory factor 1, IF
1
, inhibited apoA-I internalisation and attenuated the apoA-I-mediated decrease of ROS levels in Ins-1E cells and isolated mouse islets.

Conclusions:
These results establish that internalised apoA-I restores insulin secretion in β-cells with high cholesterol levels by improving mitochondrial redox balance.
Abstract 125: Trans-ancestry Genome-wide Association Study Of Varicose Veins In >1 Million Individuals Reveals Circulating Effectors Of Venous Disease
Authors: Levin Michael , Huffman Jennifer , Verma Anurag , Rodriguez Alexis , Bick Alexander G , Madduri Ravi , Damrauer Scott
Published: May 2022

Background:
Varicose veins (VV) represent a common cause of cardiovascular morbidity and healthcare expenditures, with limited available medical therapies. The molecular and genetic basis of VV remains uncertain.

Methods:
We identified individuals of diverse ancestry with and without diagnosis of VV in the VA Million Veteran Program (MVP). Genome-wide association studies (GWAS) were performed using logistic regression adjusted for age, sex, and population structure. Trans-ancestry meta-analysis was then performed with 6 additional VV GWAS among participants of UK Biobank (UKB), FinnGen, eMERGE, and Biobank Japan. Downstream fine-mapping, phenome-wide association (pheWAS), colocalization, and Mendelian randomization (MR) analyses were performed to identify putative causal genetic variants, clinical traits, and circulating proteins that share associations with VV.

Results:
GWAS meta-analysis included 49,765 VV cases and 1,334,301 controls, identifying 151 independent genetic loci (p < 5 x 10
-8
) associated with VV. Fine-mapping revealed 11 loci where a single causal variant was prioritized with high confidence (posterior probability > 0.7). PheWAS of lead variants revealed associations at 101 unique loci with 90 circulating proteins and 992 clinical traits/measurements assessed in UKB. Colocalization identified shared genetic signals (posterior probability > 0.7) between VV and clusters of proteins (eg. a cluster of vascular proteins at the ABO locus including vascular proteins like VEFGR2/3, and ICAM1/4/5, among others), and clusters of clinical traits (eg. a cluster of anthropometric associations at the
DLC1
locus). To separate shared genetics from causal associations we performed proteome-wide MR across 738 circulating proteins. We found significant causal associations (p < 0.05/738) between 15 proteins and VV, including vasoactive proteins like ADM; extracellular matrix and connective proteins like MFAP2, POSTN, ASPN, ECM1; and hormone-proteins like SHBG.

Conclusions:
We assembled the largest trans-ancestry GWAS of diagnosed VV to date. These results highlight shared associations between VV and anthropometric traits, and identify causal circulating proteins that may represent biomarkers or therapeutic targets.