bluuebunny/crossref_metadata_2025 huggingface dataset:
Deployment of On-Orbit Service Vehicles Using a Fuzzy Adaptive Particle Swarm Optimization Algorithm
Authors: Li Yaxiong , Sun Xinglong , Liu Xinxue , Wu Jian , Liu Qingguo
Published: June 2021

On the basis that satellites given fixed count and orbit elements can be served in bounded time when an on-orbit serving mission order is set at any uncertain time in a given time interval, the deployment of on-orbit service vehicle (OSV) serving satellites becomes a complex multiple nested optimization problem, and the essence of deployment is to determine the count and orbit elements of OSVs. In consideration of the characteristics of this deployment problem, we propose a fuzzy adaptive particle swarm optimization (FAPSO) algorithm to solve this problem. First, on the basis of double pulse rendezvous hypothesis, a transfer optimization model of a single OSV serving multiple satellites is established based on genetic algorithm (GA), and this is used to compute the indexes of the subsequent two optimization models. Second, an assignment optimization model of OSVs is established based on the discrete particle swarm optimization (DPSO) algorithm, laying the foundation of the next optimization model. Finally, the FAPSO algorithm, which improves the performance of PSO algorithm by adjusting the inertia weight, is proposed to solve the deployment problem of multiple OSVs. The simulation results demonstrate that all optimization models in this study are feasible, and the FAPSO algorithm, which has a better convergence result than that obtained using the other optimization algorithms, can effectively solve the deployment problem of OSVs.
A Kernel-Based Node Localization in Anisotropic Wireless Sensor Network
Authors: He Wenxiu , Lu Fangfang , Chen Jingjing , Ruan Yi , Lu Tingjuan , Zhang Yi
Published: June 2021

Wireless sensors localization is still the main problem concerning wireless sensor networks (WSN). Unfortunately, range-free node localization of WSN results in a fatal weakness–, low accuracy. In this paper, we introduce kernel regression to node localization of anisotropic WSN, which transfers the problem of localization to the problem of kernel regression. Radial basis kernel-based G-LSVR and polynomial-kernel-based P-LSVR proposed are compared with classical DV-Hop in both isotropic WSN and anisotropic WSN under different proportion beacons, network scales, and disturbances of communication range. G-LSVR presents the best localization accuracy and stability from the simulation results.
The Application of “Stilted Building” Technique in the Embolization of Aneurysms with Secondary Branches
Authors: Qi Yi , Sun Yongquan , Wang Yang , Jia Jianwen , Zhong Hongliang , Yang Hongchao , Lv Ming , Liu He
Published: June 2021

Objective. Many intracranial aneurysms often have branch arteries, and it is especially important to protect them during embolization. The purpose of the present study was to evaluate the curative effect and safety of the “stilted building” technique. Methods. 25 patients with intracranial aneurysms with branch arteries that have been treated by coil embolization with the “stilted building” technique were retrospectively reviewed. Clinical follow‐up was performed after endovascular treatment. Results. All 25 patients successfully underwent aneurysm embolization. During the operation, the ruptured sac and most of the body of the aneurysm were embolized using the “stilted building” technique. Immediate imaging showed that the blood flow to the branch arteries from the neck or sidewall of the aneurysm was unobstructed. The mRS scores of the 25 patients during the follow‐up period were mRS 0 for twenty‐one patients, mRS 1 for three patients, and mRS 6 for one patient. No aneurysms recurred among the patients who completed the follow‐up. Conclusions. In an aneurysm with a branch artery, when a balloon or stent cannot be effectively used to protect the branch artery, the use of “stilted building” embolization can achieve good therapeutic effects, and the short‐term follow‐up results are satisfactory; the technique can effectively protect branch arteries originating from aneurysms.
Understanding the Impact of Urinary Incontinence in Persons with Dementia: Development of an Interdisciplinary Service Model
Authors: Juliebø-Jones Patrick , Coulthard Elizabeth , Mallam Elizabeth , Archer Hilary , Drake Marcus J.
Published: June 2021

Introduction. Prevalence of urinary symptoms such as incontinence (UI) in patients with dementia is estimated to exceed 50%. The resultant psychological and socio-economic burden can be substantial. Our aim was to develop a dedicated urology service within a cognitive impairment clinic in order to treat and better understand the bothersome urinary symptoms suffered by persons with dementia. Methods. Patients attending this clinic were invited to be assessed and interviewed by urologist, together with their family and/or carer. In addition, formal history, examination and relevant investigations, themes of importance such as quality of life, and select question items were drawn from validated questionnaires. Multidisciplinary team (MDT) meeting was carried out on the same day. Outcomes of the first 75 patients with UI and dementia have been reported. Results. Average age was 70 years (range 58–98). Majority of persons had a diagnosis of Alzheimer’s disease (n = 43, 57%). Average score for how much urine leakage interferes with everyday life was 7.7/10 (range 2–10). 58.7% (n = 44) revealed some degree of sleep disturbance due to UI. 83% (n = 62) stated daily activities were limited due to UI. Two-thirds of persons with dementia (n = 50) stated their bladder problem makes them feel anxious. 88% (n = 67) felt the topic was socially embarrassing. All carers stated that the person’s continence issues affect the care they provide. Less than one-third of carers (30.7%, n = 23) were aware of or had been in contact with any bladder and bowel community service. More than half of the carers (n = 46, 65%) were concerned incontinence may be a principal reason for future nursing home admission. Conclusion. UI can be distressing for persons with dementia. Care partners were concerned about loss of independence and early nursing home admission. Awareness of bladder and bowel services should be increased.
Studying the Effect of Taking Statins before Infection in the Severity Reduction of COVID‐19 with Machine Learning
Authors: Davoudi Alireza , Ahmadi Mohsen , Sharifi Abbas , Hassantabar Roshina , Najafi Narges , Tayebi Atefeh , Kasgari Hamideh Abbaspour , Ahmadi Fatemeh , Rabiee Marzieh
Published: June 2021

Statins can help COVID‐19 patients’ treatment because of their involvement in angiotensin‐converting enzyme‐2. The main objective of this study is to evaluate the impact of statins on COVID‐19 severity for people who have been taking statins before COVID‐19 infection. The examined research patients include people that had taken three types of statins consisting of Atorvastatin, Simvastatin, and Rosuvastatin. The case study includes 561 patients admitted to the Razi Hospital in Ghaemshahr, Iran, during February and March 2020. The illness severity was encoded based on the respiratory rate, oxygen saturation, systolic pressure, and diastolic pressure in five categories: mild, medium, severe, critical, and death. Since 69.23% of participants were in mild severity condition, the results showed the positive effect of Simvastatin on COVID‐19 severity for people that take Simvastatin before being infected by the COVID‐19 virus. Also, systolic pressure for this case study is 137.31, which is higher than that of the total patients. Another result of this study is that Simvastatin takers have an average of 95.77 mmHg O2Sat; however, the O2Sat is 92.42, which is medium severity for evaluating the entire case study. In the rest of this paper, we used machine learning approaches to diagnose COVID‐19 patients’ severity based on clinical features. Results indicated that the decision tree method could predict patients’ illness severity with 87.9% accuracy. Other methods, including the K‐nearest neighbors (KNN) algorithm, support vector machine (SVM), Naïve Bayes classifier, and discriminant analysis, showed accuracy levels of 80%, 68.8%, 61.1%, and 85.1%, respectively.
Multiparametric Photoacoustic Analysis of Human Thyroid Cancers In Vivo
Authors: Kim Jeesu , Park Byullee , Ha Jeonghoon , Steinberg Idan , Hooper Sarah M. , Jeong Chaiho , Park Eun-Yeong , Choi Wonseok , Liang Tie , Bae Ja Seong , Managuli Ravi , Kim Yongmin , Gambhir Sanjiv S. , Lim Dong-Jun , Kim Chulhong
Published: June 2021

Thyroid cancer is one of the most common cancers, with a global increase in incidence rate for both genders. Ultrasound-guided fine-needle aspiration is the current gold standard to diagnose thyroid cancers, but the results are inaccurate, leading to repeated biopsies and unnecessary surgeries. To reduce the number of unnecessary biopsies, we explored the use of multiparametric photoacoustic (PA) analysis in combination with the American Thyroid Association (ATA) Guideline (ATAP). In this study, we performed in vivo multispectral PA imaging on thyroid nodules from 52 patients, comprising 23 papillary thyroid cancer (PTC) and 29 benign cases. From the multispectral PA data, we calculated hemoglobin oxygen saturation level in the nodule area, then classified the PTC and benign nodules with multiparametric analysis. Statistical analyses showed that this multiparametric analysis of multispectral PA responses could classify PTC nodules. Combining the photoacoustically indicated probability of PTC and the ATAP led to a new scoring method that achieved a sensitivity of 83% and a specificity of 93%. This study is the first multiparametric analysis of multispectral PA data of thyroid nodules with statistical significance. As a proof of concept, the results show that the proposed new ATAP scoring can help physicians examine thyroid nodules for fine-needle aspiration biopsy, thus reducing unnecessary biopsies.

Significance:

This report highlights a novel photoacoustic scoring method for risk stratification of thyroid nodules, where malignancy of the nodules can be diagnosed with 83% sensitivity and 93% specificity.
РОЗВИТОК КІНЕЗІТЕРАПІЇ У ФРАНЦІЇ (1970–2020)
Authors: Данилевич М. В. , Романчук О. В. , Коваль Р. С. , Федчишин Н. О.
Published: June 2021

У статті проаналізовано розвиток кінезітерапії у Франції з 1970 до 2020 р. Наукову новизну роботи пояснюємо фактором того, що до сьогодні історія кінезітерапії у Франції не привертала уваги українських науковців, навіть не зважаючи на той факт, що якість надання медичних та реабілітаційних послуг у системі охорони здоровʼя цієї держави вважають однією з найвищих у світі.

У результаті проведеного аналізу виявлено, що у 80-х та 90-х роках ХХ століття відбувалося вдосконалення системи підготовки фахівців з кінезітерапії. У цей час було уточнено понятійно-категоріальний апарат, запропоновано визначення професійних дій, технік, методик; окреслено повноваження й обовʼязки кінезітерапевтів; запроваджено диплом працівника медичної сфери, спільний для багатьох парамедичних професій.

Зазначено, що у 2002 р. спеціальною постановою пацієнтам був наданий доступ до їхньої історії хвороби. У 2006 р. регламентовано перелік медичних засобів, які масажисти-кінезітерапевти можуть використовувати, засновано Національне обʼєднання масажистів-кінезітерапевтів. У 2008 р. був прийнятий, а у 2020 р. доповнений Кодекс деонтології у кінезітерапії.

Реформа системи підготовки масажистів-кінезітерапевтів розпочинається з 2015 р. зміною тривалості навчання з трьох на чотири роки, не враховуючи однорічний курс, спільний для всіх, хто навчається на медичних спеціальностях, а оцінка частини модулів здійснюється в університетах.

Інститути, які провадять підготовку фахівців галузі, сьогодні вводять доказову практику, що має на меті набуття необхідних компетенцій для пошуку теоретичної та клінічної інформації, її оцінювання щодо доцільності подальшого використання у професійній діяльності. У галузі починають активно застосовуватися цифрові технології. Політика у сфері охорони здоровʼя і новітні технології зумовили обовʼязкове ведення професійної документації, зокрема інформаційної картки пацієнта, яка вважається параметром якості та безпеки, і дозволяє повністю відслідковувати всі надані пацієнту медичні послуги.

На сьогодні у Франції функціонує ціла низка організацій, робота яких стосується професійної діяльності масажистів-кінезі­терапевтів. У 2016 р. запропоновано нове визначення галузі, однак тривають дискусії стосовно найменування самої сфери, ролі масажиста-кінезітерапевта, його співпраці з іншими фахівцями.
ОСОБЛИВОСТІ ДИСТАНЦІЙНОГО НAВЧAННЯ СТУДЕНТІВ СПЕЦІАЛЬНОСТІ «МЕДСЕСТРИНСТВО» ПРИ ВИВЧЕННІ ДИСЦИПЛІНИ «БІОЛОГІЧНА ХІМІЯ»
Authors: Летняк Н. Я. , Кузьмак І. П.
Published: June 2021

У стaтті описано oсoбливoсті виклaдaння дисципліни «Біологічна хімія» в умoвaх кaрaнтину. В умовах пандемії COVID-19 дистанційне навчання є однією з провідних світових тенденцій в освіті. Ця технологія реалізує принцип безперервної освіти і здатна задовольнити постійно зростаючий попит на знання в інформаційному суспільстві. Сучaсні реaлії життя, які вимaгaють ширoкoгo викoристaння дистaнційнoгo нaвчaння у ВНЗ Укрaїни, мають свoї перевaги тa недоліки. Поширення пандемії COVID-19 і необхідність дотримання всіх карантинних заходів задля збереження здоров’я та життя всіх учасників освітнього процесу поставили нові виклики перед здобувачами вищої освіти, подолати які необхідно спільними зусиллями всіх зацікавлених сторін, і з підвищення мотиваційного фактора у здобутті нових знань. В умовах карантинних обмежень застосування дистанційних технологій дозволяє проводити освітній процес на достатньо високому рівні. Найбільш придатними для потреб дистанційного навчання є платформи Microsoft Teams. Бaгaтoрічний дoсвід викoристaння нoвітніх іннoвaційних технoлoгій у Тернoпільськoму нaціoнaльнoму медичнoму університеті імені І. Я. Гoрбaчевськoгo МОЗ України сприяв ефективній oргaнізaції дистaнційнoгo нaвчaння нa кaфедрі медичної біохімії. При викoнaнні зaвдaнь студенти кoристувaлися мaтеріaлaми СДO Moodle ТНМУ, щo дoзвoлилo їм oтримaти якісні та глибoкі знaння.
S. Y. Agnon: do Folclore à Ficção
Authors: Rozenchan Nancy
Published: June 2021

A atuação do autor israelense Shmuel Yossef Agnon, agraciado com o Prêmio Nobel de literatura em 1966, pode ser definida pelo seu perfil único de produção literária que incluiu obras que vão do folclore à ficção e que se estendeu por seis décadas. Tendo vivido por vários anos em diversas cidades em três países, absorveu delas elementos variados que deram os tons judaico e universal à sua obra. Todavia, estas influências não se manifestaram em geral de imediato em seus escritos; destarte, o desconcerto entre tom, temática e abordagem com a época e local em que foram produzidas é um dos aspectos muitos específicos dos seus livros. Destacam-se, aqui, alguns dos traços perceptíveis da escrita dos períodos da Galícia, da Palestina sob Mandato Britânico, da Alemanha e de Israel.
O sistema de escrita da língua japonesa e alguns aspectos da sua história
Authors: Ota Junko
Published: June 2021

O presente artigo tem como objetivo descrever o atual sistema de escrita adotado pelos japoneses e abordar alguns aspectos das letras que contribuíram historicamente para a formação desse sistema.
As escritas coreana e japonesa: dois caminhos tradutórios
Authors: Im Yun Jung
Published: June 2021

Por muito tempo, os coreanos e os japoneses tiveram a escrita chinesa como a única forma de documentação, instrução, educação, enfim, da cultura letrada. Visto de outro ângulo, os coreanos e os japoneses, falantes de duas línguas ural-altaicas, eram obrigados a escreverem em outra língua, da família sino-tibetana. É desse descompasso que ambos acabarão por desenvolver as suas próprias escritas tendo como ponto de partida a chinesa, processo no qual são revelados modos diferentes de lidar com essa diferença, dando, inclusive, margem a ricos ensaios em estudos culturais.
As cidades, a fauna e a flora do Brasil no testemunho ocular de um viajante árabe
Authors: Farah Paulo Daniel
Published: June 2021

O imã bagdali ‘Abdurrahman al-Baghdádi viajou ao Brasil em um navio do Império Otomano na segunda metade do século XIX. Al-Baghdádi permaneceu aproximadamente três anos no Rio de Janeiro, na Bahia e em Pernambuco. No relato que escreveu sobre a experiência, o imã descreve as cidades brasileiras, sua flora, sua fauna e sua gente.
Abstract 103: Circulating sRAGE is Elevated in Patients with Marfan Syndrome and Decreases After Surgical Replacement of Diseased Aortic Segments
Authors: Lai Eric K , Wytowich Daniel J , Ferrari Giovanni , Bavaria Joseph E , Pyeritz Reed E , Branchetti Emanuela
Published: June 2021

Backgound:
The Receptor for Advanced Glycation End products (RAGE) and its ligands are associated with vascular remodeling and trigger the release of a soluble receptor (sRAGE). We previously demonstrated that sRAGE levels are elevated in patients with bicuspid aortic valve and ascending aortic aneurysm. Circulating sRAGE in these patients correlates with the presence of a dysfunctional aortic structure but do not linearly correlate with an increase in the aortic diameter. Severe aortic disease occurs in more than 80% of Marfan Syndrome (MFS) patients. Aortic root and ascending aorta (AA) enlargement in MFS are associated with deficiency/destabilization of fibrillin-1, which leads to a generalized structural impairment of the aortic wall. We hypothesized that sRAGE may be elevated in the plasma of MFS patients and may decrease after surgical replacement of diseased aortic tissue.

Methods:
Plasma samples and clinical information (MFS=120, Control=37) were obtained from the GenTAC bioregistry and the Tissue Biobank at UPENN. Samples were collected either a few days prior to aortic surgery or at least one year post-surgery. sRAGE was tested using ELISA. Univariate and multivariate analysis were performed.

Results:
sRAGE levels are significantly higher in MFS patients compared to control (1404±64.35 vs 592±34.86 pg/ml, p<0.001) and are associated with the presence of MFS, independent of age, gender and comorbidities (p<0.001). sRAGE levels are significantly higher in MFS patients undergoing aortic surgery when compared to MFS patients monitored for aortic disease (1485±116.8 vs 1209±82.63 pg/ml, p=0.05). Circulating sRAGE is significantly lower in patients who have received aortic surgery (1185±63.31 pg/ml, p=0.02) and even lower in patients who received more extensive replacement (aortic valve/root and AA) versus those who underwent only aortic valve and root replacement (1313±81.83 vs 963.5±92.54 pg/ml, p=0.008). sRAGE levels do not linearly correlate with root and/or AA diameter.

Conclusion:
Plasma sRAGE levels are associated with the presence of ascending aortopathies independent of aortic diameter. Longitudinal studies evaluating sRAGE in MFS patients may unveil new markers for the diagnosis and risk stratification of this population.
Abstract 105: Increased Dynamic Mechanical Energy Dissipation in Human Abdominal Aortic Aneurysm
Authors: Mix Doran S , Bah Ibrahima , Toth Sandra A , Stoner Michael C , Doyle Adam J , Ellis Jennifer L , Glocker Roan , Buckley Mark R , Richards Michael
Published: June 2021

Objectives:
Individualized patient rupture risk for abdominal aortic aneurysms (AAA) remains elusive due to a limited understanding of the biomechanical events that trigger aneurysm growth and aortic wall failure. To date there has been a paucity of data describing how physiologic pulsatile energy is stored (E') and lost (E'') from AAA tissue. Our hypothesis is that AAA tissue dissipates more cyclic energy at a physiologic frequency, as determined by (E''/ E'), when compared to healthy aortic tissue.

Methods:
Human healthy aortic and AAA samples were obtained from cadaveric and surgical specimens. Specimens were stored at 4
o
C in 0.9%NS and mechanically tested within 36 hrs of explant. Uniaxial mechanical testing (ADMET BioTense) was performed in the circumferential orientation with the tissue pre-loaded to an equivalent physiologic stress of a 5 cm at a 110 mmHg mean pressure. A sinusoidal ±5% strain was applied at 1 Hz for 40 cycles with simultaneous force measurements. After mechanical testing, immunohistochemical staining was performed to confirm tissue viability.

Results:
AAA tissue was significantly stiffer when compared to healthy aorta, as demonstrated by a greater average static modulus (E) 1555.4 ± 384 vs. 970 ± 128 kPa (n=5, p=0.03). Dynamic testing of the AAA tissue noted a significantly greater energy loss (E'') 137.8±36.7 vs. 43.1±21.7 (p<0.01) and loss ratio (E''/ E') 0.090 ± 0.023 vs. 0.044 ± 0.023 (p=0.02), when compared to normal specimens. Figure #1 compares the static modulus (E) to the loss ratio (E''/ E') for the aortic tissue specimens. Histologic analysis confirmed tissue viability during of all specimens.

Conclusions:
Our data demonstrates that AAA tissue dissipates more energy (E'') and has a greater energy loss ratio (E''/ E'), suggesting that more pulsatile energy is dissipated in diseased tissue. Future work is needed to determine how this energy dissipation influences the biologic pathogenesis of AAA growth and rupture.
Abstract 106: Characterizing Aortic Wall Dynamics in Murine Models of Abdominal Aortic Aneurysms Using Ultrasound Imaging
Authors: Soepriatna Arvin H , Damen Frederick W , Vlachos Pavlos P , Goergen Craig J
Published: June 2021

The objective of this study is to use non-invasive ultrasound imaging to characterize aortic wall dynamics in abdominal aortic aneurysms (AAAs). We induced AAAs (n=5) in apolipoprotein-E deficient mice by subcutaneously implanting an osmotic pump, which systemically delivers angiotensin II at a rate of 1000 ng/kg/min for 28 days, in the back of each mouse. Once aneurysm formations were confirmed using a high frequency small animal ultrasound system (Vevo2100, Visualsonics; 40 MHz central frequency), we implemented our cardiac- and respiratory-gated volumetric ultrasound technique to acquire 3D AAA geometries throughout a cardiac cycle. Figure 1 summarizes the results obtained from a representative mouse with a suprarenal AAA. A 3D volume rendering of an abdominal aorta, with the aneurysm positioned in the center, is illustrated next to a color bar, which provides position references for both the maximum circumferential Green-Lagrangian (GL) strain and the instantaneous strain plots. Qualitative inspections of both strain plots depicted in Figure 1 demonstrate that maximum GL circumferential strain occurs during systole and is smallest within the AAA. Quantitative assessments of GL circumferential strain for all five AAAs were performed with similar results indicating that maximum GL strain decreased significantly within the aneurysm (1.1±0.2%) compared to proximal (9.3±5.3%) and distal (4.0±2.1%) regions (p<0.05). This decrease in GL circumferential strain within the aneurysmal portion of the abdominal aorta corroborates the idea that an increase in vessel stiffness is associated with the degradation of elastin and increased collagen turnover in the AAA wall. Interestingly, in all five cases, we observed a stiffer distal region, when compared to regions proximal to the aneurysm, suggesting that AAA development may also contribute to extracellular matrix remodeling of the aortic wall downstream of the aneurysm site.
Abstract 122: Use of Machine Learning to Accurately Predict Adverse Events in Patients With Peripheral Artery Disease Using Electronic Health Record Data
Authors: Ross Elsie G , Leeper Nicholas , Shah Nigam
Published: June 2021

Introduction:
Patients with peripheral artery disease (PAD) are at high risk of major adverse cardiac and cerebrovascular events (MACCE). However, no currently available risk scores accurately delineate which patients are most likely to sustain an event, creating a missed opportunity for more aggressive risk factor management. We set out to develop a novel predictive model - based on automated machine learning algorithms using electronic health record (EHR) data - with the aim of identifying which PAD patients are most likely to have an adverse outcome during follow-up.

Methods:
Data were derived from patients with a diagnosis of PAD at our institution. Novel machine-learning algorithms including random forest and penalized regression predictive models were developed using structured and unstructured data that including lab values, diagnosis codes, medications, and clinical notes. Patients were matched for total follow-up time to remove length of patient records as a biasing factor in our predictive models.

Results:
After matching for length of follow-up, 3,807 patients were included in our models. A total of 1,269 patients had a MACCE event after PAD diagnosis. The median time to MACCE was 2.8 years after PAD diagnosis. Utilizing 1,492 different variables extracted from the EHR, our best predictive model was able to very accurately predict which patients would go on to have a MACCE event after diagnosis of PAD with an AUC of 0.98, with a sensitivity, specificity and positive predictive value of 0.90, 0.96, and 0.93, respectively.

Conclusions:
Hypothesis-free, machine-learning algorithms using freely available data in the EHR can accurately predict which PAD patients are most likely to go on to develop future MACCE. While these findings require validation in an independent data set, there is hope that these informatics approaches can be applied to the medical record in an automated fashion to risk stratify patients with vascular disease and identify those who might benefit from more aggressive disease management in real-time.
Abstract 126: Differential Effects of Respectively Blocking Two BET Bromodomains on Vascular Smooth Muscle Cell Phenotype Transformation
Authors: Zhang Mengxue , Wang Bowen , Kent Craig , Guo Lian-Wang
Published: June 2021

Introduction:
Intimal hyperplasia (IH) occurs primarily due to vascular smooth muscle cell (SMC) transformation from quiescent to pathogenic phenotypes (e.g. proliferation and inflammation). Identification and effective targeting of key epigenetic factors governing SMC pathogenic transformation may lead to novel therapeutic methods for prevention of IH. We previously found that globally blocking the bromo- and extra-terminal (BET) epigenetic “reader” family abrogated SMC phenotype transformation and IH. We further investigated the functions of the two BET bromodomains (Bromo1 and Bromo2).

Hypothesis:
Bromo1 and Bromo2 play different roles in SMC pathogenic transformation.

Methods and Results:
We pre-treated rat primary aortic SMCs (for 2h) with Olinone or RVX208, inhibitors specific for Bromo1 and Bromo2 respectively, and then stimulated SMC phenotype transformation. Whereas RVX208 abrogated PDGF-BB-stimulated SMC proliferation (BrdU assay) in a dose dependent manner, Olinone enhanced SMC proliferation at high concentrations (>20 μM). RVX208 at 50 μM reduced TNFα-induced SMC inflammation (MCP-1 ELISA) by 80%,but Olinone at the same concentration slightly increased MCP-1. Furthermore, whereas RVX208 abolished PDGF-BB or TNFα-induced STAT3 phosphorylation (Western blotting), Olinone slightly increased phospho-STAT3.

Conclusions:
Our results reveal that blocking two BET bromodomains respectively produces distinct effects on SMC phenotype transformation, suggesting their differential epigenetic functions. Further elucidation of the underlying molecular mechanisms should contribute to precise targeting of the BET family for optimal mitigation of IH.
Abstract 130: Il-6 Mediates Vein Wall Response to Thrombosis in a Model Dependent Manner
Authors: Obi Andrea T , Kimball Andrew , Elfline Megan , Luke Catherine , Diaz Jose , Wakefield Thomas W , Henke Peter K
Published: June 2021

Background:
Venous thrombosis (VT) and the vein wall responses may be related to interleukin 6 (IL-6) signaling in humans and mice. Inflammatory and fibrotic effects of IL-6 largely signal through the trans pathway: IL-6/soluble IL-6Rα complex associates with ubiquitously expressed signal transducing protein gp130. We hypothesized that IL-6 signaling would differ depending upon thrombosis mechanism (complete v. partial stasis), and disruption of IL-6/IL-6Rα/gp130 axis would alter vein wall response to VT.

Methods:
Wild type C57BL/6 or IL-6-/- mice underwent induction of VT via inferior vena cava (IVC) stenosis (partial stasis) or ligation (complete stasis). Select WT mice received sgp130Fc chimera to inhibit trans pathway signaling. Vein wall, thrombus, and plasma were harvested at various time points and analyzed by PCR, western blot, ELISA or immunohistochemistry.

Results:
Compared to sham animals, those undergoing VT (complete or partial stasis) exhibited elevated vein wall IL-6 on post-VT day 4 (n=6-9, p<0.0001) but only complete stasis also had significantly elevated IL-6Rα (n=6-9, p<0.0001) and downstream intracellular signaling pathway molecule pSTAT3 (n=6-9, p=0.0002). Complete stasis VT in IL-6-/- mice was characterized by decreased circulating gp130 (n=4-6 p=0.0257), similar size thrombi to WT controls (0.020±0.005 v. 0.023±0.006, p=ns), and decreased CD68+ macrophage recruitment to the vein wall (n=3-5, p=0.0279). The IL-6-/- mice were protected from endothelial to mesenchymal-like transformation, as reflected by decreased FSP-1 (n=3-6, p<0.0001) and increased VE cadherin (n=3-6, p=0.0421) as compared with WT. Disruption of trans-signaling pathway via gp130Fc chimera resulted in less vein IL-6 (n=6-7, p=0.0027), TGF-β (n=6-7, p=0.0094), and decreased CD68 cell recruitment (n=3, p=0.0299).

Conclusions:
Experimental VT stimulates IL-6 and downstream signaling processes and is dependent on the mechanism of thrombosis. Genetic deletion of IL-6 and selective disruption of trans-signaling pathway by sgp130 decreases vein wall inflammation and influences vein wall remodeling. Targeting of IL-6 trans-signaling pathway may represent a therapeutic option to treat vein wall inflammation post thrombosis.
Abstract 132: Biomarkers of Cardiovascular Toxicity Following Benzene Exposure
Authors: Abplanalp Wesley , DeJarnett Natasha , Riggs Daniel , Li Xiaoping , Conklin Daniel , Xie Zhengzhi , Srivastava Sanjay , Bhatnagar Aruni , O'Toole Timothy
Published: June 2021

Benzene is a ubiquitous environmental pollutant abundant in plastics, petroleum products and cigarette smoke. Although hematopoietic and hepatic toxicity of benzene has been extensively studied, little is known about the effect of benzene on cardiovascular health. In this study, we assessed benzene exposure in a cohort of 210 participants with moderate to high CVD risk by measuring urinary benzene metabolite - trans, trans-muconic acid (t,t-MA). After adjusting for confounding variables we observed a 9% decrease in circulating levels of both early (AC133+) and late (AC133-) angiogenic cells for every 0.1mg t,t-MA/g creatinine increase in the urine. Uriniary t,t,MA levels were also positively associated with hyperlipidemia (P<0.02). Although smoking was associated with higher urinary levels of, t,t-MA, the association between benzene exposure and CVD risk was independent of smoking. In non-smokers, t,t-MA levels were positively associated with increased Framingham Risk Scores. Next, we examined the association of surrogate markers of cardiovascular functions and injury in male C57BL/6 mice exposed to HEPA-filtered air or benzene (50 ppm) for 6 hours/day for two (n=34/treatment) or six weeks (n=20/treatment). Both at two and six weeks of exposure to benzene increased fasting plasma glucose (13%, P<0.05), fasting insulin (39%, P<0.05) and HOMA-IR (72%, P<0.05); and platelet-leukocyte aggregates (PLAggs), a marker of platelet activation in vivo. This was accompanied by 26% decrease (P<0.05) in hepatic reduced glutathione level and activation of NF-κB in the liver and skeletal muscle. Moreover, after 6 weeks of benzene exposure plasma LDL and HDL were increased by 25% (P<0.05) and 5% (P<0.05) respectively; circulating endothelial microparticles were increased by 60% (P<0.05); and blood endothelial progenitor cells (EPCs) were decreased by 52% (P<0.05). These data suggest that exposure to benzene is associated with potential deficits in vascular repair and increased CVD risk.
Abstract 151: miR-29b and miR-146b Mediate the Chronic Inflammatory Response in Radiotherapy-induced Vascular Disease
Authors: Eken Suzanne M , Christersdottir Tinna , Pirault John , Sangsuwan Traimate , Jin Hong , Chernogubova Ekaterina , Korzunowicz Greg , Haghdoost Siamak , Hansson Göran K , Halle Martin , Maegdefessel Lars
Published: June 2021

Radiotherapy is an established therapeutic method in many different cancer types. The success of modern cancer treatment raises a new problem, namely radiotherapy-induced vascular disease (vRTx) or vasculopathy, which typically emerges in irradiated areas of the heart, neck and brain and manifests as coronary disease, heart failure or carotid stenosis. A chronic inflammatory response likely underlies vRTx. Like in atherosclerosis, complex biological processes such as vascular cell proliferation, remodeling, oxidative stress, DNA repair, and tumor growth factor β (TGF-β)-regulated nuclear factor kappa B (NF-κB) activation are involved. These processes are tightly regulated by a multitude of factors, which on their own are difficult to influence therapeutically.

In other diseases, a set of miRNAs is known to orchestrate these processes. It is likely that they also play a role in vRTx, and might be modifiable in order to treat or prevent this disease. We selected miR-29b, miR-125a, miR-126, miR-143, miR-145, miR-146, miR-155, miR-221 and miR-222, and determined their potential contribution to vRTx. Using qRT-PCR screening of human material from microvascular free tissue transfer reconstructions, where irradiated (R) vascular tissue (branches from external carotid arteries and internal jugular veins) can be compared with non-irradiated control tissue (NR) within the same patient (
n
=15), we found miR-29b and miR-146b to be deregulated after irradiation. These miRNAs target genes involved in the innate immune response, which we could confirm with Affymetrix-based tissue gene expression analysis in the same human cohort. In vascular smooth muscle and endothelial cells
in vitro
receiving two radiation doses of 2 Gy, miR-29b and miR-146b, respectively, were deregulated 24 hours after exposure. Using local irradiation in
Apoe
-/-
mice as a model for vRTx, we are currently analyzing the expression and localization of miR-29b and miR-146b in R
vs
NR vascular tissue at various time points after a single, 14 Gy irradiation dose. In this model, we aim to modulate miRNA expression in order to dampen radiation-induced inflammatory responses at an early stage, thereby exploring miRNA modulation as a therapeutic option to prevent vRTx in cancer survivors.
Abstract 162: Resident Aortic Intimal Mononuclear Phagocytes (MNPs) in the Promotion of Atherosclerosis
Authors: Williams Jesse W , Kim Ki-Wook , Ivanov Stoyan , Epelman Slava , Lavine Kory , Zinselmeyer Bernd H , Randolph Gwendalyn J
Published: June 2021

Atherosclerosis is an underlying cause of cardiovascular disease (CVD) and a leading cause of morbidity and mortality worldwide. Atherosclerosis promotes CVD through plaque formation, restricted blood flow, and thrombotic events. Macrophage accumulation in plaques, their uptake of cholesterol, and subsequent local death drive disease progression, however, there is growing appreciation for more diverse roles of myeloid cells during disease progression. Here, we focused on characterization of so-called vascular dendritic cells (DCs), which we refer to as aortic mononuclear phagocytes (MNP), that reside under the endothelium in plaque-prone areas. Using en face whole-mount confocal microscopy of aortas, we confirm a uniform resident CD11c+ CX3CR1+ MHCII+ MNP population, even in C57/BL6 mice resistant to atherosclerosis. We find aortic MNPs require M-CSF and Flt3 signaling for survival, but are independent of CCR2 and GM-CSF receptor signaling, making them a distinct myeloid population. They express macrophage-restricted genes LysM and CD64, but not dendritic cell specific genes zBTB46 or L-myc. Lineage-tracing analysis using CD115creER and Flt3cre reporter mice indicate that aortic MNPs likely differentiate from definitive hematopoiesis and not early yolk sac progenitors. Parabiosis experiments show that aortic MNPs are self-maintained independent of blood-born progenitors, failing to exchange with blood progenitors for up to 5 months. Aortic MNPs are different from either typical DCs or macrophages and instead appear to blend distinguishing features of each, more closely resembling macrophages. Using our characterization data, we hope to develop an inducible cell-tracking and a cell-depletion model to differentiate the function of aortic MNPs during the progression of atherosclerosis. Overall, we anticipate these functional analyses will reveal, for the first time, the role of resident aortic MNPs in atherosclerosis.
Abstract 175: High Glucose Pre-treatment Suppresses Rankl-induced Macrophage Activation via Down-regulation of Glucose Uptake Through Decreased Insulin Receptor and Insulin Receptor Substrate 1 Expression
Authors: Kurihara Chitaru , Tanaka Teruyoshi , Yamanouchi Dai
Published: June 2021

Background:
Previous studies have suggested that the pathogenesis of abdominal aortic aneurysm (AAA) is associated with the local proteinases activation and the degradation of matrix proteins by matrix metalloproteinases (MMPs) produced from activated macrophages. One of the major features of diabetes mellitus (DM)-induced vascular pathology is severe arterial calcification. Although recent large epidemiological studies have shown that DM is an independent negative risk factor for AAA, the effects of hyperglycemia on macrophages are still controversial. We have hypothesized that hyperglycemia suppresses macrophage activation through altered glucose transportation.

Methods and Results:
RAW264.7 cells, a murine macrophage cell line were cultured under high glucose conditions (HG group, 15.5 mM glucose) or normal glucose conditions (NG group, 5.5 mM glucose) for 7days. Cells from both groups were then transferred to normal glucose condition and stimulated with recombinant murine sRANKL. Macrophage activation, confirmed by TRAP staining positive cells, and MMP-9 expression were induced in NG group but were significantly suppressed in HG group. Glucose uptake was increased during osteoclastogenesis in NG group but not in HG group. To elucidate the underlying mechanism for this observation, we studied glucose transporters (GLUTs). Although GLUT-1 and GLUT-3 expression were not affected in either groups, the membrane translocation of GLUT-1 was significantly increased in NG group during macrophage activation but not in HG group. Insulin receptor and insulin receptor substrate-1 (IRS-1) mRNA, known to stimulate membrane translocation of GLUT, were both decreased in HG group compared to NG group.

Conclusions:
Our results showed hyperglycemia suppresses macrophage activation. Our results also indicated that under normal conditions, recombinant murine sRANKL increases glucose uptake during macrophage activation. In contrast, this increase is impaired in high glucose pre-treated cells. We conclude that this impairment is due, in part, to suppressed GLUT-1 membrane translocation through down regulation of insulin receptor and IRS-1
Abstract 176: O-GlcNAc Transferase Promotes Vascular Smooth Muscle Cell De-differentiation
Authors: Leslie Kristen , Xie Yi , Ostriker Allison , Martin Kathleen
Published: June 2021

Vascular smooth muscle cells (VSMCs) in mature vessels have a differentiated, contractile phenotype but retain the ability to reversibly de-differentiate in response to environmental cues. Plasticity is necessary for development and wound healing, but also contributes to pathologies such as atherosclerosis and intimal hyperplasia.
O-
linked
N-
acetylglucosamine (
O
-GlcNAc) transferase (OGT) mediates nutrient-sensitive post-translational modification of serine and threonine residues and has been implicated in multiple diseases, but its role in VSMC phenotypic modulation is not known. In human coronary SMCs, we found that OGT knockdown significantly increased contractile marker expression, including
MYH11
and
ACTA2,
at the mRNA and protein levels. OGT knockdown also decreased proliferation rates after serum treatment in VSMCs. In addition, rapamycin, a differentiating agent, decreased OGT protein expression and
O-
GlcNAc levels. Conversely, de-differentiation with PDGF treatment increased OGT expression and global
O-
GlcNAc. Neither treatment affected OGT mRNA levels. OGT has been shown to increase the protein stability of EZH2, the enzyme that generates the inhibitory histone epigenetic mark H3K27me3. We found that OGT knockdown did not affect EZH2 mRNA levels but significantly decreased EZH2 protein expression as well as global H3K27me3 in VSMCs. Similar to OGT, EZH2 expression was decreased upon rapamycin treatment and increased with PDGF. A decrease in ubiquitination of EZH2 was observed after PDGF treatment, suggesting an increase in protein stability. Importantly, EZH2 knockdown increased protein expression of SMC contractile markers while EZH2 overexpression repressed these markers. Wire injury of mouse femoral arteries increased H3K27me3 levels after 21 days. OGT expression was elevated in the innermost layer of the neointima at the same time point. These data demonstrate that OGT inhibits VSMC differentiation and that OGT and its target EZH2 are both dynamically regulated during phenotypic modulation. Future work will illuminate if OGT promotes VSMC de-differentiation through EZH2-mediated histone modification at contractile gene promoters.
Abstract 177: Adenosine Receptor 2A-mediated Endothelial Glycolysis Critically Contributes to Pathological Angiogenesis of Retina
Authors: Liu Zhiping , Yan Siyuan , Wang Jiaojiao , Wang Yong , Xu Yiming , Yang Qiuhua , Li Qinkai , Hong Mei , Huo Yuqing
Published: June 2021

Pathological proliferative retinopathy is the most common cause of blindness in patients of all ages worldwide. Investigation of the molecular mechanisms underlying pathological retina neovascularization is critical to the development of new therapeutic strategies. In the current study, we investigated the effect of macrophage or endothelial cell adenosine receptor 2A (A
2A
R) deletion in pathological retinal vascular growth, and further explored the potential mechanism. Our results showed that:
(1)
A
2A
R expression was localized to retinal vessels and was markedly induced in pathological neovascularization tufts in a mouse model of oxygen-induced proliferative retinopathy (OIR) (Figure A);
(2)
endothelial cell, but not macrophage, -specific A
2A
R deletion significantly decreased pathological neovascularization in the mouse OIR model (Figure B);. The levels of glycolytic enzymes, angiogenic factors and lactate secretion were markedly reduced in retina of endothelial cell-specific A
2A
R knockout mice;
(3)
in human retinal microvascular endothelial cells (HRMECs), hypoxia markedly induced the expression of A
2A
R, but not A
1
R, A
2B
R and A
3
R, by activating HIF-2α. Deletion or blockade of A
2A
R by small interfering RNA (siRNA) or antagonist ZM241385 decreased hypoxia or adenosine-induced glycolytic enzyme expression, lactate secretion and cell proliferation via suppression of the cAMP/PKA/CREB/HIF-1α pathway;
(4)
blockade of glycolysis by 3PO or 2-DG abolished the adenosine-induced HRMEC proliferation under hypoxic conditions. Taken together, we have demonstrated a critical role of endothelial cell A
2A
R in promoting pathological vascular development and revealed a novel glycolysis-driven mechanism for endothelial cell A
2A
R-mediated pathological angiogenesis in proliferative retinopathy. Thus, A
2A
R is a promising therapeutic target in the treatment of proliferative retinopathy.
Abstract 180: The Myristolated Alanine-Rich C Kinase Substrate (MARCKS) Differentially Regulates Proliferation of Vascular Smooth Muscle Cells and Endothelial Cells through Affecting Protein Stability and Proteolytic Processing of the Kinase Interacting with Stathmin (KIS)
Authors: Yu Dan , Drucker Charles , Sarkar Rajabrata , Strickland Dudley K , Monahan Thomas S
Published: June 2021

Objective:
Presently, the antiproliferative agents used in drug eluting stents and drug coated balloons inhibit both VSMC and endothelial cell (EC) proliferation, and thus these patients require dual antiplatelet therapy indefinitely. Identification of a VSMC-specific target to prevent proliferation represents a significant unmet clinical need. Previously we found that knockdown of MARCKS arrests VSMC proliferation through a p27
kip1
-dependent mechanism. Interestingly MARCKS knockdown increases EC proliferation. p27
kip1
is phosphorylated by KIS allowing it to exit the nucleus and be degraded. Here we seek to understand how MARCKS influences KIS protein expression in these two cell types.

Approach and Results:
We performed siRNA-mediated knock down of MARCKS in human coronary artery endothelial cells (CAECs) and human coronary artery smooth muscle cells (CASMCs). MARCKS knockdown did not affect KIS mRNA expression as determined with RT-PCR in either cell type. KIS protein stability was evaluated in the presence of cyclohexamide with Western blot. In CAECs, MARCKS knockdown increased KIS stability, however, in CASMCs, MARCKS knockdown significantly decreased KIS protein stability. In CASMCs, MARCKS knockdown significantly increased KIS ubiquitinization where as in CAECs, MARCKS knockdown decreased KIS ubiquitinization. Interestingly, the well-studied functional domain of MARCKS(ED domain) is not directly involved in KIS regulation. MARCKS mutants (S4G and S4D) rescued proliferation in VSMCs. MARCKS knockdown in vivo in the murine femoral wire injury model resulted in decreased medial bromodeoxyuridine (BrdU) integration and neointima formation. MARCKS knockdown enhanced endothelial barrier function recovery four days after injury as assessed by Evans Blue integration.

Conclusions:
MARCKS differentially regulates the protein stability and proteolytic processing of KIS in VSMCs and ECs. The differential interaction of MARCKS and KIS likely explains the observed difference in proliferation observed with MARCKS knockdown in these two cell types.