bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Teaching Quality of English Courses in Comprehensive Universities under Multiple Indicators
Authors: Song Haiying
Published: September 2022

With the continuous development of internationalization and the task of cultivating graduates with high comprehensive quality for the society, the importance of English teaching in comprehensive universities has been increasing. In this paper, based on the analysis of the evaluation subjects of university English teaching quality, 16 evaluation indexes are constructed from five aspects: teaching content, teaching method, teaching process, teaching literacy, and teaching effect, and the Particle Swarm Optimization-Least Squares Support Vector Machine (PSO-LSSVM) algorithm is used to comprehensively evaluate the teaching quality, and finally English teaching in universities is selected as the object of empirical research. The research results show that PSO-LSSVM algorithm has high applicability in evaluating ECCU and can provide over reference for universities to improve teaching quality and develop reform programs. Due to the lack of training data, although the evaluation index system in this paper is scientific and feasible, it still needs to be further adjusted and optimized according to the specific practice situation.
A Partnership of Virtual Power Plant in Day-Ahead Energy and Reserve Markets Based on Linearized AC Network-Constrained Unit Commitment Model
Authors: Haghighi Yadollah , Bahmani-Firouzi Bahman , Nafar Mehdi
Published: September 2022

This paper presents coordinated energy management as a virtual power plant (VPP) framework with a wind farm, a storage system, and a demand response program in the transmission network according to the cooperation of VPPs in day-ahead energy and reserve markets. This strategy is based on a bilevel method, where it maximizes the expected VPP revenue in the proposed markets subject to constraints of renewable and flexible sources and the VPP reserve model in the upper-level problem. Also, a market-clearing model based on network-constrained unit commitment (NCUC) is explained in the lower-level problem so that it minimizes the expected operating cost of generation units constrained to a linearized AC-NCUC model. The scenario-based stochastic programming (SBSP) models the uncertainties of loads and WF power generation. Then, the master/slave decomposition method solves the bilevel problem to achieve an optimal solution at a low computational time. Also, since the lower-level problem is mixed-integer linear programming, the Benders decomposition algorithm is adopted to solve this problem. Finally, the suggested approach is implemented on IEEE test networks in GAMS software, and numerical results confirm the efficiency of the coordinated VPP management in DA energy and reserve markets and its capabilities in improving network operation.
Nanoclay Reinforced Ternary Blends Based on Biodegradable Polymers for Drug Delivery Application
Authors: Ali Mohsin , Mir Sadullah , Abid Obaid-Ur-Rahman , Yawer Mirza Arfan , Ullah Ihsan
Published: September 2022

In this study, ternary blends based on chitosan, polyvinyl alcohol, and polyethylene glycol reinforced with organically modified montmorillonite (nanoclay) clay were synthesized. These ternary blends were evaluated as transdermal drug delivery patches using tramadol as a model drug. The FTIR study showed interaction among important functional groups and compatibility among the mixing components. Among drug-loaded formulations, composite MA12 shows maximum thermal stability with 27.9% weight residue at 540°C. The prepared formulations exhibited crystalline nature as observed by XRD analysis. SEM studies revealed that there are no gaps and cracks in prepared films and nanoclay was found dispersed in the formulations. The swelling ratio was higher in pH 1.2 as compared to pH 4.5 and pH 6.8 buffers, and there was an increase in swelling with an increase in PVA concentration. Moreover, the drug release test performed in phosphate buffer pH 6.8 showed that tramadol release from nanocomposite films increases with an increase in PEG concentration. Permeation studies indicated that the rate of permeation increased with a decrease in PVA concentration. The permeation rate was found to be higher for samples without nanoclay. The overall results suggest nanocomposite films as excellent candidates for transdermal drug delivery application.
Deep Learning-Enabled Automatic Detection of Bridges for Promoting Transportation Surveillance under Different Imaging Conditions
Authors: Han Peng , Yang Xiaoxia
Published: September 2022

The reliable and accurate detection of bridges plays an important role in imaging-driven transportation surveillance. It is capable of timely providing the traffic information, leading to safer and more convenient transportation. However, the visual quality of observed images is often inevitably reduced owing to the adverse weather conditions, e.g., haze and low lightness. It is still difficult to adopt the existing powerful deep learning methods to reliably and accurately detect the bridges under different imaging conditions. To achieve satisfactory bridge detection results, we first propose to exploit the data augmentation strategy and physical imaging method to generate the natural-looking experimental dataset, which contains latent high-quality images and their hazy and low-light versions. We then investigate how to further promote the deep learning-based bridge detection methods through the manually generated dataset. It is obvious that the generalization abilities of these deep neural networks are significantly improved using this data augmentation strategy. In this work, we constructed an original dataset consisting of 3500 images of size 900×600, collected under normal imaging condition. Extensive detection experiments will be performed based on the augmented dataset. Experimental results have demonstrated that our automatic bridge detection framework could generate more reliable and accurate results compared with existing detection methods.
Route Control and Behavior Decision of Intelligent Driverless Truck Based on Artificial Intelligence Technology
Authors: Wang Feng , Zhang Zhaofeng
Published: September 2022

With the increase in global car ownership, the demand for traffic safety is very strong. Research shows that drivers account for more than 90% of global traffic accidents. Driverless cars can reduce traffic accidents caused for these reasons and greatly improve traffic safety. At the same time, driverless real-time path planning can select the best driving route for vehicles, reduce traffic congestion, and improve the efficiency of transportation. To sum up, driverless vehicles are considered an important solution to ensure traffic safety, improve traffic efficiency, reduce energy consumption and pollution, and change travel mode. An intelligent driverless vehicle is a key component of the intelligent transportation system, which organically combines various functions such as. Among them, path tracking and motion control play a very important role in intelligent driverless technology. At the same time, accurately tracking the desired feasible path and stable motion control are the basis of intelligent unmanned driving. Based on this, this paper uses artificial intelligence technology to study the path control and behavior decision-making of intelligent driverless trucks, and an improved tracking control method is proposed. Through this improved method, the intelligent unmanned vehicle can track the desired feasible path under different curvatures more accurately and stably. Finally, through the road test experiment of the intelligent unmanned vehicle experimental platform in the actual environment, the effectiveness of the scheme design and related algorithms of intelligent unmanned vehicle motion control in this paper is verified.
Technique for Large-Scale Antenna Beamforming Based on Neural Network
Authors: Chaochen Xie , Rujing Guo , Jianzhou Zhao
Published: September 2022

The commercialization of the fifth-generation technology and the rapid development of Internet of Things technology have made mobile communication networks increasingly complex. Simultaneously, the massive terminal connections have caused serious interference between networks. Large-scale array antennas have become a hot topic of recent studies to improve the wireless transmission characteristics and spectrum resource utilization efficiency. This study was aimed at exploring using large-scale array antennas combined with neural networks in ultradense cells to improve the wireless signal transmission quality. The simulation results showed that the scheme realized not only the wireless signal transmission with a neural network but also the effective recovery of the source signal. Similarly, the application of this scheme effectively reduced the power consumption during signal transmission, the delay, and the interference.
Propagation of Partially Coherent Flat-Topped Vortex Hollow Beams in Anisotropic Turbulent Plasma
Authors: Alkelly Abdu A. , Khaled M. A. H. , Hassan Labiba F.
Published: September 2022

The propagation properties of partially coherent circular flat-topped (FT) vortex hollow/nonvortex beams are studied in anisotropic turbulent plasma. The analytical expression of the optical intensity of these beams is obtained by employing the extended Huygens–Fresnel integral. The effects of the source and turbulent plasma parameters on the intensity distribution of partially coherent circular FT vortex hollow/nonvortex beams are analyzed numerically. The results show that partially coherent circular FT vortex hollow/nonvortex beams will finally converge into a Gaussian intensity profile at increasing propagation distances. The results also showed that the partially coherent FT vortex hollow/nonvortex beams with higher coherence are less affected by anisotropic turbulent plasma than the less coherent beams.
Large-Area Saline-Alkali-Tolerant Rice Growth Environment Monitoring System Based on LoRa+UAV
Authors: Mo Chunmei , Xie Zaimi , Wang Ji
Published: September 2022

A wireless sensor network (WSN) monitoring system for saline-alkali-tolerant rice based on long-range + unmanned aerial vehicle (LoRa + UAV) has been proposed in this paper to meet the requirements of difficult deployment, low scalability, and poor network reliability of traditional farmland environmental monitoring systems. The system automatically forms a double-layer star topology network through the terminal node and central node (intranet), central node, and UAV mobile node (extranet). Data transmission is carried out through LoRa technology, routing planning is carried out for UAV mobile receiving nodes at different flight altitudes, and an early warning mechanism for UAV energy is added. It effectively prevents the UAV from destroying the communication capability of the external network due to energy exhaustion during operation. The system transmits information remotely to the server of the management center through a 5G network, which analyzes and processes the data and publishes it on the Web. The system has been tested in the field, and the reliable communication range of the node is 1∼4 km under the saline-alkali-tolerant rice environment, and the service life of the terminal node can reach more than 3 months. During continuous operation, the maximum packet loss rate of the internal and external integrated networks is 1.45%. The system can stably and real-time monitor saline-alkali-tolerant rice environmental information, and the error rate is less than 10%, which can meet the performance requirements of the saline-alkali-tolerant rice environmental monitoring systems, such as low power consumption, wide coverage, stability, and reliability, and has a good engineering significance.
Prediction and Analysis Method of Mine Blasting Quality Based on GA-BP Neural Network
Authors: Yu Jianyang , Ren Shijie
Published: September 2022

Selecting reasonable blasting parameters of ore and rock is an important measure to achieve good blasting effect. In the mining process, rock fragmentation is an important index to evaluate the blasting effect, which directly affects the technical scheme, equipment selection, economic effect, and other issues of the mine and even seriously threatens the sustainable safety production of the mine. With the rapid development of information technology, the development of computer intelligent image recognition technology is becoming more and more perfect, and its role is becoming more and more important. Based on the neural network method, this paper studies the computer intelligent image recognition technology. In this paper, the GA-BP network image recognition model is established by combining genetic algorithm with BP algorithm and analyzing the principles of intelligent image recognition, image pattern recognition, and BP neural network learning algorithm. On the basis of experimental analysis, the average accuracy of prediction can reach 67.4%. For the efficiency analysis of computer mathematical analysis, it will generally reach 64.3%. In this paper, taking the lump rate and blasting cost as the optimization objective function, the comparison and selection of multiple schemes of production blasting design are carried out, which provides quantitative decision-making basis for the rational selection of production blasting design parameters.
ALKBH5-Mediated m6A Demethylation of GLUT4 mRNA Promotes Glycolysis and Resistance to HER2-Targeted Therapy in Breast Cancer
Authors: Liu Hao , Lyu Hui , Jiang Guanmin , Chen Danyang , Ruan Sanbao , Liu Shuang , Zhou Lukun , Yang Minqiang , Zeng Shanshan , He Zhimin , Wang Hongsheng , Li Hongsheng , Zheng Guopei , Liu Bolin
Published: September 2022

Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of patients with breast cancer with HER2-positive tumors. Through a global mass spectrometry–based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacologic targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib, both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating patients with breast cancer refractory to HER2-targeted therapies.

Significance:

GLUT4 upregulation by ALKBH5-mediated m6A demethylation induces glycolysis and resistance to HER2-targeted therapy and represents a potential therapeutic target for treating HER2-positive breast cancer.
Liver Complications in Untreated Treatment-Ineligible versus Treated Treatment-Eligible Patients with Hepatitis B
Authors: Huang Daniel Q. , Lee Dong Hyun , Le Michael H. , Le An , Yeo Yee Hui , Trinh Huy N. , Chung Mimi , Nguyen Vy , Johnson Tiffani , Zhang Jian Q. , Wong Clifford , Wong Christopher , Li Jiayi , Cheung Ramsey , Nguyen Mindie H.
Published: September 2022

Background: A substantial number of patients who do not meet treatment criteria for chronic hepatitis B (CHB) later develop adverse outcomes such as cirrhosis and hepatocellular carcinoma (HCC). Our aim was to determine whether current practice guidelines adequately identify CHB patients who will benefit from antiviral therapy. Methods: We performed a retrospective cohort study comparing the incidence of adverse liver outcomes (cirrhosis and/or HCC) in untreated treatment-ineligible (at baseline and throughout follow-up) versus treated treatment-eligible patients according to standard American Association for the Study of Liver Diseases (AASLD) 2018 guidance (alanine aminotransferase [ALT] >70/50 U/L for men/women plus hepatitis B virus [HBV] DNA >20,000/2,000 IU/mL for HBeAg+/−) and with a sensitivity analyses using a lower threshold (ALT >40 U/L and HBV DNA >2,000 IU/mL). Results: We reviewed records of 5,840 patients from 5 clinics in California and identified 2,987 treatment-naive non-HCC CHB patients. Of those, 271 patients remained untreated treatment-ineligible, 514 patients were treatment-eligible and initiated treatment, with 5-year cumulative adverse liver incidences of 12.5% versus 7.2%, p = 0.074. On multivariable analysis adjusting for age, sex, diabetes, albumin, platelet count, and HBV DNA, compared to treated treatment-eligible patients, untreated treatment-ineligible patients had a significantly higher risk of adverse liver outcomes (adjusted hazard ratio: 2.38, 95% confidence interval 1.03–5.48, p = 0.04) in main analysis by AASLD 2018 criteria but not in sensitivity analysis using the lower treatment threshold (p = 0.09). Conclusion: Patients never meeting standard AASLD 2018 criteria for antiviral therapy and never treated had twice the risk of developing cirrhosis and/or HCC when compared to eligible and treated patients.
Abstract 001: Germline Mutagenesis Induces Blood Pressure And Heart Rate Variation In Mice Uncovering Novel Insights On The Genesis Of Cardiovascular Disease Risks
Authors: Kuwada Teixeira Samantha , Pontes Roberto , Zuleta Luiz Fernando , Rosa Rogerio , Bertoline Letícia , Wang Jianhui , xu darui , Russell Jamie L , Zhan Xiaoming , Choi Mihwa , Tang Miao , Li Xiaohong , Ludwig Sara , Beutler Bruce , Krieger Jose E
Published: September 2022

Resting blood pressure (BP) and heart rate (HR) levels are independent risk factors for cardiovascular diseases and mortality. Both phenotypes are critical for lifetime maintenance of the cardiovascular homeostasis and are under the influence of multiple factors. The estimated heritability for both phenotypes is high, but their main genetic determinants remain elusive. To address this shortcoming, we used a strategy to systematically identify genes affecting BP and HR regulation through high-throughput N-ethyl-N-Nitrosurea-induced germline mutagenesis. First, the random chemical-induced mutations were identified in founder animals by whole exome G1 progenitor sequencing and their zygosity established in G2/G3 mice before phenotypic assessment. We used the noninvasive tail cuff method to assess BP and HR in conscious G3 mice distributed in pedigrees of 30-100 G1 descendants. The quantitative traits were then analyzed with Linkage Analyzer in single or multiple combined pedigrees, detecting significant linkage between individual mutations and altered phenotypic scores in heterozygous or homozygous mice. Here, we report the initial results of BP and HR candidate genes selected during the screening of 45,261 G3 mice from 878 pedigrees, testing the effects of 45,317 variant alleles within 14,575 genes, in which 23 % of all autosomal genes were severely damaged. The data indicate that ENU mutagenesis effectively identified 85 candidate genes affecting BP and 132 HR levels, including only 13 and 18 genes previously known to influence BP and HR, respectively. Moreover, we validated the influence of three and seven new genes on BP and HR control through reverse genetics that may be associated with ageing, vascular integrity and cardiac development. These findings shed light on novel underlying mechanisms associated with both phenotypes and highlight sub-systems contributing to the genesis of critical risk factors associated with cardiovascular diseases.
Abstract 007: Hypertension-induced Neurovascular Dysfunction At Single-cell Resolution
Authors: Schaeffer Samantha M , Santisteban Monica M , Faraco Giuseppe , Garcia-bonilla Lidia , Anrather Josef , Iadecola Costantino
Published: September 2022

Hypertension (HTN) disrupts vital neurovascular control mechanisms, thereby increasing the brain’s susceptibility to vascular insufficiency, white matter lesions, and cognitive impairment. Yet, the distinct vascular, neuronal, and glial cell types targeted by HTN, as well as the ensuing cellular network disruption driving the neurovascular and cognitive deficits remain undefined. Here we sought to uncover transcriptomic changes in neurons and vascular cells using unbiased, single-cell RNA sequencing on the neocortex of 10-week old C57BL/6 male mice with angiotensin II (AngII) HTN. Vehicle or AngII (600ng/kg/min s.c.) were administered for 3 days, when blood-brain barrier (BBB) permeability start to increase, or 42 days, when neurovascular and cognitive dysfunction are fully developed (n=3/group). We analyzed 39,451 single-cell transcriptomes comprising 26 cell types. Surprisingly, 3 days of AngII induced significantly greater transcriptional changes in venular ECs compared to arteriolar ECs (EdgeR; pval< 0.05, logFC> 2), supporting the notion that venular ECs are uniquely sensitive to the early effects of HTN (Hypertension 76:795, 2020). Gene ontology analysis of differentially expressed genes prominently implicated altered venular immune signaling, BBB dysfunction, and, notably, a secretory phenotype characteristic of senescence (pval <0.05). Moreover, unbiased ligand-receptor interaction analysis (CellChat) demonstrated that senescent venular ECs strongly communicate with oligodendrocyte precursors, and NPY-expressing interneurons, pointing to a previously unrecognized early disruption in the oligo-vascular niche, essential for maintaining white matter integrity, and neuronal network stability. Furthermore, at 42 days of AngII we observed an overrepresentation of aging and neurodegeneration-linked genes in oligos and NPY interneurons, relating to myelin disruption, synaptic dysfunction, and metabolic dysregulation. The data reveal a novel endothelial-oligo-interneuron crosstalk and transcriptomic alterations underlying the impact of HTN on the brain. Future studies will establish how these transcriptomic changes are linked to neurovascular dysfunction, white matter damage and cognitive impairment.
Abstract 011: Epigenetic Determinants Of Renin Cell Identity
Authors: Smith Jason P , Martini Alexandre G , Sheffield Nathan , Sequeira Lopez Maria , Gomez Roberto A
Published: September 2022

Renin secreting cells are restricted in adult mammals within the walls of renal arterioles near the entrance to the glomeruli and are therefore known as juxtaglomerular (JG) cells. These JG cells are critical for survival through the maintenance of homeostasis via the release of the peptide hormone renin in response to changes in blood pressure. By performing independently paired scATAC-seq and scRNA-seq during mouse kidney development, we sought to identify epigenetic markers of renin cell identity. While we lack spatial information, we identified putative JG cells through the identification of cells enriched in canonical markers (Ren1 and Akr1b7) of JG cell identity using both expression and accessibility derived measures of gene activity. We constructed a pseudotime trajectory of cells that lead to the mature JG population and performed pairwise comparisons of cell populations to identify the genomic regions and transcription factors (TFs) contributing to JG cell identity. As JG cells form along this trajectory, significantly different (Log2FC>0.5 and FDR<0.1) regions of accessible chromatin define the JG cell population. Within these open regions, the MEF2 family of TF motifs are significantly enriched (log10Padj > 20). We further identify a specific region of accessible chromatin (chr1:133345385-133345885) unique to the initial population of JG cells located within a Ren1 super enhancer previously identified by our group. This region is co-accessible with several regions of open chromatin within the greater Ren1 gene region (correlation > 0.75) where we identify putative binding sites for Mef2b, 2c, and 2d at these co-accessible regions. As the mature renin-expressing cells further differentiate into terminally differentiated cell populations including pericytes and mesangial cells, we continue to see significant enrichment of the MEF2 TF family within the JG cell population compared to downstream populations (log10Padj > 646.6891). Overall, we have presented the first investigation and finding using single-cell -omics of the JG cell population and uncover the importance of the MEF2 family of TFs as significant drivers of JG cell formation and identity.
Abstract 012: L-type Calcium Channel Subunit Alpha1d (CACNA1D) Gene Polymorphisms Associate With Higher Blood Pressure And Salt Sensitivity Of Blood Pressure
Authors: Stanton Ana Maria , Heydarpour Mahyar , Williams Jonathan S , Williams Gordon H , Adler Gail K
Published: September 2022

Somatic activating mutations in CACNA1D can result in aldosterone producing adrenal adenomas and hypertension. Using the environmentally controlled HyperPATH cohort, we assessed whether germline mutations (variance in the CACNA1D gene) associate with blood pressure (BP), salt sensitivity of BP (SSBP) and two proximate mechanisms of SSBP--- plasma renal activity (PRA)/aldosterone (ALDO) and renal plasma flow (RPF). Participants completed a cross-over intervention of liberal and restricted Na
+
diets for 7 days. CACNA1D genotyping with a Multi-Ethnic Genotyping Array yielded 264 single nucleotide variants (SNVs) of which 104 met quality control. SNV rs7612148 strongly associated with systolic BP and was selected for analysis. Individuals with the SNV (n=521) were analyzed in 2 populations: 1) hypertensive, and 2) hypertensive plus normotensive. Multivariate linear regression analyses (table) identified an association with the risk allele and increased SSBP driven by a higher BP on the liberal Na
+
diet. Associations were also observed with reduced PRA and ALDO, and reduced RPF with increase in dietary Na
+
.

In conclusion, we identified a novel CACNA1D SNV that associates with SSBP likely related to an impaired ability to increase RPF with increased dietary sodium intake, but not related to an increase in ALDO production.
Abstract 014: Gestational Diabetic Cd4+ T Cells Cause Increased Glucose, Blood Pressure And Placental Mitochondrial Dysfunction In A Novel Rat Model Of Diabetes During Pregnancy
Authors: Deer Evangeline M , Williams Jan M , Amaral Lorena , Fitzgerald Sarah , Herrock Owen , Campbell Nathan , Lamarca Babbette B
Published: September 2022

Hypertensive (HTN) disorders complicate ~10% of all pregnancies worldwide and contribute to maternal and fetal morbidity and mortality. HTN increases risks for preeclampsia and preterm labor in women with gestational diabetes mellitus (GDM) and is characterized by hyperglycemia resulting from defects in insulin activity/secretion or both. Also, increased levels of maternal glucose, inflammatory mediators, abnormal placental vascular function, and cytokines are associated with the pathogenesis of GDM, however, we don’t know the importance of placental factors, inflammatory cells, and cytokines in causing HTN or other pathophysiological factors associated with GDM. We hypothesize placental CD4+T cells from pregnant DM patients (GDM) causes a DM phenotype in pregnant athymic nude rats. CD4+T cells were magnetically separated from placentas from GDM patients and injected into athymic nude rats on Gestation Day (GD) 12. On GD19, blood pressure (MAP), blood and tissues were collected and glucose was measured from GDM CD4+T cell recipients and pregnant nude control rats.Mitochondrial respiration and mtROS were measured as indicators of tissue function from isolated placental mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. A student’s t-test was used for statistical analysis. On GD19, MAP increased to 117±5.3 mmHg (n=3) in GDM T cell recipients compared to control pregnant athymic nude rats 102±0.0 mmHg (n=5). Blood glucose levels were elevated with GDM CD4+ T cells (275 ± 80 mg/dl, n=3, p<0.05) compared to pregnant athymic nude rats (91 ± 16 mg/dl, n=5).Placental state 3 (10±1 vs 433±113 pmol/sec/mg, p<0.05), indicative of ATP production, was reduced with GDM CD4+ T cells (n=3) compared to control pregnant athymic nude rats(n=5). Placental mtROS (H2O2) was increased with GDM CD4+ T cells (264 ± 14 % gated, n=3, p<0.05) compared to pregnant athymic nude rats (100 ± 26 % gated, n=5).Collectively, these data indicate that GDM CD4+T cells cause the GDM phenotype during pregnancy by increasing glucose and blood pressure in association with placental mitochondrial dysfunction/ROS during pregnancy, thereby introducing a new model to investigate mechanisms and new therapies for diabetes during pregnancy.
Abstract 015: Hypertensive Stretch On The Regulation Of The Immunological Synapse And Secretomes Of Male And Female Renal Endothelial Cells
Authors: Colvert Alex , Semenikhina Marharyta , Deleon-Pennell Kristine Y , Oates Jim , Palygin Oleg , Van Beusecum Justin P
Published: September 2022

Immune cells and inflammation contribute to the development of hypertension and renal injury. While endothelial cells are recognized as professional antigen presenting cells, they can express both Major Histocompatibility Complex (MHC) I and II and possess antigen-presenting functions. Endothelial cell activation and inflammation are critical in the development of hypertension. However, the mechanisms by which inflammatory hypertensive stimuli regulate renal endothelial immunological synapse proteins remains unknown. We hypothesize that inflammatory hypertensive mechanical stretch promotes the regulation of MHC I and II and costimulatory molecules on mouse renal endothelial cells (MRECs) in a sex-dependent manner. MRECs derived from both sexes underwent normotensive (5%; 1 Hz), hypertensive (10%, 1 Hz), and supra-hypertensive (15% 1 Hz) uniaxial cyclical stretch for 48 hours. We then assessed CD80, CD86, MHC II, MHC I, CD70, and CD40 by immunoblot analysis. A proteome multiplex assay was used to analyze male and female MREC secretomes during 5%, 10%, and 15% stretch. Hypertensive 10% stretch significantly increased only CD40 expression in males, while it upregulated CD80 and CD70 expression in females (p<0.05). Under 15% stretch, males significantly upregulated MHC I, CD70, and CD40 compared to I-Ab, CD80, CD86, and CD70 in females MRECs (p<0.05). We investigated sex differences and found that females significantly increased CD70 in both 10% and 15% stretch compared to males MRECs (p<0.05). We compared sex differences from our secretome proteomics in male and female MRECs at 10% and 15% stretch. We found that pathways associated with wound healing, Th17 activation, IL-6, and NF-κB signaling were upregulated in male MRECs undergoing 10% stretch. Interestingly, Th17 activation, natural killer cell signaling, and IL-23 signaling were downregulated in female MRECs undergoing 10% stretch. Under 15% stretch, IL-13 signaling, HMBG1 signaling, B cell signaling, and IL-13 signaling were downregulated in MRECs from both sexes. Our data provides novel insights into how inflammatory hypertensive stretch regulates immunological synapse proteins and secretomes in renal endothelial cells by stretch and sex-dependent manner.
Abstract 017: Dual Immune Checkpoint Inhibitor Therapy Is Associated With Increased Blood Pressure In Melanoma Patients
Authors: Turker Isik , Sharma Ananya , Huang Shi , Johnson Douglas , Alexander Matthew R
Published: September 2022

Background:
Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer therapy through activating immune cells to overcome tumor immune evasion. Increasing evidence suggests that adaptive immune cells play an important role in blood pressure elevations in the pathogenesis of hypertension. Whether ICI therapy enhances blood pressure remains unclear.

Methods:
We performed a retrospective cohort study of patients with advanced melanoma treated with ICIs in a single academic center. Baseline and 2-year blood pressure readings after initiation of ICI therapy were compared. To determine the relationship between the demographic and treatment variables and the change in blood pressure at two years, a multivariable linear regression model was used.

Results:
A total of 259 individuals were identified with 2-year follow-up. Of the entire cohort, 31% were treated with nivolumab, 47% with pembrolizumab, and 23% with ipilimumab and nivolumab combination therapy. In the total cohort, ICIs were not associated with significant changes in systolic (SBP) or diastolic (DBP) blood pressure at 2 years compared to baseline (132.2 mmHg
vs
. 133.2 mmHg, p=0.17, and 78.6
vs
. 78.1 mmHg, p=0.50, respectively). There were also no statistically significant changes in SBP or DBP in patients treated with nivolumab or pembrolizumab alone. However, in those treated with ipilimumab and nivolumab as combination therapy, SBP increased by 5.5 mmHg (128.2 vs. 133.7 mmHg, p=0.005). After adjusting for age, sex, weight, ICI type and duration, steroid and tyrosine kinase inhibitor use, and antihypertensive medication use at baseline and 2-years, combination therapy with ipilimumab and nivolumab remained a significant predictor of SBP change at two years. Holding the baseline SBP constant, the predicted SBP was 6.2 mmHg (95% CI 0.08 - 12.0 mmHg, p=0.047) higher for combined therapy than nivolumab alone.

Conclusions:
Patients who received combination ICI therapy had a higher SBP compared to those treated with single agent therapy. These findings suggest immune cell activation with ICI therapy contributes to blood pressure elevations and that close follow-up of blood pressure is needed in cancer survivors, particularly those previously treated with combination ICI therapy.
Abstract 018: B Cells Induce Hypertension, AT1AA, And Complement Activation In Preeclampsia Or In Response To A Prior Covid-19 Infection During Pregnancy
Authors: Herrock Owen T , Amaral Lorena M , Deer Evangeline M , Campbell Nathan , Morris Rachael , Fitzgerald Sarah , Zheng Baoying , Hardy-Hardin Ja'Nasa , Cockrell Kathy , Lamarca Babbette B
Published: September 2022

Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental ischemia and chronic inflammation that includes increased CD4+ T cells, B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1AA), and activation of the complement system. Previous studies have shown AT1-AA is produced in patients with COVID-19 infection. Interestingly, having had COVID-19 during pregnancy is associated with increased incidence of developing a PE phenotype during pregnancy. We have previously shown an important role for B cell depletion or AT1AA inhibition to attenuate HTN in rat models of PE. Collectively, this data suggests B cells contribute to PE development and that B cells may increase incidence of PE in patients with a history (Hx) of COVID-19 during pregnancy through production of the AT1AA. We hypothesize B cells from PE or CV Hx PE patients produce AT1AA resulting in HTN and complement activation in pregnancy. Placental B cells were isolated from normal pregnant (NP), PE, normotensive (NT) CV Hx, or PE CV Hx patients at delivery. B cells were transferred i.p. into pregnant athymic rats at gestation (GD) 12. On GD18, carotid catheters were inserted. On GD19, blood pressure was measured and tissues collected. PE B cell recipients had increased Mean Arterial Pressure (MAP) (115±3 mmHg n=6) compared to NP B cell recipients (97±4 mmHg n=6 p<0.05). PE B cell recipients had increased AT1AA (20±2 ΔBPM n=4) compared to NP B cell recipients (6±1 ΔBPM n=4 p<0.05). PE B cell recipients had increased markers of complement activation such as reduced plasma C4 (1302±169 μg/mL n=4) and C3 (516±45 μg/mL n=4) compared to recipients of NP B cells (2348±338 μg/mL n=4 p<0.05) and (790±66 μg/mL n=4 p<0.05) respectively. CV Hx PE B cell recipients had elevated MAP (108±3 mmHg n=4) compared to CV Hx NT B cell recipients (101±7 mmHg n=4) and increased AT1AA (24±3 ΔBPM n=3) compared to CV Hx NT B cell Recipients (4±1 ΔBPM n=4 p<0.05). Collectively, this study demonstrates an important role for B cells to cause HTN during pregnancy; and indicates that B cells contribute to a higher incidence of PE in women with a Hx of CV infection during pregnancy possibly by secreting AT1-AA.
Abstract 020: Nox5 Regulates Vascular Smooth Muscle Cell De-differentiation In Human Hypertension
Authors: Camargo Livia , Mary Sheon , Lilla Sergio , Zanivan Sara , Hartley Richard , Delles Christian , Fuller William , Rios Francisco J , Montezano Augusto C , Touyz Rhian M
Published: September 2022

Nox5 is an important source of reactive oxygen species and aberrant redox-sensitive signalling in vascular smooth muscle cells (VSMC) in human hypertension. We aimed to characterize the VSMC proteomic profile and investigate the effects of Nox5-derived ROS on VSMC phenotype in human hypertension. VSMC from resistance arteries from normotensive (NT) and hypertensive (HT) subjects were studied. Proteins were labelled with isobaric tandem mass tags and identified by liquid chromatography tandem mass spectrometry. The oxidative proteome was assessed using stable isotope-labelled iodoacetamide to target cysteine thiols. Nox5 silencing was performed by siRNA. Protein expression was detected by western blotting. Pro-inflammatory cytokines (IL-6, IL-8) and pro-collagen I was measured by ELISA in the culture media. Proteomic analysis identified 207 proteins upregulated in HT subjects (fold change>1.5, p<0.05). Gene ontology enrichment analysis showed proteins upregulated in HT were involved in extracellular matrix (ECM) organization, immune response and cell proliferation. ECM proteins (COL1A1, COL9A1, COL10A1, FBN1, FBLN1) and proteins related to interferon and IL-1β pathways (IFIT1, IFIT2, IFIT3, MX1, MX2, ABCA1, ABCA2, IL1RAP, CD36, ICAM1) were increased in cells from HT subjects. The VSMC oxidative proteome analysis identified 88 cysteine-containing peptides highly oxidized in HT (fold change>1.5, p<0.05), including COL11A1, COL16A1, FBLN1 and FBLN2. VSMCs from HT exhibit increased expression of the proliferation marker, PCNA (0.162±0.3 vs NT:0.051±0.04RFU, p<0.05) and pro-collagen I (23.6±2 vs NT:13.2±0.3ng/ml, p<0.05). Production of pro-inflammatory cytokines IL-6 (501.8±23.6 vs NT:121.7±6.4pg/mL) and IL-8 (373.6±34.1 vs NT:262.5±24.6pg/mL, p<0.05) were increased in HT. Nox5 silencing in VSMC from HT subjects reduced PCNA expression(43%), pro-collagen I release (8%), baseline and LPS-induced IL-6 (30% baseline, 43% LPS-induced) and IL-8 (21% baseline, 23% LPS-induced) release (p<0.05). We provide new insights into the proteomic changes related to vascular phenotype in hypertension and demonstrated that Nox5 plays an important role in VSMC phenotypic switching associated with vascular dysfunction in hypertension.
Abstract 021: Activated Cd8
+
T Cells Interact With Distal Convoluted Tubules To Promote Salt-sensitive Hypertension Through The Ifnγ-pdl1 Pathway
Authors: Benson Lance N , Liu Yunmeng , Guo Yunping , Xiong Yunzhao , Deck Katherine , Mora Christoph , Mu Shengyu
Published: September 2022

Background & Hypothesis:
The immune system plays a critical role in the development of hypertension. We recently found that CD8
+
T cells (CD8Ts) infiltrate the kidneys and stimulate distal convoluted tubular cells (DCTs), upregulating sodium-chloride co-transporter (NCC) activity, leading to excessive sodium retention. However, the precise molecules driving this direct interaction between CD8Ts and DCTs have not yet been identified.
Here we hypothesize that activated CD8Ts release gamma interferon (IFNγ) that primes the tubular cell to express PDL1 which functions as a co-stimulatory ligand promoting interactions between activated CD8Ts and DCTs contributing to the development of salt-sensitive hypertension.
We predict blocking this molecular pathway will reduce CD8T-homing into the kidney, lowering blood pressure.

Results:
We found that CD8Ts isolated from DOCA-salt treated hypertensive mice exhibit higher activity compared to those from sham normotensive mice. Pre-activated CD8Ts demonstrated augmented ability to interact with DCTs compared to naïve CD8Ts, and as a consequence, DCTs that had been co-cultured with pre-activated CD8Ts demonstrated increased expression of NCC (7 fold) and increased PDL1 and high sodium retention (47% vs. 0-3%). These effects were abolished by neutralizing IFNγ or knockdown of PDL1 in DCTs.
In-vivo
results verified the
in-vitro
studies. We found that IFNγ-KO mice demonstrated reduced blood pressure elevation and T cell infiltration within their kidneys to DOCA-salt compared to WT mice receiving the same treatment (last day systolic blood pressure average 155.2 mmHg compared to 189 mmHg from WT). Blood pressure elevation was blunted in DOCA-salt treated mice with renal tubule-specific knockdown of PDL1 (last day systolic blood pressure average 124 mmHg for mice with siPDL1 nanoparticle and 144 mmHg for mice with scrambled siRNA); NCC elevation was also blunted in this model.

Conclusion:
Activated CD8Ts demonstrate enhanced ability to interact with DCTs leading to increased expression of NCC and sodium retention through a IFNγ-PDL1 mediated mechanism. Blocking the IFNγ-PDL1 pathway prevents CD8T-DCT interaction both
in vitro
and
in vivo
, thereby ameliorating salt-sensitive hypertension.
Abstract 024: Arterial Stiffness Before Hypertension: A New Paradigm In Youth
Authors: Henson Sarah , Gao Zhiqian , Urbina Elaine M
Published: September 2022

Arterial stiffness (AS) in adults is an independent predictor of cardiovascular mortality. Historically, AS and increased left ventricular mass index (LVMi) have been identified as consequences of hypertension. However, recent studies have shown that AS and LVMi can predict hypertension development in adults. AS and LVMi as determinants of pediatric BP have not been studied. We hypothesized that AS and LVMi are independent determinants of BP in youth. Baseline BP and AS data were collected on participants enrolled in a cohort study comparing the effects of type 2 diabetes and obesity on the cardiovascular system in youth to lean and obese controls. Follow up BP and AS were obtained 5-7 years after initial measurements. General linear models were used to determine if central AS (Pulse Wave Velocity, PWV) or wave reflections (Augmentation Index, Aix) or LVMi remained significant predictors of follow-up systolic or diastolic BP z-scores (SBPz, DBPz) after adjusting for covariates. A total of 425 participants were included in this study. The mean age at baseline was 17.6 years and at follow up 22.9 years. Baseline and change in PWV, LVMi and Aix predicted follow up SBPz and DBPz (
p=
<0.001). After adjusting for age, sex, race, BMI, waist/height ratio, diabetes and BP, lipid and metabolic medications, both baseline and change in PWV remained independently associated with follow up SBPz and DBPz (
p=
<0.001). LVMi remained independently associated with follow up SBPz (
p=
<0.001), but not DBPz. Aix was no longer significant after adjusting for PWV and LVMi. In conclusion, central AS and LVMi predict future BP and may be useful in the identification of youth at risk for hypertension.
Abstract 027: Early Life Sodium Restriction Programs Long-term Changes In Energy Flux And Autonomic Activity
Authors: Ziegler Alisha A , Grobe Connie C , Reho John J , Grobe Justin L , Segar Jeffrey L
Published: September 2022

As sodium (Na) retention by the kidney is not fully efficient until the final weeks of a normal gestation, prematurely born infants are at high risk of Na depletion. We hypothesize that early-life sodium depletion contributes to delayed somatic growth and increased cardiometabolic risks associated with premature birth, via programmed increases in autonomic activity. To model early-life Na depletion, mice were weaned at 3 weeks of age onto custom variations of a soy-free diet (Teklad 2920x) containing either low (0.04% n=6m+8f) or high (0.30% n=8m+8f) Na. At 6 weeks of age, all mice were returned to standard (0.15% Na) diet. Energy flux was studied using NMR and a multiplexed phenotyping system (Promethion) at 6, 7, 8, 10, and 18 weeks of age, and data were analyzed by General Linear Modeling to account for covariates such as fat-free mass (FFM) and fat mass. Low Na supply caused delayed gains in FFM (diet x age interaction p<0.01) but no change in fat mass (p>0.77) in both sexes. In male mice supplied low Na in early life, food intake was reduced for weeks to months after return to normal diet even after correction for FFM and fat masses (diet p<0.01, diet x age p=0.93), primarily due to smaller meal sizes. Water intake was increased (diet p<0.01, diet x age p=0.03), primarily due to more drinking events. Total daily energy expenditure was also increased even after correction for FFM mass, fat mass, and food intake (diet p<0.01, diet x age p>0.99), though no changes in locomotion were observed (p>0.60). Throughout, female mice exhibited qualitatively similar yet quantitatively smaller effects. A parallel study indicated that after low Na supply, basal metabolic rate was increased at 8 weeks of age (n=8m each, +16%, p=0.01), and this increase was abolished with autonomic blockade via hexamethonium (30 mg/kg, ip; p=0.02). Finally, preliminary data (n=4 vs 5) indicate
Ucp1
mRNA may be increased in inguinal fat at 6 (2.8-fold p=0.08) and 18 weeks of age (2.2-fold p=0.12) in the low Na group. Together these findings support the concept that Na depletion in early life is sufficient to program persistent cardiometabolic and autonomic dysfunctions long after Na repletion.
Abstract 033: Anti-hypertensive Treatment With Acei Vs Arbs: The Differential Effect On Brain Microstructural Integrity Parameters Of Raas-targeting Treatments
Authors: Carnevale Lorenzo , Berardi Valeria , Carnevale Daniela , Lembo Giuseppe
Published: September 2022

Treating hypertension by drugs targeting the RAAS either blocking the Angiotensin receptor (ARBs) or inhibiting the Angiotensin Converting Enzyme (ACEi) have beneficial effects on cardiovascular health, preventing MI, stroke and global CV mortality. It is worth noting that no study investigated whether the two strategies targeting the RAAS have different effects on brain injury in hypertensive patients. To this aim, we investigated the correlation among microstructural integrity by DTI-MRI and the use of either class of drug. We recruited 51 hypertensives on ACEi or ARBs treatment and subjected them to advanced neuroimaging. DTI measures were normalized and analyzed by general linear model with age, sex, BMI, alcohol, smoke, SBP and DBP levels, heart rate as confounders to highlight alterations correlated to either treatment. The analysis shows that ARBs and ACEi exhibit an opposite and significant correlation with the microstructural integrity of the anterior commissure and the temporal subsection of the cingulum, reflecting a preserved microstructure in patients treated with ARBs compared with ACEi. This difference is also shown in pairwise comparison on anterior commissure (Table 1). In conclusion, our data suggest that ARBs may preserve specific white matter tracts integrity, suggesting that in hypertensive patients with cognitive dysfunction the use of ARBs should be preferred to protect brain microstructural integrity.