bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3055: Cholesterol And Amino Acids Derived From Dietary Sources Drive Atherosclerosis Via Synergistic Activation Of Macrophage Mtorc1 Signaling.
Authors: Zhang Xiangyu , Rodirguez-Velez Astrid , Yeh Yu-Sheng , Liu Ziyang , Razani Babak
Published: July 2024

The pathogenic role for lipids, especially cholesterol, in atherosclerosis is well established although relevant mechanisms of action continue to be uncovered. Recent studies linking cholesterol, cholesterol sensing, and the induction of proatherogenic mammalian target of rapamycin (mTOR) signaling is one area with significant therapeutic potential. Our previous studies demonstrated a critical role for amino acids, especially leucine, derived from dietary protein in promoting plaque progression through activation of macrophage mTORC1. We thus aimed to understand the role of cholesterol in macrophage mTOR signaling, its relation to amino acid-mediated effects, and cooperation between dietary lipids and protein in plaque mTOR activation and atherosclerosis. Here, we show LDL cholesterol as well as atherogenic lipids containing modified cholesterol (7-Ketocholesterol and oxLDL) are potent inducers of macrophage mTORC1 especially inconcert with leucine. Importantly, cholesterol and leucine synergistically dampen autophagy/mitophagy, resulting in mitochondrial dysfunction and apoptosis, a process which is completely mTORC1-dependent. In vivo, we find lesional macrophage mTORC1 is stimulated by elevation of plasma cholesterol in ApoE-null mice (n=8-10 per group) fed a Western Diet, while increases in circulating amino acids and cholesterol as a result of diets enriched in protein and lipids lead to mTORC1 hyperactivation and concomitant reduction in autophagy. In conclusion, our study identifies a previously unrecognized signaling role for cholesterol in macrophages and highlights a unique and therapeutically relevant mechanism by which dietary nutrients such as lipids and amino acids can cooperate to drive atherosclerosis.
Abstract 3068: Epha2 Ligand-dependent And Ligand-independent Signaling In Vascular Smooth Muscle Cell Proliferation And Migration
Authors: Scott Matthew L , Finney Alexandra , Vital Shantel , Pearson-Gallion Brenna , Shum Alika , Orr Wayne W
Published: July 2024

Vascular smooth muscle cells (VSMCs) participate in atherogenesis, during which VSMCs undergo phenotypic modulation from a contractile phenotype to a fibroproliferative phenotype. Within plaques, SMCs deposit extracellular matrix to form a fibrous cap that stabilizes the plaque. EphA2, a cancer-associated receptor tyrosine kinase, was recently shown to play a role in atherogenesis. We determined that EphA2 regulates SMC phenotype and proliferation both
in vitro
and
in vivo.
Interestingly, our data show that EphA2 is required for maximal SMC proliferation and migration, but is detrimental to both processes, dependent upon the context of EphA2 activation in that EphA2 ligation antagonizes Erk1/2 and Akt activation, proliferation, and migration. Further, serum treatment of VSMCs promotes robust S897 (ligand-independent) activation and promotes proliferation and migration. The S897 activating kinase differs between stimuli; but, in VSMCs, we observe that only Erk1/2 and RSK inhibition blunts S897 phosphorylation. RSK activation is Erk-dependent, so we used siRNA against RSK1 and RSK2 and observed that loss of RSK2 significantly reduces S897 activation. Interestingly, RSK2-KD abrogation of S897 phosphorylation did not affect SMC proliferation, but does prevent EphA2 localization to lamellipodia structures, implicating S897 phosphorylation in VSMC migration. Lastly, a 14 day wire injury model in SMC-EphA2 KO mice revealed significantly reduced medial expansion and SMC proliferation. Understanding how EphA2 modulates SMC behavior in terms of phenotypic modulation, migration, and proliferation will provide a basis to target this receptor to stabilize plaques, preventing deadly thrombotic events.
Abstract 3088: Inferior Vena Cava (IVC) Thrombosis In A Patient With May Thurner Syndrome: A Rare Case Of Thrombotic Iliocaval Obstruction In Octogenarian Population.
Authors: Sabri Muhammad , Landau Joseph , Mallavarapu Vamshi
Published: July 2024

Introduction:
May Thurner Syndrome is an extrinsic compression of the left common iliac vein by the right common iliac artery against lumbar spine. It is a rare cause of the lower extremity deep venous thrombosis (DVT) in octogenarian population. There is barely any data to document the association of IVC thrombosis with May Thurner Syndrome. Blood stasis in the setting of venous compression can increase the risk for DVT distally but proximal DVT is rare in absence of any other risk factors of thromboembolism.

Case Representation:
We present a unique case of 86-year-old female who was incidentally diagnosed with IVC thrombosis, left common iliac vein thrombosis, and left sided May Thurner Syndrome that is never documented before in octogenarian population. She had IVC thrombosis extending to the left common iliac vein with extrinsic compression by the right common iliac artery. This case is unique as our patient did not have any risk factor for venous thrombosis other than May Thurner Syndrome.

Conclusion:
May Thurner Syndrome can increase the risk for DVT proximal propagation and IVC thrombosis. The management of IVC thrombosis and May Thurner Syndrome in octogenarian population needs to account for risk of pulmonary embolism and mortality when avoiding anticoagulation compared to risk of morbidity and mortality from bleeding with anticoagulation. The decision to further manage depends upon clinical features, risk factors and institutional resources.
Abstract 3092: Smooth Muscle Cell Tgf-β Receptor Knockout Improves Arteriovenous Fistula Maturation Via Attenuation Of Autophagy
Authors: Zhang Weichang , Bai Hualong , Gonzalez Luis , Li Zhuo , Ohashi Yuichi , Thaxton Carly , aoyagi yukihiko , Yatsula Bogdan , Kano Masaki , Xie Yangzhouyun , Cai Yujun , Chang Shu , Dardik Alan
Published: July 2024

Objectives:
Arteriovenous fistulae (AVF) are the preferred vascular access for patients with end-stage renal disease (ESRD) but have high rates of primary failure. Models of AVF using mice with chronic kidney disease (CKD) show diminished maturation and increased failure compared to AVF using wild type mice. Since mice with CKD show increased TGF-β1 expression and activity in the AVF model, and TGF-β1 signaling can alter autophagy, we hypothesized that CKD increases autophagy during AVF maturation, whereas inhibition of the smooth muscle cell (SMC) TGF-β receptor would attenuate autophagy and promote AVF maturation.

Methods:
An aortocaval fistula or sham procedure was created in mice that had CKD induced by 5/6 nephrectomy (5/6 Nx) or sham nephrectomy (0/6 Nx).

Myh11-CreER
T2
; Tgfbr1
fl/fl
; Tgfbr2
fl/fl
; mT/mG

mice (TGFβRI II-KO) and control C57BL/6J mice were used. The diameter of the IVC was determined using ultrasound at days 0, 7, 14, and 21. AVF were harvested at day 7 or 21 for histology and immunoreactivity. Deidentified human AVF and control vein specimens were collected for analysis from second stage basilic vein transpositions.

Results:
In C57BL/6J mice, AVF had significantly decreased diameter (p=0.0051), increased wall thickness (p=0.0002), as well as increased immunoreactivity of collagen-1 (p=0.0163), collagen-3 (p=0.0029), TGF-β1 (p=0.0184) and fibronectin (p=0.00321) in mice with CKD compared to control mice (n=6). SMC showed increased markers of autophagy (LC3B and P62) in mice with CKD compared to control mice (LC3B, p<0.0001; P62, p=0.006; n=6); similarly, autophagy makers were increased in human AVF compared with the control veins (LC3B, p=0.0023; P62, p=0.006; n=6). In SMC-TGFβR II-KO mice, AVF had significantly decreased wall thickness (p<0.0001), increased diameter (p=0.0258), and decreased expression of autophagy markers (LC3B, p=0.0014; P62, p=0.0046; n=6).

Conclusion:
CKD increases neointimal hyperplasia that is associated with increased autophagy during AVF failure, and diminished TGF-β signaling reduces autophagy and wall thickness as well as increases AVF diameter. Suppression of SMC autophagy might be a novel therapeutic approach to improve AFV function.
Abstract 3105: Lamin Mutations: Single Nuclei Multiomic Analysis Reveals Endothelial Cell Dysfunction And Its Cardiovascular Implications
Authors: Wu David , Tripathi Dipti , Noishiki Chikage , Manhas Amit , Dexheimer Ryan , Turbes Naima C , Liu Lu , Cheng Paul , Boyd Jack , Woo Joseph , Sallam Karim , Wu Joseph C , Sayed Nazish
Published: July 2024

Background:
LMNA-related dilated cardiomyopathy (DCM) or cardiolaminopathy is an autosomal dominant trait with complete penetrance resulting in left ventricular enlargement and cardiac dysfunction. LMNA mutations in DCM have been shown to cause to ventricular arrythmias and conduction deficits. The interplay between the LMNA gene and other cell types have yet to be fully elucidated. Notably, cardiolaminopathy patients present with prominent cardiac fibrosis, but the mechanistic link between LMNA mutations and the development of fibrosis remains inconclusive. Additionally, LMNA is expressed in the endothelium, and patients with cardiolaminopathy exhibit distinct endothelial dysfunction.

Hypothesis:
We hypothesize that LMNA mutations prompt a cascade of pathological alterations on the endothelium, causing vascular dysfunction and fibrosis through endothelial to mesenchymal transition (EndoMT).

Aims:
Next generation sequencing platforms are critical to identifying these epigenetic and transcriptomic changes in the endothelium. Combining sequencing technology with our iPSC platform, we aim to unravel the mechanism behind vascular dysfunction and fibrosis in LMNA-DCM to uncover novel therapeutic targets and treatment strategies.

Methods:
We performed single nuclei multiome (RNA and ATAC) on cardiac tissue from one patient with LMNA-dilated cardiomyopathy. Frozen tissues were minced into pieces before digestion. We then utilized patient-specific induced pluripotent stem cells (iPSCs) and CRISPR-generated isogenic controls. We differentiated to endothelial cells (iPSC-ECs) and nuclei capture was performed after 24hr flow.

Results:
Endothelial cell clusters from cardiac tissue exhibit increased stress and mesenchymal markers. Phenotypic shift and EC dysfunction was corroborated with iPSC-ECs derived from two LMNA-DCM patients.

Conclusion:
These results present important considerations highlighting vascular dysfunction in LMNA-DCM and notes the importance of the endothelium in cardiac health. By analyzing these datasets produced from LMNA-DCM cardiac tissue and our iPSC-EC platform, there is opportunity to both define the mechanisms that causes cardiac fibrosis and to develop new therapeutic strategies.
Abstract 3112: Identifying NogoB Receptor As A Resilience Factor In Preventing Diabetes-associated Vasculature Complications Through The Regulation Of Histone Acetylation
Authors: Mohiuddin Mohammad Sarif , Hu Wenquan , Choubey Mayank , Barua Rashu , Tirumalasetty Munichandra Babu , Wahiduzzaman Md , Miao Qing R
Published: July 2024

The COVID-19 pandemic has underlined the link between cytokine storms and acute lung injury (ALI). Importantly, diabetic patients demonstrate a higher susceptibility to severe lung injury and increased mortality, indicating that hyperglycemia could compromise the host's resilience necessary to counteract cytokine-induced lung injury. Single-nucleus RNA-seq data from COVID-19 patients reveal a significant decline in endothelial cells expressing the Nogo-B receptor (NgBR). Our recent research confirms that NgBR plays a pivotal role in maintaining the structural integrity of blood vessels by regulating KAT7-mediated histone acetylation.To investigate NgBR's resilience role, we examined its expression in response to hyperglycemic stress. We found a reduction in NgBR expression levels in endothelial cells (ECs) isolated from db/db mice, mirroring observations in ECs from Streptozocin (STZ)-injected mice. Moreover, when human microvascular endothelial cells (HMECs) were exposed to high glucose levels, NgBR expression increased initially but subsequently declined with extended exposure. This inhibitory effect of high glucose on NgBR expression was both time- and dose-dependent and was mediated through the DNA methylation mechanism.We also examined the effects of NgBR loss on the integrity of pulmonary vasculature and the pathogenesis of lung injury. We induced genetic depletion of NgBR in ECs through tamoxifen administration and found severe lung hemorrhage in NgBR inducible endothelial cell-specific knockout (iecKO) mice. Impaired EC junctions were identified by reduced VE-cadherin immunostaining. Following exposure to a lipopolysaccharide (LPS), ALI model, we observed increased neutrophil accumulation in the alveolar or interstitial space, alveolar wall thickening, and edema in the lungs of either NgBR iecKO or diabetic mice. RNA-seq analysis revealed that NgBR knockdown resulted in decreased transcription of CDC42, a key gene regulating endothelial adherens junction through KAT7-mediated histone acetylation. Our findings indicate that NgBR is a resilience factor for maintaining vascular integrity, and epigenetic medicine can rescue NgBR loss in endothelial cells and the severity of diabetes-associated acute lung injury.
Abstract 3115: Mechanics And Genomic Profiles Reveal Aging And Developmental Lineage Heterogeneities In Human Induced Pluripotent Stem Cell-derived Smooth Muscle Cells.
Authors: Wiener Robert , Chen Wanqiu , Wang Charles , Schaniel Christoph , Qiu Hongyu , Costa Kevin D
Published: July 2024

Effective stem cell therapies and disease modeling depend on understanding epigenetic factors of aging. Accurately modeling age-dependent phenotypes such as aortic, and smooth muscle cell stiffening, requires cell models that reflect donor age. Improved knowledge of how donor aging influences stem cell-derived smooth muscle cells is essential for precise disease modeling and creating targeted therapeutics. We hypothesize that traits of vascular aging are retained in human induced pluripotent stem cells (iPSCs) and manifest in differentiated smooth muscle cells (SMCs). We aim to compare iPSC stiffness and gene expression between young (under 40, n=5 lines) and old (over 60, n=4 lines) donors, and examine age-dependent differences in their iPSC-SMCs. We measured cell stiffness using atomic force microscopy (AFM), and analyzed bulk and single-cell RNA gene expression in iPSCs and iPSC-SMCs of neuroectoderm (NE) or paraxial mesoderm (PM) lineages, respectively. AFM revealed no significant age-related differences in iPSC colony stiffness. Bulk RNA expression showed high similarity (>94% Pearson correlation) between young and old donor iPSCs, with principal component analysis indicating low variability and no clear age separation. Single-cell stiffness measurements found old NE-SMCs significantly stiffer than young ones (p=0.032), with no marked difference in PM-SMCs between ages. Old and young NE-SMCs were stiffer than their respective PM-SMC counterparts (old, p=0.006; young, p=0.007). UMAP analysis of single-cell RNA expression displayed distinct groupings for old and young NE-SMCs, but not for PM-SMCs. Cluster analysis revealed three clusters predominantly of old NE-SMCs and one of young NE-SMCs. Our study reveals age-related stiffening in NE lineage iPSC-SMCs, but not in PM lineage or iPSCs, indicating that iPSCs preserve certain donor age-related traits that manifest as lineage-specific phenotypes in SMCs post-differentiation. RNA sequencing showed similar expression patterns in young and old iPSCs, but age-specific differences in NE-SMCs. The integration of AFM and RNA expression data sheds light on the emergence of age-dependent phenotypes in differentiated, sensitive cell types, which are not present in immature cells.
Abstract 3117: Cannabis Use Disorder And The Risk Of Atherosclerotic Cardiovascular Diseases
Authors: Sharma Pranav , Paranjpe Ishan , Judy Renae , Yuan Shuai , Lee Daniel J , Nathanson Katherine L , Levin Michael G , Damrauer Scott M
Published: July 2024

Introduction:
With the legalization of cannabis, concerns have emerged regarding the long-term health impact of excessive use. The current literature has struggled to address questions about the adverse effects of cannabis, particularly in the context of atherosclerotic cardiovascular disease (ASCVD). Using genetic approaches to causal inference, we explored the relationship between cannabis use disorder (CUD) and ASCVD.

Methods:
Genetic instruments were constructed from a multi-population GWAS comprising 64,314 individuals with and 990,051 without CUD. Outcome data for coronary artery disease (CAD), ischemic stroke, peripheral artery disease (PAD), and abdominal aortic aneurysms (AAA) were derived from multi-population GWAS. Univariable Mendelian randomization (MR) was performed using the inverse-variance weighted (IVW) method to test the association of CUD with each outcome. Multivariable MR (MVMR) was performed to assess if the impact of cardiometabolic risk factors accounted for the association of CUD with ASCVD using summary statistics from publicly available GWAS of cardiometabolic risk factors.

Results:
CUD was associated with increased risk of CAD (OR 1.27; 95% CI 1.17-1.38; P=<0.01), ischemic stroke (OR 1.10; 95%CI 1.03-1.19; P=<0.01), PAD (OR 1.31; 95% CI 1.17-1.46; P=<0.01), and AAA (OR 1.37; 95% CI 1.21-1.55; P=<0.01). CUD also had a significant impact on cardiometabolic risk factors including triglycerides, waist-to-hip ratio, BMI, type 2 diabetes, obesity, and heart failure. The effect of CUD on ASCVD, other than stroke, remained largely independent of traditional risk factors except for lipids and tobacco smoking. Controlling for lifetime smoking index attenuated all associations between CUD and ASCVD except CAD, which remained significant (OR 1.21; 95% CI 1.11-1.31).

Conclusion:
Excessive cannabis use has the potential to increase ASCVD risk, independent of cardiometabolic risk factors, although this risk may in part be attributable to shared susceptibility to lipids and tobacco use. Awareness of the long-term risks of excessive cannabis use should be considered when formulating medical advice and public policy.
Abstract 3122: The Role Of Oct4 In Endothelial Cell Sexual Dimorphism And Angiogenesis
Authors: Shin Junchul , Krukovets Irene , Cherepanova Olga A
Published: July 2024

Background:
Biological sex differences play a critical role in vascular diseases. Using endothelial (
EC
) lineage tracing atherosclerotic mice and cultured mouse and human aortic EC, we recently found that female EC have lower angiogenic potential, higher expression of pro-inflammatory genes and intracellular ROS, and worse mitochondria functions than male EC. However, the mechanisms responsible for this EC sexual dimorphism are still unknown. We previously identified the pluripotency factor OCT4 as a critical regulator of EC characteristics, including angiogenic potential, ROS accumulation, and mitochondrial functions. Therefore, this study aimed to test whether OCT4 is responsible for sex-dependent differences in EC
in vivo
and
in vitro
.

Methods:
We used male and female EC-specific tamoxifen-inducible OCT4 knockout and EC-lineage tracing (EC-OCT4 KO) mice to study the role of OCT4 in non-atherosclerotic conditions leading to pro-inflammatory angiogenesis, such as hind-limb ischemia and skin injury models. Male and female mouse aortic EC (MAEC) were isolated from EC-OCT4 KO and wild-type littermate mice for
in vitro
experiments. We performed BrdU assay, EC tube formation in Matrigel (in vitro angiogenesis), wound scratch assay, and angiogenic proteome profile array to evaluate angiogenic potential.

Results:
Compared to wild-type mice, EC-OCT4 KO male mice exhibited accelerated blood flow recovery and wound healing after hind-limb ischemia and skin injury. However, EC-OCT4 KO female mice showed no difference in blood flow recovery and delayed skin wound healing compared to control mice.
In vitro
, although male and female OCT4-KO MAEC had higher angiogenic potential than control, the phenotype in female EC was less pronounced. Mechanistically, we found that male OCT4 KO MAEC express higher levels of monocyte cytokine protein 1 (
MCP1
). Furthermore, the inhibition of MCP1 in male OCT4 KO MAEC, but not in female cells, led to significant decreases in cell migration, proliferation, and endothelial tube formation in Matrigel.

Conclusions:
Our data indicate that OCT4-dependent mechanisms contribute to the sex differences observed in EC, suggesting a novel biological role for pluripotency signaling in vascular pathologies and homeostasis.
Abstract 3123: Sex Disparities In In-hospital Outcomes After Percutaneous Coronary Intervention In Patients With Acute Myocardial Infarction And A History Of Coronary Artery Bypass Grafting: A Nationwide Inpatient Sample-matched Analysis (2016-2019)
Authors: Yan Rui , Jia Shaobin , Cong Guangzhi , Ma Xueping , Yan Ru
Published: July 2024

Background:
The role of sex disparities in in-hospital outcomes after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in patients with a history of coronary artery bypass grafting (CABG) remains underexplored. This study aimed to identify sex disparities in in-hospital outcomes after PCI in patients with AMI and a history of CABG.

Methods:
Using the National Inpatient Sample database, we identified patients hospitalized for AMI with a history of CABG who underwent PCI between 2016 and 2019. Outcomes were compared between male and female patients using multiple logistic regression and 1:1 propensity score matching. The relationship between age and in-hospital mortality among male and female patients was explored using smooth curve fitting and subgroup analysis.

Results:
In total, 75,185 weighted hospitalizations of patients who underwent PCI were identified, with 25.2% being female patients. Compared with male patients, female patients had a higher burden of Elixhauser comorbidities (comorbidity index >4; 33.10% vs. 27.11%,
P
<0.001). Regarding in-hospital outcomes, female patients exhibited elevated risk of in-hospital mortality (3.72% vs. 2.85%,
P
=0.0095). After propensity score matching, female patients still had higher in-hospital mortality rates than did male patients (3.8% vs. 2.8%,
P
=0.019). Multivariable logistic regression (adjusted odds ratio [aOR]: 1.48; 95% confidence interval [CI]: 1.14-1.92) and propensity score matching (aOR: 1.50; 95% CI: 1.08-2.09) showed a consistently higher risk of in-hospital mortality among female patients than among male patients. There was an upward trend in in-hospital mortality across all age categories, with a steeper increase in patients aged >60 years. Female patients aged >60 years were more vulnerable to in-hospital mortality than were their male counterparts (3.06% vs. 4.15%,
P
=0.0003, aOR: 1.55; 95% CI: 1.18-2.04).

Conclusions:
Female patients who underwent PCI for AMI with a history of CABG had a higher in-hospital mortality rate, which was particularly evident among older patients aged >60 years. Therefore, sex- and age-specific investigations and interventions are required to reduce disparities within this high-risk population.
Abstract 3128: Cardio-respiratory Protection In Sepsis By Endothelial-targeted Recombinant Cd39.
Authors: Savvidou Ioanna , Willcox Abbey , Vuong Amy , Lee Natasha , Bonnard Thomas , Wright David , Calvello Ilaria , Selan Carly , Hauw Wei (Wayne) , Wang Xiaowei , Peter Karlheinz , Robson Simon , Sashindrnath Maithili , Nandurkar Harshal
Published: July 2024

Introduction:
Sepsis results in inflammatory cytokine storm and endothelial activationleading to ARDS and cardiac stress. CD39 is an endothelial cell(EC)-anchored enzyme working in concert with CD73 to hydrolyze extracellular ATP (pro-inflammatory) /ADP (pro-thrombotic) to adenosine which is anti-inflammatory, vasodilatory,and anti-thrombotic. 'Anti-VCAM1-CD39’ is novel therapeutic containing a scFv recognizingVCAM-1 (receptor expressed on activated ECs) fused to human soluble CD39.

Aim:
To demonstrate that Anti-VCAM-CD39 can reduce inflammation and cardiac stressafter lipopolysaccharide (LPS) challenge.

Methods:
Mice were challenged with LPS 5mg/kg and treated with either Anti-VCAM-CD390.8mg/Kg or buffer control after 1 hr and anlysed at 3, 6, 24 and 48 h.

Results:
1: LPS challenge leads to upregulation of VCAM-1 in the lungs (Q-PCR) and in the heart (imaged with MRI after administration of magnetic particles of iron oxidecoated with VCAM1 antibody or IgG control) (data not shown).2: LPS leads to reduction in plasma levels of protective adenosine (P<05).3: Treatment with anti-VCAM-CD39 reduces hypothermia, decreases pulmonary cytokinestorm and hypoxic drive (HIF1a) (Fig 1) and alleviatesmyocardial stress expressed (transcription of atrial natriuretic peptide (Nppa) and troponinat 24h) (Fig 2), reduces features of ARDS on lung histology (not shown) and suppressesinflammasome (NLRP3 by Western blot, not shown)

Conclusion:
Anti-VCAM-CD39 suppresses inflammation and offers cardiorespiratoryprotection in sepsis.Fig 1: Treatment with anti-VCAM-CD39 0.8mg/Kg reduces pulmonary cytokine storm (IL-1B,IL-6, TNFalpha, MCP1/CCL2) and hypoxic drive (HIF1a)(Statistics: One-way ANOVA; *=0.034, **=0.009)Fig 2: Treatment with anti-VCAM-CD39 0.8mg/Kg alleviates myocardial stress expressed(transcription of atrial natriuretic peptide (Nppa) and troponin at 24h)1

Additional Data referenced in the Abstract but could not be included due to space:
LPS leads to reduction in plasma levels of protective adenosine(One-way Anova, P values shown)Treatment with anti-VCAM-CD39 0.8mg/Kg reduces hypothermia(Statistics: One-way ANOVA)Treatment with anti-VCAM-CD39 0.8mg/Kg suppresses inflammation (NLRP3 by Westernblot)
Abstract 3132: Examining The Role Of The Lung Endothelial Cell Anti-apoptotic Protein C-iap2 In Schistosomiasis-associated Pulmonary Hypertension
Authors: Villarreal Elizabeth S , Marinho Ygor , Castellon Maricela , Williams David , Oliveira Suellen Darc
Published: July 2024

Introduction:
Schistosomiasis-associated Pulmonary Hypertension (Sch-PH) is the most common form of group I PH worldwide and remains with no targeted therapy. Previously, we observed that the loss of the anti-inflammatory protein caveolin-1 (Cav-1) in lung endothelial cells (EC) contributed to the survival of the abnormal EC phenotype in Sch-PH. Abnormal cell survival has been associated with some members of the inhibitor of apoptosis protein (IAP) family, but their role in Sch-PH is unknown.

Hypothesis:
The major etiological agent of Sch-PH, i.e.,
S. mansoni
, may contribute to the abnormal lung EC phenotype via altered IAP family expression, specifically the inducible member c-IAP2.

Methods/Methods:
To test this hypothesis, we first quantified constitutive c-IAP1 and inducible c-IAP2 expression on lung samples from male and female control and pre-clinical
S. mansoni
egg-exposed mice (240 eggs/gram body weight intraperitoneally followed by intravenous injection of 175 eggs/gram body weight). Then, the specific contribution of EC-c-IAP2 expression to the progression of the disease was evaluated in our new mouse model (

Cdh5.CreERT2;cIAP1
-/-
,cIAP2
fl/fl
-

Cdh5.CreERT2;cIAP1
+/-
,cIAP2
+/fl

). EC-

Cav1
-/-

mice were also evaluated to test the contribution of EC-Cav-1 to lung c-IAP2 expression.

Results/Discussion:
Western blot and immunohistochemistry analysis revealed a reduction in c-IAP2 expression in the whole lung tissue of
S. mansoni
egg-exposed mice compared to controls (1.21 ± 0.12; 0.88 ± 0.06, control and egg-exposed mice respectively; p<0.05; n=6). No difference was observed in c-IAP1 expression. Preliminary data indicate that genetic ablation of c-IAP2 in EC heterozygous mice promoted a mild increase in microvascular thickness and area in
Masson’s Trichrome
-stained lung sections. Consistent with our previous findings, c-IAP2 expression was also significantly impaired when Cav-1 expression was absent in lung ECs, suggesting that EC-Cav-1 may contribute to reduced lung c-IAP2 expression, leading to the severe vascular remodeling that underlies the development of Sch-PH.

Conclusion:
Our data is uncovering whether c-IAP2 expression is a novel and specific molecular target for future therapeutic approaches against chronic Sch-PH.
Abstract 3134: Integrated Multi-Omics Profiling Reveals Neutrophil Extracellular Traps Promote Aortic Dissection
Authors: Zhao Yufei , Wang Lixin
Published: July 2024

Background:
Negative aortic remodeling increases the risk of aorta-related adverse events (AAEs) after thoracic endovascular aortic repair (TEVAR) for patients with aortic dissection (AD).
Research Questions and Aims:
It is worth investigating prognostic indicators to streamline the identification of individuals at elevated risk for postoperative AAEs, and therapeutic targets to optimize the efficacy of TEVAR.

Methods:
We performed single-cell transcriptomic and proteomic profiling of aortic lesions and peripheral blood samples, respectively. We then integrated single-cell with publicly accessible bulk data to identify phenotype-relevant subpopulations. We further confirmed the results in human plasma samples and in mouse models. The Cox regression analysis were used to identify independent risk factors.

Results:
Integrated multi-omics analysis identified a highly phenotype-associated and disease-relevant macrophage subset, which closely interacted with neutrophil via CXCL3/CXCR2 axis, and promoted neutrophil extracellular traps (NETs) within aortic lesion. Likewise, increased NETs formation is a defining feature of systemic immunity of AD, with an expansion of inflammatory cytokines in the peripheral blood. Furthermore, we demonstrated that in a prospective cohort of 115 patients with a median follow-up of 13 months, the level of citrullinated histone H3 (CitH3), a NETs marker, could serve as a risk factor for the occurrence of AAEs following TEVAR (HR 8.78, p < .001). The CitH3 level, determined at a cut-off value of 6.9 ng/ml, predicted the postoperative AAEs with a sensitivity and specificity of 0.6 and 0.9, respectively, and an area under the curve of 0.75. In addition, inhibiting NETs formation through the blockade of CitH3 alleviated the progression and rupture of AD in mice.

Conclusions:
The multi-omics profiling reveals highly disease-relevant macrophage subpopulation, which promotes NETs formation and inflammation infiltration in the development of AD. Increased NETs formation is a defining feature of both aortic lesion and peripheral blood of patients with AD. CitH3 could facilitate the risk stratification and prognostic evaluation, and might serve as potential therapeutic targets of patients with AD.
Abstract 3136: Protection From Hypertension Phenotype By A Mitochondrial Division Inhibitor In Mice Infused With Angiotensin II
Authors: Nakayama Yuki , Preston Kyle J. , Kawai Tatsuo , Torimoto Keiichi , Eguchi Satoru
Published: July 2024

Mitochondrial dysfunction has been implicated in various types of cardiovascular diseases including hypertension. Mitochondrial fission fusion balance is critical for mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular diseases. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. The goal of this study is to explore the role of mitochondrial fission in hypertension and associated vascular pathology. Accordingly, we have tested our hypothesis that inhibition of mitochondrial fission attenuates development of hypertension and associated vascular remodeling. C57BL6 mice were infused with 1000 ng/kg/min angiotensin II for 2 weeks with or without treatment of mitochondrial fission inhibitor mdivi1 (25 mg/kg/day). Cultured vascular endothelial cells and adventitial fibroblasts from rat aortas were stimulated with 100 nM angiotensin II in the presence or absence of mdivi1 (20 uM). In C57BL6 mice infused with angiotensin II for 2 weeks, co-treatment of mitochondrial fission inhibitor mdivi1 significantly inhibited angiotensin II-induced development of hypertension assessed by telemetry (mean 149 vs 119 mmHg, day 9 p<0.01). Histological assessment of hearts and aortas demonstrated that mdivi1 inhibited vessel fibrosis and hypertrophy induced by angiotensin II. This was associated with attenuation of angiotensin II-induced decline in mitochondrial aspect ratio seen in both endothelium and media of aortas (aortas 1.620 vs 2.168, p<0.001). Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight body weight ratio (7.823 vs 6.336 mg/g, p<0.001) as well as by echocardiogram. Proteomic analysis on endothelial cell culture media with angiotensin II and/or mdivi1 treatment revealed that mdivi1 inhibited endothelial cell hypersecretory phenotype induced by angiotensin II. In addition, mdivi1 attenuated angiotensin II-induced protein induction of periostin, a myofibroblast marker in cultured vascular fibroblasts. In conclusion, these data suggest that mdivi1 prevented angiotensin II-induced hypertension and cardiovascular remodeling via multicellular mechanisms in the vasculature.
Molecular phylogeny and morphology reveal a new wood-inhabiting fungal species, Hyphoderma guangdongense (Polyporales, Basidiomycota), from China
Authors: SU JIANGQING , ZHANG XUNCHI , ZHAO CHANGLIN , ZHOU HONGMIN
Published: July 2024

Hyphoderma is one of the most important representative groups of wood-inhabiting fungi. These fungi secrete various enzymes capable of degrading cellulose, hemicellulose, and lignin into simple inorganic substances. The taxa within the genus cause the white rot of wood, play a key role in the carbon cycle, and are the most efficient wood decomposers in the forest ecosystem. This study proposes a new wood-inhabiting fungal taxon, Hyphoderma guangdongense, based on morphological features and molecular evidence. It is characterized by the white hymenial surface, a monomitic hyphal system having the generative hyphae with clamp connections, the presence of the septate and tubular cystidia, and cylindrical basidiospores (6–10 × 3–5 µm). The phylogenetic tree inferred from a combination of the internal transcribed spacers (ITS) and large subunit (nrLSU) of the nuclear ribosomal DNA (rDNA) sequences revealed that H. guangdongense placed into the genus Hyphoderma, in which it is closely related to a clade comprising two taxa, H. setigerum, and H. floccosum. A full description, illustrations, and results of the new species' phylogenetic analysis are provided.
Association between Homelessness and Temperature-Related Health Emergencies in the United States
Authors: Harris Andrea W. , Albrecht Jennifer
Published: July 2024

Temperature-related illness (TRI) encompasses heat-related illness, such as heat exhaustion and heatstroke, and cold-related illness, such as frostbite and hypothermia. TRI is typically the result of exposure to ambient weather conditions; because of this, unhoused individuals are hypothesized to have higher risk of TRI. However, no national epidemiological studies have been completed to determine this risk. The objective of this study was to determine the association between homelessness and emergency department (ED) diagnosis of TRI in the United States. We conducted a cross-sectional study of adult ED visits in the United States from 2005 through 2020 using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS), a nationally representative sample of nonfederal ED patient visits. Housing status (housed versus unhoused) was measured using NHAMCS patient residence category, with blank responses excluded. TRI was defined as ED clinician diagnosis of heat- or cold-related illness using International Classification of Disease, versions 9 and 10 (ICD-9 and ICD-10) codes. Multivariable logistic regression was used to determine adjusted odds of TRI by housing status. There were 323 606 nonpediatric ED visits in the NHAMCS sample. TRI diagnosis was present in 288 (0.09%) visits. 4099 visits (0.9%) were categorized as unhoused. After adjusting for sex, mental health diagnosis, and alcohol or substance use or use disorder, the odds ratio of TRI diagnosis in unhoused individuals was 4.08 (95% CI 2.09, 7.95) compared to housed individuals. We found a higher adjusted odds ratio of TRI diagnosis at an ED visit among unhoused individuals compared with housed individuals.

Significance Statement

Temperature-related health emergencies, or illnesses caused by exposure to ambient weather conditions, affect numerous Americans each year and are expected to become more common as climate change continues. We wanted to understand whether unhoused individuals are at higher risk of these health emergencies. We used a national sample of emergency department visits in the United States to study this and found out that unhoused individuals are at more than four times the risk of these illnesses than housed individuals. Our work highlights the need for prevention of homelessness, stable housing for housing insecure populations, and heating and cooling centers during weather emergencies.
Invisible fish: The selective (dis)connection of elite Chinese gated community residents from urban public space
Authors: Liu Yixin , Atkinson Rowland
Published: July 2024

Gated communities remain identified with strong forms of socio-physical segregation, yet there has been relatively light engagement with the question of how their residents engage with the city more broadly. This relationship, of protected privacy to open public space, is important because segregation is found in modes of mobility as well as in fixed residential spaces. This article contributes to the understanding of mobile forms of segregation by examining the use of public space, and sites of work, leisure and city services, by the (upper) middle-class residents of two high-end gated communities in Zhanjiang, a middle-tier Chinese city. In these relatively new elite residential spaces, newly status-conscious inhabitants reveal how their use of private modes of travel, avoidance of public transportation systems and efforts at seamless traversal of urban spaces connect to ideas of social achievement. Through extensive qualitative fieldwork in these two sites, we are granted a privileged insight into the ways in which China’s nascent middle classes utilise shielded addresses from which to access what they see as status-conferring lifestyle and taste destinations through private modes of mobility.
Worldwide application and valuation of extracorporeal membrane oxygenation support during the COVID-19 pandemic (WAVES)
Authors: Zaaqoq Akram M , Heinsar Silver , Yoon Hwan-Jin , White Nicole , Griffee Matthew J , Suen Jacky Y , Bassi Gianluigi L , Fanning Jonathon P , Shehatta Ahmad Labib , Alexander Peta M.A. , Jacobs Jeffrey P. , Dalton Heidi J , Lorusso Roberto , Cho Sung-Min , Peek Giles J , Fraser John F ,   COVID-19 Critical Care Consortium (COVID Critical)
Published: July 2024

Objective

The outcomes of COVID-19 patients on venovenous extracorporeal membrane oxygenation (VV-ECMO) varied. We aim to investigate the variability concerning location and timeframe. We conducted a retrospective analysis of data from 351 institutions in 53 countries. The primary outcome was survival to hospital discharge or death up to 90 days from ECMO start. The associations between calendar time (month and year) of ECMO initiation and the primary outcome were examined by Cox regression modeling. Multivariable survival analyses were adjusted for the time of ECMO start, age, body mass index, APACHE II, SOFA, and the duration of mechanical ventilation before ECMO.

Results

1060 adult COVID-19 patients enrolled in the COVID-19 Critical Care Consortium (COVID Critical) international registry and required VV-ECMO support. The study period is from January 2020 to December 2021. The median age was 51 years old, and 70% were male patients. Most patients were from Europe (39.3%) and North America (37.4%). The in-hospital mortality of the entire cohort was 47.12%. In North America and Europe, there was an increased probability of death from May 2020 through February 2021. Latin America showed a steady rate of survival until late in the study. South Asia, the Middle East, and Africa showed an increased chance of mortality around May 2020. In the Asian-Pacific region, after February 2021, there was an increased probability of death. The time of ECMO initiation and advanced patient age were associated with increased mortality.

Conclusion

Variability in the outcomes of COVID-19 patients on VV-ECMO existed within different regions. This variability reflects the differences in resources, policies, patient selection, management, and possibly COVID-19 virus subtypes. Our findings might help guide global response in the future by early adoption of patient selection protocols, worldwide policies, and delivery of resources.
Short-Term Origin-Destination Demand Prediction Based on Spatiotemporal Encoder-Decoder Network with a Residual Feature Extractor
Authors: Zhong Xiaohui , Zhang Jinlei , Hua Qiang , Yang Lixing , Gao Ziyou
Published: July 2024

Online ride-hailing services play a crucial role in daily transportation, However, challenges persist in certain regions with limited access, and drivers encounter difficulties in receiving orders. Accurate prediction of short-term origin-destination (OD) demand is crucial for addressing these issues. This study leverages recent advancements in artificial intelligence and big data to introduce a spatiotemporal encoder-decoder network with a residual feature extractor (RF-STED) for short-term OD demand prediction in online ride-hailing services. The RF-STED model, built on deep learning models such as graph convolutional networks and convolutional long short-term memory (Conv-LSTM), includes spatiotemporal networks, encoding layers, and a residual feature extractor. The spatiotemporal network has two branches: branch one processes multi-pattern OD data using a multi-pattern temporal feature extraction module, utilizing a multi-channel Conv-LSTM to capture temporal correlations. Branch two utilizes a multi-spatial feature extraction module to convert OD pair associations into a spatial topology, extracting multi-spatial correlations. The encoding layer captures spatiotemporal dependencies, while the residual feature extractor decodes compressed vectors back into an OD graph for forecasting future demand. Experiments with a Manhattan taxi dataset in the U.S. show the RF-STED model outperforms 10 baseline models and four ablation models. The results emphasize the model’s strength and robustness in short-term OD flow prediction.
Mode Choice and Value of Time on Long-Distance Vacation Trips
Authors: Bursa Bartosz
Published: July 2024

Long-distance travel for leisure purposes, especially international travel, has grown dramatically over the past decades. Although its share of the total number of trips is small, it accounts for a significantly larger share of total distance and greenhouse gas emissions, with the accompanying adverse environmental consequences. One remedy might be to urge tourists to travel on vacation by rail rather than car, which is less harmful to the environment. However, it is not clear how to persuade them to do so, since knowledge of the determinants of mode choice for international vacation travel is quite limited. To fill this gap, we collected survey data among tourists, mostly international, visiting the Austrian Alps and estimated a choice model between personal vehicle and rail. The results revealed a cost dumping effect, and the significant influence of factors related to overall travel convenience, luggage transport, travel party size, and the accessibility of the destination by rail. The tourists reacted with little elasticity to changes in cost and travel time, and exhibited a higher value of time than in other studies on long-distance travel, which was also higher than the hourly wage in their home countries. This article delivers valuable evidence that could contribute to improved long-distance rail services, more accurate project appraisals, and better marketing campaigns and transportation policies to make rail more competitive against the personal vehicle, and facilitate more sustainable vacation travel.
Identification of Risk Factors for Severe Younger and Older Driver Crashes in Massachusetts
Authors: Gooch Jeff , Mahmud Md Shakir , Gross Frank , Polin Bonnie
Published: July 2024

Systemic safety analysis is a comprehensive and proactive approach to identifying and addressing high-risk roadway features and crash types that contribute to severe crashes. The Massachusetts Department of Transportation identified 14 emphasis areas for systemic improvement, including younger and older driver crashes. Research was undertaken to conduct separate comprehensive analyses of fatal and serious injury crashes involving younger and older drivers, using a systemic safety approach to develop risk factors and identify critical locations within the state. The study utilized crash, roadway, driver’s license, citation, healthy aging, and environmental justice data from various sources. Negative binomial regression models were developed to relate crash frequency with town-specific traffic, behavior, and site characteristics, considering exposure and spatial variance. The findings highlighted the significance of multiple risk factors contributing to severe crash frequency. For younger drivers, the presence of young drivers in the town, risk-taking behaviors such as unbelted and impaired driving, and infrastructure characteristics, particularly high-speed facilities and historically underinvested infrastructure, were key contributors to crash frequency. Older drivers’ crash frequency was influenced by the presence of older drivers, healthy aging indicators, risk-taking behaviors, and high-speed facilities. Based on the model results, risk scores were developed for each variable in the model and applied to each town. Towns were ranked using percentile ranking to classify them into primary and secondary risk categories. The towns identified in the primary risk category (18 towns in the top 5 percentiles) captured approximately 13.5% of severe younger driver crashes and 14.5% of severe older driver crashes.
A Comparison of Test-Retest Reliability and Practice Effects of Short Portable Mental State Questionnaire and Montreal Cognitive Assessment in Patients with Stroke
Authors: Chen Ta-Cheng , Lee Ya-Chen , Wang Yi-Ching , Hsieh Ton-Lin , Chen Mei-Hsiang
Published: July 2024

Objective

To compare the test-retest reliabilities and minimal detectable change (MDC) of the Short Portable Mental State Questionnaire (SPMSQ) and the Montreal Cognitive Assessment (MoCA) in patients with stroke.

Methods

63 patients were recruited from 1 medical center. The SPMSQ and MoCA were administered twice, 2 weeks apart.

Results

Both measures showed high intraclass correlation coefficients (SPMSQ: 0.87; MoCA: 0.89) and acceptable MDC%s (SPMSQ: 14.8%; MoCA: 19.6%). A small correlation ( r = 0.30) was found between the absolute difference and average in each pair of assessments in the SPMSQ, which was close to the criterion of heteroscedasticity. A small practice effect was observed in the MoCA (Cohen’s d = 0.30).

Conclusion

The SPMSQ demonstrated smaller random measurement error and an absence of practice effect. When comparing the psychometric properties of the SPMSQ and MoCA as outcome measures for assessing cognitive function in patients with stroke, the SPMSQ appears to be a more suitable choice than the MoCA.