bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 193: Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglyceride and Incident Cardiovascular Disease in the Atherosclerosis Risk in Communities Study: Can Genetic Variants Provide New Insights on Triglycerides and Atherogenic Lipoproteins?
Authors: Saeed Anum , Feofanova Eleana , Yu Bing , Virani Salim S , Sun Wensheng , Nambi Vijay , Heiss Gerardo , Guild Cameron S , Coresh Josef , Boerwinkle Eric , Ballantyne Christie M , Hoogeveen Ron 
Published: July 2021

Recent genetic studies have focused on the atherogenicity of remnant-like particle cholesterol (RLPC) with paucity of data on TGs in LDL (LDL-TG). We examined the association of RLPC and LDL-TG with incident CVD and the genetic variants associated with their levels in the biracial ARIC study.
Fasting plasma RLPC and LDL-TG were measured by automated homogeneous assays (Denka Seiken, Tokyo) in 9334 men and women without prevalent CVD at baseline. Incident CHD and stroke over 16-y follow-up were obtained from medical records. Associations between LDL-TG and RLPC and the genomic variants (Illumina HumanExome Beadchip) were assessed using single variant analysis for common variants and gene-based burden tests for rare variants. Variants with minor allele frequency >1% were analyzed individually.

RLPC and LDL-TG were correlated with elevated TG (r=0.85 and 0.64, p<0.0001). In minimally adjusted analyses, both were associated with CVD risk, but after adjusting for traditional CVD risk factors including lipids, only LDL-TG was positively associated with incident CHD (HR 1.28 [95% CI 1.10-1.50]) and stroke (HR 1.47 [95% CI 1.13-1.92]; p<0.01). Single variant tests showed a common
APOE
variant (rs7412) had the strongest association with LDL-TG and RLPC in both races (p<5x10
-8
). Since rs7412 defines apoE isoforms, we assessed
APOE
haplotypes and found E2/2 was associated with reduced LDL-TG and increased RLPC (Fig).

Although elevated TGs are associated with increased RLPC and LDL-TG, only LDL-TG remained significant for CVD risk in multivariable-adjusted models. ApoE2 locus variants were associated with RLPC and LDL-TG, but individuals with apoE2/E2 had decreased LDL-TG and increased RLPC. These findings, and prior studies showing that apoE2 is associated with lower CVD risk, suggest that the increased risk of CVD with high TGs may be related more to LDL-TG than RLPC. Further research is needed to understand whether LDL-TG plays a causal role in CVD and is a target for therapy.
Abstract 226: C-type Lectin Receptor Clec9a on Cd8a+ Dendritic Cells Promotes the Development of Atherosclerosis in Mice
Authors: Yacine Haddad , Lahoutte Charlotte , Clément Marc , Laurans Ludivine , Sarvenaz.Metghalchi Sarvenaz.Metghalchi , Zeboudj Lynda , Giraud Andreas , Loyer Xavier , Vandestienne Marie , Wain-Hobson Julien , Esposito Bruno , Potteaux Stephane , Ait-Oufella Hafid , Reis e Sousa Caetano , Tedgui Alain , Mallat Ziad , Taleb Soraya 
Published: July 2021

Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. We hypothesized that sensing of necrotic cells by CLEC9A, a C-type lectin receptors selectively expressed by the CD8α
+
subset of dendritic cells (CD8α
+
DCs), plays a determinant role in the inflammatory response of atherosclerosis.

Reconstitution of lethally-irradiated Ldlr-/- with bone marrow from CLEC9A-/- mice significantly reduced atherosclerotic lesion size in aortic root after 5 weeks of high fat diet (HFD) (-45%, p=0,0059) and after 7 weeks of HFD (-40%, p=0,0017), as compared to mice transplanted with wild-type bone marrow-derived cells. However, no effect of CLEC9A was observed after 13 weeks of HFD (p=0,4996), suggesting early effect of CLEC9A on atherosclerosis development.
The same phenotype was observed in 20-week-old Apoe-/-CLEC9A-/- compared to Apoe-/- mice put on chow diet (-50%, p=0,0022).

Interestingly, an increase of IL-10 expression (+60%, p=0,0093) was observed in spleens of mice deficient for CLEC9A. Furthermore, the beneficial effect observed in CLEC9A-/- was abolished in CLEC9A-/-IL-10-/- compared to IL-10-/- (p=0,4452). Moreover, a specific deletion of Clec9a in CD8α
+
DC cells significantly increases Il10 expression, reduces macrophage and T cell contents within the lesions, and significantly limits the development of atherosclerosis. In conclusion, our results identify a new role of Clec9a in regulating vascular inflammation and atherosclerosis development and potentially identify a new target for disease modulation.
Abstract 383: Patient-Specific Coronary Models Combining Intravascular Ultrasound and Optical Coherence Tomography Lead to More Accurate Plaque Cap Thickness and Stress/Strain Quantifications
Authors: Guo Xiaoya , Monoly David , Yang Chun , Samady Habib , Zheng Jie , Wang Liang , Mintz Gary S , Maehara Akiko , Pei Xuan , Li Zhi-Yong , Tang Dalin , Giddens Don P 
Published: July 2021

Accurate cap thickness and stress/strain quantifications are of fundamental importance for vulnerable plaque research. An innovative modeling approach combining intravascular ultrasound (IVUS) and optical coherence tomography (OCT) is introduced for more accurate patient-specific coronary morphology and stress/strain calculations.
In vivo IVUS and OCT coronary plaque data were acquired from two patients with informed consent obtained. IVUS and OCT images were segmented, co-registered, and merged to form the IVUS+OCT data set, with OCT providing accurate cap thickness. Biplane angiography provided 3D vessel curvature. Due to IVUS resolution (150 μm), original virtual histology (VH) IVUS data often had lipid core exposed to lumen since it sets cap thickness as zero when cap thickness <150 μm. VH-IVUS data were processed with minimum cap thickness set as 50 and 180 μm to generate IVUS50 and IVUS180 data sets for modeling use. 3D fluid-structure interaction models based on IVUS+OCT, IVUS50 and IVUS180 data sets were constructed to investigate the impact of OCT cap thickness improvement on stress/strain calculations.
Figure 1 is a brief summary of results from 27 slices with cap covering lipid cores from 2 patients. Mean cap thickness (unit: mm) from Patient 1 was 0.353 (OCT), 0.201 (IVUS50), and 0.329 (IVUS180), respectively. Patient 2 mean cap thickness was 0.320 (OCT), 0.224 (IVUS50), and 0.285 (IVUS180). IVUS50 underestimated cap thickness (27 slices) by 34.5%, compared to OCT cap values. IVUS50 overestimated mean cap stress (27 slices) by 45.8%, compared to OCT cap stress (96.4 vs. 66.1 kPa). IVUS50 maximum cap stress was 59.2% higher than that from IVUS+OCT model (564.2 vs. 354.5 kPa). Differences between IVUS and IVUS+OCT models for mean cap strain and flow shear stress were modest (cap strain: <12%; FSS <2%).

Conclusion:
IVUS+OCT data and models could provide more accurate cap thickness and stress/strain calculations which will serve as basis for plaque research.
Abstract 458: Role of Colony Stimulating Factor 1 Receptor in Graft Vascular Disease
Authors: Almonte Vanessa , Wunimenghe Oriyanhan , Riascos-Bernal Dario F , Chinnasamy Prameladevi , Jayakumar Smitha , Sibinga Nicholas E 
Published: July 2021

Heart and kidney transplants are effective treatments for end-stage organ failure, but their long-term success is limited by graft vascular disease (GVD), the leading cause of solid organ transplant failure. This process manifests as concentric thickening of vessel walls due to neointimal hyperplasia in the donor organ, characterized by expansion of cells, notably smooth muscle-like cells (SMLCs) and macrophages (MPs), which accumulate, proliferate, and eventually occlude the lumen of arteries. Our lab recently reported that loss of colony stimulating factor-1 (CSF1) expression in either donor or recipient mice limits GVD, and showed that SMLCs isolated from neointimal lesions express high levels of CSF1 and its receptor, CSF1R. While CSF1-mediated activation of CSF1R has been studied extensively in MP biology, its role in SMLCs and GVD has not been well characterized. We hypothesize that CSF1R activation in neointimal MPs and SMCs occurs after organ transplantation and promotes the development of GVD.
To test this idea, carotid arteries from 8-12 week old C57/B6J male mice were transplanted orthotopically into female or male mice. At day 30 post transplantation, sex-mismatched transplants developed significant neointimal lesions not seen in sex-matched controls. Neointimal, adventitial, and to a lesser extent medial cells were positive for CSF1R and CD68, which were scarcely detected in control untransplanted arteries. Cells in the media of transplanted vessels co-stained for smooth muscle alpha actin (SMA) and calponin. SMA-positive cells were found in neointimal lesions, with few cells co-expressing calponin. Proliferation, assessed by Phospho-histone H3 staining, was evident in cells of uncertain origin in the media and neointima. In conclusion, H-Y antigen-driven histoincompatibility in this mouse transplant model yielded vascular lesions that resemble GVD, with significant neointima formation, preservation of medial cells, and evidence of CSF1R expression and of cell proliferation. Future studies will focus on lineage tracing of smooth muscle and myeloid cells to evaluate neointimal cell origins, plus genetic depletion of CSF1R in these cell lineages to determine the requirement for CSF1R expression in the development of GVD.
Abstract 475: Novel Gene Therapy Facilitates Critical Limb Ischemia Reperfusion in Mouse Hindlimb Gangrene Model
Authors: Parikh Punam P , Lassance-Soares Roberta , Regueiro Manuela , Shao Hongwei , Li Yan , Liu Zhao-Jun , Velazquez Omaida C 
Published: July 2021

Lack of a reliable animal hindlimb gangrene model limits molecular investigation of critical limb ischemia. We sought to develop a mouse hindlimb gangrene model, used to assess the efficacy of novel gene therapy. We hypothesized that priming ischemic hindlimb tissue with E-selectin/adeno-associated virus (AAV) enhances therapeutic angiogenesis and attenuates gangrene.
We tested two methods to induce hindlimb gangrene. First, FVB mice underwent femoral artery ligation (FAL) to achieve critical limb ischemia. Second, FVB underwent combined FAL and administration of NG-nitro-L-arginine methyl ester (L-NAME), nitric oxide synthase inhibitor, which further reduces hindlimb perfusion. Prior to FAL and L-NAME use, gangrene-induced mice were intramuscularly administered E-selectin/AAV (treatment) or LacZ/AAV (control) to the hindlimb. Gangrene was assessed with a standardized ischemia score ranging from 0 (no gangrene) to 11 (forefoot gangrene), recorded on postoperative day (POD)’s 2,7,14. Hindlimb reperfusion using Laser doppler imaging was quantified by mean perfusion of ligated:non-ligated limb on same POD’s. Live animal Dil perfusion plus laser scanning confocal microscopy quantified limb neovascularization.
Most FVB did not develop gangrene with FAL-only (n=2/8, 25% gangrene incidence). Combined FAL and L-NAME consistently induced hindlimb gangrene (n=14/14, 100% gangrene incidence). Laser doppler imaging score on POD 7 for E-selectin/AAV (n=7) and LacZ/AAV (n=7) was 0.41 vs 0.27 (P=0.071) and on POD 14 was 0.54 vs 0.29 (P=0.017). Dil perfused ligated hindlimb in E-selectin/AAV and LacZ/AAV revealed significantly higher mean neovascularization intensity score of 44 vs 21 (P=0.037). Dil perfused non-ligated limb in respective mice demonstrated mean intensity score of 50 vs 25 (P=0.006). Mean limb ischemia score on POD 2,7,14 for E-selectin/AAV and LacZ/AAV was 1.9, 2.9, 3.7 vs 2.7, 3.9, 5.3 (P=0.104).
We developed a highly reliable mouse hindlimb gangrene model where E-selectin-based novel gene therapy improved limb reperfusion and neovascuclarization in critical limb ischemia. This hindlimb gangrene model can be used to further understand Redox pathways contributing to gangrene, facilitating future translational studies.
Abstract 579:
In vitro
Models Concur With Clinical Results to Confirm Pleiotropic Mechanisms of Action for Gemcabene
Authors: Oniciu Daniela C , Bisgaier Charles L 
Published: July 2021

Introduction:
Gemcabene, a fraudulent fatty acid, induces biological properties in nonclinical models, of which many translate to clinical findings in dyslipidemia patients. Its known mechanism of action includes reduction of the overall hepatic
de novo
triglyceride and cholesterol synthesis, and increase in VLDL clearance. Clinical benefits in various human populations infer that other mechanisms are involved that warrant evaluation.

Methods and Results:
We assessed the gemcabene effects in other molecular mechanistic models, particularly to study inhibition of human ATP Citrate Lyase (hACL), apolipoprotein gene expression in Sandwich-Cultured Transporter Certified
TM
Human Hepatocytes (SCHH), and expression of genes related to inflammation and cell signaling.

Gemcabene, MEDICA-16, palmitic acid and their CoA thioesters were studied in a recombinant hACL in vitro assay system. Gemcabene-CoA thioester, but not the parent compound, inhibited recombinant hACL activity in vitro in a dose-dependent manner, in agreement with results obtained with palmitoyl-CoA and palmitic acid. Unlike palmitic acid, MEDICA-16, and bempedoic acid, gemcabene does not form a CoA ester in human hepatocytes: radioisotope studies show 98.8% parent gemcabene.
Further, gemcabene potential on the gene expression of lipogenesis and inflammation markers was assessed in SCHH. Gemcabene showed significant regulation of HMG-CoA synthase 2 (HMGCS2) and CRP mRNAs. A marked induction response of the HMGCS2 mRNA content was observed, ranging from 2.26- to 2.73-fold (p ≤ 0.05) over control in SCHH treated with all concentrations of gemcabene (500, 1000, and 1500 μM). Also, a clear and statistically significant (p-value ≤ 0.05) concentration-related suppression response of CRP mRNA content was observed, ranging from (-2.58)- to (-2.65)-fold below control in SCHH treated with 1000 and 1500 μM gemcabene.

Finally, RT-PCR analysis of liver samples from STAM
TM
mice treated with gemcabene revealed its downregulating effect on inflammatory, lipogenic, lipoprotein metabolism, and cell signaling genes: TNF-α, MCP-1, NF-κB, ApoC-III, and ACC1.

Conclusion:
Gemcabene manifests its pharmacological profile in lipid management and inflammation by multiple mechanisms of action.
Abstract P134: Genome-wide Association Study of Heart Rate Response to Mental Stress
Authors: Huang Yunfeng , Hui Qin , Hammadah Muhammad , Pimple Pratik M , Al Mheid Ibhar , Wilmot Kobina , Ramadan Ronnie , Shah Amit J , Pearce Brad , Garcia Ernest V , Kutner Michael , Bremner J. Douglas , Esteves Fabio , Raggi Paolo , Sheps David S , Vaccarino Viola , Quyyumi Arshed A , Sun Yan 
Published: July 2021

Ischemia results from an imbalance between myocardial oxygen supply and demand. Ischemia associated with mental stress (MS) has been associated with adverse outcomes in patients with coronary artery diseases (CAD). Higher heart rate (HR) and blood pressure responses to MS are associated with a greater likelihood of MS-induced ischemia. Although multiple genetic loci have been associated with baseline HR, genetic associations for HR responses to MS remain unknown. We aimed to discover the genetic determinants of HR response to MS in a bi-ethnic population.
A sample of 499 Caucasian and 271 African American patients with CAD were recruited into the Mental Stress Ischemia Prognosis (MIPS) study. Race was defined using genetic ancestry. Genome-wide SNP data were genotyped using Illumina’s Multi-Ethnic Genotyping (MEG) chip and then imputed to the 1000 Genome Project phase 3 panel. Cardiovascular risk factors, demographic, behavioral, and medication history data were obtained by questionnaires and chart reviews. MS was induced by a public speaking task and the HR response to MS was measured as post-stress HR minus pre-stress HR. We conducted genome-wide association analysis of HR response to MS using multiple linear regression adjusted for age, sex, beta-blocker use, the pre-stress HR and ethnicity. A meta-analysis was performed across the two ethnicities.

After multiple-testing correction, no significant associations with HR response to MS were identified among Whites .However, fourteen SNPs located in gene
ITGA1
with a mean minor allele frequency of 36.5% (range: 36.3% - 37.1%) were significantly associated with the HR response to MS in Blacks (meta-analysis p<5х10
-8
). The minor alleles of all 14 variants were associated with a higher HR response. On average heterozygotic and homozygotic Blacks of the minor allele in any of these SNPs have a 4.558 beat/min (range: 4.514 – 4.659 beat/min) and 9.116 beat/min (range: 9.028 – 9.318 beat/min) increase in HR response to MS, correspondingly. The
ITGA1
gene encodes the alpha-1 subunit of integrin receptors. This protein heterodimerizes with the beta-1 subunit to form a cell-surface receptor for collagen and laminin. The heterodimeric receptor is involved in cell-cell adhesion and may play a role in inflammation and fibrosis. Further functional studies to follow up these genetic loci may provide insight into regulatory mechanisms of HR response to mental stress that may be prognostically informative for CAD patients.
Legal Features of the Provisions of Unjust Enrichment in Jordanian Civil Law and Comparative Law
Authors: al-Fatlawi Sahib , al-Daboubi Derar 
Published: July 2021

Abstract
Unjust enrichment is considered one source of obligations, which stands in contrast to harmful acts as another source of obligation in the Jordanian Civil Code (JCC). The Unjust Enrichment Rule has developed historically from Roman law, through Islamic jurisprudence, then French law and jurisprudence to modern laws, such as that in Egypt influenced by French law. All these laws have recognised the Unjust Enrichment Rule as an independent source of obligation. Although the JCC was influenced by Islamic jurisprudence, Arab laws, such as the Egyptian Civil Code, and foreign-influenced Arab laws, its features distinguish it from other laws, either in terms of naming the source or the details related to its legal provisions. JCC’s special features need to be highlighted, defined and evaluated for comparison with other laws, i.e., proving beneficial when enacting a new JCC or defining it as unique rather than a copy of other precedent Arab laws.
Good Faith Principle in Contract Law: A Comparative Study under Sharīʿah, Islamic Law Jurisdictions with Emphasis on Iranian Law
Authors: Shoarian Ebrahim , Jafari Mahsa 
Published: July 2021

Abstract
Unlike civil law jurisdictions, the good faith principle in Islamic law is a notion not directly discussed, the foundations of which this article seeks to root out through an analysis of related, but distinct, Islamic law doctrines. As such, since Islamic law is a significant source of codification and adjudication in many Islamic countries, the perspective of some MENA countries as well as Iran towards good faith is also explored. In practice, courts and tribunals could invoke the good faith principle where Islamic law or Islamic-based laws govern the contractual relationships. This article contends that good faith permeates every sphere of a contractual relationship, particularly negotiation under Islamic law.
Citizen Wayn? The Struggle of Parliament in Contemporary Jordan
Authors: Esber Paul Maurice 
Published: July 2021

Abstract
This article is part of the Special Issue “Parliaments in the Middle East and North Africa: A Struggle for Relevance.” Because the politics of citizenship is felt at all stages of the parliamentary process, the very question of parliamentary relevance itself cannot be answered without reference to the citizenry. That Jordan’s citizenship regime influences and impedes parliamentary politics is explored through two cases. The first being decentralization, understood as a relocating of tasks, decision-making and mandates from a centralized location to different, more localized levels. The second study focuses on the uprisings occurring from May 30, 2018 against the draft domestic tax law introduced to parliament by the government of then-Prime Minister Hani al-Mulki. Both cases are implicated in the Kingdom’s parliamentary politics, and their selection is a conscious move away from election analysis. Taken together they elucidate how citizenship is a key battleground on which any future emancipation/development of parliament will be fought.
Event Types and (In)Directness of Causation in Akan
Authors: Duah Reginald Akuoko , Osam E. Kweku , Amfo Nana Aba A. 
Published: July 2021

Abstract
This paper presents a proposal on the form-function correlation between direct causation and non-periphrastic causatives on one hand, and indirect causation and periphrastic causatives on the other hand. The study argues that notions of direct and indirect causation are actually features of event types of causation and vary across different event types. We present five event types of causation found in Akan causatives and isolate their properties with regard to the causer, causee, control of resultant state/event and (in)direct physical contact between causer and causee. We show that in Akan, all types of causatives, lexical, cause-effect SVC and analytic causatives can encode any of the major event types of causation. Consequently, rather than mapping causative expressions with notions of direct or indirect causation, we analyze (in)directness of causation as a feature of event types of causation, not of causative expressions themselves. Thus, although the form-function correlation in causatives may hold in some languages we argue that (in)direct causation is not encoded separately in causative forms and constructions.
Effect of national cultural dimensions and consumption rates on stigma toward alcohol and substance use disorders
Authors: Simha Aditya , Ahmed Sana , Prasad Ramakrishna , Dinesh Akshay S. , Kandasamy Arun , Rao Naren P 
Published: July 2021

Background: Despite the notion of stigma as a socio-cultural process with the concept rooted in social space rather than in individual space, global studies examining impact of cultural differences on stigma toward substance use disorders are lacking. Aim: In this study, we aim to study the influence of national culture differences on stigma toward alcohol and substance use disorders. Methods: We analyzed individual-level data from 68,041 respondents from 49 countries on stigma toward alcohol and substance use disorders. We examined the effect of the national culture dimensions and national alcohol and substance consumption rates on stigma toward alcohol and substance use disorders using hierarchical linear modeling. Results: Our hierarchical linear modeling results indicate that cultural dimensions and consumption rates significantly influence stigma. We found significant positive associations between stigma toward AUD and institutional collectivism and assertiveness, but a negative association with future orientation dimension. Like AUD, stigma toward SUD was also positively associated with institutional collectivism and assertiveness, but negatively associated with power distance. Conclusions: The study findings have immense implications for national interventions to decrease stigma and influence policy making.