tbuckley/cabot-search huggingface dataset:
Abstract 5431: Activation of Myocardin Function by an Ubiquitin E3 Ligase, EDD
Authors: Guoqing Hu, Xiaobo Wang, Darren Saunders, Michelle Henderson, Amanda Russell, Brian Herring, Jiliang Zhou
Journal: Circulation (2009)

Fully differentiated mature smooth muscle cells (SMCs) are characterized by the presence of a unique repertoire of contractile proteins. The expression of these proteins is markedly attenuated during the de-differentiation of smooth muscle that occurs under many pathological conditions. SRF is a transcription factor that plays a central role in the expression of these smooth muscle-specific genes through physical association with various cell-restricted or signal dependent accessory factors. Of the SRF-associated proteins identified, myocardin is the most potent for stimulating expression of smooth muscle-specific genes. Although several proteins have been identified that can modify myocardin function, the mechanism of how myocardin regulation is still poorly understood. To identify additional myocardin associated proteins that are required for myocardin-dependent activation smooth muscle-specific genes we performed a yeast 2-hybrid screen of mouse embryo cDNA library using myocardin as bait. From this screen we identified a HECT domain containing protein EDD as a myocardin binding protein. Previous studies have shown that HECT domain containing proteins are ubiquitin E3 ligases that play an important role in protein degradation. EDD has however, also been shown to regulate transcription independent of its E3 ligase activity. In the current study we demonstrated that the amino-terminal domain of myocardin bound to the HECT domain of EDD. We also show that EDD specifically enhanced trans-activation of smooth muscle-specific promoters by myocardin. Furthermore, EDD significantly augmented myocardin’s ability to induce expression of endogenous SMC marker genes, and these effects of EDD were independent on its E3 ligase function. Conversely, depletion of endogenous EDD in fibroblast cells by RNAi attenuated myocardin-induced smooth muscle-specific gene expression, and EDD knockdown in smooth muscle cells resulted in down-regulation of smooth muscle-specific genes. Ongoing experiments are investigating the mechanism by which EDD activates myocardin function. This study reveals an unexpected role for the ubiquitin E3 ligase EDD as an activator of smooth muscle differentiation through its ability to potentiate myocardin function. This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5129: Importance of Heart Rate for the Effects of Chronic Mental Stress on Endothelial Function and Ischemic Stroke
Authors: Florian Custodis, Karen Gertz, Vincent Prinz, Mustafa Balkaya, Michael Böhm, Matthias Endres, Ulrich Laufs
Journal: Circulation (2009)

BACKGROUND: The vascular effects of chronic mental stress are only partially understood. We therefore studied the effects of chronic mental stress on endothelial function and focal brain ischemia and characterized the role of heart rate and oxygen free radicals. METHODS AND RESULTS: Male C57/Bl6-mice were subjected to an established chronic stress protocol (restraint, exposure to rat, tail hanging) for 6 weeks. Mice were treated with the I( f )-channel-inhibitor ivabradine, 10 mg/kg/d, p.o. or vehicle. Chronic stress increased heart rate, which was reduced by ivabradine treatment (vehicle 514±10 bpm, vehicle/stress 570±14 bpm; iva/stress 485±7 bpm). Endothelium-independent vasorelaxation induced by glyceroltrinitrate and vasoconstriction induced by phenylephrine and KCl were similar in all groups, however, endothelium-dependent relaxation of aortic rings by carbachol was significantly impaired in mice exposed to stress. Heart rate reduction by ivabradine improved endothelial function in stressed animals in contrast to vehicle treatment. Vascular NADPH oxidase activity was increased to 223±38% and lipid hydroperoxides were increased to 314±26% in mice exposed to stress. Heart rate reduction with ivabradine significantly reduced NADPH oxidase activity (169±44%) and lipid peroxidation (187±58%). To test the relevance of these findings, mice were subjected to 30 min filamentous middle cerebral artery occlusion (MCAo), followed by 72 h reperfusion. Mice exposed to chronic stress before MCAo exhibited a markedly increased lesion size in comparison to unstressed controls (vehicle/naive: 23.92±2.41 mm 3 vs placebo/stress: 33.72±2.34 mm 3 ). Heart reduction by ivabradine significantly reduced cerebral lesion size (iva/stress: 12.88±3.31 mm 3 ). P&lt;0.05 for all comparisons. CONCLUSIONS: Chronic exposure to mental stress impairs endothelial function and increases lesion area following ischemic stroke. Heart rate reduction by ivabradine diminishes the negative effects of chronic stress and protects from focal brain ischemia via reduction of vascular oxidative stress and amelioration of endothelial function. Those results identify the impact of heart rate as an important mediator of vascular effects induced by chronic mental stress.
Abstract 4959: Imaging of Atherosclerotic Lesions in Apoe−/− Mice by Targeting of CD40
Authors: Michael Grafe, Thore Dietrich, Dietger Stibenz, Jan Klohs, Esther Lutgens, Petra Schulz, Carsten Groetzinger, Riad Bourayou, Eckart Fleck, Kristof Graf
Journal: Circulation (2009)

We investigated whether in-vivo imaging of the CD40 receptor can be used for identification of inflammatory atherosclerotic lesions. Methods: Monoclonal antibodies against CD40 (CD40ab), IgGA2 (Coab) and Fab2 fragments (CD40Fab) were coupled to the near-infrared fluorescence (NIRF) dyes Cy5′5 or Cy7. Apolipoprotein E deficient mice (apoE−/−) and apoE−/−CD40−/− deficient mice (apoE−/−CD40−/−) were fed with high cholesterol diet for 8 –12 month. Antibody conjugates were injected into the tail vein and mice were investigated 6 to 48 hours after injection by conventional NIRF imaging, fluorescence microscopy of the aortic arch and in-vivo 3D fluorescence molecular tomography (FMT). Sudan staining and histological analysis were performed after imaging procedures. Results: Application of Cy5′5-labeled CD40ab resulted in accumulation of fluorescence signal intensity mainly in Sudan-positive areas of the thoracic aorta, which was also seen with the Coab at high concentrations. Fluorescence increased slightly after 24 hours compared to 6 hours after injection. In vivo imaging was not feasible using conjugated antibodies due to circulating intravasal fluorescence (&gt;48h). Significant background fluorescence was detected after application of CD40ab and Coab in all mice, probably due to FC receptor-dependent binding. Application of Cy7-CD40Fab induced strong in-vivo fluorescence detected by FMT in projection to the aortic arch and carotid arteries of apoE−/− (n=4), but not in apoE−/−CD40−/− mice (n=4). No signal was observed in mice injected with unlabelled Cy7. Ex-vivo imaging of the thoracic aorta confirmed a Cy7 signal in atherosclerotic lesions of apoE−/−, but not in apoE−/−CD40−/− after application of CD40Fab. Data were also confirmed by microscopic fluorescence imaging of the aortic wall and atherosclerotic lesions. Conclusion: In vivo detection of CD40 in atherosclerotic plaques was feasible using antibody fragments but not with full anti-CD40 antibodies. The approach is applicable for detection of vascular inflammation, since CD40 is strongly associated with inflammatory lesion formation.
Abstract 5082: Interferon- <i>γ</i> Plays a Pivotal Role in Hypertension-Induced Cardiac Remodeling and Diastolic Heart Failure
Authors: Anthony G Garcia, Richard M Wilson, Joline Heo, Namita Murthy, Deepa S De Silva, Flora Sam
Journal: Circulation (2009)

Background: Diastolic heart failure (DHF) is clinical conundrum and accounts for ~50% of all HF admissions. There remains a paucity of therapies. Hypertension is the major cause of DHF and is associated with LV hypertrophy (LVH). Inflammatory cytokines are increased in hypertension but it is unknown if they mediate hypertension-induced cardiac remodeling. We tested the hypothesis that interferon- γ plays a pivotal role in the progression from hypertension-induced LVH to DHF. Methods: Twelve-week old BALB/c (WT) and interferon- γ deficient (IFN γ KO) mice underwent either saline (saline; n=10) or aldosterone-infusion (ALDO; n=20). All underwent uninephrectomy and drank 1% salt water for 4-weeks. Four-weeks after surgery, tail-cuff blood pressure (BP), echocardiogram and gene/protein analyses were performed. Isolated adult rat ventricular myocytes (ARVM) were treated with either interferon- γ (500nM) and/or aldosterone (50nM) for 30min. Results: BP was increased in WT-ALDO vs. WT-saline mice (P&lt;0.01). Interestingly BP was not as increased in IFN γ KO-ALDO vs. WT-ALDO mice (127±5 vs. 136±4mmHg, P=NS). There was LVH in WT-ALDO vs. WT-saline mice (P&lt;0.05). LVH was further increased in IFN γ KO-ALDO vs. WT-ALDO mice (HW/BW ratio: 4.9±0.1 vs. 4.3±0.1mg/g; P&lt;0.01). LV end diastolic dimension was no different between IFNã KO-ALDO vs. WT-ALDO hearts. However, LV end systolic dimension (LVESD) was significantly smaller in IFNã KO-ALDO vs. IFNã KO-saline and WT-ALDO mice (1.12±0.1 vs. 1.4±0.1, and 2.1±0.3, respectively; P &lt;0.05 for both). LVH was associated with an increase in myocardial ANP gene and protein expression in WT-ALDO hearts (P&lt;0.05 vs. WT-sham). Intriguingly ANP gene and protein expression was not increased in IFNã KO-ALDO vs. WT-ALDO hearts. In ARVM pretreatment with interferon-ã prior to aldosterone significantly inhibited aldosterone-induced ERK1/2 phosphorylation, another marker of cardiomyocyte hypertrophy (P&lt;0.05). Conclusions: Interferon- γ modulates cardiomyocyte hypertrophy partly independently of BP. There is a propensity to adverse cardiac remodeling with interferon- γ deficiency in this model of hypertension and DHF. Our findings suggest that interferon- γ may represent a novel target for hypertensive heart disease and DHF.
2006 Stroke Council Award and Lecture—Patent Foramen Ovale and Stroke: What We Have Learned and What We Still Need to Know
Authors: Jeffrey Saver
Journal: Circulation (2006)

Management of patients with cryptogenic stroke and a patent foramen ovale (PFO) is a common clinical dilemma for cardiologists, neurologists, and primary care physicians and is a rapidly growing public health challenge for society. Between 50 000 and 100 000 Americans each year present with a PFO and an ischemic stroke of otherwise undetermined etiology. Collaborative studies by cardiovascular and cerebrovascular physician-scientists over the past 2 decades have advanced our understanding of the epidemiology, pathophysiology, and management of patients with patent foramen ovale and ischemic brain disease. The recurrent stroke rate among young cryptogenic stroke patients with a PFO is modest but higher than normal for age. Coexisting atrial septal aneurysm is a substantial—and the only definite—potentiator of stroke risk in patients with PFO, but PFO size, degree of functional shunting, and coexisting hyper-coagulable state likely are additional risk factors. Pelvic computed tomographic and magnetic resonance venography has improved our ability to detect source venous thromboemboli and underlies new management strategies. Close analysis of randomized clinical trial results suggests that brain imaging demonstration of a superficial convexity stroke location indicative of a highly probable embolic stroke top may usefully guide the selection of anticoagulation versus antiplatelet therapy in medically managed patients. The completion of ongoing randomized clinical trials comparing percutaneous closure devices with medical management is likely to be hastened by the recent withdrawal of humanitarian device exemption approvals and is urgently needed to provide definitive data to guide management of these patients with a linked disorder of heart and brain.
Abstract 5457: Angiotensinogen Hypomorphic Mice Have Markedly Reduced Hypercholesterolemia-induced Atherosclerosis
Authors: Hong Lu, Mingming Zhao, Lisa A Cassis, Alan Daugherty
Journal: Circulation (2009)

Background and Objective: The renin angiotensin system exerts profound effects on experimental atherosclerosis. Although multiple enzymes are proposed to generate the increasingly complex array of angiotensin peptides, angiotensinogen is the unique precursor of all angiotensin peptides. Angiotensinogen deficiency in mice leads to poor neonatal survival rate and multiple organ dysfunctions that present barriers to atherosclerosis studies. Therefore, we generated a hypomorphic angiotensinogen (hypoAGT) mouse model to determine the effects of reduced angiotensinogen on atherosclerosis in LDL receptor −/− mice. Methods and Results: hypoAGT mice were developed by insertion of a neomycin resistance cassette in the second intron of the angiotensinogen gene. Although hypoAGT mice have almost undetectable plasma angiotensinogen concentrations and markedly higher renin concentrations compared to the wild type control, these mice have normal neonatal survival rate and grossly normal growth development. To determine the contribution of angiotensinogen to atherosclerosis, male wild type and hypoAGT mice in an LDL receptor −/− background were fed a saturated fat-enriched diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) for 12 weeks. Body weight was monitored weekly. hypoAGT mice had modestly lower body weight at the initiation of the study. When fed the saturated fat-enriched diet for 12 weeks, wild type mice increased body weight by 49% compared to a 6% increase in hypoAGT mice. Systolic blood pressure (SBP) was measured using a non-invasive tail-cuff system on conscious mice. hypoAGT mice had lower SBP at baseline and when fed the saturated fat-enriched diet. Both wild type and hypoAGT mice were hypercholesterolemic, although hypoAGT mice had lower plasma cholesterol concentrations (wild type versus hypoAGT: 2789±115 versus 1647±106 mg/dl). Atherosclerotic lesion areas were measured on the intima of the aortic arch by the en face technique. hypoAGT mice had a virtual ablation of the development of atherosclerotic lesions (wild type versus hypoAGT: 20.5±2.4 versus 1.1±0.8%). Conclusion: Profound reduction of angiotensinogen strikingly attenuates development of hypercholesterolemia-induced atherosclerosis in LDL receptor −/−mice.
Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma
Authors: Monica Tang, Annabelle R Charbit, Mats W Johansson, Nizar N Jarjour, Loren C Denlinger, Wilfred W Raymond, Michael C Peters, Eleanor M Dunican, Mario Castro, Kaharu Sumino, Serpil C Erzurum, Suzy A Comhair, Wendy C Moore, Bruce D Levy, Elliot Israel, Wanda Phipatanakul, Brenda R Phillips, David T Mauger, Eugene R Bleecker, Sally E Wenzel, Merritt L Fajt, Prescott G Woodruff, Annette T Hastie, John V Fahy
Journal: Journal of Allergy and Clinical Immunology (2024)

The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain.
Electrospun Poly‐<scp>l</scp>‐Lactic Acid Membranes Promote M2 Macrophage Polarization by Regulating the PCK2/AMPK/mTOR Signaling Pathway
Authors: Daiyuan Tang, Bing Han, Chengkai He, Yunrong Xu, Zhui Liu, Weizhou Wang, Zaitian Huang, Zhenping Xiao, Fei He
Journal: Advanced Healthcare Materials (2024)

Electrospun membranes are widely used in tissue engineering. Regretfully, there is limited research on how its morphological characteristics precisely regulate macrophage activation and immune response. Therefore, electrospun poly-l-lactic acid (PLLA) membranes with different alignments (align and random) and diameters (nanoscale and microscale) are prepared to investigate the effects of different surface morphologies on M2 macrophage polarization. Additionally, transcriptome, proteome, and phosphoproteome sequencings are combined to examine the underlying regulatory mechanisms. The results show that the electrospun PLLA membranes with different surface morphologies have good biocompatibility and can regulate the phenotype and function of macrophages by changing the micromorphology of the matrix surface. Especially, macrophages cultured on the electrospun membranes of the A600 group exhibit higher M2 macrophage polarization than the other three groups. Furthermore, the findings demonstrate that electrospun PLLA membranes enhance AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) signaling activation by upregulating the expression of integrin phosphoenolpyruvate carboxykinase 2 (PCK2), which is critical for M2 macrophage polarization. Taken together, electrospun PLLA membranes promote M2 macrophage polarization by regulating the PCK2/AMPK/mTOR signaling pathway. This research can provide further theoretical bases for scaffold design, immunoregulatory mechanisms, and clinical application based on electrospinning technology in the future.
A Review of Brain-Inspired Cognition and Navigation Technology for Mobile Robots
Authors: Yanan Bai, Shiliang Shao, Jin Zhang, Xianzhe Zhao, Chuxi Fang, Ting Wang, Yongliang Wang, Hai Zhao
Journal: Cyborg and Bionic Systems (2024)

Brain-inspired navigation technologies combine environmental perception, spatial cognition, and target navigation to create a comprehensive navigation research system. Researchers have used various sensors to gather environmental data and enhance environmental perception using multimodal information fusion. In spatial cognition, a neural network model is used to simulate the navigation mechanism of the animal brain and to construct an environmental cognition map. However, existing models face challenges in achieving high navigation success rate and efficiency. In addition, the limited incorporation of navigation mechanisms borrowed from animal brains necessitates further exploration. On the basis of the brain-inspired navigation process, this paper launched a systematic study on brain-inspired environment perception, brain-inspired spatial cognition, and goal-based navigation in brain-inspired navigation, which provides a new classification of brain-inspired cognition and navigation techniques and a theoretical basis for subsequent experimental studies. In the future, brain-inspired navigation technology should learn from more perfect brain-inspired mechanisms to improve its generalization ability and be simultaneously applied to large-scale distributed intelligent body cluster navigation. The multidisciplinary nature of brain-inspired navigation technology presents challenges, and multidisciplinary scholars must cooperate to promote the development of this technology.
New genes helped acorn barnacles adapt to a sessile lifestyle
Authors: Zhaofang Han, Zhixuan Wang, Daniel Rittschof, Zekun Huang, Liying Chen, Huanhuan Hao, Shanshan Yao, Pei Su, Miaoqin Huang, Yuan-Ye Zhang, Caihuan Ke, Danqing Feng
Journal: Nature Genetics (2024)
Hematopoietic Clonal Evolution Goes Spatial
Authors: Rebecca Austin, Iannis Aifantis
Journal: Blood Cancer Discovery (2024)

The spatial distribution of cells carrying clonal hematopoiesis mutations in the bone marrow and the potential role of interactions with the microenvironment are largely unknown. This study takes clonal evolution to the spatial level by describing a novel technique examining the spatial location of mutated clones in the bone marrow and the first evidence that mutated hematopoietic clones are spatially constrained and have heterogenous locations within millimeters of distance. See related article by Young et al., p. 153 (10).
The dichotomy of diagnostics: exploring the value for consumers, clinicians and care pathways
Authors: Dylan Powell, Aiden Hannah
Journal: npj Digital Medicine (2024)

Diagnostics play a crucial role in screening, detecting, and stratifying patients, yet can account for only 2–3% of healthcare spending. With advancements in wearable technology and direct-to-consumer testing, the market for consumer health continues to rise. The potential benefits of more holistic and continuous measurement offer a promising opportunity for earlier disease detection and proactive health management. Many health systems are in a parallel transition from legacy analogue approaches to digitally enabled infrastructures. The evolving role of the clinical workforce, including medical ethics, regulation, will be closely coupled and a critical lever in success. This includes on a patient and clinician level, balancing the benefits and risks of interventions, and care pathway level, promoting responsible data utilisation with greater contextualisation based on the latest evidence of clinical efficacy. Moving forward a balance may need to be struck between increased data capture, analysis and reuse, with proportionate ethics, regulation, trust and governance.
Augmented non-hallucinating large language models as medical information curators
Authors: Stephen Gilbert, Jakob Nikolas Kather, Aidan Hogan
Journal: npj Digital Medicine (2024)

Reliably processing and interlinking medical information has been recognized as a critical foundation to the digital transformation of medical workflows, and despite the development of medical ontologies, the optimization of these has been a major bottleneck to digital medicine. The advent of large language models has brought great excitement, and maybe a solution to the medicines' 'communication problem' is in sight, but how can the known weaknesses of these models, such as hallucination and non-determinism, be tempered? Retrieval Augmented Generation, particularly through knowledge graphs, is an automated approach that can deliver structured reasoning and a model of truth alongside LLMs, relevant to information structuring and therefore also to decision support.
Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration
Authors: Jiayi Wu, Feifei Li, Peng Yu, Changhao Yu, Chuyi Han, Yitian Wang, Fanyuan Yu, Ling Ye
Journal: International Journal of Oral Science (2024)

Abstract Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.
Revisiting the Association of ECOG Performance Status With Clinical Outcomes in Diverse Patients With Cancer
Authors: Deepika Kumar, Elad Neeman, Shiyun Zhu, Hongxin Sun, Dinesh Kotak, Raymond Liu
Journal: Journal of the National Comprehensive Cancer Network (2024)

The ECOG performance status (PS) scale was developed to support national clinical trials, but the degree to which ECOG PS predicts clinical outcomes in patient subgroups outside of clinical trials is relatively unknown. This study examined associations between ECOG PS and adverse outcomes in a diverse community oncology population.