bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of extracellular vesicles from patients with severe aortic stenosis undergoing transcatheter aortic valve implantation and assessment of their coagulation potential
Authors: Skogseid E L , Khandagale A , Siegbahn A , Christersson C 
Published: May 2024

Abstract

Funding Acknowledgements
None.

Background
The pathogenesis of aortic stenosis (AS) includes processes of inflammation and calcification. Patients with aortic stenosis have increased risk of stroke. The amount of circulating extracellular vesicles (EVs) is elevated in patients with severe AS and decreases following valve intervention. The function of these EVs in the clinical setting of severe AS is not fully known.

Aim
With flow cytometry characterize EVs in patients with severe AS before and after Transcatheter Aortic Valve Implantation (TAVI). To investigate whether these EVs have a procoagulant effects by themselves or when incubated with human aortic endothelial cells (hAoECs), human cardiac microvascular endothelial cells (hCMVEC), human cardiac myocytes (hCM) and spheroids of hCMVEC and hCM.

Methods
25 patients with severe AS were included in the study and blood samples collected before and 2 months after TAVI. The CytoFLEX flow cytometer (Beckman Coulter) was used for characterization of surface antigens on purified EVs. 2D-cultures of hAoECs, hCMVEC and hCM were incubated with EVs (100 mg/mL) for 6 hours (h) and spheroids of hCM and hCMVEC with EVs for 48h. An inhouse assay determining Tissue Factor (TF) activity by means of FXa generation in cell lysates were utilized. TF activity in purified EVs alone was determined using Tissue Factor Activity Assay kit (Human, colorimetric) from abcam.

Results
We found an increased level of TF positive EVs, phosphatidylserine (PS) positive EVs as well as double positive PS / TF expressing EVs in AS patients before TAVI compared to healthy controls and reduction of PS+ and TF+/PS+ expressing EVs after TAVI (Fig 1). When analyzing TF activity by means of FXa generation we found no procoagulant effect in the purified EVs alone nor when incubating EVs with hAoEC or hCM. In contrast, we found an increased TF activity in hCMVEC and spheroids of hCM and hCMVEC after incubation with EVs from AS patients compared to healthy EVs.

Conclusion
Patients with AS have increased amount of EVs expressing typically procoagulant surface antigens. The EVs by themselves have no procoagulant activity. However, upon interaction with hCMVEC and spheroids, consisting of hCMVEC and hCM, EVs appear to induce procoagulant activity in the recipient cells thus suggesting a possible link to thromboembolic events in coronary arteries. Additional studies are warranted to elaborate the mechanism and function of these TF, PS and TF / PS positive EVs.
Increased oxidative stress alters coronary microvascular tone in exercising swine with multiple comorbidities
Authors: Van Drie R W A , Sorop O , Van De Wouw J , Duncker D J , Merkus D 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Cardiovascular Alliance

Background/Objectives
We have previously shown, in female swine that the combination of three cardiovascular risk factors (diabetes mellitus (DM), hypercholestolemia (HC) and chronic kidney disease (CKD)) induces systemic inflammation, oxidative stress, coronary endothelial dysfunction and impaired myocardial perfusion due to impaired nitric oxide (NO) bioavailability. In the present study we hypothesized that the reduced bioavailability of nitric oxide (NO) is the result of increased production of reactive oxygen species (ROS) and ROS scavenging will restore myocardial oxygen balance thereby improving myocardial perfusion.

Methods
12 female swine, with DM (streptozotocin 3x50mg/kg iv), CKD (renal embolization), and HC (high fat, high sugar, high salt diet) and 9 female healthy swine on normal pig chow (Normal) were included. The effect of ROS scavenging on the coronary microvascular tone control was studied in vivo, at rest and during graded treadmill exercise before and after infusion of the ROS scavengers (MPG+Tempol). Additionally, vasodilation to bradykinin was studied in the presence of MPG and TEMPOL and after subsequent addition to catalase, in isolated left ventricle small coronary arteries, in vitro using wire-myography.

Results
6 months of DM+HC+CKD resulted in hyperglycemia (18.0±1.3 vs 8.4±0.9mmol/L), hypercholesterolemia (13.4±2.1 vs 1.7±0.1mmol/l), renal dysfunction (plasma creatinine: 166±9 vs 119±3µmol/l), and systemic inflammation (TNFα: 63±8 vs 41±4pg/ml, all P&lt;0.05) associated with impaired endothelium-dependent vasodilator response to bradykinin in vitro. Furthermore, myocardial oxidative stress was increased in DM+HC+CKD animals (8-isoprostane 13±1 vs 10±1pg/ml) and total antioxidant capacity was reduced (0.67±0.02 vs 0.72±0.01nmol Trolox eq./mg protein, both P&lt;0.05). Surprisingly, in vivo ROS scavenging resulted in an even further increase in myocardial oxygen extraction in DM+HC+CKD while it had no effect in Normal, indicating the involvement of a vasodilator ROS (most likely H2O2) in the control of coronary microvascular tone. This was supported by increased activity of catalase in the myocardium of DM+HC+CKD animals (44±3 vs 31±4nmol/min/ml, both P&lt;0.05) and the vascular relaxation response to bradykinin when catalase was added on top of the ROS scavenging in vitro.

Conclusion
In swine exposed for 6 months to multiple comorbidities, impaired myocardial perfusion is mediated by a loss of NO bioavailability due to increased oxidative stress which was partially compensated by increased H2O2-mediated coronary vasodilation.
Targeting the histone methyltransferase SETD7 rescues diabetes-induced impairment of angiogenic response by transcriptional repression of semaphorin 3G
Authors: Mohammed S A , Hoxha E , Albiero M , Karsai G , Masi S , Mengozzi A , Spinetti G , Ruschitzka F , Fadini G P , Costantino S , Paneni F 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science Foundation (n. 310030_197557), the Swiss Heart Foundation (n. FF19045)

Background
Peripheral artery disease (PAD) is highly prevalent in patients with diabetes (DM) and associates with a poor prognosis (1). Revascularization strategies failed to improve outcome, highlighting the need to develop new strategies to promote blood vessel growth (2). Histone modifications have emerged as key modulators of gene expression (3), however their role in angiogenic response in DM remains poorly understood. The present study investigates the role of chromatin remodelling in DM-related impairment of angiogenic response.

Methodology
Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) levels for 48 hours. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq). Cell migration and tube formation were employed to study angiogenic properties in HAECs. Levels of the histone methyltransferase SETD7 and its chromatin signature at histone 3 on lysine 4 (H3K4me1) were investigated by Western blot and chromatin immunoprecipitation (ChIP). Pharmacological blockade of SETD7 was achieved by using the selective inhibitor (R)-PFI-2 while the inactive enantiomer (S)-PFI-2 was used as a control. Mice with streptozotocin-induced DM were orally treated with (R)-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation. Blood flow was analysed at 24 hours, 7 and 14 days by laser Doppler imaging. Our experimental findings were also translated in endothelial cells (ECs) and gastrocnemius muscle samples obtained from DM patients with PAD.

Results
RNA-seq in HG-treated HAECs unveiled the histone methyltransferase SETD7 as the top-ranking transcript. SETD7 upregulation was associated with increased H3K4me1 levels as well as with impaired HAECs migration and tube formation. Both SETD7 silencing and inhibition by (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7-induced H3K4me1 enables the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA-3G) by increasing chromatin accessibility to PPARγ. Moreover, SEMA-3G overexpression mimicked the impairment of angiogenic response observed during hyperglycemia. In DM mice with hindlimb ischemia, (R)-PFI-2 improved limb perfusion by suppressing SEMA-3G. Finally, RNAseq in vascular specimens from DM patients with PAD confirmed the upregulation of SETD7/SEMA3G signalling, whereas SETD inhibition restored angiogenic properties in ECs from DM patients.

Conclusion
SETD7 is a novel epigenetic target to boost neovascularization in DM patients with PAD.
Are telocytes related to maintenance of vascular homeostasis in normal and pathological aorta?
Authors: Borges L , Falcao R S P , Taboga S R , Gutierrez P S , Michel J B 
Published: May 2024

Abstract
Funding Acknowledgements
None.
The telocyte (TC) is a new interstitial cell type described in a wide variety of organs and loose connective tissues around small vessels, but its presence in large arteries remains unexplored. TCs have small cell bodies and remarkably thin, long, moniliform processes called telopods (Tps). Using transmission electron microscopy and immunofluorescence, we identified TCs in normal human thoracic aortas and in those with aneurysm and acute dissection (TAAD). In normal aortas the TCs were distributed throughout the connective tissue of the adventitial layer, in its innermost portion and at the zone of transition with the medial layer, with their long axes oriented parallel to the external elastic lamellae, forming a three-dimensional network, without prevalence in the media layer. In contrast, TAAD TCs were present in the medial layer and in regions of neovascularization. The most important feature of the adventitia of diseased aortas was the presence of numerous contacts between TCs and stem cells, including vascular progenitor cells. Although the biologically functional correlations need to be elucidated, the morphological observations presented here provide strong evidence of the involvement of TCs in maintaining vascular homeostasis in pathological situations of tissue injury.
Exploring the role of air pollution on the development of atherosclerosis disorder in human endothelial cells
Authors: Alenany R , Shawkat T , Korashy H 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): QU - NSPP

Introduction
Atherosclerosis, the main cause of cardiovascular and cerebrovascular diseases, is a global health threat. Rising cardiovascular disease prevalence, unexplained by traditional risk factors, prompts exploration of the impact of occupational exposure to environmental toxins as a risk factor. benzo[a]pyrene (BaP) is a polyaromatic compound that mediate its toxicity through activation of the Aryl hydrocarbon receptor (AhR). The molecular mechanisms of involvement of environmental toxins and the role of AhR/CYP1A pathway in atherosclerosis development remain not fully investigated.

Purpose
The current study explores the AhR pathway activation in endothelial cells upon exposure to environmental toxins in order to elucidate the molecular mechanisms of atherosclerotic cardiovascular diseases and plaque formation through investigating pro-inflammatory (CYP1A1, CYP1B1, TNF-a) and pro-apoptotic markers (BCL-2, Caspase-3).

Methods
EA. hy926 cell line underwent treatment with increasing concentrations of BaP (0-20 microM), as well as 10nm of TCDD, to confirm the results. DSMO was used as a control. Total RNA and protein were isolated to investigate mRNA expression and protein expression of AhR, CYP1A1, CYP1B1, as well as caspase-3, Bcl-2, and TNF-α using RT-PCR and Western Blot analysis. Statistical analysis was done using one-way ANOVA.

Results
The results showed that BaP induce significant dose-dependent upregulation of AhR and target genes (CYP1A1, CYP1B1). At 20uM, expression of AhR (3-fold), CYP1A1 (2.5-fold) and CYP1B1 (2-fold) was significantly high as compared to their respective controls and low doses. As for apoptotic markers, Bcl-2 was significantly downregulated at the highest concentrations 10uM and 20uM (0.7- and 0.6-fold, respectively). Caspase-3 showed no significant change but exhibited upregulation across all doses. TCDD 10nM significantly upregulated AhR (2.0-fold), CYP1A1 (1.5-fold), CYP1B1 (1.7-fold). Bcl-2 downregulated (0.6-fold), TNF-α significantly upregulated (1.8-fold) at 10nM. Caspase-3 increased 2-folds but was not statistically significant.

Conclusion
This study illustrated that AhR inducers, such as BaP, can accelerate the pathological progress of atherosclerosis by evoking oxidative stress and inflammation response molecules in human endothelial cells, demonstrated by the reduced expression of anti-apoptotic markers and the increased expression of inflammatory markers.
Estrogen and the estrogen receptor in ZSF1 rats with heart failure with preserved ejection fraction
Authors: Buettner P , Werner S , Thiele H 
Published: May 2024

Abstract

Funding Acknowledgements
None.

Background
Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women, so declining estrogen levels after menopause may be involved in genesis of the disease. Estrogen is cardio-protective, affecting blood pressure and vasodilatation and endothelial dysfunction is discussed as HFpEF pathomechanism. However, the potential connection between HFpEF and estrogen levels remains poorly understood. The well-established HFpEF ZSF1 rat model was used to analyze endothelial dysfunction, and a pronounced imbalance of the NO synthase substrates arginine and homoarginine was observed. Of note, estrogen levels in woman are directly and positively associated to homoarginine levels.

Purpose
We characterized serum estrogen levels and the expression of the estrogen receptor alpha (ERα) in the hearts of female ZSF1 HFpEF rats to investigate a possible contribution of estrogen signaling in HFpEF manifestation and to evaluate the suitability of this animal model in the context of estrogen and HFpEF.

Methods
In total, 12 obese ZSF1 rats with HFpEF (O-ZSF1) and 12 lean healthy ZSF1 rats (L-ZSF1) at 20 weeks of age and 5 animals of either phenotype aged 32 weeks were analyzed. Further, six O-ZSF1 rats were supplemented with homoarginine (hArg) when HFpEF was manifest and were observed up to 32 weeks of age. The manifestation of HFpEF was confirmed by echocardiography and determination of NT-proBNP by ELISA. Circulating estradiol (E2) in serum was determined using ELISA. Expression of the estrogen receptor alpha was determined by Western Blot analysis in the left ventricle (LV), septum and right ventricle (RV).

Results
Serum estradiol levels were similar in age-matched L-ZSF1 and O-ZSF1, but were ~2-fold increased at an age of 32 weeks compared to 20 weeks (p=0.002). The canonical ERα-66kDa was very weakly expressed in all tissues. ERα-45kDa expression in the LV was lower in O-ZSF1 at an age of 20 weeks (-46%, p=0.008) and at 32 weeks (-46%, p=0.002).
ERα-45kDa expression in LV was 2-fold higher than in septum and 5-fold higher than in RV in rats aged 20 weeks (p&lt;0.001). In RV, no differences in ERα-45kDa expression were observed. Supplementation of O-ZSF1 with hArg reestablished the ERα-45kDa expression in the LV (p=0.005 vs. O-ZSF1 without supplementation).

Conclusion
The manifestation and progression of HFpEF in ZSF1 rats is accompanied by a decrease of the ERα-45kDa expression in the LV, whereas the RV is not affected. Supplementation with homoarginine normalizes ERα-45kDa expression. The ERα-45kDa isoform was found to suppress the transcriptional activity of the classical ERα-66kDa isoform and to be an acute regulator of endothelial NO synthase in response to estrogen. These results suggest that altered ERα expression in the LV may represent a novel pathomechanism in HFpEF. In combination with decreasing estrogen levels in woman, adverse consequences for NO production in the LV seem likely.
The maximally selected likelihood ratio test in random coefficient models
Authors: Horváth Lajos , Trapani Lorenzo , VanderDoes Jeremy 
Published: May 2024

Summary
In a recent contribution, we developed a family of cumulative sum-based change-point tests in the context of a random coefficient autoregressive model of order 1. In the current paper, we complement the results in that contribution by studying the (maximally selected) likelihood ratio statistic. We show that this has power versus breaks occurring even as close as periods from the beginning/end of sample; moreover, the use of quasi-maximum likelihood-based estimates yields better power properties, with the added bonus of being nuisance-free. Our test statistic has the same distribution—of the Darling–Erdős type—irrespective of whether the data are stationary or not, and can therefore be applied with no prior knowledge of this. Our simulations show that our test has very good power and, when applying a suitable correction to the asymptotic critical values, the correct size. We illustrate the usefulness and generality of our approach through applications to economic and epidemiological time series.
A Novel Dual-Language Touch-Screen Intervention to Slow Down Cognitive Decline in Older Adults: A Randomized Controlled Trial
Authors: Yow Wei Quin , Sou Ka Lon , Wong Alina Clarise 
Published: May 2024

Abstract

Background and Objectives
Bilingualism has been suggested to protect older adults from cognitive aging and delay the onset of dementia. However, no studies have systematically explored bilingual usage as a tool to mitigate age-related cognitive decline. We developed the Dual-Language Intervention in Semantic memory—Computerized (DISC), a novel cognitive training program with three training tasks (object categorization, verbal fluency, and utility of things) designed specifically for older adults that featured two modes: single-language (SL) exposure mode and dual-language (DL) exposure mode.

Research Design and Methods
The final sample included 50 cognitively healthy (CH; 33 female, Mage = 72.93 years, range = 53.08–87.43 years) and 48 cognitively impaired (CI; 35 female, Mage = 80.93 years, range = 62.31–96.67 years) older adults, randomly assigned them into one of three groups: SL group, DL group, and control group (no training). Participants in SL and DL groups used DISC in either SL mode (i.e., training instructions were spoken in only one language throughout the entire training) or DL mode (i.e., training instructions alternated between two languages), respectively, for 24 sessions. Participants in the control group were asked to continue with their normal daily activities (e.g., playing bingo and reading newspapers).

Results
For CH older adults, we found significant improvements in the Rey Auditory Verbal Learning Test (RAVLT) Trial 5 score and the Clock Drawing Test score in the DL group but not in the SL and control groups posttraining compared with pretraining. For CI older adults, there was a delayed improvement in the RAVLT Trial 1, six months later.

Discussion and Implications
Our findings provided novel evidence that implementing DL cognitive training benefits CH older adult’s late verbal learning and visuospatial construction skills, and a delayed improvement in CI older adults’ early verbal learning abilities.
Evolution of Litter Size: Proximate and Ultimate Mechanisms
Authors: Wilsterman Kathryn , Bautista Anna Isabel , Butler Chloe E , Juergens Makenna Y , Larson Ashley M 
Published: May 2024

Synopsis
Relative reproductive success and failure are the ultimate determinants of Darwinian fitness. As such, reproductive traits and variations therein have an immediate and considerable impact on the evolutionary trajectory of lineages. Historically, significant attention has been paid to the ecological and evolutionary processes (ultimate factors) that shape the diversity and canalization of reproductive traits within groups to better our understanding of organismal diversity and population or species resilience. In contrast, the physiological systems that mediate variation within and among species (i.e., the proximate factors) in reproductive traits remain a significant black box. To date, there is comparatively little information about how proximate mechanisms constrain or promote evolutionary potential in reproductive traits. In this mini-review, we focus on litter size in Eutherian mammals as a trait with relatively well-defined diversity (litter sizes are well-described both within and across species) and for which some genetic determinants have been identified. We discuss both the ultimate and potential proximate determinants of litter size with special attention to the breadth of physiological traits that may act as “toggle” switches for evolution of litter size. We close with a brief discussion of the role that physiological plasticity may play in the evolution of litter size and lay out several forward-looking areas for future research.
Robust estimation of smooth graph signals from randomized space–time samples
Authors: Huang Longxiu , Needell Deanna , Tang Sui 
Published: May 2024

Abstract
Heat diffusion processes have found wide applications in modelling dynamical systems over graphs. In this paper, we consider the recovery of a $k$-bandlimited graph signal that is an initial signal of a heat diffusion process from its space–time samples. We propose three random space–time sampling regimes, termed dynamical sampling techniques, that consist in selecting a small subset of space–time nodes at random according to some probability distribution. We show that the number of space–time samples required to ensure stable recovery for each regime depends on a parameter called the spectral graph weighted coherence, which depends on the interplay between the dynamics over the graphs and sampling probability distributions. In optimal scenarios, as little as $\mathcal{O}(k \log (k))$ space–time samples are sufficient to ensure accurate and stable recovery of all $k$-bandlimited signals. Dynamical sampling typically requires much fewer spatial samples than the static case by leveraging the temporal information. Then, we propose a computationally efficient method to reconstruct $k$-bandlimited signals from their space–time samples. We prove that it yields accurate reconstructions and that it is also stable to noise. Finally, we test dynamical sampling techniques on a wide variety of graphs. The numerical results on synthetic and real climate datasets support our theoretical findings and demonstrate the efficiency.