Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of ...CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.
ABSTRACT
Engineering offers new educational opportunities for students, yet also poses challenges about how to conceptualize the disciplinary core ideas, crosscutting concepts, and science and ...engineering practices of the disciplinary fields of engineering. In this paper, we draw from empirical studies of engineering in professional and school settings to propose a set of epistemic practices of engineering that can inform curriculum development, teacher education, and research in science and engineering education. We examine the ways that these practices emerge from the work of engineering and serve to guide problem solving across a range of engineering fields. The proposed epistemic practices for education take into consideration social contexts of engineering, the salience of evidence for decision making, the types of tools and strategies used to construct knowledge, and need for creativity and innovation. The article concludes with suggestions for research in engineering education.
Engineering design provides unique ways to include epistemic tools to support collaborative sense‐making, reasoning with evidence, and assessing knowledge. Engineering design processes often require ...students to apply science concepts to solve problems. We draw from five engineering curricular units that engaged students in specific epistemic practices of engineering: constructing models and prototypes, making trade‐offs between criteria and constraints, and communicating through uses of conventionalized verbal, written, and symbolic models. Through analysis of curriculum products, student artifacts, and classroom discourse, we show how engaging in such practices requires the use of epistemic tools that shape, and are shaped by, the knowledge construction work of the members of the classrooms. The epistemic tools foster creating, sharing, and assessing knowledge claims. Six principles of practice for education demonstrate how such tools can be educative. These principles evince how epistemic tools support goal‐directed, concerted activity that can support the learning of disciplinary knowledge and practice and offer the potential to increase student agency.
The novel 2019 coronavirus disease (COVID-19), resulting from severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2) infection, typically leads to respiratory failure in severe cases; however, ...cardiovascular injury is reported to contribute to a substantial proportion of COVID-19 deaths. Preexisting cardiovascular disease (CVD) is among the most common risk factors for hospitalization and death in COVID-19 patients, and the pathogenic mechanisms of COVID-19 disease progression itself may promote the development of cardiovascular injury, increasing risk of in-hospital death. Sex differences in COVID-19 are becoming more apparent as mounting data indicate that males seem to be disproportionately at risk of severe COVID-19 outcome due to preexisting CVD and COVID-19-related cardiovascular injury. In this review, we will provide a basic science perspective on current clinical observations in this rapidly evolving field and discuss the interplay sex differences, preexisting CVD and COVID-19-related cardiac injury.
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•Cardiovascular complications are prominent in COVID-19.•Preexisting cardiovascular disease is a risk factor for COVID-19 severity.•Cardiovascular disease, smoking and obesity burden more male COVID-19 patients•Cardiac injury and systemic inflammation are pronounced in male COVID-19 patients.•No sex disparities were observed in arrhythmia and thrombosis in COVID-19 patients.
The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular ...understanding of preclinical models and facilitate their rational use and interpretation.
To determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.
Single-cell RNA sequencing was performed on the lungs of monocrotaline (MCT), Sugen-hypoxia (SuHx), and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA
hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.
Distinct changes in genes and pathways in numerous cell types were identified in SuHx and MCT lungs. Widespread upregulation of NF-κB signaling and downregulation of IFN signaling was observed across cell types. SuHx nonclassical monocytes and MCT conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in SuHx nonclassical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.research.idre.ucla.edu/PVDSingleCell/).
Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.
Surprisingly, being female is protective against the development of pulmonary hypertension (PH) in various animal models (2). Because this effect has largely been attributed to the protective effects ...of estradiol, the phenomenon is known as the "estrogen paradox" (3, 4). Mouse studies in which the number and type of sex chromosomes were independent of gonadal sex indicated that sex chromosomes contribute to sex differences in autoimmune disease, metabolic dysfunction, neurodegeneration, and cardiovascular disease (6, 7). ...genes encoded on the sex chromosomes have already been shown to have strong effects that contribute to sex differences in various phenotypes, including disease susceptibility and progression. In mice, four proteincoding Y genes are expressed in lungs (Ddx3y Y-linked DEAD-box helicase 3, Eif2s3y eukaryotic translation initiation factor 2, subunit 3, structural gene Y-linked, Kdm5d lysine demethylase 5D, and Uty ubiquitously transcribed tetratricopeptide repeat containing, Y-linked), and therefore are candidates to explain the protective effect of the Y chromosome in PH (Table 1). Because gonadal hormones also contribute to sex differences in PH (2, 3), we expect that they interact with Y chromosome factors to affect PH development.
Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to ...reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Understandably, a recent report drawing an association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal or incidental nature of this association and the implications for AAV vector safety. Here we describe and functionally characterize a previously unknown liver-specific enhancer-promoter element in the wild-type AAV2 genome that is found between the stop codon of the cap gene, which encodes proteins that form the capsid, and the right-hand inverted terminal repeat. This 124-nt sequence is within the 163-nt common insertion region of the AAV genome, which has been implicated in the dysregulation of known HCC driver genes and thus offers added insight into the possible link between AAV integration events and the multifactorial pathogenesis of HCC.
Epigenetic regulation of gene expression is integral to cell differentiation, development, and disease. Modes of epigenetic regulation-including DNA methylation, histone modifications, and ...ncRNA-based regulation-alter chromatin structure, promotor accessibility, and contribute to posttranscriptional modifications. In the cardiovascular system, epigenetic regulation is necessary for proper cardiovascular development and homeostasis, while epigenetic dysfunction is associated with improper cardiac development and disease.Early sexualization of tissues, including X-inactivation in females and maternal and paternal imprinting, is also orchestrated through epigenetic mechanisms. Furthermore, sex chromosomes encode various sex-specific genes involved in epigenetic regulation, while sex hormones can act as regulatory cofactors that may predispose or protect males and females against developing diseases with a marked sex bias.The following book chapter summarizes the field of epigenetics in the context of cardiovascular development and disease while also highlighting the role of epigenetic regulation as a powerful source of sex differences within the cardiovascular system.
Affordances of engineering with English learners Cunningham, Christine M.; Kelly, Gregory J.; Meyer, Natacha
Science education (Salem, Mass.),
March 2021, 2021-03-00, 20210301, Volume:
105, Issue:
2
Journal Article
Peer reviewed
Open access
In this position paper, we draw from previous research and theoretical developments in the field to propose a set of affordances of engineering with English learners (ELs). Students learning both the ...language of instruction (e.g., English) and academic subject matter (e.g., engineering, mathematics, science) face the challenge of making sense of linguistically complex terminology of disciplinary knowledge. We posit that engineering provides a unique set of benefits for such learners due to a number of factors associated with the discipline of engineering, including the materiality of the knowledge, the potential for multimodal communication, and the contextualization of knowledge in specific task‐oriented activities. We also recognize that engineering benefits from participation by diverse learners including ELs as solutions are strengthened by a multitude of ideas and perspectives. Although this paper focuses on ELs, we recognize that such affordances are also valuable for all students, including native English speakers, and that they may be particularly important for students who may benefit from additional linguistic supports for developing academic literacies. We identify the affordances, anchoring them in elementary classroom experiences and teacher testimonials, and propose a research agenda for future study.
BACKGROUND:We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying ...mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G-protein–coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein–coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
METHODS:Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein–coupled receptor 40 antagonist (GW1100, 10 µM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml · kg · min maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV).
RESULTS:G-protein–coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product2,186 ± 1,783 n = 7 vs. 11,607 ± 4,347 n = 8; left ventricular developed pressure22.6 ± 10.4 vs. 63.8 ± 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 ± 386 vs. 2,098 ± 792, P < 0.001; dP/dtmin = −443 ± 262 vs. −1,447 ± 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR302 ± 17 vs. 312 ± 38; ejection fraction69 ± 3% vs. 73 ± 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 ± 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 ± 8%, fractional shortening = 38 ± 6%).
CONCLUSIONS:G-protein–coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
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