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  • 1
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    Just 2% of SARS-CoV-2−positive individuals carry 90% of the virus circulating in communities
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 21 ( 2021-05-25)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 21 ( 2021-05-25)
    Abstract: We analyze data from the fall 2020 pandemic response efforts at the University of Colorado Boulder, where more than 72,500 saliva samples were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using qRT-PCR. All samples were collected from individuals who reported no symptoms associated with COVID-19 on the day of collection. From these, 1,405 positive cases were identified. The distribution of viral loads within these asymptomatic individuals was indistinguishable from what has been previously observed in symptomatic individuals. Regardless of symptomatic status, ∼50% of individuals who test positive for SARS-CoV-2 seem to be in noninfectious phases of the disease, based on having low viral loads in a range from which live virus has rarely been isolated. We find that, at any given time, just 2% of individuals carry 90% of the virions circulating within communities, serving as viral “supercarriers” and possibly also superspreaders.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2104547118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 2
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    Abstract 266: Sex Differences in Survival and Pathological Responses of Hearts, Cardiac Myocytes and Fibroblasts
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Research Vol. 123, No. Suppl_1 ( 2018-08-03)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 123, No. Suppl_1 ( 2018-08-03)
    Abstract: Introduction: Biological sex is an important modifier of cardiovascular disease (CVD). However, women and female animals have traditionally been excluded from clinical trials and most preclinical research studies, resulting in therapeutics that are not as effective, or with different side effects, in women relative to men. Methods and Results: We show here that expression of α- and β-adrenergic receptors, cardiac stiffness, myofibroblast proliferation, and expression of fibrotic markers are sexually dimorphic at baseline. To determine whether pathogenesis was different between the sexes, the β-adrenergic agonist, isoproterenol (ISO), was administered to rats. In response to 7-days of ISO treatment, female animals were more likely to survive than their male counterparts (percent survival: 44% in males versus 77% in females). Both sexes developed significant cardiac hypertrophy, activation of cardiac fetal genes (ANF and β-MHC) compared to vehicle controls. Cardiac myocytes from ISO treated animals took less time to reach peak shortening and displayed increased departure velocity; however, only male ISO treated cells exhibited reduced relaxation times and increased return velocities. Importantly, ISO treated animals developed significant fibrosis prompting us to analyze isolated cardiac fibroblasts at baseline and in response to ISO. We observed significantly increased expression of α-SMA and Col1a, two indicators of myofibroblast activation, only in fibroblasts isolated from ISO treated males. Both ISO treated male and female fibroblasts showed significant increases in periostin and decreases in TCF21, indicative of increases in myofibroblasts and decreases in quiescent fibroblasts, respectively. In addition, both sexes revealed increased fibroblast proliferation in vivo , as measured by EdU incorporation, in response to ISO. Conclusions: Chronic in vivo β-adrenergic receptor stimulation revealed dramatic sex differences in mortality, cardiac hypertrophy, myocyte contractility, and cardiac fetal gene expression. Increases in myofibroblast differentiation and fibroblast proliferation should lead to a robust fibrotic response in both male and female ISO treated animals.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.123.suppl_1.266
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467838-X
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  • 3
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    Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Journal of the American Heart Association Vol. 10, No. 11 ( 2021-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. 11 ( 2021-06)
    Abstract: Biological sex is an important modifier of cardiovascular disease and women generally have better outcomes compared with men. However, the contribution of cardiac fibroblasts (CFs) to this sexual dimorphism is relatively unexplored. Methods and Results Isoproterenol (ISO) was administered to rats as a model for chronic β‐adrenergic receptor (β‐AR)‐mediated cardiovascular disease. ISO‐treated males had higher mortality than females and also developed fibrosis whereas females did not. Gonadectomy did not abrogate this sex difference. To determine the cellular contribution to this phenotype, CFs were studied. CFs from both sexes had increased proliferation in vivo in response to ISO, but CFs from female hearts proliferated more than male cells. In addition, male CFs were significantly more activated to myofibroblasts by ISO. To investigate potential regulatory mechanisms for the sexually dimorphic fibrotic response, β‐AR mRNA and PKA (protein kinase A) activity were measured. In response to ISO treatment, male CFs increased expression of β1‐ and β2‐ARs, whereas expression of both receptors decreased in female CFs. Moreover, ISO‐treated male CFs had higher PKA activity relative to vehicle controls, whereas ISO did not activate PKA in female CFs. Conclusions Chronic in vivo β‐AR stimulation causes fibrosis in male but not female rat hearts. Male CFs are more activated than female CFs, consistent with elevated fibrosis in male rat hearts and may be caused by higher β‐AR expression and PKA activation in male CFs. Taken together, our data suggest that CFs play a substantial role in mediating sex differences observed after cardiac injury.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.120.018876
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2653953-6
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  • 4
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    Expression of Normally Repressed Myosin Heavy Chain 7b in the Mammalian Heart Induces Dilated Cardiomyopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Journal of the American Heart Association Vol. 8, No. 15 ( 2019-08-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 15 ( 2019-08-06)
    Abstract: In mammals, muscle contraction is controlled by a family of 10 sarcomeric myosin motors. The expression of one of its members, MYH 7b, is regulated by alternative splicing, and while the protein is restricted to specialized muscles such as extraocular muscles or muscle spindles, RNA that cannot encode protein is expressed in most skeletal muscles and in the heart. Remarkably, birds and snakes express MYH 7b protein in both heart and skeletal muscles. This observation suggests that in the mammalian heart, the motor activity of MYH 7b may only be needed during development since its expression is prevented in adult tissue, possibly because it could promote disease by unbalancing myocardial contractility. Methods and Results We have analyzed MYH 7b null mice to determine the potential role of MYH 7b during cardiac development and also generated transgenic mice with cardiac myocyte expression of MYH 7b protein to measure its impact on cardiomyocyte function and contractility. We found that MYH 7b null mice are born at expected Mendelian ratios and do not have a baseline cardiac phenotype as adults. In contrast, transgenic cardiac MYH 7b protein expression induced early cardiac dilation in males with significantly increased left ventricular mass in both sexes. Cardiac dilation is progressive, leading to early cardiac dysfunction in males, but later dysfunction in females. Conclusions The data presented show that the expression of MYH 7b protein in the mammalian heart has been inhibited during the evolution of mammals most likely to prevent the development of a severe cardiomyopathy that is sexually dimorphic.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.119.013318
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 5
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    Abstract 382: Cell Type-specific Fibroblast Growth Factor Receptors That are Regulated in Human Heart Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Research Vol. 119, No. suppl_1 ( 2016-07-22)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. suppl_1 ( 2016-07-22)
    Abstract: Chronic kidney disease (CKD) is characterized by increased serum levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23), the development of left ventricular hypertrophy, and increased risk of mortality due to cardiovascular disease. The FGF receptors (FGFRs) responsible for facilitating the effect of FGF23 on the heart and the expression patterns of FGFRs in the different cell types in the heart remain largely uncharacterized. We hypothesized that cardiomyocytes express a different FGFR profile than cardiac fibroblasts and that this differential expression profile could contribute to cell type-specific responses to FGF23. We measured FGFR mRNA levels at baseline and following pro-hypertrophic growth factor stimulation in isolated adult rat ventricular cardiomyocytes (ARVMs), neonatal rat ventricular cardiomyocytes (NRVMs), and neonatal rat ventricular fibroblasts (NRVFs). At baseline, NRVMs expressed predominantly FGFR1 but also expressed FGFRs 2 and 3. In ARVMs, FGFRs 1 and 3 predominated while FGFRs 2 and 4 were expressed at very low levels. FGFRs in ARVMs and NRVMs were unchanged by growthfactor stimulation. At baseline, NRVFs expressed equal amounts of FGFRs 1, 2 and 3 which were all downregulated with FGF23 stimulation. To determine whether these results translated to human hearts, we examined the FGFR profile in a cohort of non-failing, hypertrophic cardiomyopathy (HCM), and ischemic cardiomyopathy (ICM) human patient samples. Compared to non-failing patients, we found FGFR2 was significantly increased in HCM patients and trended towards an increase in ICM patients. The cardiac FGFR2 profile matched the FGF23 profile. In addition, we found that FGFR4 was significantly down regulated in both ICM and HCM compared to non-failing patients. In conclusion, different cell types in the heart differ in their FGFR profiles at baseline. The FGFR profile does not change in NRVMs or ARVMs in response to FGF23 treatment, but the expression of FGFRs 1, 2, and 3 decrease in NRVFs in response to FGF23. HCM and ICM in humans is characterized by an increase in FGFR2 and FGF23 expression accompanied with a downregulation of FGFR4 expression. Modulating FGFRs in the myocardium may provide a novel therapeutic target in CKD patients.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.119.suppl_1.382
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467838-X
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  • 6
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    Saliva TwoStep for rapid detection of asymptomatic SARS-CoV-2 carriers
    eLife Sciences Publications, Ltd ; 2021
    In:  eLife Vol. 10 ( 2021-03-29)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 10 ( 2021-03-29)
    Abstract: Here, we develop a simple molecular test for SARS-CoV-2 in saliva based on reverse transcription loop-mediated isothermal amplification. The test has two steps: (1) heat saliva with a stabilization solution and (2) detect virus by incubating with a primer/enzyme mix. After incubation, saliva samples containing the SARS-CoV-2 genome turn bright yellow. Because this test is pH dependent, it can react falsely to some naturally acidic saliva samples. We report unique saliva stabilization protocols that rendered 295 healthy saliva samples compatible with the test, producing zero false positives. We also evaluated the test on 278 saliva samples from individuals who were infected with SARS-CoV-2 but had no symptoms at the time of saliva collection, and from 54 matched pairs of saliva and anterior nasal samples from infected individuals. The Saliva TwoStep test described herein identified infections with 94% sensitivity and 〉 99% specificity in individuals with sub-clinical (asymptomatic or pre-symptomatic) infections.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.65113
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2021
    detail.hit.zdb_id: 2687154-3
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  • 7
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    Abstract 455: The Burmese Python as a Model of Metabolic Protection
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation Research Vol. 121, No. suppl_1 ( 2017-07-21)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 121, No. suppl_1 ( 2017-07-21)
    Abstract: Introduction: The postprandial Burmese python displays a remarkable level of cardiac adaptation to high levels of circulating triglycerides and an increased metabolic rate without any evidence of cardiac pathology. To challenge the level of cardioprotection, we designed an experiment to attempt to induce metabolic syndrome in the Burmese python. Metabolic syndrome is typically defined as obesity concomitant with other metabolic abnormalities which contribute to an increased risk for cardiovascular disease. Methods and Results: Unlike mice or rats who readily undergo hypertrophy in response to pressure-overload or β-adrenergic receptor stimulation, inducing pathological hypertrophy in the Burmese python is challenging. In the current study, we attempted to induce metabolic syndrome through overfeeding. We offered Burmese pythons a meal equivalent to 25% of the python’s body mass every 4 days for a period of 2 months. Two similar groups of pythons were maintained on our standard python feeding schedule (one meal equivalent to 25% of their body weight every 28 days) over the same time course. At the end of 2 months, the weight of the overfed pythons (6197g ± 180g) dramatically increased when compared to fasted (2352g ± 23g) or normal fed pythons (3044g ± 62g). In addition to an overall increase in body weight, the ventricle weight/brain weight ratio increased significantly in the overfed pythons (19.5 ± 1.1) compared to fasted (7.5 ± 0.2) or normal fed pythons (8.8 ± 0.2) indicating considerable hypertrophy. However, despite developing hypertrophy, there was no evidence of aberrant gene expression or impaired glucose tolerance when compared to normal fed pythons. Conclusions: Despite repeatedly consuming a large meal, nearly tripling in body weight, and developing significant hypertrophy, the Burmese python is protected from developing metabolic abnormalities such as impaired glucose tolerance. Fetal gene expression markers of pathological cardiac hypertrophy were not induced in overfed pythons. Thus, studying the mechanisms of cardiac adaptation in the Burmese python may potentially provide insights into therapeutic targets for combating metabolic syndrome in patients.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.121.suppl_1.455
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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    Abstract MP105: Python Post-prandial Cardiac Adaptation is Supported by Enhanced Metabolism, Reduced Sarcomere Passive Tension, and Epigenetic Remodeling
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Research Vol. 127, No. Suppl_1 ( 2020-07-31)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 127, No. Suppl_1 ( 2020-07-31)
    Abstract: Pythons are infrequent feeders that can ingest meals equal to their own body mass. The extreme metabolic response required to digest such large meals is associated with a dramatic increase in the mass of most organs, including the heart. Recently, we have been able to assess functional effects of feeding using isolated python cardiomyocytes and myofibrils, advancing our understanding of extreme cardiac adaptation in python ( Python regius ). Twenty-four hours after feeding, python cardiomyocytes showed prolonged Ca 2+ transients, increased maximal tension and Ca 2+ sensitivity of myofibrils as compared to fasted pythons. Post-prandial positive inotropy was accompanied by enhanced metabolic output via increased mitochondrial ATP production rate and by AMP-dependent kinase (AMPK) activation and phosphofructokinase-2 reduction, suggesting a key role for fatty acid, but not glucose, metabolism after feeding. In addition, 24h post-fed hearts had significantly reduced tissue stiffness and myofibril passive tension. Finally, chromatin condensation was reduced about 30% after feeding in python cardiomyocytes and confirmed by increased histone acetylation, indicating a predominant role for epigenetics in post-prandial adaptation. These results suggest that feeding promotes positive cardiac inotropy in python via a number of coordinated mechanisms to enhance energy production, increase myofibril and tissue compliance, and increase chromatin accessibility. As heart failure is commonly characterized by depressed contractility, compromised energetics, and increased tissue stiffness, assessing post-prandial adaptation in python hearts provides us with powerful insights that could inform the development of therapeutics for human heart diseases.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.127.suppl_1.MP105
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467838-X
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  • 9
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    Regression from pathological hypertrophy in mice is sexually dimorphic and stimulus specific
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 322, No. 5 ( 2022-05-01), p. H785-H797
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 322, No. 5 ( 2022-05-01), p. H785-H797
    Abstract: Pathological cardiac hypertrophy is associated with increased morbidity and mortality. Understanding the mechanisms whereby pathological cardiac growth can be reversed could be of therapeutic value. Here, we show that pathways leading to regression of pathological cardiac hypertrophy are strongly dependent on the hypertrophic trigger and are significantly modified by sex. Two pathological stimuli causing hypertrophy via distinct pathways were administered to male and female mice: angiotensin II (ANG II) or isoproterenol (Iso). Stimuli were removed after 7 days of treatment, and left ventricles (LVs) were studied at 1, 4, and 7 days. ANG II-treated females did not show regression after stimulus removal. Iso-treated males showed rapid LV hypertrophy regression. Somewhat surprisingly, RNAseq analysis at day 1 after removal of triggers revealed only 45 differentially regulated genes in common among all the groups, demonstrating distinct responses. Ingenuity pathway analysis predicted strong downregulation of the TGFβ1 pathway in all groups except for ANG II-treated females. Consistently, we found significant downregulation of Smad signaling after stimulus removal including in ANG II-treated females. In addition, the ERK1/2 pathway was significantly reduced in the groups showing regression. Finally, protein degradation pathways were significantly activated only in Iso-treated males 1 day after stimulus removal. Our data indicate that TGFβ1 downregulation may play a role in the regression of pathological cardiac hypertrophy via downregulation of the ERK1/2 pathway and activation of autophagy and proteasome activity in Iso-treated males. This work highlights that the reversal of pathological hypertrophy does not use universal signaling pathways and that sex potently modifies this process. NEW & NOTEWORTHY Pathological cardiac hypertrophy is a major risk factor for mortality and is thought to be largely irreversible in many individuals. Although cardiac hypertrophy itself has been studied extensively, very little is understood about its regression. It is important that we have a better understanding of mechanisms leading to regression, why this process is not reversible in some individuals and that sex differences need to be considered when contemplating therapies.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00644.2021
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 10
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    RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome
    Springer Science and Business Media LLC ; 2023
    In:  Human Genomics Vol. 17, No. 1 ( 2023-09-05)
    Details
    In: Human Genomics, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2023-09-05)
    Abstract: RUNX1 is a transcription factor and a master regulator for the specification of the hematopoietic lineage during embryogenesis and postnatal megakaryopoiesis. Mutations and rearrangements on RUNX1 are key drivers of hematological malignancies. In humans, this gene is localized to the ‘Down syndrome critical region’ of chromosome 21, triplication of which is necessary and sufficient for most phenotypes that characterize Trisomy 21. Main body Individuals with Down syndrome show a higher predisposition to leukemias. Hence, RUNX1 overexpression was initially proposed as a critical player on Down syndrome-associated leukemogenesis. Less is known about the functions of RUNX1 in other tissues and organs, although growing reports show important implications in development or homeostasis of neural tissues, muscle, heart, bone, ovary, or the endothelium, among others. Even less is understood about the consequences on these tissues of RUNX1 gene dosage alterations in the context of Down syndrome. In this review, we summarize the current knowledge on RUNX1 activities outside blood/leukemia, while suggesting for the first time their potential relation to specific Trisomy 21 co-occurring conditions. Conclusion Our concise review on the emerging RUNX1 roles in different tissues outside the hematopoietic context provides a number of well-funded hypotheses that will open new research avenues toward a better understanding of RUNX1-mediated transcription in health and disease, contributing to novel potential diagnostic and therapeutic strategies for Down syndrome-associated conditions.
    Type of Medium: Online Resource
    ISSN: 1479-7364
    URL: Article
    DOI: 10.1186/s40246-023-00531-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2147618-4
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