Publications
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Strong R, Miller RA, Cheng CJ, et al., 2022, Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice., Aging Cell, Vol: 21
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
Svenson KL, Krasinski SD, Ellis M, et al., 2022, Animals, quality and the pursuit of relevance, DISEASE MODELS & MECHANISMS, Vol: 15, ISSN: 1754-8403
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- Citations: 1
Snyder JM, Casey KM, Galecki A, et al., 2022, Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice, GEROSCIENCE, ISSN: 2509-2715
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- Citations: 1
Auchampach J, Han L, Huang GN, et al., 2022, Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 322, Pages: H579-H596, ISSN: 0363-6135
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- Citations: 4
Squiers GT, McLellan MA, Ilinykh A, et al., 2022, Corrigendum to: Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones., Cardiovasc Res, Vol: 118
Forte E, Ramialison M, Nim HT, et al., 2022, Adult mouse fibroblasts retain organ-specific transcriptomic identity, ELIFE, Vol: 11, ISSN: 2050-084X
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- Citations: 2
Mohenska M, Tan NM, Tokolyi A, et al., 2021, 3D-cardiomics: A spatial transcriptional atlas of the mammalian heart, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 163, Pages: 20-32, ISSN: 0022-2828
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- Citations: 4
Squiers GT, McLellan MA, Ilinykh A, et al., 2021, Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: 2252-2261, ISSN: 0008-6363
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- Citations: 16
Plikus M, Wang X, Sinha S, et al., 2021, Fibroblasts: Origins, definitions, and functions in health and disease, CELL, Vol: 184, Pages: 3852-3872, ISSN: 0092-8674
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- Citations: 106
Debuque RJ, Nowoshilow S, Chan KE, et al., 2021, Distinct toll-like receptor signaling in the salamander response to tissue damage, DEVELOPMENTAL DYNAMICS, Vol: 251, Pages: 988-1003, ISSN: 1058-8388
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- Citations: 8
Harrison DE, Strong R, Reifsnyder P, et al., 2021, 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex, AGING CELL, Vol: 20, ISSN: 1474-9718
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- Citations: 22
Kuraitis D, Rosenthal N, Boh E, et al., 2021, Macrophages in dermatology: pathogenic roles and targeted therapeutics, ARCHIVES OF DERMATOLOGICAL RESEARCH, Vol: 314, Pages: 133-140, ISSN: 0340-3696
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- Citations: 5
Forte E, McLellan MA, Skelly DA, et al., 2021, Ex uno, plures-From One Tissue to Many Cells: A Review of Single-Cell Transcriptomics in Cardiovascular Biology, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22
Tombor LS, John D, Glaser SF, et al., 2021, Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction, NATURE COMMUNICATIONS, Vol: 12
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- Citations: 62
Macchiarini F, Miller RA, Strong R, et al., 2021, NIA Interventions Testing Program: A collaborative approach for investigating interventions to promote healthy aging, Handbook of the Biology of Aging, Pages: 219-235, ISBN: 9780128159620
The NIA Interventions Testing Program (ITP) investigates the potential of dietary interventions to promote healthy aging and provides preliminary data on cellular mechanisms and pathways that affect aging. Members of the research community propose compounds for study, and lifespan and health studies are performed at three sites to demonstrate the degree of reproducibility. A genetically heterogeneous mouse model is used to reduce the influence of strain-specific characteristics on the outcomes, and sufficient mice are used to detect a 10% change in mean lifespan with 80% power if at least two sites contribute data. There have been several positive findings that have prompted additional studies within the ITP and from the broader research community, including data on rapamycin, acarbose, 17α-estradiol, nordihydroguaiaretic acid, Protandim, and glycine. This chapter describes the ITP structure, summarizes findings to date and how they have led to additional studies, and discusses the future role of the ITP in promoting research on antiaging interventions.
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, Vol: 25, Pages: 229-243, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Debuque RJ, Hart AJ, Johnson GH, et al., 2021, Identification of the Adult Hematopoietic Liver as the Primary Reservoir for the Recruitment of Pro-regenerative Macrophages Required for Salamander Limb Regeneration., Front Cell Dev Biol, Vol: 9, ISSN: 2296-634X
The lack of scar-free healing and regeneration in many adult human tissues imposes severe limitations on the recovery of function after injury. In stark contrast, salamanders can functionally repair a range of clinically relevant tissues throughout adult life. The impressive ability to regenerate whole limbs after amputation, or regenerate following cardiac injury, is critically dependent on the recruitment of (myeloid) macrophage white blood cells to the site of injury. Amputation in the absence of macrophages results in regeneration failure and scar tissue induction. Identifying the exact hematopoietic source or reservoir of myeloid cells supporting regeneration is a necessary step in characterizing differences in macrophage phenotypes regulating scarring or regeneration across species. Mammalian wounds are dominated by splenic-derived monocytes that originate in the bone marrow and differentiate into macrophages within the wound. Unlike mammals, adult axolotls do not have functional bone marrow but instead utilize liver and spleen tissues as major sites for adult hematopoiesis. To interrogate leukocyte identity, tissue origins, and modes of recruitment, we established several transgenic axolotl hematopoietic tissue transplant models and flow cytometry protocols to study cell migration and identify the source of pro-regenerative macrophages. We identified that although bidirectional trafficking of leukocytes can occur between spleen and liver tissues, the liver is the major source of leukocytes recruited to regenerating limbs. Recruitment of leukocytes and limb regeneration occurs in the absence of the spleen, thus confirming the dependence of liver-derived myeloid cells in regeneration and that splenic maturation is dispensable for the education of pro-regenerative macrophages. This work provides an important foundation for understanding the hematopoietic origins and education of myeloid cells recruited to, and essential for, adult tissue regeneration.
Yucel N, Chang AC, Day JW, et al., 2020, Humanizing the mdx mouse model of DMD: the long and the short of it (vol 3, 4, 2018), NPJ REGENERATIVE MEDICINE, Vol: 5
Forte E, Perkins B, Sintou A, et al., 2020, Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart, Circulation, Vol: 143, Pages: 821-836, ISSN: 0009-7322
Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helperand CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross priming DC in post-MI myocardial impairment through presentation of self-antigen fromnecrotic cardiomyocytes to cytotoxic CD8+ T cells.Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function.Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely dueto dampened activation of cytotoxic CD8+ T cells.Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.
Miller RA, Harrison DE, Allison DB, et al., 2020, Canagliflozin extends life span in genetically heterogeneous male but not female mice, JCI INSIGHT, Vol: 5
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- Citations: 18
McLellan MA, Skelly DA, Dona MSI, et al., 2020, High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy, Circulation, Vol: 142, Pages: 1448-1463, ISSN: 0009-7322
BACKGROUND: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative effect of disparate cell populations on cardiac fibrosis, remain unclear. METHODS: We developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome, the network of cells that forms the heart. This method was used to profile the cardiac cellular ecosystem in response to 2 weeks of continuous administration of angiotensin II, a profibrotic stimulus that drives pathological cardiac remodeling. RESULTS: Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations, Fibroblast-Cilp and Fibroblast-Thbs4, emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key profibrotic cell population. After angiotensin II treatment, Fibroblast-Cilp develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after angiotensin II treatment that promote the development of a profibrotic cellular microenvironment. Furthermore, the cellular responses to angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. CONCLUSIONS: These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, high
Forte E, Daigle S, Rosenthal NA, 2020, Protocol for Isolation of Cardiac Interstitial Cells from Adult Murine Hearts for Unbiased Single Cell Profiling., STAR Protoc, Vol: 1
Interstitial cells have a crucial role in cardiac fibrosis and repair of the mammalian heart. Single-cell profiling using droplet-based technology has revolutionized the investigation of cell states and identities. Here, we present a protocol for the efficient isolation of high-quality live nucleated non-cardiomyocytes from adult murine heart, for unbiased single-cell RNA sequencing using 10× Chromium technology. This protocol has been applied to homeostatic and injured hearts from different mouse strains. For complete details on the use and execution of this protocol, please refer to Forte et al. (2020).
Sintou A, Mansfield C, Iacob A-O, et al., 2020, Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X
Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.
Bouvet M, Claude O, Roux M, et al., 2020, Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells., Scientific Reports, Vol: 10, Pages: 11404-11404, ISSN: 2045-2322
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.
Epstein JA, Rosenthal N, Feldman AM, 2020, Teasing the immune system to repair the heart, New England Journal of Medicine, Vol: 382, Pages: 1660-1662, ISSN: 0028-4793
Ferrini A, Skaalure S, Furtado MB, et al., 2020, 4D ECHOCARDIOGRAPHY AND MYOCARDIAL MECHANICS ASSESSMENT FOLLOWING INJECTION OF A THERMORESPONSIVE HYDROGEL FOR HEART FAILURE TREATMENT, Publisher: SPRINGER, Pages: 282-282
Forte E, Skelly DA, Chen M, et al., 2020, Dynamic interstitial cell response during myocardial infarction predicts resilience to rupture in genetically diverse mice, Cell Reports, Vol: 30, Pages: 3149-3163.e6, ISSN: 2211-1247
Cardiac ischemia leads to the loss of myocardial tissue and the activation of a repair process that culminates in the formation of a scar whose structural characteristics dictate propensity to favorable healing or detrimental cardiac wall rupture. To elucidate the cellular processes underlying scar formation, here we perform unbiased single-cell mRNA sequencing of interstitial cells isolated from infarcted mouse hearts carrying a genetic tracer that labels epicardial-derived cells. Sixteen interstitial cell clusters are revealed, five of which were of epicardial origin. Focusing on stromal cells, we define 11 sub-clusters, including diverse cell states of epicardial- and endocardial-derived fibroblasts. Comparing transcript profiles from post-infarction hearts in C57BL/6J and 129S1/SvImJ inbred mice, which displays a marked divergence in the frequency of cardiac rupture, uncovers an early increase in activated myofibroblasts, enhanced collagen deposition, and persistent acute phase response in 129S1/SvImJ mouse hearts, defining a crucial time window of pathological remodeling that predicts disease outcome.
Sattler S, Baxan N, Chowdhury R, et al., 2019, Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multi-parametric quantitative cardiac MRI, Disease Models & Mechanisms, Vol: 12, Pages: 1-10, ISSN: 1754-8403
Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the TLR-7 agonist Resiquimod induces auto-antibodies and systemic tissue damage including in the heart, and is used as an inducible mouse model of Systemic Lupus Erythematosus (SLE).Here, we show that over-activation of the TLR-7 pathway of viral recognition by Resiquimod-treatment of CFN mice induces severe thrombocytopenia and internal bleeding which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results to ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed a detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes.In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis will improve interpretation of disease mechanisms and diagnostic sensitivity.
Ascenzi F, Barberi L, Dobrowolny G, et al., 2019, Effects of IGF-1 isoforms on muscle growth and sarcopenia, Aging Cell, Vol: 18, ISSN: 1474-9718
The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin‐like growth factor‐1 (IGF‐1) has been implicated in many anabolic pathways in skeletal muscle. IGF‐1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF‐1Ea and IGF‐1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF‐1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF‐1Ea or IGF‐1Eb transgenes was protective against age‐related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1‐α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF‐1Ea and MLC/IGF‐1Eb mice during aging. These data suggest that IGF‐1 is a promising therapeutic agent in staving off advancing muscle weakness.
Ferrini A, Stevens MM, Sattler S, et al., 2019, Toward regeneration of the heart: Bioengineering strategies for immunomodulation, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X
Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF development. Two newly emerging fields of biomedical research, immunomodulatory therapies and cardiac bioengineering, provide potential options to target the causative mechanisms underlying HF development. Combining these two fields to develop biomaterials for delivery of immunomodulatory bioactive molecules holds great promise for HF therapy. Specifically, minimally invasive delivery of injectable hydrogels, loaded with bioactive factors with angiogenic, proliferative, anti-apoptotic and immunomodulatory functions, is a promising route for influencing the cascade of immune events post-MI, preventing adverse left ventricular remodeling, and offering protection from early inflammation to fibrosis. Here we provide an updated overview on the main injectable hydrogel systems and bioactive factors that have been tested in animal models with promising results and discuss the challenges to be addressed for accelerating the development of these novel therapeutic strategies.
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