RESUMEN
Low aerobic capacity is strongly associated with all-cause mortality and risk for Alzheimer's disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aß42) and tau hyperphosphorylation (pTauthr181/total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aß42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging.
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Envejecimiento , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Mitocondrias , Proteoma , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Femenino , Masculino , Mitocondrias/metabolismo , Envejecimiento/metabolismo , Envejecimiento/fisiología , Ratas , Encéfalo/metabolismo , Proteoma/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Condicionamiento Físico Animal/fisiología , Fosforilación , Modelos Animales de EnfermedadRESUMEN
The COVID-19 pandemic was a key policy issue during the 2020 election in the United States. As such, it is important to analyze how voters evaluated government responses to the pandemic. To this end, in this article, we examine factors that influenced Americans' evaluations of state-level COVID-19 policy responses. We find that during the pandemic onset period, Americans typically rated their state governments' responses more favorably if their governor was a co-partisan. In contrast, during the re-opening period, we find that Democrats relied on both partisanship and policy to evaluate their state-level responses, while Republicans continued to rely solely on partisanship. We contend that given the complex policy environment surrounding COVID-19, Americans may have not been fully aware of the policies their state governments adopted, so they relied on partisan cues to help them evaluate their state-level policy responses. But by the re-opening period, Americans likely had enough time to better understand state-level policy responses; this allowed Democrats to also evaluate their state-level responses based on policy. These findings shed light on how Americans evaluated COVID-19 responses just prior to the 2020 election.
RESUMEN
OBJECTIVE: The aim of this study was to test whether increased energy expenditure (EE), independent of physical activity, reduces acute diet-induced weight gain through tighter coupling of energy intake to energy demand and enhanced metabolic adaptations. METHODS: Indirect calorimetry and quantitative magnetic resonance imaging were used to assess energy metabolism and body composition during 7-day high-fat/high-sucrose (HFHS) feeding in male and female mice housed at divergent temperatures (20°C vs. 30°C). RESULTS: As previously observed, 30°C housing resulted in lower total EE and energy intake compared with 20°C mice regardless of sex. Interestingly, housing temperature did not impact HFHS-induced weight gain in females, whereas 30°C male mice gained more weight than 20°C males. Energy intake coupling to EE during HFHS feeding was greater in 20°C versus 30°C housing, with females greater at both temperatures. Fat mass gain was greater in 30°C mice compared with 20°C mice, whereas females gained less fat mass than males. Strikingly, female 20°C mice gained considerably more fat-free mass than 30°C mice. Reduced fat mass gain was associated with greater metabolic flexibility to HFHS, whereas fat-free mass gain was associated with diet-induced adaptive thermogenesis. CONCLUSIONS: These data reveal that EE and sex interact to impact energy homeostasis and metabolic adaptation to acute HFHS feeding, altering weight gain and body composition change.
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Metabolismo Energético/fisiología , Animales , Dieta Alta en Grasa , Ingestión de Energía , Femenino , Vivienda para Animales , Masculino , Ratones , Factores Sexuales , Temperatura , TermogénesisRESUMEN
KEY POINTS: Low intrinsic aerobic capacity is associated with increased all-cause and liver-related mortality in humans. Low intrinsic aerobic capacity in the low capacity runner (LCR) rat increases susceptibility to acute and chronic high-fat/high-sucrose diet-induced steatosis, without observed increases in liver inflammation. Addition of excess cholesterol to a high-fat/high-sucrose diet produced greater steatosis in LCR and high capacity runner (HCR) rats. However, the LCR rat demonstrated greater susceptibility to increased liver inflammatory and apoptotic markers compared to the HCR rat. The progressive non-alcoholic fatty liver disease observed in the LCR rats following western diet feeding was associated with further declines in liver fatty acid oxidation and mitochondrial respiratory capacity compared to HCR rats. ABSTRACT: Low aerobic capacity increases risk for non-alcoholic fatty liver disease and liver-related disease mortality, but mechanisms mediating these effects remain unknown. We recently reported that rats bred for low aerobic capacity (low capacity runner; LCR) displayed susceptibility to high fat diet-induced steatosis in association with reduced hepatic mitochondrial fatty acid oxidation (FAO) and respiratory capacity compared to high aerobic capacity (high capacity runner; HCR) rats. Here we tested the impact of aerobic capacity on susceptibility for progressive liver disease following a 16-week 'western diet' (WD) high in fat (45% kcal), cholesterol (1% w/w) and sucrose (15% kcal). Unlike previously with a diet high in fat and sucrose alone, the inclusion of cholesterol in the WD induced hepatomegaly and steatosis in both HCR and LCR rats, while producing greater cholesterol ester accumulation in LCR compared to HCR rats. Importantly, WD-fed low-fitness LCR rats displayed greater inflammatory cell infiltration, serum alanine transaminase, expression of hepatic inflammatory markers (F4/80, MCP-1, TLR4, TLR2 and IL-1ß) and effector caspase (caspase 3 and 7) activation compared to HCR rats. Further, LCR rats had greater WD-induced decreases in complete FAO and mitochondrial respiratory capacity. Intrinsic aerobic capacity had no impact on WD-induced hepatic steatosis; however, rats bred for low aerobic capacity developed greater hepatic inflammation, which was associated with reduced hepatic mitochondrial FAO and respiratory capacity and increased accumulation of cholesterol esters. These results confirm epidemiological reports that aerobic capacity impacts progression of liver disease and suggest that these effects are mediated through alterations in hepatic mitochondrial function.
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Dieta , Hígado Graso/metabolismo , Hígado Graso/patología , Carrera/fisiología , Animales , Colesterol/metabolismo , Citrato (si)-Sintasa/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Hígado/patología , Masculino , Mitocondrias Hepáticas/metabolismo , Oxidación-Reducción , Palmitatos/metabolismo , Ácido Pirúvico/metabolismo , RatasRESUMEN
Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1(-/-) mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1(-/-) primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating that this is an early event in tumorigenesis. Functional evaluation of these heterozygous mutations in Stat1(-/-) mouse embryonic fibroblasts showed that co-expression of truncated and wild-type PRLR led to aberrant STAT3 and STAT5 activation downstream of the receptor, cellular transformation in vitro, and tumor formation in vivo. In conclusion, truncating mutations of PRLR promote tumor growth in a model of human ERα+ breast cancer and warrant further investigation.
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Carcinoma/genética , Receptor alfa de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Animales/genética , Mutación , Receptores de Prolactina/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma/metabolismo , Carcinoma/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Embrión de Mamíferos , Receptor alfa de Estrógeno/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Ratones , Ratones Noqueados , Receptores de Prolactina/metabolismo , Factor de Transcripción STAT1/deficiencia , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Transducción de SeñalRESUMEN
Despite successful therapeutic options for estrogen receptor-α (ERα)+ breast cancer, resistance to endocrine therapy frequently occurs leading to tumor recurrence. In addition to intrinsic changes in the cancer cells, herein we demonstrate that tumor cell-microenvironment interactions can drive recurrence at specific sites. By using two ERα+ cell lines derived from spontaneous mammary carcinomas in STAT1-/- mice (SSM2, SSM3), we establish that the bone microenvironment offers growth advantage over primary site or lung in the absence of ovarian hormones. While SSM3 did not engraft at primary and skeletal locations in the absence of estrogen, SSM2 selectively grew in bone of ovariectomized mice and following administration of aromatase inhibitors. However, SSM2 growth remained hormone-dependent at extraskeletal sites. Unexpectedly, bone-residing SSM2 cells retained ERα expression and JAK2/STAT3 activation regardless of the hormonal status. These data position the bone microenvironment as a unique site for acquisition of tumor/estrogen independency and identify the first ERα+ hormone-independent tumor model in immunocompetent mice.
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Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Animales , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Estrógenos/farmacología , Femenino , Masculino , Ratones , Ratones Noqueados , Metástasis de la Neoplasia , Trasplante de Neoplasias , Ovario/metabolismo , Fenotipo , Receptores de Progesterona/metabolismo , Microambiente TumoralRESUMEN
PURPOSE: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [(18)F]FDG (to measure glucose uptake), [(18)F]FES [to measure estrogen receptor (ER) levels], or [(18)F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen-deprivation therapy. EXPERIMENTAL DESIGN: [(18)F]FDG, [(18)F]FES, and [(18)F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [(18)F]FFNP uptake in ERα(+) mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC). RESULTS: The levels of [(18)F]FES and [(18)F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [(18)F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [(18)F]FFNP tumor uptake, indicating that [(18)F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy. CONCLUSIONS: Monitoring the acute changes in ERα activity by measuring [(18)F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [(18)F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Receptores de Progesterona/metabolismo , Animales , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/farmacología , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , Diagnóstico por Imagen , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno , Femenino , Fluorodesoxiglucosa F18 , Humanos , Ligandos , Neoplasias Mamarias Experimentales , Ratones , Tomografía de Emisión de Positrones , Promegestona/farmacología , Tomografía Computarizada por Rayos XRESUMEN
Systemic hypoxia results in rapid increases in leukocyte-endothelial adherence (LEA) and emigration, vascular permeability, and mast cell activation in several microcirculations. Observations in cremaster muscle suggest that this response is initiated by a mediator released from a distant site (Dix R, Orth T, Allen JA, Wood JG, and Gonzalez NC. J Appl Physiol 95: 2495-2502, 2003). The present experiments in rat cremaster muscle tested the hypothesis that, if a circulating mediator triggers hypoxia-induced inflammation, then plasma from hypoxic rats should elicit LEA in normoxic cremaster venules. Plasma from conscious donor rats breathing 10% O2-90% N2 for 5 min was applied topically to the cremaster of normoxic anesthetized rats. In this and all other groups described below, the donor plasma had attained normoxic PO2 when applied to the cremaster. LEA (leukocytes/100-microm venule) increased from 2.7 +/- 0.8 to 12.3 +/- 2.4, and venular shear rate and arteriolar diameter decreased to 79 +/- 9% (P < 0.05, n = 6) and 77 +/- 5% of control (P < 0.05, n = 5), respectively, 10 min after application of plasma from hypoxic donors. The decrease in venular shear rate was exclusively due to a reduction of venular blood flow, secondary to the upstream arteriolar vasoconstriction. Plasma from normoxic donors had no effects. Plasma from blood equilibrated in vitro for 5 min with 5% CO2-95% N2 did not alter LEA or shear rate of normoxic cremasters, suggesting that the putative mediator does not originate in blood cells. The effects of plasma from hypoxic rats persisted when the donors were pretreated with the mast cell stabilizer cromolyn, which prevents hypoxia-induced LEA. This suggests that the effects of hypoxic plasma are not due to inflammatory mediators released by adherent leukocytes in the donor rat. There was a positive correlation between LEA and mast cell degranulation observed histologically. These results support the idea that systemic hypoxia produces the release of a substance transported by the circulation that initiates the microvascular inflammation.
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Endotelio Vascular/patología , Hipoxia/sangre , Leucocitos/patología , Músculo Esquelético/irrigación sanguínea , Plasma/química , Vénulas/efectos de los fármacos , Vénulas/patología , Animales , Endotelio Vascular/efectos de los fármacos , Hipoxia/metabolismo , Leucocitos/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Systemic hypoxia produces microvascular inflammation in several tissues, including skeletal muscle. Exercise training (ET) has been shown to reduce the inflammatory component of several diseases. Alternatively, ET could influence hypoxia-induced inflammation by improving tissue oxygenation or increasing mechanical antiadhesive forces at the leukocyte-endothelial interface. The effect of 5 wk of treadmill ET on hypoxia-induced microvascular inflammation was studied in the cremaster microcirculation of rats using intravital microscopy. In untrained rats, hypoxia (arterial Po(2) = 32.3 +/- 2.1 Torr) increased leukocyte-endothelial adherence from 2.3 +/- 0.4 to 10.2 +/- 0.3 leukocytes per 100 microm of venule (P < 0.05) and was accompanied by extravasation of FITC-labeled albumin after 4 h of hypoxia (extra-/intravascular fluorescence intensity ratio = 0.50 +/- 0.07). These responses were attenuated in ET (leukocyte adherence was 1.5 +/- 0.4 during normoxia and 1.8 +/- 0.7 leukocytes per 100 mum venule after 10 min of hypoxia; extra-/intravascular fluorescence intensity ratio = 0.11 +/- 0.02; P < 0.05 vs. untrained) despite similar reductions of arterial (32.4 +/- 1.8 Torr) and microvascular Po(2) (measured with an oxyphor-quenching method) in both groups. Shear rate decreased during hypoxia to similar extents in ET and untrained rats. In addition, circulating blood leukocyte count was similar in ET and untrained rats. The effects of ET on hypoxia-induced leukocyte-endothelial adherence remained up to 4 wk after discontinuing training. Thus ET attenuated hypoxia-induced inflammation despite similar effects of hypoxia on tissue Po(2), venular shear rate, and circulating leukocyte count.