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Sugar-sweetened beverages (SSB) are a health policy target. Indigenous populations are among the highest consumers of SSB in Canada. However, the Truth and Reconciliation Commission calls on governments to recognize health disparities among Indigenous populations as a consequence of colonialism and governmental policies. The purpose of this analysis was to explore emergent perspectives of Indigenous adults on experiences and perspectives of SSB consumption. We conducted a community-based participatory study in partnership with three Indigenous-led organizations. From 2019 to 2022, we completed qualitative interviews with Indigenous adults living in Island Lake Anisininew First Nation, Flin Flon, and Winnipeg's North End, a neighbourhood with high concentration of Indigenous people. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically. Seventy-four adults participated in interviews, including 46 women, 26 men, and two identifying as two-spirit. Many participants, across all three locations, repeatedly and consistently described SSB or sugar as an addiction, which formed the primary theme for this analysis: addictive-like consumption of SSB. Addictive-like SSB consumption included comparison to other addictive substances, loss of control, and physical symptoms resulting from SSB intake (both positive and adverse) or attempting to reduce SSB intake. We identified two other secondary themes, i) perceived drivers and contexts of SSB consumption, and ii) health outcomes as a motivator for change. Perceived drivers or contexts included consuming SSB as a means to cope with stress, boredom, and poverty; SSB intake as being intertwined with other addictions or addictive substances; and drinking alone. In conclusion, addictive-like SSB consumption was reported by Indigenous adults. To address SSB intake among Indigenous populations, trauma-informed approaches should be explored that consider the colonial context.
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While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
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Antígeno B7-H1 , Interferon Tipo I , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Feminino , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Glicólise , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Ácido Láctico/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Transdução de Sinais , MasculinoRESUMO
BACKGROUND AND AIMS: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE. METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks. RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT. CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.
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Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.
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Sobrevivência Celular , Mitocôndrias , Células-Tronco Neurais , Células-Tronco Neurais/metabolismo , Mitocôndrias/metabolismo , Animais , Camundongos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/genética , Fator 4 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/genética , Estresse Fisiológico , Estresse OxidativoRESUMO
Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11sut/sut mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11sut/sut primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11sut/sut muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11sut/sut mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.
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Sistema y+ de Transporte de Aminoácidos , Diferenciação Celular , Metabolismo Energético , Glutationa , Músculo Esquelético , Oxirredução , Animais , Camundongos , Glutationa/metabolismo , Músculo Esquelético/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Desenvolvimento Muscular , Células Satélites de Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Cistina/metabolismoRESUMO
BACKGROUND: Virtual reality simulation (VRS) is an innovative modality in nursing professional development that has the potential to affect patient outcomes. METHOD: An experimental cluster randomized controlled trial was performed with RNs on two inpatient units at a large academic health system. The purpose of this study was to evaluate the effect of VRS compared with traditional education on Clostridium difficile rates. Return on investment of nursing professional development activities was also measured to support decision-making and resource allocation. RESULTS: Rates of C. difficile infection were significantly lower for both groups for the 3-month postintervention period compared with the 10-month period preintervention. Financial analysis showed a return on investment for both modalities, with VRS having higher yields over time. CONCLUSION: Findings showed that VRS was an effective instructional method. [J Contin Educ Nurs. 2024;55(7):351-358.].
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Clostridioides difficile , Infecções por Clostridium , Educação Continuada em Enfermagem , Recursos Humanos de Enfermagem Hospitalar , Realidade Virtual , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Infecções por Clostridium/prevenção & controle , Recursos Humanos de Enfermagem Hospitalar/educação , Treinamento por Simulação/economia , Treinamento por Simulação/métodos , Análise Custo-BenefícioRESUMO
Mitochondrial electron transport chain complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SCs remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in citric acid cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.
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Complexo I de Transporte de Elétrons , Mitocôndrias , Transporte de Elétrons , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/genética , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético , Mitocôndrias/genética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Humanos , Células HEK293RESUMO
Virtual reality simulation (VRS) has emerged as an educational methodology in nursing professional development. A cluster randomized controlled trial was conducted with a sample of clinical registered nurses to compare effectiveness of VRS and traditional education on knowledge and behavior related to Clostridioides difficile prevention. No significant differences were found in the effectiveness of the two modalities, suggesting the usefulness of VRS as a teaching methodology.
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Clostridioides difficile , Enfermeiras e Enfermeiros , Estudantes de Enfermagem , Realidade Virtual , Humanos , Competência Clínica , Simulação por ComputadorRESUMO
In a quantitative study to determine nursing professional development (NPD) practitioners' self-perceived influence, influence was operationally defined as political skill. A sample of 989 NPD practitioners reported high-average overall levels of political skill. For those without formal leadership positions, networking ability, a subscale of political skill, was predicted by NPD certification and a graduate degree or higher. NPD practitioners can enhance their influence competency through education, certification, professional development, mentoring, and coaching.
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Tutoria , Mentores , Humanos , LiderançaRESUMO
OBJECTIVES: The purpose of this study was to explore the perspectives of Indigenous adults on consuming beverages with non-nutritive sweeteners. METHODS: In this work, we used a community-based, participatory design in partnership with National Indigenous Diabetes Association, Four Arrows Regional Health Authority, and Fearless R2W. We conducted 74 qualitative interviews with Indigenous adults living in Manitoba, including Island Lake First Nations (n=39), Flin Flon (n=15), and the North End neighbourhood of Winnipeg (n=20). Data were indexed in NVivo, and transcripts were analyzed thematically. RESULTS: Participants exclusively discussed beverages with non-nutritive sweeteners (BNNSs) as an alternative to regular pop or sugary drinks, which were widely available, accessible, and consumed. Why or how BNNSs were viewed as an alternative comprised 3 subthemes: an alternative for health reasons; divergent taste preferences; and an alternative with mysterious but negative health effects. Participants who reported regular consumption of BNNSs largely described consuming them to manage type 2 diabetes. Fewer participants discussed BNNS as a means of weight management or as a preventive health behaviour. Participants who did not report regular BNNS consumption described not liking the taste of BNNSs. Finally, many participants described negative health impacts of consuming BNNSs, and specifically aspartame, although few articulated what those negative impacts were. CONCLUSIONS: Divergent perspectives among Indigenous adults regarding the health implications of consuming BNNSs may reflect ongoing scholarly debates. These findings have implications for the prevention and dietary management of type 2 diabetes in Indigenous communities.
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Diabetes Mellitus Tipo 2 , Adoçantes não Calóricos , Humanos , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Adulto , Manitoba/epidemiologia , Pessoa de Meia-Idade , Bebidas , Canadenses Indígenas/psicologia , Idoso , Adulto Jovem , Povos Indígenas/psicologiaRESUMO
SARS-CoV-2 infection is associated with both acute and post-acute neurological symptoms. Emerging evidence suggests that SARS-CoV-2 can alter mitochondrial metabolism, suggesting that changes in brain metabolism may contribute to the development of acute and post-acute neurological complications. Monoamine oxidase B (MAO-B) is a flavoenzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of monoamine neurotransmitters. Computational analyses have revealed high similarity between the SARS-CoV-2 spike glycoprotein receptor binding domain on the ACE2 receptor and MAO-B, leading to the hypothesis that SARS-CoV-2 spike glycoprotein may alter neurotransmitter metabolism by interacting with MAO-B. Our results empirically establish that the SARS-CoV-2 spike glycoprotein interacts with MAO-B, leading to increased MAO-B activity in SH-SY5Y neuron-like cells. Common to neurodegenerative disease pathophysiological mechanisms, we also demonstrate that the spike glycoprotein impairs mitochondrial bioenergetics, induces oxidative stress, and perturbs the degradation of depolarized aberrant mitochondria through mitophagy. Our findings also demonstrate that SH-SY5Y neuron-like cells expressing the SARS-CoV-2 spike protein were more susceptible to MPTP-induced necrosis, likely necroptosis. Together, these results reveal novel mechanisms that may contribute to SARS-CoV-2-induced neurodegeneration.
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Natural killer (NK) cells are predominant innate lymphocytes that initiate the early immune response during infection. NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection. Tumor necrosis factor-alpha (TNFα) is a well-known inflammatory cytokine that enhances NK cell function; however, the mechanism underlying NK cell proliferation in response to TNFα is not well established. Here, we demonstrated that upon infection/inflammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity, and effector function. Notably, IL-18 can induce TNFR2 expression in NK cells, augmenting their sensitivity toward TNFα. Mechanistically, TNFα-TNFR2 signaling upregulates the expression of CD25 (IL-2Rα) and nutrient transporters in NK cells, leading to a metabolic switch toward aerobic glycolysis. Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice. Accordingly, our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation, glycolysis, and effector function.
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Receptores Tipo II do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa , Camundongos , Animais , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células Matadoras Naturais , Citocinas/metabolismo , Proliferação de CélulasRESUMO
Insulin resistance and blunted mitochondrial capacity in skeletal muscle are often synonymous, however, this association remains controversial. The aim of this study was to perform an in-depth multifactorial comparison of skeletal muscle mitochondrial capacity between individuals who were lean and active (Active, n = 9), individuals with obesity (Obese, n = 9), and individuals with obesity, insulin resistance, and type 2 diabetes (T2D, n = 22). Mitochondrial capacity was assessed by ex vivo mitochondrial respiration with fatty-acid and glycolytic-supported protocols adjusted for mitochondrial content (mtDNA and citrate synthase activity). Supercomplex assembly was measured by Blue Native (BN)-PAGE and immunoblot. Tricarboxylic (TCA) cycle intermediates were assessed with targeted metabolomics. Exploratory transcriptomics and DNA methylation analyses were performed to uncover molecular differences affecting mitochondrial function among the three groups. We reveal no discernable differences in skeletal muscle mitochondrial content, mitochondrial capacity, supercomplex assembly, TCA cycle intermediates, and mitochondrial molecular profiles between obese individuals with and without T2D that had comparable levels of confounding factors (body mass index, age, and aerobic capacity). We highlight that lean, active individuals have greater mitochondrial content, mitochondrial capacity, supercomplex assembly, and TCA cycle intermediates. These phenotypical changes are reflected at the level of DNA methylation and gene transcription. The collective observation of comparable muscle mitochondrial capacity in individuals with obesity and T2D (vs. individuals without T2D) underscores a dissociation from skeletal muscle insulin resistance. Clinical trial number: NCT01911104.NEW & NOTEWORTHY Whether impaired mitochondrial capacity contributes to skeletal muscle insulin resistance is debated. Our multifactorial analysis shows no differences in skeletal muscle mitochondrial content, mitochondrial capacity, and mitochondrial molecular profiles between obese individuals with and without T2D that had comparable levels of confounding factors (BMI, age, aerobic capacity). We highlight that lean, active individuals have enhanced skeletal muscle mitochondrial capacity that is also reflected at the level of DNA methylation and gene transcription.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Resistência à Insulina/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Mitocôndrias Musculares/metabolismoRESUMO
The differentiation and activation of macrophages are critical regulatory programs that are central to host inflammation and pathogen defense. However, the transcriptional regulatory pathways involved in these programs are not well understood. Herein, we demonstrate that the activity and expression of the transcription factor ATF2 is precisely regulated during primary human monocyte-to-macrophage differentiation and that its activation is linked to M1 polarization and antibacterial responses. Genetic perturbation experiments demonstrated that deletion of ATF2 (THP-ΔATF2) resulted in irregular and abnormal macrophage morphology, whereas macrophages overexpressing ATF2 (THP-ATF2) developed round and pancake-like morphology, resembling classically activated (M1) macrophages. Mechanistically, we show that ATF2 binds to the core promoter of PPM1A, a phosphatase that regulates monocyte-to-macrophage differentiation, to regulate its expression. Functionally, overexpression of ATF2 sensitized macrophages to M1 polarization, resulting in increased production of major histocompatibility complex class II, IL-1ß, and IP-10; improved phagocytic capacity; and enhanced control of the intracellular pathogen Mycobacterium tuberculosis. Gene expression profiling revealed that overexpression of ATF2 reprogramed macrophages to promote antibacterial pathways enriched in chemokine signaling, metabolism, and antigen presentation. Consistent with pathways analysis, metabolic profiling revealed that genetic overexpression or stimuli-induced activation of ATF2 alters the metabolic capacity of macrophages and primes these cells for glycolytic metabolism during M1 polarization or bacterial infection. Our findings reveal that ATF2 plays a central role during macrophage differentiation and M1 polarization to enhance the functional capacities of macrophages.
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Macrófagos , Monócitos , Humanos , Macrófagos/metabolismo , Monócitos/metabolismo , Fagócitos , Leucócitos , Diferenciação Celular/fisiologia , Ativação de Macrófagos , Fator 2 Ativador da Transcrição/genética , Fator 2 Ativador da Transcrição/metabolismo , Proteína Fosfatase 2C/metabolismoRESUMO
Preceptors are an important part of meeting perioperative workforce demands. A secondary analysis of data collected for the 2020 Association for Nursing Professional Development National Preceptor Practice Analysis Study focused on 400 perioperative nurse preceptors and compared their responses to nonperioperative preceptors. Most perioperative respondents had participated in preceptor training; they spent significantly more time orienting experienced nurse preceptees in the perioperative specialty and its diverse settings (eg, orthopedic surgery, open-heart surgery) than preceptors in nonperioperative settings and specialties. Perioperative preceptors spent significantly less time precepting students, suggesting the presence of an opportunity to address the nursing shortage by promoting student exposure to the perioperative setting. To align with the AORN position statements on orientation and nurse residencies, perioperative nurse leaders should ensure that properly educated preceptors are available to assist RNs who are transitioning to perioperative practice. The Ulrich Precepting Model provides an evidence-based framework for preceptor training.
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Educação em Enfermagem , Enfermeiras e Enfermeiros , Humanos , Preceptoria , Recursos HumanosRESUMO
Findings from the 2020 Association for Nursing Professional Development National Preceptor Practice Analysis study validated the Ulrich precepting model. This secondary data analysis examines the influence of preceptor training, experience, and education on perceptions of the importance of the preceptor roles, domains (knowledge and practice), and required competencies. Preceptor training compared with education and experience best predict nurses' perceived importance of precepting and its seven roles.