RESUMO
The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular identity, mPTP conductance is restored. In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies oxidative phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo. Additionally, differentiating pluripotent stem cells (PSCs) acquire greater organization of mitochondrial cristae and hematopoietic activity following knockdown of the CypD gene, Ppif. Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate.
Assuntos
Células-Tronco Hematopoéticas , Mitocôndrias , Poro de Transição de Permeabilidade Mitocondrial , Animais , Mitocôndrias/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Camundongos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Hematopoese , Peptidil-Prolil Isomerase F/metabolismo , Peptidil-Prolil Isomerase F/genética , Diferenciação Celular , Fosforilação Oxidativa , Feminino , Camundongos Endogâmicos C57BLRESUMO
There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate cancer progression. Additionally, optimized machine learning classifier analysis reveals proteomic signatures capable of detecting the disease prior to biopsy, performing on par with an accepted clinical risk calculator benchmark.
Assuntos
Biomarcadores Tumorais , Neoplasias da Próstata , Proteômica , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/sangue , Biomarcadores Tumorais/sangue , Proteômica/métodos , Espectrometria de Mobilidade Iônica/métodos , Antígeno Prostático Específico/sangue , Idoso , Aprendizado de Máquina , Pessoa de Meia-IdadeRESUMO
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII are associated with lysosomal accumulation of heparan sulphate and manifest with neurological deterioration. Most of these neurological MPS currently lack effective treatments. Here, we report that, compared to controls, neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and in mouse models of MPS I, II, IIIA, IIIB and IIIC, but not of other neurological lysosomal disorders not presenting with heparan sulphate storage. We further show that accumulated heparan sulphate disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), ß-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) necessary to maintain enzyme activity, and that NEU1 deficiency is linked to partial deficiencies of GLB1 and GALNS in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brain samples of human MPS III patients and MPS IIIC mice implicated insufficient processing of brain N-linked sialylated glycans, except for polysialic acid, which was reduced in the brains of MPS IIIC mice. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of the excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1-/PSD95-positive puncta in cortical neurons derived from iPSC of an MPS IIIA patient. Together, our data demonstrate that heparan sulphate-induced secondary NEU1 deficiency and aberrant sialylation of glycoproteins implicated in synaptogenesis, memory, and behaviour constitute a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.
RESUMO
The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Masculino , Animais , Camundongos , Nefropatias Diabéticas/genética , Diabetes Mellitus Experimental/genética , Membranas Mitocondriais , Rim , Mitocôndrias , Complexo I de Transporte de Elétrons/genéticaRESUMO
Lactate, an intermediary between glycolysis and mitochondrial oxidative phosphorylation, reflects the metabolic state of neurons. Here, we utilized a genetically-encoded lactate FRET biosensor to uncover subpopulations of distinct metabolic states among Drosophila glutamatergic neurons. Neurons within specific subpopulations exhibited correlated lactate flux patterns that stemmed from inherent cellular properties rather than neuronal interconnectivity. Further, individual neurons exhibited consistent patterns of lactate flux over time such that stimulus-evoked changes in lactate were correlated with pre-treatment fluctuations. Leveraging these temporal autocorrelations, deep-learning models accurately predicted post-stimulus responses from pre-stimulus fluctuations. These findings point to the existence of distinct neuronal subpopulations, each characterized by unique lactate dynamics, and raise the possibility that neurons with correlated metabolic activities might synchronize across different neural circuits. Such synchronization, rooted in neuronal metabolic states, could influence information processing in the brain.
RESUMO
Single-cell whole-genome sequencing (scWGS) enables the assessment of genome-level molecular differences between individual cells with particular relevance to genetically diverse systems like solid tumors. The application of scWGS was limited due to a dearth of accessible platforms capable of producing high-throughput profiles. We present a technique that leverages nucleosome disruption methodologies with the widely adopted 10× Genomics ATAC-seq workflow to produce scWGS profiles for high-throughput copy-number analysis without new equipment or custom reagents. We further demonstrate the use of commercially available indexed transposase complexes from ScaleBio for sample multiplexing, reducing the per-sample preparation costs. Finally, we demonstrate that sequential indexed tagmentation with an intervening nucleosome disruption step allows for the generation of both ATAC and WGS data from the same cell, producing comparable data to the unimodal assays. By exclusively utilizing accessible commercial reagents, we anticipate that these scWGS and scWGS+ATAC methods can be broadly adopted by the research community.
Assuntos
Cromatina , Nucleossomos , Cromatina/genética , Nucleossomos/genética , Análise de Sequência de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , GenomaRESUMO
Despite the common use of religious buffers, African Americans are disproportionately affected by depressive symptoms. Communal coping may serve as one factor in helping religious African American couples alleviate the symptoms of depression. This study examines the association between relational sanctification and depressive symptoms as mediated by the communal coping of 467 African American married and cohabiting couples. Data from the sampled couples were analyzed using a common fate model, and analyses revealed higher scores on the measure of sanctification were associated with more communal coping; more communal coping was associated with fewer depressive symptoms among women and men, and communal coping acted as a mediator between relational sanctification and depressive symptoms in both partners. Findings from this study underscore the importance of considering how the religiosity and cooperative action of African American couples relate to depressive symptoms.
RESUMO
The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generated diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model to investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that these conditional mice exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping proteins in linking NDUFS4 with improved cristae morphology. Taken together, we discover the central role of NDUFS4 as a powerful regulator of cristae remodeling, respiratory supercomplexes assembly, and mitochondrial ultrastructure in vitro and in vivo. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
RESUMO
Sugar-sweetened beverages (SSBs) are implicated in weight gain and adverse cardiometabolic heath. Social networks of stakeholders involved in providing potable water and sugar-sweetened beverages (SSBs) in high schools in Costa Rica were studied using social analysis network. In public and private schools, the interactions between the stakeholders in charge of providing beverages are fragmented and their role in preventing the availability of SSBs is weak. School canteen owners ultimately decide what beverages are available at school, which may cause students to choose beverages that increase the risk of overweight/obesity. It is therefore urgently necessary to improve the capacity for two-way interactions between the stakeholders to enhance their roles in the provision of beverages. Hence, it is essential to reinforce the stakeholders' leadership, and set up innovative ways to exert it in order to develop a shared vision of the types of drinks that should be available in the school environment.
Assuntos
Bebidas , Bebidas Adoçadas com Açúcar , Humanos , Costa Rica , Bebidas/efeitos adversos , Instituições Acadêmicas , Bebidas Adoçadas com Açúcar/efeitos adversos , Rede SocialRESUMO
This case study describes the application of a theory-informed, stakeholder-driven intervention with a group of 19 multi-sector stakeholders from an existing coalition to promote whole-of-community change that supports childhood obesity prevention. The intervention applied community-based system dynamics to design and implement activities that promoted insights into the systems driving childhood obesity prevalence and helped participants prioritize actions to influence those systems. This led to three new priority areas for the coalition: addressing food insecurity; building power among historically marginalized voices within the community; and supporting advocacy efforts to promote community-wide change beyond the coalition's previous focus on organizational-level policy, systems and environment change. The intervention spurred the application of community-based system dynamics to other health issues and in partner organizations, which demonstrates paradigm shifts about how to address complex public health issues in the community.
Assuntos
Serviços de Saúde Comunitária , Obesidade Infantil , Humanos , South Carolina/epidemiologia , Redes Comunitárias , Medicina Comunitária , Segurança Alimentar , Apoio Nutricional , Estilo de Vida , Obesidade Infantil/epidemiologia , Obesidade Infantil/prevenção & controle , Política de SaúdeRESUMO
Maintaining protein homeostasis is essential for cellular health. During times of proteotoxic stress, cells deploy unique defense mechanisms to achieve resolution. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response (MCSR), a unique stress response activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPR ER ), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPR ER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2a signaling pathway, increasing phosphorylation of eIF2a and improving the ER's capacity to manage greater proteostasis load. MERSR activation in both poly-glutamine (poly-Q) and amyloid-beta (Aß) C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provides further evidence for the importance of intercompartmental signaling.
RESUMO
The nuclear pore complex (NPC) comprises more than 30 nucleoporins (NUPs) and is a hallmark of eukaryotes. NUPs have been suggested to be important in regulating gene transcription and 3D genome organization. However, evidence in support of their direct roles remains limited. Here, by Cut&Run, we find that core NUPs display broad but also cell-type-specific association with active promoters and enhancers in human cells. Auxin-mediated rapid depletion of two NUPs demonstrates that NUP93, but not NUP35, directly and specifically controls gene transcription. NUP93 directly activates genes with high levels of RNA polymerase II loading and transcriptional elongation by facilitating full BRD4 recruitment to their active enhancers. dCas9-based tethering confirms a direct and causal role of NUP93 in gene transcriptional activation. Unexpectedly, in situ Hi-C and H3K27ac or H3K4me1 HiChIP results upon acute NUP93 depletion show negligible changesS2211-1247(22)01437-1 of 3D genome organization ranging from A/B compartments and topologically associating domains (TADs) to enhancer-promoter contacts.
Assuntos
Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas Nucleares , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Poro Nuclear , Genoma , Cromatina , Proteínas de Ciclo Celular/genéticaRESUMO
BACKGROUND: While most coalition research focuses on studying the effects of peer relationship structure, this study examines the coevolution of coalition structure and behavior across three communities in the U.S. with the goal of identifying coalition dynamics that impact a childhood obesity prevention intervention. METHODS: Over two years (2018-2020), three communities within the U.S. participated in a childhood obesity prevention intervention at different times. This intervention was guided by the Stakeholder-Driven Community Diffusion theory, which describes an empirically testable mechanism for promoting community change. Measures are part of the Stakeholder-driven Community Diffusion (SDCD) survey with demonstrated reliability, which include knowledge of and engagement with childhood obesity prevention and social networks. Data from three coalition-committees and their respective networks were used to build three different stochastic actor-oriented models. These models were used to examine the coevolution of coalition structure with coalition behavior (defined a priori as knowledge of and engagement with obesity prevention) among coalition-committee members and their nominated alters (Network A) and coalition-committee members only (Network B). RESULTS: Overall, coalitions decrease in size and their structure becomes less dense over time. Both Network A and B show a consistent preference to form and sustain ties with those who have more ties. In Network B, there was a trend for those who have higher knowledge scores to increase their number of ties over time. The same trend appeared in Network A but varied based on their peers' knowledge in and engagement with childhood obesity prevention. Across models, engagement with childhood obesity prevention research was not a significant driver of changes in either coalition network structure or knowledge. CONCLUSIONS: The trends in coalition Network A and B's coevolution models may point to context-specific features (e.g., ties among stakeholders) that can be leveraged for better intervention implementation. To that end, examining tie density, average path length, network diameter, and the dynamics of each behavior outcome (i.e., knowledge in and engagement with childhood obesity prevention) may help tailor whole-of-community interventions. Future research should attend to additional behavioral variables (e.g., group efficacy) that can capture other aspects of coalition development and that influence implementation, and to testing the efficacy of network interventions after trends have been identified.
Assuntos
Obesidade Infantil , Criança , Humanos , Obesidade Infantil/prevenção & controle , Reprodutibilidade dos Testes , Rede Social , Inquéritos e QuestionáriosRESUMO
BACKGROUND: A strong body of evidence links young children's intake of sugar-sweetened beverages (SSBs) with myriad negative outcomes. OBJECTIVES: Our research provides insight into whether and to what extent potential intervention strategies can reduce young children's consumption of SSBs. METHODS: We built an agent-based model (ABM) of SSB consumption representing participants in the Project Viva longitudinal study between ages 2 and 7 y. In addition to extensive data from Project Viva, our model used nationally representative data as well as recent, high-quality literature. We tested the explanatory power of the model through comparison to consumption patterns observed in the Project Viva cohort. Then, we applied the model to simulate the potential impact of interventions that would reduce SSB availability in 1 or more settings or affect how families receive and respond to pediatrician advice. RESULTS: Our model produced age-stratified trends in beverage consumption that closely match those observed in Project Viva cohort data. Among the potential interventions we simulated, reducing availability in the home-where young children spend the greatest amount of time-resulted in the largest consumption decrease. Removing access to all SSBs in the home resulted in them consuming 1.23 (95% CI: 1.21, 1.24) fewer servings of SSBs per week on average between the ages of 2 and 7 y, a reduction of â¼60%. By comparison, removing all SSB availability outside of the home (i.e., in schools and childcare) had a smaller impact (0.77; CI: 0.75, 0.78), a reduction of â¼40%. CONCLUSIONS: These results suggest that interventions reducing SSB availability in the home would have the strongest effects on SSB consumption.
Assuntos
Bebidas Adoçadas com Açúcar , Bebidas , Criança , Pré-Escolar , Humanos , Estudos Longitudinais , Políticas , EdulcorantesRESUMO
Adults with hearing loss demonstrate a reduced range of emotional responses to nonspeech sounds compared to their peers with normal hearing. The purpose of this study was to evaluate two possible strategies for addressing the effects of hearing loss on emotional responses: (a) increasing overall level and (b) hearing aid use (with and without nonlinear frequency compression, NFC). Twenty-three adults (mean age = 65.5 years) with mild-to-severe sensorineural hearing loss and 17 adults (mean age = 56.2 years) with normal hearing participated. All adults provided ratings of valence and arousal without hearing aids in response to nonspeech sounds presented at a moderate and at a high level. Adults with hearing loss also provided ratings while using individually fitted study hearing aids with two settings (NFC-OFF or NFC-ON). Hearing loss and hearing aid use impacted ratings of valence but not arousal. Listeners with hearing loss rated pleasant sounds as less pleasant than their peers, confirming findings in the extant literature. For both groups, increasing the overall level resulted in lower ratings of valence. For listeners with hearing loss, the use of hearing aids (NFC-OFF) also resulted in lower ratings of valence but to a lesser extent than increasing the overall level. Activating NFC resulted in ratings that were similar to ratings without hearing aids (with a moderate presentation level) but did not improve ratings to match those from the listeners with normal hearing. These findings suggest that current interventions do not ameliorate the effects of hearing loss on emotional responses to sound.
Assuntos
Auxiliares de Audição , Perda Auditiva Neurossensorial , Perda Auditiva , Percepção da Fala , Adulto , Idoso , Emoções , Perda Auditiva/psicologia , Perda Auditiva Neurossensorial/reabilitação , Perda Auditiva Neurossensorial/terapia , Testes Auditivos , Humanos , Pessoa de Meia-Idade , Som , Percepção da Fala/fisiologiaRESUMO
PURPOSE: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. METHODS: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. RESULTS: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. CONCLUSION: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.
Assuntos
Leucoencefalopatias , Estudos Transversais , Progressão da Doença , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , FenótipoRESUMO
Over the past two decades, sexual and gender minority (SGM) youth health inequities have remained the same or widened, highlighting the need for new approaches to foster health equity. Complex systems science (CSS) techniques must be added to our armamentarium because of the following: CSS techniques can model cyclical feedback loops inherent in the relationships between SGM youth health outcomes and their multilevel causes, thereby enhancing the integration of real-world complexity in scientific models; and CSS can simulate multiple hypothetical interventions, thereby identifying future interventions with great potential impact. We describe four promising CSS techniques for advancing SGM youth health equity.
Assuntos
Pesquisa Biomédica/organização & administração , Equidade em Saúde/organização & administração , Minorias Sexuais e de Gênero , Análise de Sistemas , Adolescente , Feminino , Humanos , MasculinoRESUMO
A classic paradigm used to quantify the perceptual weighting of binaural spatial cues requires a listener to adjust the value of one cue, while the complementary cue is held constant. Adjustments are made until the auditory percept appears centered in the head, and the values of both cues are recorded as a trading relation (TR), most commonly in µs interaural time difference per dB interaural level difference. Interestingly, existing literature has shown that TRs differ according to the cue being adjusted. The current study investigated whether cue-specific adaptation, which might arise due to the continuous, alternating presentation of signals during adjustment tasks, could account for this poorly understood phenomenon. Three experiments measured TRs via adjustment and via lateralization of single targets in virtual reality (VR). Targets were 500 Hz pure tones preceded by silence or by adapting trains that held one of the cues constant. VR removed visual anchors and provided an intuitive response technique during lateralization. The pattern of results suggests that adaptation can account for cue-dependent TRs. In addition, VR seems to be a viable tool for psychophysical tasks.
Assuntos
Localização de Som , Realidade Virtual , Estimulação Acústica , Sinais (Psicologia) , Fatores de TempoRESUMO
Recent perspectives on Indigenous health have recognized language, culture, and values as central to well-being and recovery from historical trauma. Health coalitions, which identify community health concerns and mobilize members to implement strategies for change, have begun to shift their focus from programs to policy, systems, and environmental change but have been slower to recognize the possibilities of centering Indigenous ways of being in their work. This article details a case study of the Menominee Wellness Initiative, an Indigenous health coalition that has increasingly made language, culture, and collective values the focus of their health promotion work, and often due to the participation and influence of community organizers in the coalition. The study is presented as a collaborative writing effort between coalition members and academic partners. Qualitative data were gathered through observations of coalition meetings; in-depth, semistructured interviews with coalition members; and interactive data analysis discussions within the collaborative writing team. In the results, we describe how the shift in the coalition's framework came to be and the influence this shift has had on the coalition, its activities, and its community impacts. These findings illustrate and extend understanding of several principles of Collaborating for Equity and Justice and supports literature and practice related to health promotion through the centering of Indigenous ways.