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1.
Mol Brain ; 16(1): 11, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658656

RESUMO

Although dyslipidemia in the brain has been implicated in neurodegenerative disorders, the molecular mechanisms underlying its pathogenesis have been largely unclear. PDZD8 is a lipid transfer protein and mice deficient in PDZD8 (PDZD8-KO mice) manifest abnormal accumulation of cholesteryl esters (CEs) in the brain due to impaired lipophagy, the degradation system of lipid droplets. Here we show the detailed mechanism of PDZD8-dependent lipophagy. PDZD8 transports cholesterol to lipid droplets (LDs), and eventually promotes fusion of LDs and lysosomes. In addition, PDZD8-KO mice exhibit growth retardation, hyperactivity, reduced anxiety and fear, increased sensorimotor gating, and impaired cued fear conditioned memory and working memory. These results indicate that abnormal CE accumulation in the brain caused by PDZD8 deficiency affects emotion, cognition and adaptive behavior, and that PDZD8 plays an important role in the maintenance of brain function through lipid metabolism.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Encéfalo , Dislipidemias , Animais , Camundongos , Encéfalo/fisiopatologia , Cognição , Dislipidemias/complicações , Medo , Metabolismo dos Lipídeos , Proteínas Adaptadoras de Transdução de Sinal/genética
3.
Allergol. immunopatol ; 51(1): 98-109, ene. 2023. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-214039

RESUMO

Anisakids are nematodes responsible for different clinical patterns in humans. The well-known human-infecting Anisakis species include members of the Anisakis simplex (AS) complex. Humans usually contract anisakiasis through ingestion of raw or undercooked seafood containing Anisakis larvae. Once Anisakis has been ingested, patients may develop disease driven directly by Anisakis larvae and/or by allergic reaction due to this nematode. The capability of inducing allergic reactions depends on the expression of specific antigens by nematodes and host factors. This study aims to resume actual knowledge about AS and Anisakiasis with regard to epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment. Particular attention is paid to Anisakis allergens and their cross-reactivity on available diagnostic methods, and defining a diagnostic pathway for Anisakis allergy. Because only a few data are available in the literature about pediatric population, we focus on this group of patients specifically (AU)


Assuntos
Humanos , Criança , Hipersensibilidade Imediata , Anisaquíase , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/terapia , Hipersensibilidade Imediata/fisiopatologia , Anisaquíase/diagnóstico , Anisaquíase/terapia , Anisaquíase/fisiopatologia , Reações Cruzadas , Testes Cutâneos
4.
In Vivo ; 37(1): 410-416, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593059

RESUMO

BACKGROUND/AIM: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. PATIENTS AND METHODS: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. RESULTS: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. CONCLUSION: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.


Assuntos
Carcinoma de Células Renais , Gônadas , Neoplasias Renais , Sunitinibe , Humanos , Masculino , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Estudos Transversais , Gônadas/efeitos dos fármacos , Gônadas/fisiopatologia , Hipogonadismo/epidemiologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Qualidade de Vida , Sunitinibe/efeitos adversos , Testosterona/análise
5.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675048

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ. This implies that patient stratification could be improved when expression levels of multiple C/EBP-family members are considered simultaneously. In this study, we assessed whether the quantification of C/EBPß or C/EBPγ in addition to that of C/EBPδ might improve the prediction of patient survival and lymph node involvement using a cohort of 68 resectable PDAC patients. Using Kaplan-Meier analyses of patient groups with different C/EBP-expression levels, we found that both C/EBPß and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPß as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPß and C/EBPδ can compensate for the lack of each other in order to reduce the risk of lymph node involvement. C/EBPγ, on the other hand, appears to promote lymph node involvement in the absence of C/EBPδ. Altogether, our results show that the redundancy of C/EBP-family members might have a profound influence on clinical prognoses and that the expression of both C/EPBß and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT , Carcinoma Ductal Pancreático , Regulação da Expressão Gênica , Neoplasias Pancreáticas , Humanos , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Linfonodos/metabolismo , Linfonodos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Metástase Linfática/genética , Metástase Linfática/patologia , Metástase Linfática/fisiopatologia , Prognóstico
7.
PLoS One ; 18(1): e0279034, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36630329

RESUMO

Confinements due to the COVID-19 outbreak affected sleep and mental health of adults, adolescents and children. Already preschool children experienced acutely worsened sleep, yet the possible resulting effects on executive functions remain unexplored. Longitudinally, sleep quality predicts later behavioral-cognitive outcomes. Accordingly, we propose children's sleep behavior as essential for healthy cognitive development. By using the COVID-19 confinement as an observational-experimental intervention, we tested whether worsened children's sleep affects executive functions outcomes 6 months downstream. We hypothesized that acutely increased night awakenings and sleep latency relate to reduced later executive functions. With an online survey during the acute confinement phase we analyzed sleep behavior in 45 children (36-72 months). A first survey referred to the (retrospective) time before and (acute) situation during confinement, and a follow-up survey assessed executive functions 6 months later (6 months retrospectively). Indeed, acutely increased nighttime awakenings related to reduced inhibition at FOLLOW-UP. Associations were specific to the confinement-induced sleep-change and not the sleep behavior before confinement. These findings highlight that specifically acute changes of children's nighttime sleep during sensitive periods are associated with behavioral outcome consequences. This aligns with observations in animals that inducing poor sleep during developmental periods affects later brain function.


Assuntos
Função Executiva , Sono , Humanos , COVID-19/prevenção & controle , Função Executiva/fisiologia , Fatores de Proteção , Estudos Retrospectivos , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Criança
8.
Cell Death Dis ; 14(1): 57, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36693836

RESUMO

There is an urgent need to identify reliable genetic biomarkers for accurate diagnosis, prognosis, and treatment of different tumor types. Described as a prognostic marker for many tumors is the neuronal protein carnitine palmitoyltransferase 1 C (CPT1C). Several studies report that CPT1C is involved in cancer cell adaptation to nutrient depletion and hypoxia. However, the molecular role played by CPT1C in cancer cells is controversial. Most published studies assume that, like canonical CPT1 isoforms, CPT1C is a mediator of fatty acid transport to mitochondria for beta-oxidation, despite the fact that CPT1C has inefficient catalytic activity and is located in the endoplasmic reticulum. In this review, we collate existing evidence on CPT1C in neurons, showing that CPT1C is a sensor of nutrients that interacts with and regulates other proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway. We argue, therefore, that CPT1C expression in cancer cells is not a direct regulator of fat burn, but rather is a regulator of lipid metabolic reprograming and cell adaptation to environmental stressors. We also review the clinical relevance of CPT1C as a prognostic indicator and its contribution to tumor growth, cancer invasiveness, and cell senescence. This new and integrated vision of CPT1C function can help better understand the metabolic plasticity of cancer cells and improve the design of therapeutic strategies.


Assuntos
Carnitina O-Palmitoiltransferase , Neoplasias , Humanos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Hipóxia/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Neurônios/metabolismo , Oxirredução
9.
Sci Rep ; 13(1): 1304, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36693893

RESUMO

The aim of this study was to clarify the effect of climatic environment on the immunological features of rheumatoid arthritis (RA). Blood samples were collected from patients with RA and healthy controls (HCs), matched by age and sex, living in two locations, Tsukuba and Karuizawa, which differ in their altitude and average air temperature and atmospheric pressure. Analysis of peripheral blood mononuclear cells (PBMCs) revealed that the proportion of T and B cell subpopulations in HCs and RA patients were significantly different between two sites. Inverse probability weighting adjustment with propensity scores was used to control for potential confounding factors. The results revealed that, in comparison with RA patients in Tsukuba, those in Karuizawa showed a significant increase in cTh1, cTfh1, and Tph cells, and significant decrease in cTh17, cTh17.1, and CD8+ Treg in T cell subpopulations, and a significant increase in DNB, DN1, DN2, and class-switched memory B cells, and a significant decrease in unswitched memory B, naïve B cells, and ABCs in B cell subpopulations. Our results suggest the possibility that climatic environment might have an effect on immune cell proportion and function, and be related to the pathogenic mechanism of RA.


Assuntos
Artrite Reumatoide , Meio Ambiente , Leucócitos Mononucleares , Humanos , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Linfócitos B/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos T/imunologia
10.
Anal Chim Acta ; 1238: 340163, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36464456

RESUMO

Misfolding of superoxide dismutase-1 (SOD1) has been correlated with many neurodegenerative diseases, such as Amyotrophic lateral sclerosis's and Alzheimer's among others. However, it is unclear whether misfolded SOD1 plays a role in another neurodegenerative disease of white matter lesions (WMLs). In this study, a sensitive and specific method based on SERS technique was proposed for quantitative detection of misfolded SOD1 content in WMLs. To fabricate the double antibodysandwich substrates for SERS detection, gold nanostars modified with capture antibody were immobilized on glass substrates to prepare active SERS substrates, and then SERS probes conjugated with a Raman reporter and a specific target antibody were coupled with active SERS substrates. This SERS substrates had been employed for quantitative detection of misfolded SOD1 levels in WMLs and exhibited excellent stability, reliability, and accuracy. Moreover, experimental results indicated that the level of misfolded SOD1 increased with the increase in age and the degree of WMLs. Hence, misfolded SOD1 may be a potential blood marker for WMLs and aging. Meanwhile, SERS-based gold nanostars have great clinical application potential in the screening, diagnosis and treatment of WMLs.


Assuntos
Doenças Neurodegenerativas , Deficiências na Proteostase , Superóxido Dismutase-1 , Substância Branca , Humanos , Anticorpos , Ouro , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Reprodutibilidade dos Testes , Superóxido Dismutase , Superóxido Dismutase-1/análise , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Substância Branca/metabolismo , Substância Branca/fisiopatologia , Deficiências na Proteostase/diagnóstico , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo
11.
J Hypertens ; 41(2): 212-219, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36583348

RESUMO

We performed a systematic review and meta-analysis to determine the relative contributions of elevated cardiac output and systemic vascular resistance to hypertension in children and adults. This included 27 studies on 11 765 hypertensive and normotensive children and adults in whom cardiac output was measured. Cardiac output but not systemic vascular resistance was elevated in hypertensive compared to normotensive children and young adults (difference in means 1.15 [0.78-1.52] l/min, P < 0.001). In older hypertensive adults, both were elevated compared to normotensive individuals (0.40 [0.26-0.55] l/min, P < 0.001 and 3.21 [1.91-4.51] mmHg min/l, P < 0.001 for cardiac output and systemic vascular resistance, respectively). The main haemodynamic alteration in primary hypertension (including obesity-hypertension) in both children and young to middle-aged adults is an elevation of cardiac output. With longer duration and greater severity of hypertension there may be progression from a 'cardiac' to a 'vascular' phenotype with increased systemic vascular resistance.


Assuntos
Hipertensão Essencial , Hemodinâmica , Humanos , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Hipertensão Essencial/fisiopatologia , Hemodinâmica/fisiologia , Resistência Vascular/fisiologia , Criança , Adulto , Adulto Jovem , Pessoa de Meia-Idade
12.
Environ Pollut ; 316(Pt 1): 120481, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341821

RESUMO

Physical activity (PA) would increase the inhalation rate and thereby inhaled dose of air pollutants. However, it's still uncertain whether the effects of air pollutants on lung function are attenuated by PA, especially in the high-polluted areas. We aimed to disentangle the interaction between air pollution and PA on lung function among healthy adults. In this study, a real-world crossover study was conducted among 74 healthy adults. Each participant underwent both rest and 15-min intermittent moderate PA exposure scenarios (consisting of 15min stationary bike riding alternating with 15min of rest), which lasted for 2 h. On the same day, the participants among active and inactive group were exposed to the same air pollution. We have monitored the fine particulate matter (PM2.5), particulate matter less than 10 µm (PM10), particulate matter less than 1 µm (PM1), black carbon (BC), nitrogen dioxide (NO2), and ozone (O3) continuously during 2-h exposure. Lung function were measured at five times points for each visit (before, immediately, 3 h, 5 h, and 24 h after the 2-h exposure scenario). Mixed-effects models were applied to explore the effects of air pollution, PA, and their interaction on lung function. The participants had a mean (standard deviation (SD)) age of 19.9 (0.9) years. The average concentration [mean ± SD] of PM2.5, PM10, PM1, BC, NO2, and O3 were 59.4 ± 45.1 µg/m3, 122.8 ± 109.0 µg/m3, 38.8 ± 29.2 µg/m3, 1.94 ± 1.17 µg/m3, 59.5 ± 26.6 µg/m3, and 74.0 ± 30.3 µg/m3, respectively. Overall, greater increasement in lung function were observed among active group compared with inactive group at all timepoints. In fully adjusted models, we observed the benefits of PA and detrimental effects of air pollutants on lung function. Our results suggested that PA, compared to rest, alleviated the detrimental effects of air pollutants on lung function. We also stressed the importance of timing of measurements for capturing association. In conclusion, our observations suggested that PA might alleviate the associations between various pollutant exposures and lung function, which would drive further research towards potential pathway.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Exposição Ambiental , Exercício Físico , Pulmão , Humanos , Adulto Jovem , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Estudos Cross-Over , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Exercício Físico/fisiologia , Pulmão/fisiopatologia , Dióxido de Nitrogênio/análise , Dióxido de Nitrogênio/toxicidade , Ozônio/toxicidade , Ozônio/análise , Material Particulado/toxicidade , Material Particulado/análise
13.
J Cell Biol ; 222(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36547519

RESUMO

Disruptions in membrane trafficking are associated with neurodevelopmental disorders, but underlying pathological mechanisms remain largely unknown. In this issue, O'Brien et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202112108) show how GARP regulates sterol transfer critical for remodeling of dendrites in flies.


Assuntos
Dendritos , Proteínas de Membrana , Transtornos do Neurodesenvolvimento , Esteróis , Dendritos/patologia , Membranas , Transtornos do Neurodesenvolvimento/fisiopatologia , Esteróis/metabolismo , Proteínas de Membrana/metabolismo
14.
Diabetologia ; 66(1): 44-56, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36224274

RESUMO

AIMS/HYPOTHESIS: South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. METHODS: We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ). RESULTS: We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women. CONCLUSIONS/INTERPRETATION: South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians. FUNDING: There was no primary direct funding for undertaking the systematic review and meta-analysis.


Assuntos
Diabetes Mellitus Tipo 2 , Feminino , Humanos , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/fisiopatologia , Fígado , Gordura Subcutânea
15.
Ann Clin Transl Neurol ; 10(1): 32-47, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36480557

RESUMO

OBJECTIVE: Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. METHODS: Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. RESULTS: Adjusting for age, sex and intracranial volume, cases (N = 40) compared to controls (N = 39) demonstrated reduced whole corpus callosum area (ß = -26.9, 95% confidence interval [CI] = -53.17, -0.58), volume (ß = -138.5, 95% CI = -267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (ß = 0.18, 95% CI = 0.004, 0.35), volume (ß = 0.04, 95% CI = 0.001, 0.079), whole corpus callosum fractional anisotropy (ß = 13.8 95% CI = 0.6, 27.1) and radial diffusivity (ß = -11.3, 95% CI = -22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. INTERPRETATION: Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.


Assuntos
Lesões Encefálicas , Cognição , Corpo Caloso , Criança , Humanos , Recém-Nascido , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Cognição/fisiologia , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética , Imageamento por Ressonância Magnética , Estudos de Casos e Controles
18.
Nature ; 613(7943): 317-323, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36544024

RESUMO

Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.


Assuntos
Implantes Cocleares , Surdez , Locus Cerúleo , Animais , Ratos , Implante Coclear , Surdez/fisiopatologia , Surdez/terapia , Audição/fisiologia , Aprendizagem/fisiologia , Locus Cerúleo/citologia , Locus Cerúleo/fisiologia , Plasticidade Neuronal , Norepinefrina/metabolismo , Córtex Auditivo/citologia , Córtex Auditivo/fisiologia , Córtex Auditivo/fisiopatologia , Neurônios/fisiologia , Recompensa , Optogenética , Fotometria
20.
Nature ; 613(7942): 169-178, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36544018

RESUMO

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.


Assuntos
Envelhecimento , Senescência Celular , Inflamação , Músculo Esquelético , Regeneração , Nicho de Células-Tronco , Idoso , Animais , Humanos , Camundongos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Células-Tronco/fisiologia , Fibrose/fisiopatologia , Nicho de Células-Tronco/fisiologia , Transcriptoma , Cromatina/genética , Gerociência
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