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Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWV), yet the causes are poorly understood. Brain structure abnormalities are observed in GWV, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWV with and without CMP. Ninety-eight GWV (10 females) with CMP and 56 GWV (7 females) controls completed T1 weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance. Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Family-wise cluster error rates were used to control for multiple comparisons (α=0.05). GWV with CMP reported greater pain and fatigue symptoms, worse mood, and engaged in less moderate-to-vigorous PA and more sedentary time than healthy GWV (all p<0.05). GWV with CMP had smaller gray matter volumes in the bilateral insula and larger volumes in the frontal pole (p<0.05adjusted). Gray matter volumes in the left insula were associated with pain symptoms (rpartial=0.26, -0.29; p<0.05adjusted). No significant associations were observed for either PA or sedentary time (p>0.05adjusted). GWV with CMP had smaller gray matter volumes within a critical brain region of the descending pain processing network and larger volumes within brain regions associated with pain sensation and affective processing which may reflect pain chronification.Significance Statement:The pathophysiology of chronic pain in Gulf War Veterans is understudied and not well understood. In a large sample of Gulf War Veterans, we report Veterans with chronic musculoskeletal pain have smaller gray matter volumes in brain regions associated with pain regulation and larger volumes in regions associated with pain sensitivity compared to otherwise healthy Gulf War Veterans. Gray matter volumes in regions of pain regulation were significantly associated with pain symptoms and encompassed the observed group brain volume differences. These results are suggestive of deficient pain modulation that may contribute to pain chronification.
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Maximal grip strength is associated with a variety of health-related outcome measures and thus may be reflective of the efficiency of foundational brain-body communication. Non-human primate models of grip strength strongly implicate the cortical lateral grasping network, but little is known about the translatability of these models to human children. Further, it is unclear how supplementary networks that provide proprioceptive information and cerebellar-based motor command modification are associated with maximal grip strength. Therefore, this study employed high resolution, multi-shell diffusion and quantitative T1 imaging to examine how variations in lateral grasping, proprioception input, and cortico-cerebellar modification network white matter microstructure are associated with variations in grip strength across 70 children. Results indicated that stronger grip strength was associated with higher lateral grasping and proprioception input network fractional anisotropy and R1, indirect measures consistent with stronger microstructural coherence and increased myelination. No relationships were found in the cerebellar modification network. These results provide a neurobiological mechanism of grip behavior in children which suggests that increased myelination of cortical sensory and motor pathways is associated with stronger grip. This neurobiological mechanism may be a signature of pediatric neuro-motor behavior more broadly as evidenced by the previously demonstrated relationships between grip strength and behavioral outcome measures across a variety of clinical and non-clinical populations.
Assuntos
Encéfalo , Substância Branca , Humanos , Criança , Substância Branca/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Força da MãoRESUMO
We examine neural correlates of discrete expressions of negative emotionality in infants to determine whether the microstructure of white matter tracts at 1 month of age foreshadows the expression of specific negative emotions later in infancy. Infants (n = 103) underwent neuroimaging at 1-month, and mothers reported on infant fear, sadness, and anger at 6, 12, and 18 months using the Infant Behavior Questionnaire-Revised. Levels and developmental change in fear, sadness, and anger were estimated from mother reports. Relations between MRI and infant emotion indicated that 1-month white matter microstructure was differentially associated with level and change in infant fear, but not anger or sadness, in the left stria terminalis (p < 0.05, corrected), a tract that connects frontal and tempo-parietal regions and has been implicated in emerging psychopathology in adults. More relaxed constraints on significance (p < 0.10, corrected) revealed that fear was associated with lower white matter microstructure bilaterally in the inferior portion of the stria terminalis and regions within the sagittal stratum. Results suggest the neurobehavioral uniqueness of fear as early as 1 month of age in regions that are associated with potential longer-term outcomes. This work highlights the early neural precursors of fearfulness, adding to literature explaining the psychobiological accounts of affective development. HIGHLIGHTS: Expressions of infant fear and anger, but not sadness, increase from 6 to 18 months of age. Early neural architecture in the stria terminalis is related to higher initial levels and increasing fear in infancy. After accounting for fear, anger and sadness do not appear to be associated with differences in early white matter microstructure. This work identifies early neural precursors of fearfulness as early as 1-month of age.
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Substância Branca , Feminino , Adulto , Lactente , Humanos , Individualidade , Medo/psicologia , Ira , EmoçõesRESUMO
BACKGROUND: Epidemiologic studies have shown that Alzheimer's disease (AD) and related dementias (ADRD) are seen more frequently with asthma, especially with greater asthma severity or exacerbation frequency. OBJECTIVE: To examine the changes in brain structure that may underlie this phenomenon, we examined diffusion-weighted magnetic resonance imaging (dMRI) and blood-based biomarkers of AD (phosphorylated tau 181, p-Tau181), neurodegeneration (neurofilament light chain, NfL), and glial activation (glial fibrillary acidic protein, GFAP). METHODS: dMRI data were obtained in 111 individuals with asthma, ranging in disease severity from mild to severe, and 135 healthy controls. Regression analyses were used to test the relationships between asthma severity and neuroimaging measures, as well as AD pathology, neurodegeneration, and glial activation, indexed by plasma p-Tau181, NfL, and GFAP, respectively. Additional relationships were tested with cognitive function. RESULTS: Asthma participants had widespread and large-magnitude differences in several dMRI metrics, which were indicative of neuroinflammation and neurodegeneration, and which were robustly associated with GFAP and, to a lesser extent, NfL. The AD biomarker p-Tau181 was only minimally associated with neuroimaging outcomes. Further, asthma severity was associated with deleterious changes in neuroimaging outcomes, which in turn were associated with slower processing speed, a test of cognitive performance. CONCLUSIONS: Asthma, particularly when severe, is associated with characteristics of neuroinflammation and neurodegeneration, and may be a potential risk factor for neural injury and cognitive dysfunction. There is a need to determine how asthma may affect brain health and whether treatment directed toward characteristics of asthma associated with these risks can mitigate these effects.
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Asma/complicações , Imagem de Difusão por Ressonância Magnética/métodos , Doenças Neurodegenerativas/diagnóstico , Neuroimagem/métodos , Adolescente , Adulto , Idoso , Asma/diagnóstico por imagem , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/etiologia , Índice de Gravidade de Doença , Adulto Jovem , Proteínas tau/sangueRESUMO
Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO, we find that induction of a danger-associated molecular pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for (PrCR) by retinal myeloid cells. Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR. Surviving rods then continue to promote glucose transport to cones, maintaining their viability.
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Alarminas/metabolismo , Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Rodopsina/química , Rodopsina/metabolismo , Animais , Feminino , Humanos , Masculino , Células Mieloides/metabolismo , Degeneração RetinianaRESUMO
Alterations in white matter (WM) development are associated with many neuropsychiatric and neurodevelopmental disorders. Most MRI studies examining WM development employ diffusion tensor imaging (DTI), which relies on estimating diffusion patterns of water molecules as a reflection of WM microstructure. Quantitative relaxometry, an alternative method for characterizing WM microstructural changes, is based on molecular interactions associated with the magnetic relaxation of protons. In a longitudinal study of 34 infant non-human primates (NHP) (Macaca mulatta) across the first year of life, we implement a novel, high-resolution, T1-weighted MPnRAGE sequence to examine WM trajectories of the longitudinal relaxation rate (qR1) in relation to DTI metrics and gestational age at scan. To the best of our knowledge, this is the first study to assess developmental WM trajectories in NHPs using quantitative relaxometry and the first to directly compare DTI and relaxometry metrics during infancy. We demonstrate that qR1 exhibits robust logarithmic growth, unfolding in a posterior-anterior and medial-lateral fashion, similar to DTI metrics. On a within-subject level, DTI metrics and qR1 are highly correlated, but are largely unrelated on a between-subject level. Unlike DTI metrics, gestational age at birth (time in utero) is a strong predictor of early postnatal qR1 levels. Whereas individual differences in DTI metrics are maintained across the first year of life, this is not the case for qR1. These results point to the similarities and differences in using quantitative relaxometry and DTI in developmental studies, providing a basis for future studies to characterize the unique processes that these measures reflect at the cellular and molecular level.
Assuntos
Substância Branca , Animais , Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Humanos , Estudos Longitudinais , Macaca mulatta , Substância Branca/diagnóstico por imagemRESUMO
J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.
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Encéfalo , Ácido gama-Aminobutírico , Artefatos , Encéfalo/diagnóstico por imagem , Criança , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância MagnéticaRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unknown brain etiology. Our knowledge to date about structural brain development across the lifespan in ASD comes mainly from cross-sectional studies, thereby limiting our understanding of true age effects within individuals with the disorder that can only be gained through longitudinal research. The present study describes FreeSurfer-derived volumetric findings from a longitudinal dataset consisting of 607 T1-weighted magnetic resonance imaging (MRI) scans collected from 105 male individuals with ASD (349 MRIs) and 125 typically developing male controls (258 MRIs). Participants were six to forty-five years of age at their first scan, and were scanned up to 5 times over a period of 16 years (average inter-scan interval of 3.7 years). Atypical age-related volumetric trajectories in ASD included enlarged gray matter volume in early childhood that approached levels of the control group by late childhood, an age-related increase in ventricle volume resulting in enlarged ventricles by early adulthood and reduced corpus callosum age-related volumetric increase resulting in smaller corpus callosum volume in adulthood. Larger corpus callosum volume was related to a lower (better) ADOS score at the most recent study visit for the participants with ASD. These longitudinal findings expand our knowledge of volumetric brain-based abnormalities in males with ASD, and highlight the need to continue to examine brain structure across the lifespan and well into adulthood.
Assuntos
Transtorno do Espectro Autista , Ventrículos Cerebrais , Corpo Caloso , Substância Cinzenta , Desenvolvimento Humano , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/crescimento & desenvolvimento , Ventrículos Cerebrais/patologia , Criança , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/crescimento & desenvolvimento , Corpo Caloso/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/crescimento & desenvolvimento , Substância Cinzenta/patologia , Desenvolvimento Humano/fisiologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
White matter (WM) development early in life is a critical component of brain development that facilitates the coordinated function of neuronal pathways. Additionally, alterations in WM have been implicated in various neurodevelopmental disorders, including psychiatric disorders. Because of the need to understand WM development in the weeks immediately following birth, we characterized changes in WM microstructure throughout the postnatal macaque brain during the first year of life. This is a period in primates during which genetic, developmental, and environmental factors may have long-lasting impacts on WM microstructure. Studies in nonhuman primates (NHPs) are particularly valuable as a model for understanding human brain development because of their evolutionary relatedness to humans. Here, 34 rhesus monkeys (23 females, 11 males) were imaged longitudinally at 3, 7, 13, 25, and 53 weeks of age with T1-weighted (MPnRAGE) and diffusion tensor imaging (DTI). With linear mixed-effects (LME) modeling, we demonstrated robust logarithmic growth in FA, MD, and RD trajectories extracted from 18 WM tracts across the brain. Estimated rate of change curves for FA, MD, and RD exhibited an initial 10-week period of exceedingly rapid WM development, followed by a precipitous decline in growth rates. K-means clustering of raw DTI trajectories and rank ordering of LME model parameters revealed distinct posterior-to-anterior and medial-to-lateral gradients in WM maturation. Finally, we found that individual differences in WM microstructure assessed at 3 weeks of age were significantly related to those at 1 year of age. This study provides a quantitative characterization of very early WM growth in NHPs and lays the foundation for future work focused on the impact of alterations in early WM developmental trajectories in relation to human psychopathology.
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Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Imagem de Tensor de Difusão/métodos , Imageamento Tridimensional/métodos , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento , Fatores Etários , Animais , Animais Recém-Nascidos , Feminino , Macaca mulatta , MasculinoRESUMO
Accumulation of tumor-associated macrophages (TAMs) associates with malignant progression in cancer. However, the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. ZEB1 is best known for driving an epithelial-to-mesenchymal transition (EMT) in cancer cells to promote tumor progression. However, a role for ZEB1 in macrophages and TAMs has not been studied. Here we describe that TAMs require ZEB1 for their tumor-promoting and chemotherapy resistance functions in a mouse model of ovarian cancer. Only TAMs that expressed full levels of Zeb1 accelerated tumor growth. Mechanistically, ZEB1 expression in TAMs induced their polarization toward an F4/80low pro-tumor phenotype, including direct activation of Ccr2 In turn, expression of ZEB1 by TAMs induced Ccl2, Cd74, and a mesenchymal/stem-like phenotype in cancer cells. In human ovarian carcinomas, TAM infiltration and CCR2 expression correlated with ZEB1 in tumor cells, where along with CCL2 and CD74 determined poorer prognosis. Importantly, ZEB1 in TAMs was a factor of poorer survival in human ovarian carcinomas. These data establish ZEB1 as a key factor in the tumor microenvironment and for maintaining TAMs' tumor-promoting functions.
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Carcinogênese/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos B/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Quimiocina CCL2/farmacologia , Fatores Estimuladores de Colônias/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Neoplasias/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fenótipo , Receptores CCR2/metabolismo , Análise de Sobrevida , Regulação para Cima/efeitos dos fármacosRESUMO
Nuclear YAP1 plays a critical role in regulation of stem cell proliferation, tissue regeneration, and organ size in many types of epithelia. Due to rapid turnover of most epithelial cell types, the cytoplasmic function of YAP1 in epithelial cells has not been well studied. The retinal pigment epithelium (RPE) is a highly polarized epithelial cell type maintained at a senescence state, and offers an ideal cell model to study the active role of YAP1 in maintenance of the adult epithelial phenotype. Here, we show that the cytoplasmic function of YAP1 is essential to maintain adult RPE differentiation. Knockout of Yap1 in the adult mouse RPE caused cell depolarization and tight junction breakdown, and led to inhibition of RPE65 expression, diminishment of RPE pigments, and retraction of microvilli and basal infoldings. These changes in RPE further prompted the loss of adjacent photoreceptor outer segments and photoreceptor death, which eventually led to decline of visual function in older mice between 6 and 12 months of age. Furthermore, nuclear ß-catenin and its activity were significantly increased in mutant RPE. These results suggest that YAP1 plays an important role in active inhibition of Wnt/ß-catenin signaling, and is essential for downregulation of ß-catenin nuclear activity and prevention of dedifferentiation of adult RPE.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Bestrofinas/fisiologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Epitélio Pigmentado da Retina/citologia , Via de Sinalização Wnt , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/genética , Proliferação de Células , Camundongos , Camundongos Knockout , Epitélio Pigmentado da Retina/metabolismo , Proteínas de Sinalização YAPRESUMO
In Alzheimer's disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration. In this study, we used neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion model, in order to investigate cortical microstructure along the clinical continuum of mild cognitive impairment (MCI) and AD dementia. Using gray matter-based spatial statistics (GBSS), we demonstrated that neurite density index (NDI) was significantly lower throughout temporal and parietal cortical regions in MCI, while both NDI and orientation dispersion index (ODI) were lower throughout parietal, temporal, and frontal regions in AD dementia. In follow-up ROI analyses comparing microstructure and cortical thickness (derived from T1-weighted MRI) within the same brain regions, differences in NODDI metrics remained, even after controlling for cortical thickness. Moreover, for participants with MCI, gray matter NDI-but not cortical thickness-was lower in temporal, parietal, and posterior cingulate regions. Taken together, our results highlight the utility of NODDI metrics in detecting cortical microstructural degeneration that occurs prior to measurable macrostructural changes and overt clinical dementia.
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Doença de Alzheimer/diagnóstico por imagem , Espessura Cortical do Cérebro , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We have previously demonstrated cross-sectional differences in magnetic resonance imaging (MRI) measurements of white matter myelin and gray matter in infants with or without the apolipoprotein ε4 allele, a major genetic risk factor for late-onset Alzheimer's disease (AD). In this study, we sought to compare longitudinal MRI white matter myelin and cognitive-behavioral changes in infants and young children with and without this allele. Serial MRI and cognitive tests were obtained on 223 infants and young children, including 74 ε4 carriers and 149 non-carriers, 2-68 months of age, matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated brain mapping algorithms and non-linear mixed models were used to characterize and compare trajectories of white matter myelin and cognitive-behavioral test scores. The APOE ε4 carriers had statistically significant differences in white matter myelin development, in the uncinate fasciculus, temporal lobe, internal capsule and occipital lobe. Additionally, ε4 carriers had a slightly greater rate of development in early learning composite a surrogate measure of IQ representative of expressive language, receptive language, fine motor, and visual skills, but displayed slightly lower non verbal development quotient scores a composite measure of fine motor and visual skills across the entire age range. This study supports the possibility that ε4 carriers have slightly altered rates of white matter and cognitive development in childhood. It continues to raise questions about the role of APOE in human brain development and the relevance of these developmental differences to the predisposition to AD.
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Apolipoproteína E4/genética , Cognição/fisiologia , Bainha de Mielina/genética , Substância Branca/patologia , Envelhecimento/genética , Alelos , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Bainha de Mielina/metabolismo , Rede Nervosa/patologia , Rede Nervosa/fisiopatologiaRESUMO
OBJECTIVE: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC. DESIGN: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. RESULTS: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1ß). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1ß production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair. CONCLUSIONS: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.
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Colite Ulcerativa/genética , Neoplasias do Colo/genética , DNA Glicosilases/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Experimentais , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Biópsia , Células Cultivadas , Colite Ulcerativa/complicações , Colite Ulcerativa/metabolismo , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , DNA Glicosilases/metabolismo , Reparo do DNA , Células Epiteliais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Neoplásico/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Dedos de ZincoRESUMO
Epidemiological research reveals that insufficient sleep in children has negative cognitive and emotional consequences; however, the physiological underpinnings of these observations remain understudied. We tested the hypothesis that the topographical distribution of deep sleep slow wave activity during the childhood predicts brain white matter microstructure (myelin) 3.5â¯y later. Healthy children underwent sleep high-density EEG at baseline (nâ¯=â¯13; ages 2.4-8.0â¯y) and follow-up (nâ¯=â¯14; ages 5.5-12.2â¯y). At follow-up, myelin (myelin water fraction) and cortical morphology were also quantified. Our investigation revealed 3 main findings. (1) The Frontal/Occipital (F/O)-ratio at baseline strongly predicted whole brain myelin at follow-up. (2) At follow-up, the F/O-ratio was only minimally (negatively) linked to brain myelin. (3) Cortical morphology was not related to the F/O-ratio, neither at baseline nor at follow-up. Our results support the hypothesis that during child development EEG markers during sleep longitudinally predict brain myelin content. Data extend previous findings reporting a link between EEG markers of sleep need and cortical morphology, by supporting the hypothesis that sleep is a necessary component to underlying processes of brain, and specifically myelin, maturation. In line with the overarching theory that sleep contributes to neurodevelopmental processes, it remains to be investigated whether chronic sleep loss negatively affects white matter myelin microstructure growth during sensitive periods of development.
Assuntos
Ondas Encefálicas/fisiologia , Desenvolvimento Infantil/fisiologia , Bainha de Mielina , Sono de Ondas Lentas/fisiologia , Biomarcadores , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: To evaluate whether placental transfusion influences brain myelination at 4 months of age. STUDY DESIGN: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. RESULTS: In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. CONCLUSION: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01620008.
Assuntos
Encéfalo/metabolismo , Desenvolvimento Infantil/fisiologia , Parto Obstétrico/métodos , Ferritinas/sangue , Bainha de Mielina/metabolismo , Cordão Umbilical/cirurgia , Adulto , Fatores Etários , Transfusão de Sangue , Encéfalo/diagnóstico por imagem , Constrição , Feminino , Maternidades , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , Idade Materna , Monitorização Fisiológica/métodos , Neuroimagem/métodos , Gravidez , Prognóstico , Método Simples-Cego , Nascimento a Termo , Fatores de Tempo , Estados UnidosRESUMO
Müller cells are the major supportive and protective glial cells in the retina with important functions in histogenesis and synaptogenesis during development, and in maintenance of mature neurons as they show to secrete various cytokines and manifest potentials of self-renewal and transdifferentiation into retinal neurons following injury in the vertebrate retinas. The swine retina has a visual streak structure similar to the human macular where cone photoreceptors are highly concentrated, thereby can serve as a better model for studying retinal diseases and for formulating cell-based therapeutics than the rodent retinas. Like most differentiated somatic mammalian cells, the isolated swine and human Müller glia become senescent over passages in culture, which restricts their potential application in basic and clinic researches. Here, we demonstrate that the senescence of swine and human Müller cells is caused by telomere attrition upon multiplications in vitro; and the senescent cells can be rejuvenated by sphere suspension culture. We also provide evidence that sphere-induced extension of telomeres in swine and human Müller glia is achieved by alternative lengthening of telomeres or/and by telomerase activation. Stem Cells 2017;35:1579-1591.
Assuntos
Células Ependimogliais/metabolismo , Rejuvenescimento , Esferoides Celulares/citologia , Homeostase do Telômero , Telômero/metabolismo , Animais , Células Cultivadas , Senescência Celular , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Humanos , Modelos Biológicos , Células-Tronco/metabolismo , Sus scrofa , Telomerase/metabolismoRESUMO
Cortical maturation, including age-related changes in thickness, volume, surface area, and folding (gyrification), play a central role in developing brain function and plasticity. Further, abnormal cortical maturation is a suspected substrate in various behavioral, intellectual, and psychiatric disorders. However, in order to characterize the altered development associated with these disorders, appreciation of the normative patterns of cortical development in neurotypical children between 1 and 6 years of age, a period of peak brain development during which many behavioral and developmental disorders emerge, is necessary. To this end, we examined measures of cortical thickness, surface area, mean curvature, and gray matter volume across 34 bilateral regions in a cohort of 140 healthy children devoid of major risk factors for abnormal development. From these data, we observed linear, logarithmic, and quadratic patterns of change with age depending on brain region. Cortical thinning, ranging from 10% to 20%, was observed throughout most of the brain, with the exception of posterior brain structures, which showed initial cortical thinning from 1 to 5 years, followed by thickening. Cortical surface area expansion ranged from 20% to 108%, and cortical curvature varied by 1-20% across the investigated age range. Right-left hemisphere asymmetry was observed across development for each of the 4 cortical measures. Our results present new insight into the normative patterns of cortical development across an important but under studied developmental window, and provide a valuable reference to which trajectories observed in neurodevelopmental disorders may be compared.
Assuntos
Córtex Cerebral/anatomia & histologia , Córtex Cerebral/crescimento & desenvolvimento , Mapeamento Encefálico , Criança , Desenvolvimento Infantil , Pré-Escolar , Feminino , Substância Cinzenta/anatomia & histologia , Substância Cinzenta/crescimento & desenvolvimento , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Caracteres SexuaisRESUMO
Cortical development and white matter myelination are hallmark processes of infant and child neurodevelopment, and play a central role in the evolution of cognitive and behavioral functioning. Non-invasive magnetic resonance imaging (MRI) has been used to independently track these microstructural and morphological changes in vivo, however few studies have investigated the relationship between them despite their concurrency in the developing brain. Further, because measures of cortical morphology rely on underlying gray-white matter tissue contrast, which itself is a function of white matter myelination, it is unclear if contrast-based measures of cortical development accurately reflect cortical architecture, or if they merely represent adjacent white matter maturation. This may be particularly true in young children, in whom brain structure is rapidly maturing. Here for the first time, we investigate the dynamic relationship between cortical and white matter development across early childhood, from 1 to 6years. We present measurements of cortical thickness with respect to cortical and adjacent myelin water fraction (MWF) in 33 bilateral cortical regions. Significant results in only 14 of 66 (21%) cortical regions suggest that cortical thickness measures are not heavily driven by changes in adjacent white matter, and that brain imaging studies of cortical and white matter maturation reflect distinct, but complimentary, neurodevelopmental processes.
Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Bainha de Mielina/fisiologia , Substância Branca/crescimento & desenvolvimento , Criança , Pré-Escolar , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Lactente , Imageamento por Ressonância Magnética , MasculinoRESUMO
Optimal myelination of neuronal axons is essential for effective brain and cognitive function. The ratio of the axon diameter to the outer fiber diameter, known as the g-ratio, is a reliable measure to assess axonal myelination and is an important index reflecting the efficiency and maximal conduction velocity of white matter pathways. Although advanced neuroimaging techniques including multicomponent relaxometry (MCR) and diffusion tensor imaging afford insight into the microstructural characteristics of brain tissue, by themselves they do not allow direct analysis of the myelin g-ratio. Here, we show that by combining myelin content information (obtained with mcDESPOT MCR) with neurite density information (obtained through NODDI diffusion imaging) an index of the myelin g-ratio may be estimated. Using this framework, we present the first quantitative study of myelin g-ratio index changes across childhood, examining 18 typically developing children 3months to 7.5years of age. We report a spatio-temporal pattern of maturation that is consistent with histological and developmental MRI studies, as well as theoretical studies of the myelin g-ratio. This work represents the first ever in vivo visualization of the evolution of white matter g-ratio indices throughout early childhood.