Parkinson’s disease (PD) is characterized by Lewy bodies (composed predominantly of alpha-synuclein aSyn) and loss of pigmented midbrain dopaminergic neurons comprising the nigrostriatal pathway. ...Most PD patients show significant deficiency of gangliosides, including GM1, in the brain, and GM1 ganglioside appears to keep dopaminergic neurons functioning properly. Thus, supplementation of GM1 could potentially provide some rescuing effects. In this study, we demonstrate that intranasal infusion of GD3 and GM1 gangliosides reduces intracellular aSyn levels. GM1 also significantly enhances expression of tyrosine hydroxylase (TH) in the substantia nigra pars compacta of the A53T aSyn overexpressing mouse, following restored nuclear expression of nuclear receptor related 1 (Nurr1, also known as NR4A2), an essential transcription factor for differentiation, maturation, and maintenance of midbrain dopaminergic neurons. GM1 induces epigenetic activation of the TH gene, including augmentation of acetylated histones and recruitment of Nurr1 to the TH promoter region. Our data indicate that intranasal administration of gangliosides could reduce neurotoxic proteins and restore functional neurons via modulating chromatin status by nuclear gangliosides.
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Itokazu et al. demonstrate that intranasally administered ganglioside GM1 or GD3 decreases the accretion of alpha-synuclein and GM1 upregulates epigenetically the expression of tyrosine hydroxylase via recruitment of Nurr1 transcription factor in the brain of a mouse model of Parkinson’s disease (PD). These observations suggest the possibility of using gangliosides as alternative therapeutics for PD.
Purpose
To investigate the effect of age of myopia onset on the severity of myopia later in life among myopic children.
Methods
In this prospective study, school children aged 7–9 years from the ...Singapore Cohort Of the Risk factors for Myopia (SCORM) were followed up till 11 years (n = 928). Age of myopia onset was defined either through questionnaire at baseline (age 7–9 years) or subsequent annual follow‐up visits. Age of onset of myopia was a surrogate indicator of duration of myopia progression till age 11 years. Cycloplegic refraction and axial length were measured at every annual eye examination. High myopia was defined as spherical equivalent of ≤−5.0 D. A questionnaire determined the other risk factors.
Results
In multivariable regression models, younger age of myopia onset (per year decrease) or longer duration of myopia progression was associated with high myopia (odds ratio (OR) = 2.86; 95% CI: 2.39 to 3.43), more myopic spherical equivalent (regression coefficient (β) = −0.86 D; 95% CI: −0.93 to −0.80) and longer axial length (β = 0.28 mm; 95% CI: 0.24 to 0.32) at aged 11 years, after adjusting for gender, race, school, books per week and parental myopia. In Receiver Operating Curve (ROC) analyses, age of myopia onset alone predicted high myopia by 85% (area under the curve = 0.85), while the addition of other factors including gender, race, school, books per week and parental myopia only marginally improved this prediction (area under the curve = 0.87).
Conclusions
Age of myopia onset or duration of myopia progression was the most important predictor of high myopia in later childhood in myopic children. Future trials to retard the progression of myopia to high myopia could focus on children with younger age of myopia onset or with longer duration of myopia progression.
Word embeddings that provide continuous low-dimensional vector representations of words have been extensively used for various natural language processing tasks. However, existing context-based word ...embeddings such as Word2vec and GloVe typically fail to capture sufficient sentiment information, which may result in words with similar vector representations having an opposite sentiment polarity (e.g., good and bad), thus degrading sentiment analysis performance. To tackle this problem, recent studies have suggested learning sentiment embeddings to incorporate the sentiment polarity (positive and negative) information from labeled corpora. This study adopts another strategy to learn sentiment embeddings. Instead of creating a new word embedding from labeled corpora, we propose a word vector refinement model to refine existing pretrained word vectors using real-valued sentiment intensity scores provided by sentiment lexicons. The idea of the refinement model is to improve each word vector such that it can be closer in the lexicon to both semantically and sentimentally similar words (i.e., those with similar intensity scores) and further away from sentimentally dissimilar words (i.e., those with dissimilar intensity scores). An obvious advantage of the proposed method is that it can be applied to any pretrained word embeddings. In addition, the intensity scores can provide more fine-grained (real-valued) sentiment information than binary polarity labels to guide the refinement process. Experimental results show that the proposed refinement model can improve both conventional word embeddings and previously proposed sentiment embeddings for binary, ternary, and fine-grained sentiment classification on the SemEval and Stanford Sentiment Treebank datasets.
SF3B1 is the most commonly mutated RNA splicing factor in cancer
, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing ...analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L
. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.
The traditional methods to study lipid rafts and their association with membrane proteins are based mainly on the isolation of a detergent-resistant membrane by biochemical fractionation. However, ...the use of detergents may induce lipid segregation and/or redistribution of membrane proteins during the process of sample preparation. Here, we describe a detergent-free method to study the glycolipid and growth factor receptor interaction and their association with lipid rafts. This method combines the biochemical and immunoblotting tools with confocal microscopic imaging, which allows for evaluation and verification of the membrane protein interaction and association with the lipid rafts components in a multifaceted manner.
Gangliosides are sialic acid-containing glycosphingolipids that are most abundant in the nervous system. They are localized primarily in the outer leaflets of plasma membranes and participated in ...cell–cell recognition, adhesion, and signal transduction and are integral components of cell surface microdomains or lipid rafts along with proteins, sphingomyelin and cholesterol. Ganglioside-rich lipid rafts play an important role in signaling events affecting neural development and the pathogenesis of certain diseases. Disruption of gangloside synthase genes in mice induces developmental defects and neural degeneration. Targeting ganglioside metabolism may represent a novel therapeutic strategy for intervention in certain diseases. In this review, we focus on recent advances on metabolic and functional studies of gangliosides in normal brain development and in certain neurological disorders.
Gangliosides in Nerve Cell Specification Itokazu, Yutaka; Wang, Jing; Yu, Robert K
Progress in Molecular Biology and Translational Science,
2018, Letnik:
156
Journal Article
Recenzirano
Odprti dostop
The central nervous system is generated from progenitor cells that are recognized as neural stem cells (NSCs). NSCs are defined as undifferentiated neural cells that are characterized by the capacity ...for self-renewal and multipotency. Throughout neural development, NSCs undergo proliferation, migration, and cellular differentiation, and dynamic changes are observed in the composition of carbohydrate-rich molecules, including gangliosides. Gangliosides are sialic acid-containing glycosphingolipids with essential and multifaceted functions in brain development and NSC maintenance, which reflects the complexity of brain development. Our group has pioneered research on the importance of gangliosides for growth factor receptor signaling and epigenetic regulation of ganglioside biosynthesis in NSCs. We found that GD3 is the predominant ganglioside species in NSCs (>80%) and modulates NSC proliferation by interacting with epidermal growth factor receptor signaling. In postnatal brain, GD3 is required for long-term maintenance of NSCs. Deficiency in GD3 leads to developmental and behavioral deficits, such as depression. The synthesis of GD3 is switched to the synthesis of complex, brain-type gangliosides, namely, GM1, GD1a, GD1b, and GT1b, resulting in terminal differentiation and loss of "stemness" of NSCs. In this process, GM1 is augmented by a novel GM1-modulated epigenetic gene regulation mechanism of glycosyltransferases at a later differentiation stage. Consequently, our research suggests that stage-specific gangliosides play specific roles in maintaining NSC activities and in cell fate determination.
Ganglioside GD3, a major ganglioside species in neural stem cells, plays a crucial role in maintenance of the self‐renewal capacity of these cells. However, its bioactivity in postnatally ...differentiated neurons in the neurogenic regions of adult brains has not been elucidated. Here, we describe for the first time that deletion of GD3 not only impairs neurotrophin‐induced stem cell proliferation, but also alters the dendritic structure as well as the number of synapses of nascent neurons in the dentate gyrus of adult brain. When examining the behavioral phenotypes, GD3 synthase‐knockout (GD3S‐KO) mice displayed impairment in hippocampus‐dependent memory function. To further gain insight into its cellular function, we examined GD3‐binding partners from mouse brain extract using a GD3‐specific monoclonal antibody, R24, followed by LC‐MS/MS analysis and identified a mitochondrial fission protein, the dynamin‐related protein‐1 (Drp1), as a novel GD3‐binding protein. Biochemical and imaging analyses revealed mitochondrial fragmentation in GD3‐depleted dentate gyrus neurons, suggesting that GD3 is essential for the mitochondrial Drp1 turnover that is required for efficient mitochondrial fission. These results suggest that GD3 is required for proper dendritic and spine maturation of newborn neurons in adult brain through the regulation of mitochondrial dynamics.
Gangliosides are abundantly expressed in the nervous system and are known to play important roles in neurodevelopment. We previously showed that ganglioside GD3 plays a crucial role in the maintenance of the self‐renewal capacity of neural stem cells. However, its activity on postnatally differentiated neurons in neurogenic regions of adult brains has not been elucidated. Using a GD3S‐KO mouse model, we demonstrated that GD3 was required in the morphological differentiation and synaptic integration of newborn hippocampal granule neurons in vivo. Our findings indicate that GD3 is important for the maturation of newborn neurons in the adult mouse hippocampus and reveal a novel link between GD3, mitochondrial dynamics, and maturation of the developing neurons.
The maintenance of a neural stem cell (NSC) population in mammalian postnatal and adult life is crucial for continuous neurogenesis and neural repair. However, the molecular mechanism of how NSC ...populations are maintained remains unclear. Gangliosides are important cellular membrane components in the nervous system. We previously showed that ganglioside GD3 plays a crucial role in the maintenance of the self-renewal capacity of NSCs in vitro. Here, we investigated its role in postnatal and adult neurogenesis in GD3-synthase knock-out (GD3S-KO) and wild-type mice. GD3S-KO mice with deficiency in GD3 and the downstream b-series gangliosides showed a progressive loss of NSCs both at the SVZ and the DG of the hippocampus. The decrease of NSC populations in the GD3S-KO mice resulted in impaired neurogenesis at the granular cell layer of the olfactory bulb and the DG in the adult. In addition, defects of the self-renewal capacity and radial glia-like stem cell outgrowth of postnatal GD3S-KO NSCs could be rescued by restoration of GD3 expression in these cells. Our study demonstrates that the b-series gangliosides, especially GD3, play a crucial role in the long-term maintenance NSC populations in postnatal mouse brain. Moreover, the impaired neurogenesis in the adult GD3S-KO mice led to depression-like behaviors. Thus, our results provide convincing evidence linking b-series gangliosides deficiency and neurogenesis defects to behavioral deficits, and support a crucial role of gangliosides in the long-term maintenance of NSCs in adult mice.
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive ...immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
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•Adaptive immune responses limit COVID-19 disease severity•Multiple coordinated arms of adaptive immunity control better than partial responses•CXCL10 may be a biomarker of impaired T cell responses in acute COVID-19•Aging and scarcity of naive T cells may be linked risk factors for severe COVID-19
Analysis of SARS-CoV-2-specific adaptive immune responses during acute COVID-19 identifies coordination between SARS-CoV-2-specific CD4 T cells and CD8 T cells to limit disease severity. Aged individuals often exhibit uncoordinated adaptive responses, potentially tied to scarcity of naive T cells, highlighting immunologic risk factors linked to disease severity.
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