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1.
Nat Commun ; 12(1): 4908, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389711

RESUMO

C9ORF72 hexanucleotide GGGGCC repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-containing RNA mediates toxicity through nuclear granules and dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG translation. However, it remains unclear how the intron-localized repeats are exported and translated in the cytoplasm. We use single molecule imaging approach to examine the molecular identity and spatiotemporal dynamics of the repeat RNA. We demonstrate that the spliced intron with G-rich repeats is stabilized in a circular form due to defective lariat debranching. The spliced circular intron, instead of pre-mRNA, serves as the translation template. The NXF1-NXT1 pathway plays an important role in the nuclear export of the circular intron and modulates toxic DPR production. This study reveals an uncharacterized disease-causing RNA species mediated by repeat expansion and demonstrates the importance of RNA spatial localization to understand disease etiology.


Assuntos
Proteína C9orf72/genética , Núcleo Celular/metabolismo , Íntrons/genética , Biossíntese de Proteínas/genética , RNA/genética , Transporte Ativo do Núcleo Celular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/genética , Expansão das Repetições de DNA/genética , Dipeptídeos/genética , Dipeptídeos/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Predisposição Genética para Doença/genética , Células HEK293 , Humanos , Microscopia de Fluorescência , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética
2.
Cell Rep ; 34(13): 108925, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33789100

RESUMO

Multiple cellular pathways have been suggested to be altered by the C9orf72 GGGGCC (G4C2) hexanucleotide repeat expansion (HRE), including aspects of RNA regulation such as nonsense-mediated decay (NMD). Here, we investigate the role that overexpression of UPF1, a protein involved in NMD, plays in mitigating neurotoxicity in multiple models of C9orf72 ALS/FTD. First, we show that NMD is not altered in our endogenous induced pluripotent stem cell (iPSC)-derived spinal neuron (iPSN) model of C9orf72 ALS (C9-ALS) or postmortem motor cortex tissue from C9-ALS patients. Unexpectedly, we find that UPF1 overexpression significantly reduces the severity of known neurodegenerative phenotypes without altering NMD function itself. UPF1 overexpression reduces poly(GP) abundance without altering the amount of repeat RNA, providing a potential mechanism by which UPF1 reduces dipeptide repeat (DPR) protein-mediated toxicity. Together, these findings indicate that UPF1 is neuroprotective in the context of C9-ALS, albeit independent of known UPF1-mediated NMD pathways.

3.
BMC Cancer ; 21(1): 268, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711952

RESUMO

BACKGROUND: DNA methylation is an epigenetic event involving the addition of a methyl-group to a cytosine-guanine base pair (i.e., CpG site). It is associated with different cancers. Our research focuses on studying non-small cell lung cancer hemimethylation, which refers to methylation occurring on only one of the two DNA strands. Many studies often assume that methylation occurs on both DNA strands at a CpG site. However, recent publications show the existence of hemimethylation and its significant impact. Therefore, it is important to identify cancer hemimethylation patterns. METHODS: In this paper, we use the Wilcoxon signed rank test to identify hemimethylated CpG sites based on publicly available non-small cell lung cancer methylation sequencing data. We then identify two types of hemimethylated CpG clusters, regular and polarity clusters, and genes with large numbers of hemimethylated sites. Highly hemimethylated genes are then studied for their biological interactions using available bioinformatics tools. RESULTS: In this paper, we have conducted the first-ever investigation of hemimethylation in lung cancer. Our results show that hemimethylation does exist in lung cells either as singletons or clusters. Most clusters contain only two or three CpG sites. Polarity clusters are much shorter than regular clusters and appear less frequently. The majority of clusters found in tumor samples have no overlap with clusters found in normal samples, and vice versa. Several genes that are known to be associated with cancer are hemimethylated differently between the cancerous and normal samples. Furthermore, highly hemimethylated genes exhibit many different interactions with other genes that may be associated with cancer. Hemimethylation has diverse patterns and frequencies that are comparable between normal and tumorous cells. Therefore, hemimethylation may be related to both normal and tumor cell development. CONCLUSIONS: Our research has identified CpG clusters and genes that are hemimethylated in normal and lung tumor samples. Due to the potential impact of hemimethylation on gene expression and cell function, these clusters and genes may be important to advance our understanding of the development and progression of non-small cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Epigênese Genética , Neoplasias Pulmonares/genética , Idoso , Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Biologia Computacional , Ilhas de CpG/genética , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
4.
Neurosci Lett ; 753: 135855, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33785379

RESUMO

BACKGROUND: Neonatal hypoxia-ischemia (HI) is one of the commonest conditions which seriously influences the development of infants' nervous system and causes series of neurological sequelaes. The aim of the present study was to analyze the potential regulatory mechanism of long non-coding (lnc) RNA H19 under hypoxia conditions. METHODS: Neural stem cells (NSCs) were incubated in hypoxic conditions for 8 h to induce hypoxia injury. qRT-PCR was performed to detect H19 or micro (miR)-107 expression. Cell Counting Kit-8 (CCK-8) assay and Annexin V-FITC/PI staining assay were employed to detect the effects of hypoxia on cell viability and apoptosis, respectively. Moreover, NSCs were transfected with H19 overexpressing plasmid or shRNA-H19 and then subjected to hypoxia treatment. The effects of H19/miR-107 on NSC cell biological behaviors were confirmed. Furthermore, the signaling pathways involved in HI were analyzed using western blot. RESULTS: Hypoxia treatment restrained cell viability and induced cell apoptosis in NSCs. Overexpression of lncRNA H19 attenuated hypoxia-induced NSCs injury, while knockdown of lncRNA H19 aggravated NSCs injury. Further experiments suggested that miR-107 up-regulation reversed the effects of lncRNA H19 overexpression on NSCs. Moreover, the activation of Wnt/ß-catenin and PI3K/AKT pathways triggered by H19 were reversed by miR-107 up-regulation in hypoxia-treated NSCs. CONCLUSION: LncRNA H19 overexpression attenuated hypoxia-induced NSCs injury and promoted activation of Wnt/ß-catenin and PI3K/AKT pathways through downregulating miR-107.

5.
Bioresour Technol ; 314: 123749, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32623285

RESUMO

An oxidized biochar was prepared using long-root Eichhornia crassipes through an aerobic/anaerobic hybrid calcination to recycle its waste plants after eutrophic treatments. The adsorption performances of the biochar were investigated and the results showed that the adsorption equilibrium could arrive in 30 min and the adsorption capacities for Pb2+, Cu2+, Cd2+ and Zn2+ at 30 °C were 0.57, 0.41, 0.44 and 0.48 mmol/g, respectively. The adsorption could be promoted at higher pH and temperature and the adsorption tolerance for different heavy metal ions to the existence of competing ions and organic matters was hierarchical. The adsorption was deduced to be heterozygous courses and mainly controlled by complexation of oxygen-containing groups with these heavy metal ions. It was confirmed that the biochar could be regenerated with HCl solution and the adsorption performance kept consistent in 10 adsorption-desorption cycles.


Assuntos
Eichhornia , Metais Pesados , Poluentes Químicos da Água/análise , Adsorção , Carvão Vegetal
6.
Neuron ; 104(5): 885-898.e8, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31587919

RESUMO

Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells. We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72/biossíntese , RNA Helicases DEAD-box/metabolismo , Demência Frontotemporal/metabolismo , Animais , Sistemas CRISPR-Cas , Drosophila , Humanos , Biossíntese de Proteínas/fisiologia , Sequências Repetitivas de Ácido Nucleico
7.
Cancer Inform ; 18: 1176935119880516, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631960

RESUMO

DNA methylation plays a significant role in regulating the expression of certain genes in both cancerous and normal breast tissues. It is therefore important to study within-sample co-methylation, ie, methylation patterns between consecutive sites in a chromosome. In this article, we develop 2 new methods to compare co-methylation patterns between normal and cancerous breast samples. In particular, we investigate the co-methylation patterns of 4 different methylation states/levels separately. Using these 2 methods, we focus on addressing the following questions: How often does 1 methylation state change to other methylation states and how is this change dependent on chromosome distance? What co-methylation patterns do normal and cancerous breast samples have? Do genomic sites with different methylation states/levels have different co-methylation patterns? Our results show that cancerous and normal co-methylation patterns are significantly different. We find that this difference exists even when the physical distance of 2 sites are less than 50 bases. Breast cancer cell lines tend to remain in the same methylation state more often than normal samples, especially for the no/low or high/full methylation states. We also find that the co-methylation region lengths for various methylation states (no/low, partial, and high/full methylation states) are very different. For example, the co-methylation region lengths for partial methylation regions are shorter than the unmethylated or fully methylated regions. Our research may provide a deep understanding of co-methylation patterns. These co-methylation patterns will aid in discovering and understanding new methylation events that may be related to novel biomarkers.

8.
Cancer Inform ; 18: 1176935119872959, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496635

RESUMO

DNA methylation is an epigenetic event that involves adding a methyl group to the cytosine (C) site, especially the one that pairs with a guanine (G) site (ie, CG or CpG site), in a human genome. This event plays an important role in both cancerous and normal cell development. Previous studies often assume symmetric methylation on both DNA strands. However, asymmetric methylation, or hemimethylation (methylation that occurs only on 1 DNA strand), does exist and has been reported in several studies. Due to the limitation of previous DNA methylation sequencing technologies, researchers could only study hemimethylation on specific genes, but the overall genomic hemimethylation landscape remains relatively unexplored. With the development of advanced next-generation sequencing techniques, it is now possible to measure methylation levels on both forward and reverse strands at all CpG sites in an entire genome. Analyzing hemimethylation patterns may potentially reveal regions related to undergoing tumor growth. For our research, we first identify hemimethylated CpG sites in breast cancer cell lines using Wilcoxon signed rank tests. We then identify hemimethylation patterns by grouping consecutive hemimethylated CpG sites based on their methylation states, methylation "M" or unmethylation "U." These patterns include regular (or consecutive) hemimethylation clusters (eg, "MMM" on one strand and "UUU" on another strand) and polarity (or reverse) clusters (eg, "MU" on one strand and "UM" on another strand). Our results reveal that most hemimethylation clusters are the polarity type, and hemimethylation does occur across the entire genome with notably higher numbers in the breast cancer cell lines. The lengths or sizes of most hemimethylation clusters are very short, often less than 50 base pairs. After mapping hemimethylation clusters and sites to corresponding genes, we study the functions of these genes and find that several of the highly hemimethylated genes may influence tumor growth or suppression. These genes may also indicate a progressing transition to a new tumor stage.

9.
Diagn Pathol ; 14(1): 53, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164163

RESUMO

BACKGROUND: Lung cancer is one of the common malignant tumors worldwide with high incidence and mortality. MicroRNA-423-3p (miR-423-3p) acts as an oncogene in several types of cancers. The aim of this study is to reveal the clinical significance and biological function of miR-423-3p in lung cancer. METHODS: The expression of miR-423-3p was detected in lung cancer specimens by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) assay. Kaplan-Meier survival and Cox regression analyses were used to investigate the prognostic significance of miR-423-3p in lung cancer. CCK-8 and Transwell assays were used to determine the functional role of miR-423-3p in lung cancer. RESULTS: We observed that miR-423-3p was significantly upregulated in lung cancer tissues and cell lines. Overexpression of miR-423-3p was significantly associated with lymph node metastasis, TNM stage, and poor prognosis. Multivariate Cox regression analysis results showed that miR-423-3p was an independent prognostic indicator for lung cancer patients. Results of functional analyses revealed that overexpression of miR-423-3p promoted cell proliferation, migration, and invasion in lung cancer cells. CONCLUSIONS: These results indicated that miR-423-3p acts as an oncogene and promotes cell proliferation migration, and invasion of lung cancer. And miR-423-3p may serve as a potential prognostic biomarker and therapeutic target for the treatment of lung cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/diagnóstico , MicroRNAs/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Regulação para Cima
10.
BioData Min ; 12: 9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31086568

RESUMO

Background: DNA methylation is an epigenetic event that may regulate gene expression. Because of this regulation role, aberrant DNA methylation is often associated with many diseases. Within-sample DNA co-methylation is the similarity of methylation in nearby cytosine sites of a chromosome. It is important to study co-methylation patterns. However, it is not well studied yet, and it is unclear to us what co-methylation patterns normal DNA samples have. Are the co-methylation patterns of the same tissue across several samples different? Are the co-methylation patterns of various tissues of the same sample different? To answer these questions, we conduct analyses using two sets of data: 3-sample-1-tissue (3S1T) and 1-sample-8-tissue (1S8T). Results: To study the co-methylation patterns of the two datasets, 3S1T and 1S8T, we investigate the following questions: How often does one methylation state change to other methylation states and how is this change associated with chromosome distance? Based on the 3S1T data, we find there is not significant co-methylation difference among the same spleen tissues of three different samples. However, the analysis results of 1S8T data show that there were significant differences among eight tissues of one sample. For both 3S1T and 1S8T data, we find that the no/low methylation state A and high/full methylation state D tend to remain the same along a chromosome region. We also find that the low/partial methylation state B and partial/high methylation state C tend to change to higher methylation states along a chromosome. Finally, we find that lengths of most co-methylation regions are very short with only a few hundred base pairs. In fact, only a small proportion of methylated regions are longer than 1000 base pairs. Conclusions: In this paper, we have addressed a few questions regarding within-sample co-methylation patterns in normal tissues. Our statistical analysis results and answers may help researchers to better understand the biological process of DNA methylation. This may pave the way to develop better analysis methods for future methylation research.

11.
Science ; 364(6438): 395-399, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023925

RESUMO

Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. However, the molecular mechanisms of the cellular response to acid are not fully understood. We performed an unbiased RNA interference screen and identified PAC (TMEM206) as being essential for the widely observed proton-activated Cl- (PAC) currents (I Cl,H). Overexpression of human PAC in PAC knockout cells generated I Cl,H with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse Pac abolished I Cl,H in neurons and attenuated brain damage after ischemic stroke. The wide expression of PAC suggests a broad role for this conserved Cl- channel family in physiological and pathological processes associated with acidic pH.


Assuntos
Canais de Cloreto/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Cálcio/metabolismo , Morte Celular , Canais de Cloreto/classificação , Canais de Cloreto/genética , Cloretos/metabolismo , Sequência Conservada , Evolução Molecular , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Proteínas de Membrana/classificação , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Filogenia , Interferência de RNA , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Peixe-Zebra , Proteínas de Peixe-Zebra/classificação , Proteínas de Peixe-Zebra/genética
12.
Elife ; 82019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30747709

RESUMO

Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality. Transcriptome analysis reveals mis-regulation of genes that are largely not observed upon FUS reduction. Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism. Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.


Assuntos
Autofagia , Homeostase , Lisossomos/metabolismo , Proteína FUS de Ligação a RNA/biossíntese , Proteína FUS de Ligação a RNA/toxicidade , RNA/metabolismo , Animais , Perfilação da Expressão Gênica , Humanos , Camundongos Endogâmicos C57BL , Proteínas Mutantes/biossíntese , Proteínas Mutantes/genética , Proteínas Mutantes/toxicidade , Proteína FUS de Ligação a RNA/genética
13.
BioData Min ; 11: 13, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983747

RESUMO

Background: The deadly costs of cancer and necessity for an accurate method of early cancer detection have demanded the identification of genetic and epigenetic factors associated with cancer. DNA methylation, an epigenetic event, plays an important role in cancer susceptibility. In this paper, we use DNA methylation and gene expression data integration and pathway analysis to further explore and understand the complex relationship between methylation and gene expression. Results: Through linear modeling and analysis of variance, we obtain genes that show a significant correlation between methylation and gene expression. We then examine the functions and relationships of these genes using bioinformatic tools and databases. In particular, using ConsensusPathDB, we analyze the networks of statistically significant genes to identify hub genes, genes with a large number of links to other genes. We identify eight major hub genes, all in strong association with cancer susceptibility. Through further analysis of the function, gene expression level, and methylation level of these hub genes, we conclude that they are novel potential biomarkers for breast cancer. Conclusions: Our findings have various implications for cancer screening, early detection methods, and potential novel treatments for cancer. Researchers can also use our results to develop more effective methods for cancer study.

14.
Nat Commun ; 9(1): 51, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29302060

RESUMO

Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2α-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.


Assuntos
Proteína C9orf72/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Estresse Fisiológico/genética , Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/metabolismo , Expansão das Repetições de DNA , Dipeptídeos , Retroalimentação Fisiológica , Demência Frontotemporal/genética , Células HeLa , Humanos , Íntrons , Peptídeos , Fosforilação , Biossíntese de Proteínas , Splicing de RNA , Regulação para Cima
15.
Methods Mol Biol ; 1666: 1-9, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28980238

RESUMO

Common terms used in statistical genetics with multiple meanings are explained and the terminology used in subsequent chapters is defined. Statistical human genetics has existed as a discipline for over a century, and during that time the meanings of many of the terms used have evolved, largely driven by molecular discoveries, to the point that molecular geneticists, statistical geneticists, and statisticians often have difficulty understanding each other. It is therefore imperative, now that so much of molecular genetics is becoming an in silico and statistical science, that we have a well-defined, common terminology.


Assuntos
Genética , Terminologia como Assunto , Alelos , Epistasia Genética , Loci Gênicos , Pleiotropia Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Mutação , Fenótipo , Polimorfismo Genético , Locos de Características Quantitativas , Estatística como Assunto
16.
Waste Manag ; 64: 171-181, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28325707

RESUMO

In view of the importance of environmental protection and resource recovery, recycling of spent lithium-ion batteries (LIBs) and electrode scraps generated during manufacturing processes is quite necessary. An environmentally sound leaching process for the recovery of Li, Ni, Co, and Mn from spent LiNi1/3Co1/3Mn1/3O2-based LIBs and cathode scraps was investigated in this study. Eh-pH diagrams were used to determine suitable leaching conditions. Operating variables affecting the leaching efficiencies for Li, Ni, Co, and Mn from LiNi1/3Co1/3Mn1/3O2, such as the H2SO4 concentration, temperature, H2O2 concentration, stirring speed, and pulp density, were investigated to determine the most efficient conditions for leaching. The leaching efficiencies for Li, Ni, Co, and Mn reached 99.7% under the optimized conditions of 1M H2SO4, 1vol% H2O2, 400rpm stirring speed, 40g/L pulp density, and 60min leaching time at 40°C. The leaching kinetics of LiNi1/3Co1/3Mn1/3O2 were found to be significantly faster than those of LiCoO2. Based on the variation in the weight fraction of the metal in the residue, the "cubic rate law" was revised as follows: θ(1-f)1/3=(1-kt/r0ρ), which could characterize the leaching kinetics optimally. The activation energies were determined to be 64.98, 65.16, 66.12, and 66.04kJ/mol for Li, Ni, Co, and Mn, respectively, indicating that the leaching process was controlled by the rate of surface chemical reactions. Finally, a simple process was proposed for the recovery of valuable metals from spent LiNi1/3Co1/3Mn1/3O2-based LIBs and cathode scraps.


Assuntos
Fontes de Energia Elétrica , Lítio , Eletrodos , Peróxido de Hidrogênio , Metais , Reciclagem
17.
Acta Neuropathol ; 133(6): 907-922, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28357566

RESUMO

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neurônios Motores/metabolismo , Adulto , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Neurônios Motores/patologia , Mutação , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Adulto Jovem
18.
Cancer Inform ; 15(Supple 4): 1-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27688708

RESUMO

Heterogeneous DNA methylation patterns are linked to tumor growth. In order to study DNA methylation heterogeneity patterns for breast cancer cell lines, we comparatively study four metrics: variance, I (2) statistic, entropy, and methylation state. Using the categorical metric methylation state, we select the two most heterogeneous states to identify genes that directly affect tumor suppressor genes and high- or moderate-risk breast cancer genes. Utilizing the Gene Set Enrichment Analysis software and the ConsensusPath Database visualization tool, we generate integrated gene networks to study biological relations of heterogeneous genes. This analysis has allowed us to contribute 19 potential breast cancer biomarker genes to cancer databases by locating "hub genes" - heterogeneous genes of significant biological interactions, selected from numerous cancer modules. We have discovered a considerable relationship between these hub genes and heterogeneously methylated oncogenes. Our results have many implications for further heterogeneity analyses of methylation patterns and early detection of breast cancer susceptibility.

19.
Artigo em Inglês | MEDLINE | ID: mdl-27570841

RESUMO

Normal human hematopoietic stem and progenitor cells (HPC) lose expression of MLH1, an important mismatch repair (MMR) pathway gene, with age. Loss of MMR leads to replication dependent mutational events and microsatellite instability observed in secondary acute myelogenous leukemia and other hematologic malignancies. Epigenetic CpG methylation upstream of the MLH1 promoter is a contributing factor to acquired loss of MLH1 expression in tumors of the epithelia and proximal mucosa. Using single molecule high-throughput bisulfite sequencing we have characterized the CpG methylation landscape from -938 to -337 bp upstream of the MLH1 transcriptional start site (position +0), from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing MLH1. We identify a correlation between MLH1 promoter methylation and loss of MLH1 expression. Additionally, using the CpG site methylation frequencies obtained in this study we were able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as has been previously described for many tumor cell types, we report for the first time a correlation between the loss of MLH1 expression and increased MLH1 promoter methylation in CFC derived from CD34+ selected hematopoietic stem and progenitor cells.

20.
Neuron ; 90(3): 535-50, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27112497

RESUMO

Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Demência Frontotemporal/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/genética , Oligonucleotídeos Antissenso/farmacologia , RNA/metabolismo , Esclerose Amiotrófica Lateral/genética , Animais , Proteína C9orf72 , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Camundongos Transgênicos , Neurônios/metabolismo , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/genética
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