RESUMO
Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m1A58 'writer' proteins TRMT61A and TRMT6, which confer m1A58 RNA modification on a specific subset of early expressed tRNAs. These m1A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m1A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m1A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.
Assuntos
Colite , RNA de Transferência , Transferência Adotiva , Animais , Proliferação de Células/genética , Colite/genética , Camundongos , Biossíntese de Proteínas , RNA de Transferência/genética , RNA de Transferência/metabolismo , Linfócitos T/metabolismoRESUMO
N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.
Assuntos
Adenosina/química , Hematopoese/genética , Hematopoese/imunologia , Imunidade Inata/genética , RNA de Cadeia Dupla/metabolismo , Animais , Biomarcadores , Transtornos da Insuficiência da Medula Óssea/etiologia , Transtornos da Insuficiência da Medula Óssea/metabolismo , Transtornos da Insuficiência da Medula Óssea/patologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica , Células-Tronco Hematopoéticas , Imunofenotipagem , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Knockout , RNA de Cadeia Dupla/químicaRESUMO
Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.
Assuntos
Mucosa Intestinal/citologia , MAP Quinase Quinase Quinase 2/metabolismo , Nicho de Células-Tronco , Células Estromais/citologia , Animais , Antígenos CD34 , Colite/patologia , Colite/prevenção & controle , Epigênese Genética , Feminino , Mucosa Intestinal/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Tetraspanina 28 , Trombospondinas/biossíntese , Trombospondinas/metabolismo , Antígenos Thy-1RESUMO
T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αß and γδ receptors, T cells are mainly divided into αß and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well-characterized and different developmental processes. N6 -Methyladenosine (m6 A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have demonstrated that the depletion of m6 A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αß T cells, indicating a checkpoint role of ALKBH5 and m6 A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6 A modification. In this review, we mainly summarize the potential regulation between m6 A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development.
Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta , Receptores de Antígenos de Linfócitos T gama-delta , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linhagem da Célula , Linfócitos T , Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismoRESUMO
γδ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N6-methyladenosine (m6A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m6A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γδ T cell early development.
Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Linfócitos Intraepiteliais , RNA Mensageiro , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Linfócitos Intraepiteliais/enzimologia , Linfócitos Intraepiteliais/imunologia , Proteína Jagged-1/metabolismo , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptor Notch2/metabolismo , Transdução de Sinais/genéticaRESUMO
The transcription factor methylated c-Myc heterodimerizes with MAX to modulate gene expression, and plays an important role in energy metabolism in kidney injury but the exact mechanism remains unclear. Mitochondrial solute transporter Slc25a24 imports ATP into mitochondria and is central to energy metabolism. Gene Expression Omnibus data analysis reveals Slc25a24 and c-Myc are consistently upregulated in all the acute kidney injury (AKI) cells. Pearson correlation analysis also shows that Slc25a24 and c-Myc are strongly correlated (â´ > 0.9). Mutant arginine methylated c-Myc (R299A and R346A) reduced its combination with MAX when compared with the wild type of c-Myc. On the other hand, the Slc25a24 levels were also correspondingly reduced, which induced the downregulation of ATP production. The results promoted reactive oxygen species (ROS) production and mitophagy generation. The study revealed that the c-Myc overexpression manifested the most pronounced mitochondrial DNA depletion. Additionally, the varied levels of mitochondrial proteins like TIM23, TOM20, and PINK1 in each group, particularly the elevated levels of PINK1 in AKI model groups and lower levels of TIM23 and TOM20 in the c-Myc overexpression group, suggest potential disruptions in mitochondrial dynamics and homeostasis, indicating enhanced mitophagy or mitochondrial loss. Therefore, arginine-methylated c-Myc affects mouse kidney injury by regulating mitochondrial ATP and ROS, and mitophagy via Slc25a24.
Assuntos
Injúria Renal Aguda , Proteínas de Ligação ao Cálcio , Proteínas de Transporte da Membrana Mitocondrial , Mitofagia , Proteínas Proto-Oncogênicas c-myc , Animais , Camundongos , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Trifosfato de Adenosina/metabolismo , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
The trajectory of voxel-mirrored homotopic connectivity (VMHC) after medical treatment in obsessive-compulsive disorder (OCD) and its value in prediction of treatment response remains unclear. This study aimed to investigate the pathophysiological mechanism of OCD, as well as biomarkers for prediction of pharmacological efficacy. Medication-free patients with OCD and healthy controls (HCs) underwent magnetic resonance imaging. The patients were scanned again after a 4-week treatment with paroxetine. The acquired data were subjected to VMHC, support vector regression (SVR), and correlation analyses. Compared with HCs (36 subjects), patients with OCD (34 subjects after excluding two subjects with excessive head movement) exhibited significantly lower VMHC in the bilateral superior parietal lobule (SPL), postcentral gyrus, and calcarine cortex, and VMHC in the postcentral gyrus was positively correlated with cognitive function. After treatment, the patients showed increased VMHC in the bilateral posterior cingulate cortex/precuneus (PCC/PCu) with the improvement of symptoms. SVR results showed that VMHC in the postcentral gyrus at baseline could aid to predict a change in the scores of OCD scales. This study revealed that SPL, postcentral gyrus, and calcarine cortex participate in the pathophysiological mechanism of OCD while PCC/PCu participate in the pharmacological mechanism. VMHC in the postcentral gyrus is a potential predictive biomarker of the treatment effects in OCD.
Assuntos
Transtorno Obsessivo-Compulsivo , Lobo Parietal , Humanos , Lobo Parietal/diagnóstico por imagem , Córtex Somatossensorial , Cognição , Giro do Cíngulo , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/tratamento farmacológicoRESUMO
This study aimed to detect alterations in interhemispheric interactions in patients with panic disorder (PD), determine whether such alterations could serve as biomarkers for the diagnosis and prediction of therapeutic outcomes, and map dynamic changes in interhemispheric interactions in patients with PD after treatment. Fifty-four patients with PD and 54 healthy controls (HCs) were enrolled in this study. All participants underwent clinical assessment and a resting-state functional magnetic resonance imaging scan at (i) baseline and (ii) after paroxetine treatment for 4 weeks. A voxel-mirrored homotopic connectivity (VMHC) indicator, support vector machine (SVM), and support vector regression (SVR) were used in this study. Patients with PD showed reduced VMHC in the fusiform, middle temporal/occipital, and postcentral/precentral gyri, relative to those of HCs. After treatment, the patients exhibited enhanced VMHC in the lingual gyrus, relative to the baseline data. The VMHC of the fusiform and postcentral/precentral gyri contributed most to the classification (accuracy = 87.04%). The predicted changes were accessed from the SVR using the aberrant VMHC as features. Positive correlations (p < 0.001) were indicated between the actual and predicted changes in the severity of anxiety. These findings suggest that impaired interhemispheric coordination in the cognitive-sensory network characterized PD and that VMHC can serve as biomarkers and predictors of the efficiency of PD treatment. Enhanced VMHC in the lingual gyrus of patients with PD after treatment implied that pharmacotherapy recruited the visual network in the early stages.
Assuntos
Transtorno de Pânico , Paroxetina , Humanos , Paroxetina/farmacologia , Paroxetina/uso terapêutico , Transtorno de Pânico/diagnóstico por imagem , Transtorno de Pânico/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Lobo Occipital , BiomarcadoresRESUMO
RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15ΔIEC). These mice are susceptible to infection with enteric bacteria Citrobacter rodentium (C. rod), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15ΔIEC mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.
Assuntos
Colite/imunologia , Defensinas/genética , Infecções por Enterobacteriaceae/imunologia , Celulas de Paneth/imunologia , RNA Helicases/genética , Via de Sinalização Wnt , Animais , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Defensinas/imunologia , Sulfato de Dextrana/administração & dosagem , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Celulas de Paneth/microbiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Helicases/imunologiaRESUMO
BACKGROUND: Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid generalized anxiety disorder (GAD) and depression, as well as the effect of treatment on this connectivity, remains unclear. We sought to examine functional connectivity between homotopic regions of the 2 hemispheres (voxel-mirrored homotopic connectivity [VMHC]) among people with GAD with and without comorbid depression at baseline and after a 4-week paroxetine treatment. METHODS: Drug-naïve patients with GAD, with or without comorbid depression and healthy controls underwent functional magnetic resonance imaging and clinical assessments at baseline and after treatment. We compared VMHC and seed-based functional connectivity across the 3 groups. We performed correlation analysis and support vector regression (SVR) to examine the intrinsic relationships between VMHC and symptoms. RESULTS: Both patient groups (n = 40 with GAD only, n = 58 with GAD and depression) showed decreased VMHC in the precuneus, posterior cingulate cortex and lingual gyrus compared with healthy controls (n = 54). Moreover, they showed decreased VMHC in different brain regions compared with healthy controls. However, we did not observe any significant differences between the 2 patient groups. Seeds from abnormal VMHC clusters in patient groups had decreased functional connectivity. Voxel-mirrored homotopic connectivity in the precuneus, posterior cingulate cortex and lingual gyrus was negatively correlated with cognitive impairment among patients with GAD only and among all patients. The SVR analysis based on abnormal VMHC showed significant positive correlations (p < 0.0001) between predicted and actual treatment responses. However, we did not observe significant differences in VMHC or functional connectivity after treatment. LIMITATIONS: A notable dropout rate and intergroup somatic symptom variations may have biased the results. CONCLUSION: Patients with GAD with or without comorbid depression exhibited shared and distinct abnormal VMHC patterns, which might be linked to their cognitive deficits. These patterns have the potential to serve as prognostic biomarkers for GAD.Clinical trial registration: ClinicalTrials.gov NCT03894085.
Assuntos
Disfunção Cognitiva , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Depressão , Mapeamento Encefálico/métodos , Seguimentos , Transtornos de Ansiedade/diagnóstico por imagem , Ansiedade/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagemRESUMO
RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli and adapt to the microenvironment. N6-methyladenosine (m6A) methylation, which is the most abundant mRNA modification in eukaryotes, primarily functions in the regulation of RNA splicing and degradation. However, the role of m6Amethylation in translational control and its underlying mechanism remain controversial. The role of m6A methylation in translation regulation in immune cells has received relatively limited attention. In this review, we aim to provide a comprehensive summary of current studies on the translational regulation of m6A modifications and recent advances in understanding the translational control regulated by RNA modifications during the immune response. Furthermore, we envision the possible pathways through which m6A modifications may be involved in the regulation of immune cell function via translational control.
Assuntos
Biossíntese de Proteínas , RNA/metabolismo , Sistema Imunitário , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/metabolismo , Humanos , Animais , MetilaçãoRESUMO
N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.
Assuntos
Adenosina/análogos & derivados , Homeostase , Interleucina-7/imunologia , RNA Mensageiro/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T/citologia , Adenosina/metabolismo , Transferência Adotiva , Animais , Diferenciação Celular , Proliferação de Células , Colite/prevenção & controle , Proteínas de Ligação a DNA/deficiência , Modelos Animais de Doenças , Feminino , Masculino , Metilação , Metiltransferases/deficiência , Camundongos , Estabilidade de RNA , RNA Mensageiro/química , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.
Assuntos
Células Epiteliais/imunologia , Células Epiteliais/virologia , Inflamassomos/metabolismo , Intestinos/citologia , Receptores Acoplados a Proteínas G/metabolismo , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/virologia , Rotavirus/imunologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , RNA Helicases DEAD-box/metabolismo , Células Epiteliais/metabolismo , Feminino , Imunidade Inata , Inflamassomos/química , Inflamassomos/genética , Interleucina-18/imunologia , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Fosfato , Piroptose , RNA de Cadeia Dupla/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/imunologia , Rotavirus/crescimento & desenvolvimentoRESUMO
BACKGROUND: Anomalies in regional homogeneity (ReHo) have been documented in patients with major depressive disorder (MDD) and sleep disturbances (SDs). This investigation aimed to scrutinize changes in ReHo in MDD patients with comorbid SD, and to devise potential diagnostic biomarkers for detecting sleep-related conditions in patients with MDD. METHODS: Patients with MDD and healthy controls underwent resting-state functional magnetic resonance imaging scans. SD severity was quantified using the 17-item Hamilton Rating Scale for Depression. Subsequent to the acquisition of imaging data, ReHo analysis was performed, and a support vector machine (SVM) method was employed to assess the utility of ReHo in discriminating MDD patients with SD. RESULTS: Compared with MDD patients without SD, MDD patients with SD exhibited increased ReHo values in the right posterior cingulate cortex (PCC)/precuneus, right median cingulate cortex, left postcentral gyrus (postCG), and right inferior temporal gyrus (ITG). Furthermore, the ReHo values in the right PCC/precuneus and ITG displayed a positive correlation with clinical symptoms across all patients. SVM classification results showed that a combination of abnormal ReHo in the left postCG and right ITG achieved an overall accuracy of 84.21%, a sensitivity of 81.82%, and a specificity of 87.50% in identifying MDD patients with SD from those without SD. CONCLUSION: We identified disrupted ReHo patterns in MDD patients with SD, and presented a prospective neuroimaging-based diagnostic biomarker for these patients.
Assuntos
Transtorno Depressivo Maior , Transtornos do Sono-Vigília , Humanos , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Estudos Prospectivos , SonoRESUMO
In this issue, Xu et al. (2014) show that innate antiviral RIG-I-like receptors (RLR) signaling represses TGF-ß-induced growth inhibition, epithelial-mesenchyme transition (EMT), and regulatory T cell (Treg) differentiation via IRF3-mediated Smads function.
Assuntos
Fator Regulador 3 de Interferon/fisiologia , Vírus Sendai/imunologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Animais , HumanosRESUMO
BACKGROUND: The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. METHODS: We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. RESULTS: We demonstrated that multi-layer alterations of RNA modification "writer" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these "writers" to aid the clinical benefits of immunotherapy. CONCLUSIONS: Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification "writers" in cancer therapy.
Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Farmacogenética , Processamento Pós-Transcricional do RNA , Microambiente Tumoral/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Terapia Combinada , Biologia Computacional/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Farmacogenética/métodos , Prognóstico , Modelos de Riscos Proporcionais , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Transcrição Gênica , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Background: Melancholic depression has been assumed as a severe type of major depressive disorder (MDD). We aimed to explore if there were some distinctive alterations in melancholic MDD and whether the alterations could be used to discriminate the melancholic MDD and nonmelancholic MDD. Methods: Thirty-one outpatients with melancholic MDD, thirty-three outpatients with nonmelancholic MDD, and thirty-two age- and gender-matched healthy controls were recruited. All participants were scanned by resting-state functional magnetic resonance imaging (fMRI). Imaging data were analyzed with the network homogeneity (NH) and support vector machine (SVM) methods. Results: Both patient groups exhibited increased NH in the right PCC/precuneus and right angular gyrus and decreased NH in the right middle temporal gyrus compared with healthy controls. Compared with nonmelancholic patients and healthy controls, melancholic patients exhibited significantly increased NH in the bilateral superior medial frontal gyrus and decreased NH in the left inferior temporal gyrus. But merely for melancholic patients, the NH of the right middle temporal gyrus was negatively correlated with TEPS total and contextual anticipatory scores. SVM analysis showed that a combination of NH values in the left superior medial frontal gyrus and left inferior temporal gyrus could distinguish melancholic patients from nonmelancholic patients with accuracy, sensitivity, and specificity of 79.66% (47/59), 70.97% (22/31), and 89.29%(25/28), respectively. Conclusion: Our findings showed distinctive network homogeneity alterations in melancholic MDD which may be potential imaging markers to distinguish melancholic MDD and nonmelancholic MDD.
Assuntos
Rede de Modo Padrão , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo/fisiopatologia , Adulto , Encéfalo/fisiopatologia , Transtorno Depressivo/psicologia , Transtorno Depressivo Maior/psicologia , Diagnóstico Diferencial , Feminino , Lobo Frontal/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal , Escalas de Graduação Psiquiátrica , Reprodutibilidade dos Testes , Descanso , Sensibilidade e Especificidade , Máquina de Vetores de Suporte , Lobo Temporal/fisiopatologia , Adulto JovemRESUMO
Background: Primary blepharospasm (BSP) is one of the most common focal dystonia and its pathophysiological mechanism remains unclear. An unbiased method was used in patients with BSP at rest to observe voxel-wise brain-wide functional connectivity (FC) changes. Method: A total of 48 subjects, including 24 untreated patients with BSP and 24 healthy controls, were recruited to undergo functional magnetic resonance imaging (fMRI). The method of global-brain FC (GFC) was adopted to analyze the resting-state fMRI data. We designed the support vector machine (SVM) method to determine whether GFC abnormalities could be utilized to distinguish the patients from the controls. Results: Relative to healthy controls, patients with BSP showed significantly decreased GFC in the bilateral superior medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC) and increased GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule, right superior frontal gyrus (SFG), and left paracentral lobule/supplement motor area (SMA), which were included in the default mode network (DMN) and sensorimotor network. SVM analysis showed that increased GFC values in the right postcentral gyrus/precentral gyrus/paracentral lobule could discriminate patients from controls with optimal accuracy, specificity, and sensitivity of 83.33%, 83.33%, and 83.33%, respectively. Conclusion: This study suggested that abnormal GFC in the brain areas associated with sensorimotor network and DMN might underlie the pathophysiology of BSP, which provided a new perspective to understand BSP. GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule might be utilized as a latent biomarker to differentiate patients with BSP from controls.
Assuntos
Blefarospasmo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/diagnóstico por imagem , Descanso/fisiologia , Adulto , Blefarospasmo/fisiopatologia , Encéfalo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologiaRESUMO
Lithium iron phosphate (LFP) batteries contain metals, toxic electrolytes, organic chemicals and plastics that can lead to serious safety and environmental problems when they are improperly disposed of. The published literature on recovering spent LFP batteries mainly focuses on policy-making and conceptual design. The production line of recovering spent LFP batteries and its detailed operation are rarely reported. A set of automatic line without negative impact to the environment for recycling spent LFP batteries at industrial scale was investigated in this study. It includes crushing, pneumatic separation, sieving, and poison gas treatment processes. The optimum retaining time of materials in the crusher is 3 minutes. The release rate is the highest when the load of the impact crusher is 800 g. An air current separator (ACS) was designed to separate LFP from aluminium (Al) foil and LFP powder mixture. Movement behaviour of LFP powder and Al foil in the ACS were analysed, and the optimized operation parameter (35.46 m/s) of air current speed was obtained through theoretical analysis and experiments. The weight contents of an Al foil powder collector from vibrating screen-3 and LFP powder collector from bag-type dust collector are approximately 38.7% and 52.4%, respectively. The economic cost of full manual dismantling is higher than the recovery production line. This recycling system provides a feasible method for recycling spent LFP batteries.
Assuntos
Alumínio , Lítio , Fontes de Energia Elétrica , Eletrodos , Ferro , Fosfatos , ReciclagemRESUMO
Spent lithium iron phosphate (LFP) batteries contain abundant strategic lithium resources and are thus considered attractive secondary lithium sources. However, these batteries may contaminate the environment because they contain hazardous materials. In this work, a novel process involving low-temperature heat treatment is used as an alternative pretreatment method for recycling spent LFP batteries. When the temperature reaches 300°C, the dissociation effect of the anode material gradually improves with heat treatment time. At the heat treatment time of 120 minutes, an electrode material can be dissociated. The extension of heat treatment time has a minimal effect on quality loss. The physicochemical changes in thermally treated solid cathode and anode materials are examined through scanning electron microscopy with energy-dispersive X-ray spectroscopy. The heat treatment results in the complete separation of the materials from aluminium foil without contamination. The change in heat treatment temperature has a small effect on the quality of LFP material shedding. When the heat treatment temperature reaches 300°C and the time reaches 120 minutes, heat treatment time increases, and the yield of each particle size is stable and basically unchanged. The method can be scaled up and may reduce environmental pollution due to waste LFP batteries.