RESUMEN
Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.
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Agammaglobulinemia Tirosina Quinasa , Isquemia Encefálica , Sustancia Blanca , Animales , Masculino , Ratones , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Enfermedad Crónica , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología , Sustancia Blanca/metabolismoRESUMEN
BACKGROUND: Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke . METHODS AND RESULTS: Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (ABCC2, ATRAID, BLK, CD93, CHST13, NR1H3, NRBP1, PI3, RIPK4, SEMG1, SLC22A4, SLC22A5, SLCO3A1, TEK, TLR4, and WNT10B) demonstrated the causal associations with ordinal modified Rankin Scale (P<1.892×10-5) or poor functional outcome (modified Rankin Scale 3-6 versus 0-2, P<1.893×10-5). Steiger filtering analysis suggested potential directional stability (P<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of ABCC2, NRBP1, PI3, and SEMG1 with functional outcome after ischemic stroke. Furthermore, phenome-wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting ABCC2, NRBP1, PI3, and SEMG1, but the robustness of these results was limited by low power. CONCLUSIONS: The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.
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Estudio de Asociación del Genoma Completo , Accidente Cerebrovascular Isquémico , Análisis de la Aleatorización Mendeliana , Humanos , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/fisiopatología , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Sitios de Carácter Cuantitativo , Masculino , Femenino , Anciano , Recuperación de la Función , Persona de Mediana Edad , Resultado del Tratamiento , Fenotipo , Estado FuncionalRESUMEN
Invasion and migration are the key hallmarks of cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of glioblastoma cells in previous studies. However, the effects of PRMT6 on glioblastoma cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces glioblastoma cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of glioblastoma cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation mark (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in glioblastoma cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of glioblastoma cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate glioblastoma cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting glioblastoma cell invasion and migration.
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Movimiento Celular , Proteína Potenciadora del Homólogo Zeste 2 , Glioblastoma , Invasividad Neoplásica , Estabilidad Proteica , Proteína-Arginina N-Metiltransferasas , Ubiquitinación , Animales , Femenino , Humanos , Masculino , Ratones , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Nucleares , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteolisis , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genéticaRESUMEN
The role of SLC3A2, a gene implicated in disulfidptosis, has not been characterized in gliomas. This study aims to clarify the prognostic value of SLC3A2 and its influence on glioma. We evaluated the expression of SLC3A2 and its prognostic importance in gliomas using publicly accessible databases and our clinical glioma samples and with reliance on Meta and Cox regression analysis approaches. Functional enrichment analyses were performed to explore SLC3A2's function. Immune infiltration was evaluated using CIBERSORT, ssGSEA, and single-cell sequencing data. Additionally, Tumor immune dysfunction and exclusion (TIDE) and epithelial-mesenchymal transition scores were determined. CCK8, colony formation, migration, and invasion assays were utilized in vitro, and an orthotopic glioma xenograft model was employed in vivo, to investigate the role of SLC3A2 in gliomas. Bioinformatics analyses indicated high SLC3A2 expression correlates with adverse clinicopathological features and poor patient prognosis. Upregulated SLC3A2 influenced the tumor microenvironment by altering immune cell infiltration, particularly of macrophages, and tumor migration and invasion. SLC3A2 expression positively correlated with immune therapy indicators, including immune checkpoints and TIDE. Elevated SLC3A2 was revealed as an independent risk element for poor glioma prognosis through Cox regression analyses. In vitro experiments showed that reduced SLC3A2 expression decreased cell proliferation, migration, and invasion. In vivo, knockdown of SLC3A2 led to a reduction in tumor volume and prolonged survival in tumor-bearing mice. Therefore, SLC3A2 is a prognostic biomarker and associated with immune infiltration in gliomas.
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Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Glioma , Glioma/genética , Glioma/patología , Glioma/metabolismo , Humanos , Pronóstico , Animales , Ratones , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/inmunología , Movimiento Celular , Microambiente Tumoral/inmunología , Proliferación Celular , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Cadena Pesada de la Proteína-1 Reguladora de Fusión/genética , Cadena Pesada de la Proteína-1 Reguladora de Fusión/metabolismo , Femenino , Masculino , Transición Epitelial-Mesenquimal/genética , Ratones DesnudosRESUMEN
Platelet-derived growth factor receptor ß positive (PDGFRß+) pericytes detach from the microvascular wall and migrate into the injury center following spinal cord injury (SCI), which has been widely regarded as the main source of fibrotic scar, but the mechanism of migration and fibroblast transition remains elusive. Here we show the associated spatiotemporal distribution between microglia and pericytes at three and seven days post-injury (dpi). The increased expression of Sphingosine kinase-1 (SPHK1) in microglia significantly raised the concentration of Sphingosine-1-phosphate (S1P) in the spinal cord, which promotes migration and fibroblast transition of pericyte. In vitro experiments, we found the elevated Sphingosine 1-phosphate receptor 3 (S1P3), the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted its nuclear translocation, which contributed to the formation of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1) protein, This process can be blocked by an S1P3 specific inhibitor TY52156 in vitro. The S1P/S1P3/YAP pathway might be a potential target for treatment in SCI.
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Movimiento Celular , Fibroblastos , Lisofosfolípidos , Microglía , Pericitos , Transducción de Señal , Receptores de Esfingosina-1-Fosfato , Esfingosina , Traumatismos de la Médula Espinal , Proteínas Señalizadoras YAP , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Transducción de Señal/fisiología , Lisofosfolípidos/metabolismo , Animales , Movimiento Celular/fisiología , Pericitos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Microglía/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Ratas , Fibroblastos/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Ratas Sprague-Dawley , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Células CultivadasRESUMEN
Ghost introgression, or the transfer of genetic material from extinct or unsampled lineages to sampled species, has attracted much attention. However, conclusive evidence for ghost introgression, especially in plant species, remains scarce. Here, we newly assembled chromosome-level genomes for both Carya sinensis and Carya cathayensis, and additionally re-sequenced the whole genomes of 43 C. sinensis individuals as well as 11 individuals representing 11 diploid hickory species. These genomic datasets were used to investigate the reticulation and bifurcation patterns within the genus Carya (Juglandaceae), with a particular focus on the beaked hickory C. sinensis. By combining the D-statistic and BPP methods, we obtained compelling evidence that supports the occurrence of ghost introgression in C. sinensis from an extinct ancestral hickory lineage. This conclusion was reinforced through the phylogenetic network analysis and a genome scan method VolcanoFinder, the latter of which can detect signatures of adaptive introgression from unknown donors. Our results not only dispel certain misconceptions about the phylogenetic history of C. sinensis but also further refine our understanding of Carya's biogeography via divergence estimates. Moreover, the successful integration of the D-statistic and BPP methods demonstrates their efficacy in facilitating a more precise identification of introgression types.
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Introgresión Genética , Genoma de Planta , Filogenia , Genoma de Planta/genética , Genómica , Asia Oriental , Pueblos del Este de AsiaRESUMEN
This research investigates the impact of Dendrobium officinale polysaccharides (DOP) with different molecular weights on antioxidant effects, lifespan enhancement, and obesity reduction, utilizing both in vitro analyses and the Caenorhabditis elegans (C. elegans) model. Through a series of experiments-ranging from the extraction and modification of polysaccharides, Gel Permeation Chromatography (GPC), and analysis of composition to the evaluation of antioxidant capabilities, this study thoroughly examines DOP and its derivatives (DOP5, DOP15, DOP25) produced via H2O2-Fe2+ degradation. The results reveal a direct relationship between the molecular weight of polysaccharides and their bioactivity. Notably, DOP5, with its intermediate molecular weight, demonstrated superior antioxidant properties, significantly extended the lifespan, and improved the health of C. elegans. Furthermore, DOP15 appeared to regulate lipid metabolism by affecting crucial lipid metabolism genes, including fat-4, fat-5, fat-6, sbp-1, and acs-2. These findings highlight the potential application of DOP derivatives as natural antioxidants and agents against obesity, contributing to the development of functional foods and dietary supplements.
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The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.
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Barrera Hematoencefálica , Isquemia Encefálica , Lipoproteínas LDL , Microglía , Sustancia Blanca , Microglía/metabolismo , Animales , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Ratones , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacología , Isquemia Encefálica/metabolismo , Barrera Hematoencefálica/metabolismo , Masculino , Ratones Endogámicos C57BL , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Fagocitosis/fisiología , Vaina de Mielina/metabolismoRESUMEN
Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.
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Antineoplásicos , Receptores Frizzled , Neoplasias , Vía de Señalización Wnt , Humanos , Receptores Frizzled/metabolismo , Receptores Frizzled/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Vía de Señalización Wnt/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Animales , Terapia Molecular Dirigida/métodosRESUMEN
In Dunaliella tertiolecta, a microalga renowned for its extraordinary tolerance to high salinity levels up to 4.5 M NaCl, the mechanisms underlying its stress response have largely remained a mystery. In a groundbreaking discovery, this study identifies a choline dehydrogenase enzyme, termed DtCHDH, capable of converting choline to betaine aldehyde. Remarkably, this is the first identification of such an enzyme not just in D. tertiolecta but across the entire Chlorophyta. A 3D model of DtCHDH was constructed, and molecular docking with choline was performed, revealing a potential binding site for the substrate. The enzyme was heterologously expressed in E. coli Rosetta (DE3) and subsequently purified, achieving enzyme activity of 672.2 U/mg. To elucidate the role of DtCHDH in the salt tolerance of D. tertiolecta, RNAi was employed to knock down DtCHDH gene expression. The results indicated that the Ri-12 strain exhibited compromised growth under both high and low salt conditions, along with consistent levels of DtCHDH gene expression and betaine content. Additionally, fatty acid analysis indicated that DtCHDH might also be a FAPs enzyme, catalyzing reactions with decarboxylase activity. This study not only illuminates the role of choline metabolism in D. tertiolecta's adaptation to high salinity but also identifies a novel target for enhancing the NaCl tolerance of microalgae in biotechnological applications.
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Betaína , Colina-Deshidrogenasa , Tolerancia a la Sal , Betaína/metabolismo , Tolerancia a la Sal/genética , Colina-Deshidrogenasa/metabolismo , Colina-Deshidrogenasa/genética , Colina/metabolismo , Chlorophyceae/genética , Chlorophyceae/fisiología , Chlorophyceae/enzimología , Chlorophyceae/metabolismo , Microalgas/genética , Microalgas/enzimología , Microalgas/metabolismo , Simulación del Acoplamiento Molecular , Cloruro de Sodio/farmacologíaRESUMEN
Dunaliella bardawil is a marine unicellular green algal that produces large amounts of ß-carotene and is a model organism for studying the carotenoid synthesis pathway. However, there are still many mysteries about the enzymes of the D. bardawil lycopene synthesis pathway that have not been revealed. Here, we have identified a CruP-like lycopene isomerase, named DbLyISO, and successfully cloned its gene from D. bardawil. DbLyISO showed a high homology with CruPs. We constructed a 3D model of DbLyISO and performed molecular docking with lycopene, as well as molecular dynamics testing, to identify the functional characteristics of DbLyISO. Functional activity of DbLyISO was also performed by overexpressing gene in both E. coli and D. bardawil. Results revealed that DbLyISO acted at the C-5 and C-13 positions of lycopene, catalyzing its cis-trans isomerization to produce a more stable trans structure. These results provide new ideas for the development of a carotenoid series from engineered bacteria, algae, and plants.
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Chlorophyceae , Liasas Intramoleculares , Licopeno , cis-trans-Isomerasas , Proteínas Algáceas/genética , Proteínas Algáceas/metabolismo , Proteínas Algáceas/química , Secuencia de Aminoácidos , Carotenoides/metabolismo , Carotenoides/química , Chlorophyceae/enzimología , Chlorophyceae/genética , Chlorophyceae/química , Chlorophyceae/metabolismo , Chlorophyta/enzimología , Chlorophyta/genética , Chlorophyta/química , Chlorophyta/metabolismo , cis-trans-Isomerasas/genética , cis-trans-Isomerasas/metabolismo , cis-trans-Isomerasas/química , Escherichia coli/genética , Escherichia coli/metabolismo , Licopeno/metabolismo , Licopeno/química , Simulación del Acoplamiento Molecular , Alineación de SecuenciaRESUMEN
BACKGROUND: Panic disorder (PD) involves emotion dysregulation, but its underlying mechanisms remain poorly understood. Previous research suggests that implicit emotion regulation may play a central role in PD-related emotion dysregulation and symptom maintenance. However, there is a lack of studies exploring the neural mechanisms of implicit emotion regulation in PD using neurophysiological indicators. AIM: To study the neural mechanisms of implicit emotion regulation in PD with event-related potentials (ERP). METHODS: A total of 25 PD patients and 20 healthy controls (HC) underwent clinical eva-luations. The study utilized a case-control design with random sampling, selecting participants for the case group from March to December 2018. Participants performed an affect labeling task, using affect labeling as the experimental condition and gender labeling as the control condition. ERP and behavioral data were recorded to compare the late positive potential (LPP) within and between the groups. RESULTS: Both PD and HC groups showed longer reaction times and decreased accuracy under the affect labeling. In the HC group, late LPP amplitudes exhibited a dynamic pattern of initial increase followed by decrease. Importantly, a significant group × condition interaction effect was observed. Simple effect analysis revealed a reduction in the differences of late LPP amplitudes between the affect labeling and gender labeling conditions in the PD group compared to the HC group. Furthermore, among PD patients under the affect labeling, the late LPP was negatively correlated with disease severity, symptom frequency, and intensity. CONCLUSION: PD patients demonstrate abnormalities in implicit emotion regulation, hampering their ability to mobilize cognitive resources for downregulating negative emotions. The late LPP amplitude in response to affect labeling may serve as a potentially valuable clinical indicator of PD severity.
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The presence of burrowing mammals can have extensive effects on plants and soils, creating bare soil patches in alpine meadows and potentially altering plant-soil carbon (C) and nitrogen (N). This study focuses on the plateau pika (Ochotona curzoniae) to examine the responses of plant-soil C and N to a small burrowing mammal from quadrat scale to plot scale. The density of active burrow entrances in disturbed plots was used as an indicator of the disturbance intensity of plateau pikas. The study found that the below-ground biomass (BGB) and its C and N, as well as soil C and N concentrations were significantly lower in bare soil areas than in vegetated areas and undisturbed plots. This shows that the quadrat scale limited the estimation of the C and N sequestration potential. Therefore, further research on the plot scale found that the disturbance by plateau pika significantly reduced plant biomass and BGB carbon stock. However, plateau pika did not affect soil C and N stocks or ecosystem C and N stocks. These findings suggest the bare soil patches formed by plateau pika caused plant and soil heterogeneity but had a trade-off effect on plant-soil C and N stocks at the plot scale. Nevertheless, moderate disturbance intensity increased the C and N sequestration potential in grassland ecosystems. These results provide a possible way to estimate how disturbance by small burrowing mammals affects C and N cycling in grassland ecosystems while accurately assessing the effects of small burrowing mammal densities on C and N in grassland ecosystems.
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m6A (N6methyladenosine) is the most common and abundant apparent modification in mRNA of eukaryotes. The modification of m6A is regulated dynamically and reversibly by methyltransferase (writer), demethylase (eraser), and binding protein (reader). It plays a significant role in various processes of mRNA metabolism, including regulation of transcription, maturation, translation, degradation, and stability. Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary vascular disease characterized by abnormal proliferation of pulmonary artery smooth muscle cells. Despite the existence of several effective and targeted therapies, there is currently no cure for PAH and the prognosis remains poor. Recent studies have highlighted the crucial role of m6A modification in cardiovascular diseases. Investigating the role of RNA m6A methylation in PAH could provide valuable insights for drug development. This review aims to explore the mechanism and function of m6A in the pathogenesis of PAH and discuss the potential targeting of RNA m6A methylation modification as a treatment for PAH.
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Adenosina , Hipertensión Arterial Pulmonar , Animales , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/genética , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Metilación de ARN , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
BACKGROUND: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described. METHODS: In this controlled case-ascertained household transmission study, we recruited asymptomatic children <18 years with SARS-CoV-2 nucleic acid testing performed at 12 tertiary care pediatric institutions in Canada and the United States. We attempted to recruit all test-positive children and 1 to 3 test-negative, site-matched controls. After 14 days' follow-up we assessed the clinical (ie, symptomatic) and combined (ie, test-positive, or symptomatic) secondary attack rates (SARs) among household contacts. Additionally, post-COVID-19 condition (PCC) was assessed in SARS-CoV-2-positive participating children after 90 days' follow-up. RESULTS: A total of 111 test-positive and 256 SARS-CoV-2 test-negative asymptomatic children were enrolled between January 2021 and April 2022. After 14 days, excluding households with co-primary cases, the clinical SAR among household contacts of SARS-CoV-2-positive and -negative index children was 10.6% (19/179; 95% CI: 6.5%-16.1%) and 2.0% (13/663; 95% CI: 1.0%-3.3%), respectively (relative risk = 5.4; 95% CI: 2.7-10.7). In households with a SARS-CoV-2-positive index child, age <5 years, being pre-symptomatic (ie, developed symptoms after test), and testing positive during Omicron and Delta circulation periods (vs earlier) were associated with increased clinical and combined SARs among household contacts. Among 77 asymptomatic SARS-CoV-2-infected children with 90-day follow-up, 6 (7.8%; 95% CI: 2.9%-16.2%) reported PCC. CONCLUSIONS: Asymptomatic SARS-CoV-2-infected children, especially those <5 years, are important contributors to household transmission, with 1 in 10 exposed household contacts developing symptomatic illness within 14 days. Asymptomatic SARS-CoV-2-infected children may develop PCC.
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Infecciones Asintomáticas , COVID-19 , Composición Familiar , SARS-CoV-2 , Humanos , COVID-19/transmisión , COVID-19/diagnóstico , COVID-19/epidemiología , Niño , Estudios Prospectivos , Masculino , Femenino , Canadá/epidemiología , Preescolar , SARS-CoV-2/aislamiento & purificación , Infecciones Asintomáticas/epidemiología , Estados Unidos/epidemiología , Lactante , Adolescente , Estudios de Casos y ControlesRESUMEN
Background: Growing evidence links immunological responses to Multiple sclerosis (MS), but specific immune factors are still unclear. Methods: Mendelian randomization (MR) was performed to investigate the association between peripheral hematological traits, MS risk, and its severity. Then, further subgroup analysis of immune counts and circulating cytokines and growth factors were performed. Results: MR revealed higher white blood cell count (OR [95%CI] = 1.26 [1.10,1.44], P = 1.12E-03, P adjust = 3.35E-03) and lymphocyte count (OR [95%CI] = 1.31 [1.15,1.50], P = 5.37E-05, P adjust = 3.22E-04) increased the risk of MS. In further analysis, higher T cell absolute count (OR [95%CI] = 2.04 [1.36,3.08], P = 6.37E-04, P adjust = 2.19E-02) and CD4+ T cell absolute count (OR [95%CI] = 2.11 [1.37,3.24], P = 6.37E-04, P adjust = 2.19E-02), could increase MS risk. While increasing CD25++CD4+ T cell absolute count (OR [95%CI] = 0.75 [0.66,0.86], P = 2.12E-05, P adjust = 1.72E-03), CD25++CD4+ T cell in T cell (OR [95%CI] = 0.79[0.70,0.89], P = 8.54E-05, P adjust = 5.29E-03), CD25++CD4+ T cell in CD4+ T cell (OR [95%CI] = 0.80[0.72,0.89], P = 1.85E-05, P adjust = 1.72E-03), and CD25++CD8+ T cell in T cell (OR [95%CI] = 0.68[0.57,0.81], P = 2.22E-05, P adjust = 1.72E-03), were proved to be causally defensive for MS. For the disease severity, the suggestive association between some traits related to CD4+ T cell, Tregs and MS severity were demonstrated. Moreover, elevated levels of IL-2Ra had a detrimental effect on the risk of MS (OR [95%CI] = 1.22 [1.12,1.32], P = 3.20E-06, P adjust = 1.34E-04). Conclusions: This study demonstrated a genetically predicted causal relationship between elevated peripheral immune cell counts and MS. Subgroup analysis revealed a specific contribution of peripheral immune cells, holding potential for further investigations into the underlying mechanisms of MS and its severity.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Gravedad del Paciente , Linfocitos T CD8-positivos , Causalidad , Recuento de CélulasRESUMEN
Protein arginine methyltransferase 1 (PRMT1), the predominant type I protein arginine methyltransferase, plays a crucial role in normal biological functions by catalyzing the methylation of arginine side chains, specifically monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), within proteins. Recent investigations have unveiled an association between dysregulated PRMT1 expression and the initiation and progression of tumors, significantly impacting patient prognosis, attributed to PRMT1's involvement in regulating various facets of tumor cell biology, including DNA damage repair, transcriptional and translational regulation, as well as signal transduction. In this review, we present an overview of recent advancements in PRMT1 research across different tumor types, with a specific focus on its contributions to tumor cell proliferation, metastasis, invasion, and drug resistance. Additionally, we expound on the dynamic functions of PRMT1 during distinct stages of cancer progression, elucidating its unique regulatory mechanisms within the same signaling pathway and distinguishing between its promotive and inhibitory effects. Importantly, we sought to provide a comprehensive summary and analysis of recent research progress on PRMT1 in tumors, contributing to a deeper understanding of its role in tumorigenesis, development, and potential treatment strategies.
Asunto(s)
Neoplasias , Procesamiento Proteico-Postraduccional , Humanos , Metilación , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Biología , Proteínas Represoras/metabolismoRESUMEN
In recent years, the study of hybridization and introgression has made significant progress, with ghost introgression-the transfer of genetic material from extinct or unsampled lineages to extant species-emerging as a key area for research. Accurately identifying ghost introgression, however, presents a challenge. To address this issue, we focused on simple cases involving 3 species with a known phylogenetic tree. Using mathematical analyses and simulations, we evaluated the performance of popular phylogenetic methods, including HyDe and PhyloNet/MPL, and the full-likelihood method, Bayesian Phylogenetics and Phylogeography (BPP), in detecting ghost introgression. Our findings suggest that heuristic approaches relying on site-pattern counts or gene-tree topologies struggle to differentiate ghost introgression from introgression between sampled non-sister species, frequently leading to incorrect identification of donor and recipient species. The full-likelihood method BPP uses multilocus sequence alignments directly-hence taking into account both gene-tree topologies and branch lengths, by contrast, is capable of detecting ghost introgression in phylogenomic datasets. We analyzed a real-world phylogenomic dataset of 14 species of Jaltomata (Solanaceae) to showcase the potential of full-likelihood methods for accurate inference of introgression.
Asunto(s)
Clasificación , Filogenia , Clasificación/métodos , Introgresión Genética , Hibridación Genética , Filogeografía/métodos , Simulación por ComputadorRESUMEN
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.