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Animals adapt to environmental challenges with long-term changes at the behavioral, circuit, cellular, and synaptic levels which often require new protein synthesis. The discovery of reversible N6-methyladenosine (m 6 A) modifications of mRNA has revealed an important layer of post-transcriptional regulation which affects almost every phase of mRNA metabolism and therefore translational control. Many in vitro and in vivo studies have demonstrated the significant role of m 6 A in cell differentiation and survival, but its role in adult neurons is understudied. We used cell-type specific gene deletion of Mettl14, which encodes one of the subunits of the m 6 A methyltransferase, and Ythdf1 , which encodes one of the cytoplasmic m 6 A reader proteins, in dopamine D1 receptor expressing or D2 receptor expressing neurons. Mettl14 or Ythdf1 deficiency blunted responses to environmental challenges at the behavioral, cellular, and molecular levels. In three different behavioral paradigms, gene deletion of either Mettl14 or Ythdf1 in D1 neurons impaired D1-dependent learning, whereas gene deletion of either Mettl14 or Ythdf1 in D2 neurons impaired D2-dependent learning. At the cellular level, modulation of D1 and D2 neuron firing in response to changes in environments was blunted in all three behavioral paradigms in mutant mice. Ythdf1 deletion resembled impairment caused by Mettl14 deletion in a cell type-specific manner, suggesting YTHDF1 is the main mediator of the functional consequences of m 6 A mRNA methylation in the striatum. At the molecular level, while striatal neurons in control mice responded to elevated cAMP by increasing de novo protein synthesis, striatal neurons in Ythdf1 knockout mice didn't. Finally, boosting dopamine release by cocaine drastically increased YTHDF1 binding to many mRNA targets in the striatum, especially those that encode structural proteins, suggesting the initiation of long-term neuronal and/or synaptic structural changes. While the m6A-YTHDF1 pathway has similar functional significance at cellular level, its cell type specific deficiency in D1 and D2 neurons often resulted in contrasting behavioral phenotypes, allowing us to cleanly dissociate the opposing yet cooperative roles of D1 and D2 neurons.
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OBJECTIVE: The aim of this study was to establish a simple, nonalcoholic fatty liver disease (NAFLD) screening model using readily available variables to identify high-risk individuals in Western Xinjiang, China. METHODS: A total of 40â 033 patients from the National Health Examination were divided into a training group (70%) and a validation group (30%). Univariate regression and least absolute shrinkage and selection operator models optimized feature selection, while a multivariate logistic regression analysis constructed the prediction model. The model's performance was evaluated using the area under the receiver operating characteristic curve, and its clinical utility was assessed through decision curve analysis. RESULTS: The nomogram assessed NAFLD risk based on factors such as sex, age, diastolic blood pressure, waist circumference, BMI, fasting plasma glucose, alanine aminotransferase, platelet count, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. The area under the receiver operating characteristic curves were 0.829 for men and 0.859 for women in the development group, and 0.817 for men and 0.865 for women in the validation group. The decision curve analysis confirmed the nomogram's clinical usefulness, with consistent findings in the validation set. CONCLUSION: A user-friendly nomogram prediction model for NAFLD risk was successfully developed and validated for Western Xinjiang, China.
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Screen-based sedentary behavior (SSB) is a significant risk factor for the health of school-aged children, and guidelines recommend limiting SSB to 2 hr per day. This study aimed to examine association and potential mechanisms between SSB and executive function (EF) by comparing Stroop performance and frontal hemodynamic responses between children with and without excessive SSB. A total of 70 children aged 10 to 15 years were recruited and divided into two groups: excessive screen time (≥2 hr/day; n = 35; ES group) and normal screen time (<2 hr/day; n = 35; NS group). The Chinese version of the Adolescent Sedentary Activities Questionnaire was used to assess SSB, whereas EF was evaluated using the Stroop task. The frontal hemodynamic responses during the Stroop task were measured using functional near-infrared spectroscopy. The results indicated that the ES group had lower accuracy, longer reaction times, and greater activation in the bilateral dorsolateral prefrontal cortex (DLPFC) and left pre-supplementary motor area (Pre-SMA) compared with the NS group. Furthermore, significant correlations were observed between Stroop performance and cortical activation in the left DLPFC and Pre-SMA. These findings demonstrate that excessive SSB is associated with poor EF, which may be explained by a decrease in neural efficiency of the left DLPFC and Pre-SMA.
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Función Ejecutiva , Tiempo de Pantalla , Conducta Sedentaria , Espectroscopía Infrarroja Corta , Test de Stroop , Humanos , Niño , Masculino , Femenino , Espectroscopía Infrarroja Corta/métodos , Función Ejecutiva/fisiología , Adolescente , Tiempo de Reacción , Corteza Prefontal DorsolateralRESUMEN
Loss of dopamine neurons causes motor deterioration in Parkinson's disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m 6 A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion of Ythdf1 in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinson's disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.
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During hematopoietic stem cell transplantation (HSCT), ATG depletes T cells in-vivo to improve engraftment and prevent graft-versus-host disease (GVHD). Here, we compared the clinical efficacy of two different types of ATGs: thymoglobulin and anti-human T-lymphocyte immunoglobulin (Grafalon). A total of 469 patients who received haploidentical transplantation were enrolled in this retrospective study. We applied a propensity score (PS)-matched analysis and 209 patients were assigned to each group. Clinical outcomes were compared between two groups and primary outcome was overall survival (OS). There was no significant difference in OS between two groups. Within the first 180 days after HSCT, Grafalon was associated with lower incidences of Epstein-Barr virus (EBV) viremia (31.6 vs. 54.5%, P < 0.0001) and cytomegalovirus viremia (CMV) viremia (54.5 vs. 67.9%, P = 0.005) compared to thymoglobulin. Patients receiving Grafalon had a higher rate of moderate/severe chronic GVHD (26.3 vs. 18.2%, P = 0.046). However, the incidences of engraftment failure, grade II-IV acute GVHD, relapse, non-relapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) did not differ greatly between groups. In the subgroup analysis, Grafalon improved the OS of lymphoid malignancies with young ages (< 40 years old) (HR, 0.55; P = 0.04) or with a high/very high disease risk index (HR, 0.36; P = 0.04). In the myeloid cohort, Grafalon reduced NRM in the patients who received non-female for male transplantation grafts (HR, 0.17; P = 0.02). Our results suggest the two types of ATG may differentially influence transplant outcomes and it may optimize ATG selection according to the condition of patients.
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Infecciones por Virus de Epstein-Barr , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre de Sangre Periférica , Animales , Conejos , Humanos , Masculino , Adulto , Estudios Retrospectivos , Puntaje de Propensión , Viremia , Herpesvirus Humano 4 , Suero Antilinfocítico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante/métodosRESUMEN
Hematopoietic stem cell transplantation (HSCT) offers the highest curative potential for patients with hematological malignancies. Complications including infection, graft-versus-host disease (GVHD), and relapse reflect delayed or dysregulated immune reconstitution. After transplantation, NK cells rapidly reconstitute and are crucial for immune surveillance and immune tolerance. NK cell function is tightly regulated by killer immunoglobin-like receptors (KIRs). Previous studies have revealed that donor KIRs, especially some activated KIRs (aKIRs) are closely related to transplant outcomes. Here, we performed a retrospective study, including 323 patients who received haploidentical (haplo) HSCT in our center. In univariate analysis, donor KIR2DS1, KIR2DS3 and KIR3DS1 gene protected patients with lymphoid disease from Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation, while donor KIR2DS1, KIR2DS5 and KIR3DS1 gene conferred a higher risk of CMV reactivation for patients with myeloid disease. Multivariate analysis confirmed that donor telomeric (Tel) B/x and KIR2DS3 gene best protected patients with lymphoid disease from EBV (p = 0.017) and CMV reactivation (p = 0.004). In myeloid disease, grafts lacking Tel B/x and KIR2DS5 gene correlated with the lowest risk of CMV reactivation (p = 0.018). Besides, donor aKIR genes did not influence the rates of GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS) in this study. The reactivation of EBV and CMV was associated with poor prognosis of haplo-HSCT. In conclusion, we found that donor aKIR genes might have a synergistic effect on CMV and EBV reactivation after haplo-HSCT. Whether the influence of donor aKIR genes varies with disease types remained to be studied.
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Infecciones por Citomegalovirus , Infecciones por Virus de Epstein-Barr , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Herpesvirus Humano 4/genética , Suero Antilinfocítico/uso terapéutico , Estudios Retrospectivos , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Alelos , Recurrencia Local de Neoplasia/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/genética , RecurrenciaRESUMEN
RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.
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Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Humanos , Fosforilación , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Neuronas/metabolismo , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Proteínas Ribosómicas/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Relapse is a significant barrier to allogeneic hematopoietic stem cell transplantation (allo-HSCT) success. To explore the prognosis of patients who underwent relapse after allo-HSCT, we retrospectively examined 740 consecutive acute leukemia patients in our single center transplanted between January 2013 and December 2018, of which 178 relapsed. The median survival was 204 days (95%CI, 160.7-247.3) from relapse, and the 3-year post-relapse overall survival (prOS) rate was 17.8% (95%CI, 12.5-25.3%). Overall complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 32.1% for the acute myeloid leukemia and 45.3% for acute lymphoblastic leukemia patients after salvage therapy, respectively. Grade III-IV acute graft-versus-host disease (GVHD) after transplantation and >20% bone marrow blasts at relapse were associated with worse prOS, while patients with chronic GVHD after transplantation, relapse later than 1 year after transplantation, and solitary extramedullary disease had better prOS. Therefore, we developed a concise risk scoring system for prOS based on the number of risk factors affecting prOS. This scoring system was validated with another cohort of post-transplant relapsed acute leukemia patients who received allo-HSCT between 2019 and 2020. Identifying relapse risk factors and providing personalized care for patients with poor prognoses is crucial for improving survival.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Pronóstico , Estudios Retrospectivos , Leucemia Mieloide Aguda/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Aguda , RecurrenciaRESUMEN
HLA-B*15:644 differs from HLA-B*15:17:01:02 by one nucleotide in exon 4.
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Antígenos HLA-B , Humanos , Alelos , Pueblos del Este de Asia , Antígenos HLA-B/genética , Nucleótidos , Análisis de Secuencia de ADNRESUMEN
Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10-9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish.
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The improper use of antibiotics has led to the development of bacterial resistance, resulting in fewer antibiotics for many bacterial infections. Especially, the drug resistance of hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) is distinctly serious. This research designed and synthesized two series of 3-substituted ocotillol derivatives in order to improve their anti-HA-MRSA potency and synergistic antibacterial activity. Among the synthesized compounds, 20-31 showed minimum inhibitory concentration (MIC) values of 1-64 µg/mL in vitro against HA-MRSA 18-19, 18-20, and S. aureus ATCC29213. Compound 21 showed the best antibacterial activity, with an MIC of 1 µg/mL and had synergistic inhibitory effects. The fractional inhibitory concentration index (FICI) value was 0.375, when combined with chloramphenicol (CHL) or kanamycin (KAN). The structure-activity relationships (SARs) of ocotillol-type derivatives were also summarized. Compound 21 has the potential to be developed as a novel antibacterial agent or potentiator against HA-MRSA.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Ginsenósidos/química , Cloranfenicol/farmacología , Diseño de Fármacos , Sinergismo Farmacológico , Kanamicina/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Meiosis is a highly regulated process, partly due to the need to break and then repair DNA as part of the meiotic program. Post-translational modifications are widely used during meiotic events to regulate steps such as protein complex formation, checkpoint activation, and protein attenuation. In this paper, we investigate how proteins that are obligatory components of the SUMO (small ubiquitin-like modifier) pathway, one such post-translational modification, affect the Caenorhabditis elegans germline. We show that UBC-9, the E2 conjugation enzyme, and the C. elegans homolog of SUMO, SMO-1, localize to germline nuclei throughout prophase I. Mutant analysis of smo-1 and ubc-9 revealed increased recombination intermediates throughout the germline, originating during the mitotic divisions. SUMOylation mutants also showed late meiotic defects including defects in the restructuring of oocyte bivalents and endomitotic oocytes. Increased rates of noninterfering crossovers were observed in ubc-9 heterozygotes, even though interfering crossovers were unaffected. We have also identified a physical interaction between UBC-9 and DNA repair protein MRE-11 ubc-9 and mre-11 null mutants exhibited similar phenotypes at germline mitotic nuclei and were synthetically sick. These phenotypes and genetic interactions were specific to MRE-11 null mutants as opposed to RAD-50 or resection-defective MRE-11 We propose that the SUMOylation pathway acts redundantly with MRE-11, and in this process MRE-11 likely plays a structural role.
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Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Meiosis , Mitosis , Transducción de Señal , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Daño del ADN , Reparación del ADN , Replicación del ADN , Mutación , Mapeo de Interacción de Proteínas , Transporte de Proteínas , Recombinación Genética , Estrés Fisiológico , SumoilaciónRESUMEN
BACKGROUND: The pathogenesis of autism spectrum disorders remains elusive and currently there are no diagnostic or predictive biomarkers in autism available. Proteomic profiling has been used in a wide range of neurodevelopmental disorder studies, which could produce deeper perceptions of the molecular bases behind certain disease and potentially becomes useful in discovering biomarkers in autism spectrum disorders. METHODS: Serum samples were collected from autistic children about 3 years old in age (n = 32) and healthy controls (n = 20) in similar age and gender. The samples were identified specific proteins that are differentially expressed by magnetic bead-based pre-fractionation and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS). RESULTS: Eight protein peaks were significantly different in autistic children from the healthy controls (P < 0.0001). The two peaks with the most significant differences were 6428 and 7758 Da in size. CONCLUSION: According to differences in serum protein profiles between the autistic children and healthy controls, this study identified a set of differentially expressed proteins those are significant for further evaluation and might function as biomarkers in autism.
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Trastorno Autístico/sangre , Trastorno Autístico/diagnóstico por imagen , Proteómica/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Trastorno Autístico/genética , Estudios de Casos y Controles , Preescolar , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Proyectos Piloto , Control de Calidad , Valores de Referencia , Manejo de EspecímenesRESUMEN
The pathophysiology of autistic spectrum disorder (ASD) is not fully understood and there are no diagnostic or predictive biomarkers. Glycosylation modified as many as 70% of all human proteins can sensitively reflect various pathological changes. However, little is known about the alterations of glycosylation and glycoproteins in ASD. In this study, serum glycopattern and the maackia amurensis lectin-II binding glycoproteins (MBGs) in 65 children with ASD and 65 age-matched typically developing (TD) children were compared by using lectin microarrays and lectin-magnetic particle conjugate-assisted LC-MS/MS analyses. Expression of Siaα2-3 Gal/GalNAc was significantly increased in pooled (fold change = 3.33, p < 0.001) and individual (p = 0.009) serum samples from ASD versus TD children. A total of 194 and 217 MGBs were identified from TD and ASD sera respectively, of which 74 proteins were specially identified or up-regulated in ASD. Bioinformatic analysis revealed abnormal complement cascade and aberrant regulation of response-to-stimulus that might be novel makers or markers for ASD. Moreover, increase of APOD α2-3 sialoglycosylation could sensitively and specifically distinguish ASD samples from TD samples (AUC is 0.88). In conclusion, alteration of MBGs expression and their sialoglycosylation may serve as potential biomarkers for diagnosis of ASD, and provide useful information for investigations into the pathogenesis of ASD.