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Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein a H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.Significance statement Precise timing of myelination is essential for efficient neural communication and is linked to the development of cognitive and motor skills as well as myelin repair after injury. ZFP488 is a transcriptional regulator enriched in oligodendrocytes, however its in vivo functions remain unclear. By generating ZFP488 loss-of-function mice, we demonstrated that ZFP488 is critical for the timing of myelination and remyelination and that its loss impaired the initial differentiation of oligodendrocytes but not their precursor formation and proliferation. Transcriptomic profiling showed that ZFP488 functions as a positive regulator of myelination by modulating oligodendrocyte maturation programs. Thus, our findings underscore the important role of ZFP488 in myelination and the potential of ZFP488 augmentation as an avenue to enhance oligodendrocyte regeneration.
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Neonatal white matter dysplasia (NWMD) is characterized by developmental abnormity of CNS white matter, including abnormal myelination. Besides environmental factors such as suffocation at birth, genetic factors are also main causes. Signaling pathway is an important part of gene function and several signaling pathways play important roles in myelination. Here, we performed genetic analysis on a cohort of 138 patients with NWMD and found that 20% (5/25) cause genes which referred to 28.57% (8/28) patients enriched in mammalian target of rapamycin (mTOR) signaling pathway. Depletion of mTOR reduced genesis and proliferation of oligodendrocyte progenitor cells (OPC) during embryonic stage and reduced myelination in corpus callosum besides cerebellum and spinal cord during early postnatal stages which is related to not only differentiation but also proliferation of oligodendrocyte (OL). Transcriptomic analyses indicated that depletion of mTOR in OLs upregulated expression of forkhead box O3 (FoxO3), which is a repressor of expression of myelin basic protein, and downregulating expression of FoxO3 by short interfering RNA promoted OPCs develop into MBP+ OLs. Thus, our findings suggested that mTOR signaling pathway is NWMD-related pathway and mTOR is important for myelination of the entire CNS during early developmental stages through regulating expression of FoxO3 at least partially.
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Sustancia Blanca , Diferenciación Celular/genética , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Humanos , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Transducción de Señal , Sirolimus , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Sustancia Blanca/metabolismoRESUMEN
BACKGROUND: Congenital heart defects (CHDs) are the most common type of birth defects. The genetic aetiology of CHD is complex and incompletely understood. The overall distribution of genetic causes in patients with CHD from neonatal intensive care units (NICUs) needs to be studied. METHODS: CHD cases were extracted from the China Neonatal Genomes Project (2016-2021). Next-generation sequencing results and medical records were retrospectively evaluated to note the frequency of genetic diagnosis and the respective patient outcomes. RESULTS: In total, 1795 patients were included. The human phenotype ontology term of atrial septal defect, patent ductus arteriosus and ventricular septal defect account for a large portion of the CHD subtype. Co-occurring extracardiac anomalies were observed in 35.1% of patients. 269 of the cases received genetic diagnoses that could explain the phenotype of CHDs, including 172 copy number variations and 97 pathogenic variants. The detection rate of trio-whole-exome sequencing was higher than clinical exome sequencing (21.8% vs 14.5%, p<0.05). Further follow-up analysis showed the genetic diagnostic rate was higher in the deceased group than in the surviving group (29.0% vs 11.9%, p<0.05). CONCLUSION: This is the largest cohort study to explore the genetic spectrum of patients with CHD in the NICU in China. Our findings may benefit future work on improving genetic screening and counselling for NICU patients with CHD.
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Cardiopatías Congénitas , Unidades de Cuidado Intensivo Neonatal , Recién Nacido , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Cardiopatías Congénitas/genética , ChinaRESUMEN
BACKGROUND: The occurrence of severe intraventricular hemorrhage (sIVH) was high in the very preterm infants (VPIs) in China. The management strategies significantly contributed to the occurrence of sIVH in VPIs. However, the status of the perinatal strategies associated with sIVH for VPIs was rarely described across the multiple neonatal intensive care units (NICUs) in China. We aim to investigate the characteristics of the perinatal strategies associated with sIVH for VPIs across the multiple NICUs in China. METHODS: This was a retrospective analysis of data from a prospective cohort of Chinese Neonatal Network (CHNN) dataset, enrolling infants born at 24+0-31+6 from 2019 to 2021. Eleven perinatal practices performed within the first 3 days of life were investigated including antenatal corticosteroids use, antenatal magnesium sulphate therapy, intubation at birth, placental transfusion, need for advanced resuscitation, initial inhaled gas of 100% FiO2 in delivery room, initial invasive respiratory support, surfactant and caffeine administration, early enteral feeding, and inotropes use. The performances of these practices across the multiple NICUs were investigated using the standard deviations of differences between expected probabilities and observations. The occurrence of sIVH were compared among the NICUs. RESULTS: A total of 24,226 infants from 55 NICUs with a mean (SD) gestational age of 29.5 (1.76) and mean (SD) birthweight of 1.31(0.32) were included. sIVH was detected in 5.1% of VPIs. The rate of the antenatal corticosteroids, MgSO4 therapy, and caffeine was 80.0%, 56.4%, and 31.5%, respectively. We observed significant relationships between sIVH and intubation at birth (AOR 1.52, 95% CI 1.13 to 1.75) and initial invasive respiratory support (AOR 2.47, 95% CI 2.15 to 2.83). The lower occurrence of sIVH (4.8%) was observed corresponding with the highest utility of standard antenatal care, the lowest utility of invasive practices, and early enteral feeding administration. CONCLUSIONS: The current evidence-based practices were not performed in each VPI as expected among the studied Chinese NICUs. The higher utility of the invasive practices could be related to the occurrence of sIVH.
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Hemorragia Cerebral Intraventricular , Unidades de Cuidado Intensivo Neonatal , Femenino , Humanos , Recién Nacido , Masculino , Corticoesteroides/uso terapéutico , Hemorragia Cerebral Intraventricular/epidemiología , China/epidemiología , Pueblos del Este de Asia , Recien Nacido Extremadamente Prematuro , Recien Nacido Prematuro , Enfermedades del Prematuro/epidemiología , Atención Perinatal/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND: Intensive care units (ICUs) in China primarily focus on active rescue efforts, and it is not common to provide palliative care services within the ICU. As nurses play a primary role as caregivers for end-of-life patients in the ICU, it is necessary to explore the factors that impede or facilitate palliative care from their perspective. AIM: To explore the barriers and facilitators associated with implementing palliative care in Chinese adult ICUs from nurses' perspectives. STUDY DESIGN: This study utilized a descriptive phenomenological research approach and purposive sampling to conduct face-to-face semi-structured interviews with nurses working in adult ICUs from three comprehensive hospitals in China during the period between February and May 2023. A total of 17 nurses were interviewed, and the collected data were transcribed, coded, and synthesized thematically. RESULTS: Two themes of barriers and facilitators of palliative care in the Chinese adult ICU were extracted. The three sub-themes of hindering factors are as follows: (1) The influence of Chinese traditional culture. (2) The specificity of the ICU context. (3) Lacking sufficient attention in the ICU. The three sub-themes of the promoting factors are as follows: (1) Government and society value palliative care. (2) Patients and their families have palliative care needs. (3) Nurses view palliative care positively. CONCLUSION: Currently, integrating palliative care into the ICU may face challenges such as cultural factors, the specificity of the ICU context, and insufficient attention. However, it is worth noting that as the government and society place more emphasis on palliative care, more and more people are gradually paying attention to the palliative care needs of critically ill patients and their families. RELEVANCE TO CLINICAL PRACTICE: This study serves as a reference for exploring an ICU palliative care service model that is suitable for China's national conditions, such as education and training, resource allocation, service processes, and the palliative care environment, among others.
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Actitud del Personal de Salud , Unidades de Cuidados Intensivos , Cuidados Paliativos , Investigación Cualitativa , Humanos , China , Unidades de Cuidados Intensivos/organización & administración , Cuidados Paliativos/psicología , Masculino , Femenino , Adulto , Entrevistas como Asunto , Enfermería de Cuidados Críticos , Personal de Enfermería en Hospital/psicología , Persona de Mediana EdadRESUMEN
BACKGROUND: Special AT-rich sequence-binding protein 2 is essential for the development of cerebral cortex and key molecular node for the establishment of proper neural circuitry and function. Mutations in the SATB2 gene lead to SATB2-associated syndrome, which is characterized by abnormal development of skeleton and central nervous systems. METHODS: We generated Satb2 knockout mouse model through CRISPR-Cas9 technology and performed RNA-seq and ChIP-seq of embryonic cerebral cortex. We conducted RT-qPCR, western blot, immunofluorescence staining, luciferase reporter assay and behavioral analysis for experimental verification. RESULTS: We identified 1363 downstream effector genes of Satb2 and correlation analysis of Satb2-targeted genes and neurological disease genes showed that Satb2 contribute to cognitive and mental disorders from the early developmental stage. We found that Satb2 directly regulate the expression of Ntng1, Cdh13, Kitl, genes important for axon guidance, synaptic formation, neuron migration, and Satb2 directly activates the expression of Mef2c. We also showed that Satb2 heterozygous knockout mice showed impaired spatial learning and memory. CONCLUSIONS: Taken together, our study supportsroles of Satb2 in the regulation of axonogenesis and synaptic formation at the early developmental stage and provides new insights into the complicated regulatory mechanism of Satb2 and new evidence to elucidate the pathogen of SATB2-associated syndrome. IMPACT: 1363 downstream effector genes of Satb2 were classified into 5 clusters with different temporal expression patterns. We identified Plxnd1, Ntng1, Efnb2, Ephb1, Plxna2, Epha3, Plxna4, Unc5c, and Flrt2 as axon guidance molecules to regulate axonogenesis. 168 targeted genes of Satb2 were found to regulate synaptic formation in the early development of the cerebral cortex. Transcription factor Mef2c is positively regulated by Satb2, and 28 Mef2c-targeted genes can be directly regulated by Satb2. In the Morris water maze test, Satb2+/- mice showed impaired spatial learning and memory, further strengthening that Satb2 can regulate synaptic functions.
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Proteínas de Unión a la Región de Fijación a la Matriz , Animales , Ratones , Corteza Cerebral/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Receptores de Superficie Celular/metabolismo , Sinapsis/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Malformation of cortical development (MCD) includes a variety of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. Most recently, clinical studies found that patients carrying KIF5C mutations present early-onset MCD; however, the underlying mechanisms remain elusive. METHODS: KIF5C expression level was examined in mouse primary cortical neurons and human ips-derived forebrain organoids. We studied the cortical neuronal migration, dendritic branching, and dendritic spine growth after knocking down the KIF5C gene by electroporation in vitro and in vivo. Then, we studied the transcriptome differences between the knockdown and control groups through RNA sequencing. RESULTS: We observed high KIF5C expression in neurons during the early developmental stage in mice and the human brain. Kif5c deficiency results in disturbed cortical neuronal migration, dendritic, and spine growth. Finally, we found that Kif5c knockdown affected several genes associated with cortical neuronal development in vitro. CONCLUSIONS: These results suggested a critical role for Kif5c in cortical development, providing insights into underlying pathogenic factors of kinesins in MCD. IMPACT: KIF5C mutation-related MCD might be caused by abnormal early cortical neuronal development. Kif5c deficiency led to abnormal cortical neuronal dendritic and spine growth and neuronal migration. Our findings explain how Kif5c deficiency is involved in the aberrant development of cortical neurons and provide a new perspective for the pathology of MCD.
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Epilepsia , Cinesinas , Animales , Ratones , Humanos , Cinesinas/genética , Neuronas/metabolismo , Neurogénesis , EncéfaloRESUMEN
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in the central nervous system. GBM patients have a very low 5-year survival rate and most of them died within 1 year. Conventional histopathological examination for GBM diagnosis is complicated and time-consuming, which always blocks the development of more precise and effective treatments in resection operation. Rapid evaporative ionization mass spectrometry (REIMS) is a MS technique in clinical medicine research, which combines the common diathermy device with MS to acquire the lipid profiles of tissue specimens for lipidomic analysis and real-time tumor diagnosis. In this study, the REIMS method employing bipolar forceps was optimized and validated for high-throughput lipidomics and diagnosis of GBM for the first time. Total 42 lipid metabolites were tentatively identified and 12 out of 13 lipid biomarkers showed higher intensities in GBM, which were consistent with previous studies. After this, a statistic model was built with the lipidomic data for the diagnosis of GBM tumor in real-time. The diagnostic accuracy (94.74%), sensitivity (95.38%), and specificity (93.33%) were evaluated with histopathology validated brain tissue specimens that were not used in the training set. The proposed REIMS method for the lipidomic-analysis and diagnosis of GBM tumor provides a new direction for MS-based lipidomics and precision medicine and might be used to guide surgeons to precisely resect the GBM tissue and keep the normal brain tissue in operation.
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Glioblastoma , Lipidómica , Glioblastoma/diagnóstico , Humanos , Lípidos , Espectrometría de Masas , Modelos EstadísticosRESUMEN
Diamond-based microelectromechanical systems (MEMS) enable direct coupling between the quantum states of nitrogen-vacancy (NV) centers and the phonon modes of a mechanical resonator. One example, a diamond high-overtone bulk acoustic resonator (HBAR), features an integrated piezoelectric transducer and supports high-quality factor resonance modes into the gigahertz frequency range. The acoustic modes allow mechanical manipulation of deeply embedded NV centers with long spin and orbital coherence times. Unfortunately, the spin-phonon coupling rate is limited by the large resonator size, >100 µm, and thus strongly coupled NV electron-phonon interactions remain out of reach in current diamond BAR devices. Here, we report the design and fabrication of a semiconfocal HBAR (SCHBAR) device on diamond (silicon carbide) with f × Q > 1012 (>1013). The semiconfocal geometry confines the phonon mode laterally below 10 µm. This drastic reduction in modal volume enhances defect center coupling to a mechanical mode by 1000 times compared to prior HBAR devices. For the native NV centers inside the diamond device, we demonstrate mechanically driven spin transitions and show a high strain-driving efficiency with a Rabi frequency of (2π)2.19(14) MHz/Vp, which is comparable to a typical microwave antenna at the same microwave power, making SCHBAR a power-efficient device useful for fast spin control, dressed state coherence protection, and quantum circuit integration.
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Background: This study was conducted to analyze the genetic spectrum and clinical characteristics of infantile hyperammonemia. Methods: Between January 2016 and June 2020, we retrospectively enrolled infantile hyperammonemia patients with definitive genetic diagnosis at the Children's Hospital of Fudan University. Based on the age of hyperammonemia onset, patients were grouped into neonatal and post-neonatal subgroups to compare their genetic and clinical features. Results: Collectively, 136 pathogenic or likely pathogenic variants of the 33 genes were identified. Fourteen genes were reported with hyperammonemia (42%, 14/33), with SLC25A13 and MUT being the top two detected genes. In contrast, 19 genes, which have not been previously reported with hyperammonemia, were detected (58%, 19/33), in which JAG1 and ABCC8 were the most frequently mutated genes. Compared with post-neonatal hyperammonemia, neonatal patients with hyperammonemia presented with higher rates of organic acidemia (P=0.001) and fatty acid oxidation disorder (P=0.006), but a lower rate of cholestasis (P<0.001). Patients with neonatal hyperammonemia had a higher ratio of peak plasma ammonia level ≥500 µmol/L (P=0.003) and were more likely to receive precision medicine (P=0.027); however, they had a refractory clinical course (P=0.001) and poorer prognosis than the infantile group. Conclusions: There were significant differences in the genetic spectrum, clinical features, clinical course, and outcomes between infants with different hyperammonemia onset ages.
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BACKGROUND: In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. METHODS: A cohort of 723 SGA and 1317 appropriate for gestational age (AGA) newborns were recruited between June 2018 and June 2020. Clinical exome sequencing was performed for each newborn. The gene-based rare-variant collapsing analyses and the gene burden test were applied to identify the risk genes for SGA and SGA with poor prognosis. The Gradient Boosting Machine framework was used to generate two models to predict the prognosis of SGA. The performance of two models were validated with an independent cohort of 115 SGA newborns without genetic diagnosis from July 2020 to April 2022. All newborns in this study were recruited through the China Neonatal Genomes Project (CNGP) and were hospitalized in NICU, Children's Hospital of Fudan University, Shanghai, China. RESULTS: Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P=0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P=0.012). We filtered out 3 genes (ITGB4, TXNRD2, RRM2B) as potential causative genes for SGA and 1 gene (ADIPOQ) as potential causative gene for SGA with poor prognosis. The model integrating clinical and genetic factors demonstrated a higher area under the receiver operating characteristic curve (AUC) over the model based solely on clinical factors in both the SGA-model generation dataset (AUC=0.9[95% confidence interval 0.84-0.96] vs. AUC=0.74 [0.64-0.84]; P=0.00196) and the independent SGA-validation dataset (AUC=0.76 [0.6-0.93] vs. AUC=0.53[0.29-0.76]; P=0.0117). CONCLUSION: SGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction.
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Aberraciones Cromosómicas , Unidades de Cuidado Intensivo Neonatal , Niño , Recién Nacido , Humanos , Edad Gestacional , China , PronósticoRESUMEN
BACKGROUND: Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay (NDD), but its genetic basis has not been fully characterized. This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume (WBDV). METHODS: We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years. We recruited only NDD patients without acquired etiologies or positive genetic results. Cranial magnetic resonance imaging (MRI) and clinical exome sequencing (2742 genes) data were acquired. A genetic burden test was performed, and the results were compared between patients with and without significant WBDV. Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development. RESULTS: We recruited a total of 253 NDD patients. Among them, 26 had significantly decreased WBDV (<-2 standard deviations [SDs]), and 14 had significantly increased WBDV (>+2 SDs). NDD patients with significant WBDV had higher rates of motor development delay (49.8% [106/213] vs . 75.0% [30/40], P â=â0.003) than patients without significant WBDV. Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV. Analyses of the literature further demonstrated that these genes were not randomly identified: burden genes were more related to the brain development than background genes ( P â=â1.656e -9 ). In seven human brain regions related to motor development, we observed burden genes had higher expression before 37-week gestational age than postnatal stages. Functional analyses found that burden genes were enriched in embryonic brain development, with positive regulation of synaptic growth at the neuromuscular junction, positive regulation of deoxyribonucleic acid templated transcription, and response to hormone, and these genes were shown to be expressed in neural progenitors. Based on single cell sequencing analyses, we found TUBB2B gene had elevated expression levels in neural progenitor cells, interneuron, and excitatory neuron and SOX15 had high expression in interneuron and excitatory neuron. CONCLUSION: Idiopathic NDD patients with significant brain volume changes detected by MRI had an increased prevalence of motor development delay, which could be explained by the genetic differences characterized herein.
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Trastornos del Neurodesarrollo , Niño , Humanos , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/epidemiología , Pruebas Genéticas , Fenotipo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Antecedentes Genéticos , Factores de Transcripción SOX/genéticaRESUMEN
BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) is associated with increased comorbidities in neonates. Early evaluation of hsPDA risk is critical to implement individualized intervention. The aim of the study was to provide a powerful reference for the early identification of high-risk hsPDA population and early treatment decisions. METHODS: We enrolled infants who were diagnosed with PDA and performed exome sequencing. The collapsing analyses were used to find the risk gene set (RGS) of hsPDA for model construction. The credibility of RGS was proven by RNA sequencing. Multivariate logistic regression was performed to establish models combining clinical and genetic features. The models were evaluated by area under the receiver operating curve (AUC) and decision curve analysis (DCA). RESULTS: In this retrospective cohort study of 2199 PDA patients, 549 (25.0%) infants were diagnosed with hsPDA. The model [all clinical characteristics selected by least absolute shrinkage and selection operator regression (all CCs)] based on six clinical variables was acquired within three days of life, including gestational age (GA), respiratory distress syndrome (RDS), the lowest platelet count, invasive mechanical ventilation, and positive inotropic and vasoactive drugs. It has an AUC of 0.790 [95% confidence interval (CI) = 0.749-0.832], while the simplified model (basic clinical characteristic model) including GA and RDS has an AUC of 0.753 (95% CI = 0.706-0.799). There was a certain consistency between RGS and differentially expressed genes of the ductus arteriosus in mice. The AUC of the models was improved by RGS, and the improvement was significant (all CCs vs. all CCs + RGS: 0.790 vs. 0.817, P < 0.001). DCA demonstrated that all models were clinically useful. CONCLUSIONS: Models based on clinical factors were developed to accurately stratify the risk of hsPDA in the first three days of life. Genetic features might further improve the model performance. Video Abstract (MP4 86834 kb).
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CD45, the leukocyte common antigen, is expressed on almost all cells of the immunological and hematological systems. CD45 expression is related to a variety of diseases, including leukemia and lymphoma. In this study, we analyzed the expression level of CD45 across cancers and evaluated the relationship between its expression and patient prognosis. We further integrated methylation data to explore the differences in CD45 across cancers from a multi-omics perspective. We also analyzed the relationship between CD45 expression and levels of immune cell infiltrates and immune modifiers. Our results revealed the distinct expression characteristics and prognostic value of CD45 across multiple tumors. In addition, we screened drug targets based on the immune index defined by CD45 expression and identified that GPR84 affected the proliferation of tumor cells and was associated with the inflammation caused by immunotherapy. In summary, our findings provide a comprehensive understanding of the role of CD45 in oncogenesis and its prognostic significance across cancers.
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Craniosynostosis is a premature fusion of cranial sutures, resulting in abnormally shaped skull and brain development disorder. The description of craniosynostosis in patients with BCL11B mutations is rare. Here, we firstly report a 25-month-old Chinese boy with a novel frameshift variant in BCL11B gene. The patient was identified c.2346_2361del by whole-exome sequencing and was confirmed to be de novo by parental Sanger sequencing. This patient presented clinical phenotype of craniosynostosis as well as global developmental delay. He had a small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia and craniosynostosis. Brain MRI showed brain extracerebral interval and myelination changes, and brain CT with 3D reconstruction showed multi-craniosynostosis. Our study expands the clinical phenotypes of patients with BCL11B gene mutation, and our findings may help guide clinical treatment and family genetic counseling.
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Background: Acute respiratory distress syndrome (ARDS) could account for a considerable proportion of neonatal death, while the genetic etiology and pathophysiology of neonatal ARDS remain elusive. In this case-control study, 515 neonates were enrolled in the China Neonatal Genomes Project (CNGP, NCT03931707) from August 2016 to June 2021, including 196 ARDS and 319 non-ARDS matched by sex, gestational age, birth weight, perinatal asphyxia, pneumonia, sepsis, and necrotizing enterocolitis. Clinical exome sequencing was used to detect genetic variants. Collapsing analyses together with permutation tests were used to identify ARDS risk genes enriched for rare variants in ARDS samples. In silico functional interaction analysis and expression pattern studies at different stages of lung development were used to investigate the biological functions of the risk genes. Results: Collapsing analyses identified that rare variants were significantly abundant in the genes associated with the precursor of the lamellar body and there were eight predicted risk genes with strong confidence (P < 0.01). Among them, the expression of EDNRB increased significantly in lung development and was up-regulated in ARDS (P < 0.05). In addition, 151 predicted transcriptional target proteins of EDNRB were highly enriched in the lamellar body responsible for pulmonary surfactant storage and secretion. Conclusions: In our study, the genes associated with pulmonary surfactant storage and release were highly enriched with rare variants. A novel neonatal ARDS risk gene EDNRB may be a key gene for neonatal lung development and pulmonary surfactant homeostasis. Additional validation in independent patient populations and further exploration of underlying molecular mechanisms are warranted.
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INTRODUCTION: Data on the genetic landscape of congenital microcephaly (CM) in China are scarce, and the incidence of CM caused by the most commonly mutated gene ASPM in China remains unknown. METHODS: Sixty-one neonates with CM who were hospitalized in the Children's Hospital of Fudan University between August 1, 2016, and August 31, 2020, were enrolled, and the clinical data and clinical exome-sequencing data were analyzed. An additional 18,103 parental data entries from the Chinese Children's Genetic Testing Clinical Collaboration System database were collected to estimate the incidence of ASPM-related congenital microcephaly (ASPM-CM) in East China by analyzing the carrier frequency of ASPM mutations. RESULTS: Among the 61 neonates with CM, 35 (57.4%) patients were identified with genetic findings, including 24 patients with single nucleotide variants (SNVs) and 11 patients with copy number variations (CNVs). ASPM was the most common gene with detrimental SNVs detected in 3 patients. Patients with genetic findings showed a significantly higher incidence of developmental delay (91.3%, 21/23) than those without genetic findings (60%, 9/15) (p = 0.04). All the 3 decreased patients had genetic findings. The estimated ASPM-CM incidence in East China was 1/1,295,044. CONCLUSION: Comprehensive genetic testing, detecting both SNVs and CNVs, is recommended for newborns with CM. Patients with genetic findings should be aware of the potential for developmental delay. ASPM gene defect was the most common genetic cause of CM in this study. The estimation of the incidence of ASPM-CM in East China might provide a reference for analyzing overall incidence.
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Microcefalia , Niño , Variaciones en el Número de Copia de ADN , Humanos , Recién Nacido , Microcefalia/epidemiología , Microcefalia/genética , Biología Molecular , Mutación , Proteínas del Tejido Nervioso/genéticaRESUMEN
Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing.
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Trastorno del Espectro Autista , Trastorno Autístico , Discapacidad Intelectual , Anomalías Múltiples , Trastorno Autístico/genética , China , Cromatina , ADN Helicasas/genética , Cara/anomalías , Deformidades Congénitas de la Mano , Humanos , Discapacidad Intelectual/genética , Micrognatismo , Cuello/anomalías , Proteínas Nucleares/genética , Factores de Transcripción/genéticaRESUMEN
Glioblastoma (GBM) is the most common and aggressive primary brain tumor, but the mechanisms underlying tumor growth and progression remain unclear. The protein arginine methyltransferases (PRMTs) regulate a variety of biological processes, however, their roles in GBM growth and progression are not fully understood. In this study, our functional analysis of gene expression networks revealed that among the PRMT family expression of PRMT3 was most significantly enriched in both GBM and low-grade gliomas. Higher PRMT3 expression predicted poorer overall survival rate in patients with gliomas. Knockdown of PRMT3 markedly reduced the proliferation and migration of GBM cell lines and patient-derived glioblastoma stem cells (GSC) in cell culture, while its over-expression increased the proliferative capacity of GSC cells by promoting cell cycle progression. Consistently, stable PRMT3 knockdown strongly inhibited tumor growth in xenograft mouse models, along with a significant decrease in cell proliferation as well as an increase in apoptosis. We further found that PRMT3 reprogrammed metabolic pathways to promote GSC growth via increasing glycolysis and its critical transcriptional regulator HIF1α. In addition, pharmacological inhibition of PRMT3 with a PRMT3-specific inhibitor SGC707 impaired the growth of GBM cells. Thus, our study demonstrates that PRMT3 promotes GBM progression by enhancing HIF1A-mediated glycolysis and metabolic rewiring, presenting a point of metabolic vulnerability for therapeutic targeting in malignant gliomas.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Ratones , Animales , Glioblastoma/genética , Glioblastoma/patología , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Glucólisis/genética , Proliferación Celular/genética , Apoptosis/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
CHD8 is a candidate gene for autism spectrum disorders and neurological development delay. It has been reported to be essential for neurogenesis in the cerebral cortex, but the function of CHD8 in cerebellum has not been comprehensively investigated. The potential relationship of cerebellum dysplasia with psychiatric disorders in patients with CHD8 mutations is still not clear. In this study, we establish different conditional knockout mouse models to investigate the roles of CHD8 in cerebellar development. Mice with neural stem cell-specific Chd8 deletion exhibit significant reduction of cerebellum volume and no layering structure is detected. Genetic deletion of Chd8 in cerebellar granule neuron progenitors (GNPs) leads to cerebellar hypoplasia, absent of proliferation layer and ectopic of Purkinje neuron. However, no substantial cerebellar dysplasia is detected in mice with Purkinje neuron- or oligodendrocyte-specific Chd8 ablation. Single-cell RNA sequencing indicates that ribosome-related genes and pathways are most significantly disrupted in GNPs, indicating the potential mechanism. Importantly, in addition to the ataxia phenotype, mice with GNP-specific Chd8 ablation present a neuropsychiatric phenotype in three-chamber and light/dark tests. Taken together, our results provide insights not only into the function of CHD8 in cerebellar development, but also the pathogenesis of neuropsychiatric disorders in patients with CHD8 mutations.