RESUMEN

OBJECTIVE: Accurately diagnosing patients with disorders of consciousness (DOC) is challenging and prone to errors. Recent studies have demonstrated that EEG (electroencephalography), a non-invasive technique of recording the spontaneous electrical activity of brains, offers valuable insights for DOC diagnosis. However, some challenges remain: 1) the EEG signals have not been fully used; and 2) the data scale in most existing studies is limited. In this study, our goal is to differentiate between minimally conscious state (MCS) and unresponsive wakefulness syndrome (UWS) using resting-state EEG signals, by proposing a new deep learning framework. APPROACH: We propose DOCTer, an end-to-end framework for DOC diagnosis based on EEG. It extracts multiple pertinent features from the raw EEG signals, including time-frequency features and microstates. Meanwhile, it takes clinical characteristics of patients into account, and then combines all the features together for the diagnosis. To evaluate its effectiveness, we collect a large-scale dataset containing 409 resting-state EEG recordings from 128 UWS and 187 MCS cases. MAIN RESULTS: Evaluated on our dataset, DOCTer achieves the state-of-the-art performance, compared to other methods. The temporal/spectral features contributes the most to the diagnosis task. The cerebral integrity is important for detecting the consciousness level. Meanwhile, we investigate the influence of different EEG collection duration and number of channels, in order to help make the appropriate choices for clinics. SIGNIFICANCE: The DOCTer framework significantly improves the accuracy of DOC diagnosis, helpful for developing appropriate treatment programs. Findings derived from the large-scale dataset provide valuable insights for clinics.

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Cannabinoids and the endocannabinoid system (ECS) have been intensively studied for their neuroregulatory roles in the central nervous system (CNS), especially in regulating learning and memory. However, many experimental and clinical studies obtained conflicting results indicating a complex network of interaction underlying the regulation of learning and memory by different cannabinoids and the ECS. The ECS influences neuronal synaptic communications, and therefore may exert different regulation via their different impact on other neurotransmitters. The monoaminergic system includes a variety of neurotransmitters, such as dopamine, norepinephrine, and serotonin, which play important roles in regulating mood, cognition, and reward. The interaction among cannabinoids, ECS and the monoaminergic system has drawn particular attention, especially their contributions to learning and memory. In this review, we summarized the current understanding of how cannabinoids, ECS and the monoaminergic system contribute to the process of learning and memory, and discussed the influences of monoaminergic neurotransmission by cannabinoids and ECS during this process.

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Cerebrospinal fluid (CSF) cytology of primary central nervous system lymphoma arising in the immune deficiency/dysregulation setting (IDD-PCNSL) has not been described. This study presented a case of IDD-PCNSL-DLBCL, a GCB phenotype who was successfully diagnosed by CSF cytology in conjunction with ICC, ISH, FCM and clinical information.

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The biological role of Ten-11 translocation 2 (TET2) and the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the development of extra-nodal natural killer/T-cell lymphoma (ENKTL) remains unclear. The level of 5mC and 5hmC was detected in 112 cases of ENKTL tissue specimens by immunohistochemical (IHC) staining. Subsequently, TET2 knockdown and the overexpression cell models were constructed in ENKTL cell lines. Biochemical analyses were used to assess proliferation, apoptosis, cell cycle and monoclonal formation in cells treated or untreated with L-Ascorbic acid sodium salt (LAASS). Dot-Blots were used to detect levels of genome 5mC and 5hmC. Additionally, the ILLUMINA 850k methylation chip was used to analyze the changes of TET2 regulatory genes. RNA-Seq was used to profile differentially expressed genes regulated by TET2. The global level of 5hmC was significantly decreased, while 5mC was highly expressed in ENKTL tissue. TET2 protein expression was negatively correlated with the ratio of 5mC/5hmC (p < 0.0001). The 5mC/5hmC status were related to the site of disease, clinical stage, PINK score and Ki-67 index, as well as the 5-year OS. TET2 knockdown prolonged the DNA synthesis period, increased the cloning ability of tumor cells, increased the level of 5mC and decreased the level of 5hmC in ENKTL cells. While overexpression of TET2 presented the opposite effect. Furthermore, treatment of ENKTL cells with LAASS significantly induced ENKTL cell apoptosis. These results suggest that TET2 plays an important role in ENKTL development via regulation of 5mC and 5hmC and may serve as a novel therapeutic target for ENKTL.

Asunto(s)

Metilación de ADN , Proteínas de Unión al ADN , Dioxigenasas , Linfoma Extranodal de Células NK-T , Proteínas Proto-Oncogénicas , Humanos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Masculino , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/patología , Linfoma Extranodal de Células NK-T/genética , Persona de Mediana Edad , Adulto , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Anciano , Línea Celular Tumoral , Proliferación Celular

RESUMEN

Sleep staging is essential for sleep assessment and plays an important role in disease diagnosis, which refers to the classification of sleep epochs into different sleep stages. Polysomnography (PSG), consisting of many different physiological signals, e.g. electroencephalogram (EEG) and electrooculogram (EOG), is a gold standard for sleep staging. Although existing studies have achieved high performance on automatic sleep staging from PSG, there are still some limitations: 1) they focus on local features but ignore global features within each sleep epoch, and 2) they ignore cross-modality context relationship between EEG and EOG. In this paper, we propose CareSleepNet, a novel hybrid deep learning network for automatic sleep staging from PSG recordings. Specifically, we first design a multi-scale Convolutional-Transformer Epoch Encoder to encode both local salient wave features and global features within each sleep epoch. Then, we devise a Cross-Modality Context Encoder based on co-attention mechanism to model cross-modality context relationship between different modalities. Next, we use a Transformer-based Sequence Encoder to capture the sequential relationship among sleep epochs. Finally, the learned feature representations are fed into an epoch-level classifier to determine the sleep stages. We collected a private sleep dataset, SSND, and use two public datasets, Sleep-EDF-153 and ISRUC to evaluate the performance of CareSleepNet. The experiment results show that our CareSleepNet achieves the state-of-the-art performance on the three datasets. Moreover, we conduct ablation studies and attention visualizations to prove the effectiveness of each module and to analyze the influence of each modality.

RESUMEN

The construction of peptides to mimic heterogeneous proteins such as type I collagen plays a pivotal role in deciphering their function and pathogenesis. However, progress in the field has been severely hampered by the lack of capability to create stable heterotrimers with desired functional sequences and without the effect of homotrimers. We have herein developed a set of triblock peptides that can assemble into collagen mimetic heterotrimers with desired amino acids and are free from the interference of homotrimers. The triblock peptides comprise a central collagen-like block and two oppositely charged N-/C-terminal blocks, which display inherent incompetency of homotrimer formation. The favorable electrostatic attraction between two paired triblock peptides with complementary terminal charged sequences promptly leads to stable heterotrimers with controlled chain composition. The independence of the collagen-like block from the two terminal blocks endows this system with the adaptability to incorporate desired amino acid sequences while maintaining the heterotrimer structure. The triblock peptides provide a versatile and robust tool to mimic the composition and function of heterotrimer collagen and may have great potential in the design of innovative peptides mimicking heterogeneous proteins.

Asunto(s)

Colágeno , Péptidos , Péptidos/química , Colágeno/química , Multimerización de Proteína , Secuencia de Aminoácidos , Colágeno Tipo I/química , Electricidad Estática

RESUMEN

Fagopyrum dibotrys, belonging to the family Polygonaceae and genus Fagopyrum, is used in traditional Chinese medicine and is rich in beneficial components, such as flavonoids. As its abundant medicinal value has become increasingly recognized, its excessive development poses a considerable challenge to wild germplasm resources, necessitating artificial cultivation and domestication. Considering these factors, a high-quality genome of F. dibotrys was assembled and the evolutionary relationships within Caryophyllales were compared, based on which 58 individual samples of F. dibotrys were re-sequenced. We found that the samples could be categorized into three purebred populations and regions distributed at distinct elevations. Our varieties were cultivated from the parental populations of the subpopulation in central Yunnan. F. dibotrys is speculated to have originated in the high-altitude Tibetan Plateau region, and that its combination with flavonoids can protect plants against ultraviolet radiation; this infers a subpopulation with a high accumulation of flavonoids. This study assembled a high-quality genome and provided a theoretical foundation for the future introduction, domestication, and development of cultivated varieties of F. dibotrys.

RESUMEN

BACKGROUND: The purpose of this meta-analysis was to evaluate the effectiveness and safety of thoracic manipulation (TM) in patients with neck pain (NP). OBJECTIVE: The purpose of this meta-analysis was to evaluate the effectiveness and safety of thoracic manipulation (TM) in patients with neck pain (NP). METHODS: Seven electronic databases were searched from their inception through October 2023 by two authors. The methodological quality assessments were performed with the Physiotherapy Evidence Database (PEDro) scale. Pain, cervical range of motion (ROM), disability, and quality of life (QOL) were estimated for TM treatment in patients with NP. RESULTS: Eighteen randomized controlled trials (RCTs) with 914 patients were included with a PEDro score of 6.923 ± 3.120. Pooled effect sizes of pain (SMD =-0.481, 95% CI -0.653 to -0.309, P= 0.000), disability (SMD =-1.435, 95% CI -2.480 to -0.390, P= 0.007), QOL-physical component score (PCS) (SMD = 0.658, 95% CI 0.290 to 1.025, P= 0.000), ROM of flexion (SMD = 0.921, 95% CI 0.287 to 1.555, P= 0.000), ROM of extension (SMD = 0.572, 95% CI 0.321 to 0.822, P= 0.000), ROM of left lateral flexion (SMD = 0.593, 95% CI 0.075 to 1.112, P= 0.025) and ROM of left rotation (SMD = 0.230, 95% CI 0.010 to 0.450, P= 0.04) were favored by the TM group. CONCLUSIONS: TM provides short-term effect on relieving neck pain, increasing cervical ROM, and disability in patients with NP without serious side effects. Continuous therapy and distraction therapy are recommended as optimal choice on reducing pain and improving cervical ROM, especially in patients with chronic NP (> 3 months). The TM-induced improvements in the QOL of patients with NP should be verified by more further high-quality RCTs.

Asunto(s)

Dolor de Cuello , Calidad de Vida , Rango del Movimiento Articular , Humanos , Dolor de Cuello/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Manipulación Espinal/métodos

RESUMEN

Corticotropin releasing factor (CRF) network in the oval nucleus of bed nuclei of the stria terminalis (ovBNST) is generally indicated in stress, but its role in female-biased susceptibility to anxiety is unknown. Here, we established a female-biased stress paradigm. We found that the CRF release in ovBNST during stress showed female-biased pattern, and ovBNST CRF neurons were more prone to be hyperexcited in female mice during stress in both in vitro and in vivo studies. Moreover, optogenetic modulation to exchange the activation pattern of ovBNST CRF neurons during stress between female and male mice could reverse their susceptibility to anxiety. Last, CRF receptor type 1 (CRFR1) mediated the CRF-induced excitation of ovBNST CRF neurons and showed female-biased expression. Specific knockdown of the CRFR1 level in ovBNST CRF neurons in female or overexpression that in male could reverse their susceptibility to anxiety. Therefore, we identify that CRFR1-mediated hyperexcitation of ovBNST CRF neurons in female mice encode the female-biased susceptibility to anxiety.

Asunto(s)

Ansiedad , Hormona Liberadora de Corticotropina , Neuronas , Receptores de Hormona Liberadora de Corticotropina , Animales , Femenino , Masculino , Ratones , Ansiedad/metabolismo , Reacción de Prevención/fisiología , Conducta Animal , Hormona Liberadora de Corticotropina/metabolismo , Neuronas/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de Hormona Liberadora de Corticotropina/genética , Núcleos Septales/metabolismo , Estrés Psicológico/metabolismo

RESUMEN

The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S-, P-, Si- and B-stereocenters over the past decades, the catalyst-controlled strategies to govern the formation of N-stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen-stereogenic compounds through a desymmetrization approach. Intriguingly, the pro-chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene-bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N-oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N-oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

RESUMEN

Polysomnography (PSG) recordings have been widely used for sleep staging in clinics, containing multiple modality signals (i.e., EEG and EOG). Recently, many studies have combined EEG and EOG modalities for sleep staging, since they are the most and the second most powerful modality for sleep staging among PSG recordings, respectively. However, EEG is complex to collect and sensitive to environment noise or other body activities, imbedding its use in clinical practice. Comparatively, EOG is much more easily to be obtained. In order to make full use of the powerful ability of EEG and the easy collection of EOG, we propose a novel framework to simplify multimodal sleep staging with a single EOG modality. It still performs well with only EOG modality in the absence of the EEG. Specifically, we first model the correlation between EEG and EOG, and then based on the correlation we generate multimodal features with time and frequency guided generators by adopting the idea of generative adversarial learning. We collected a real-world sleep dataset containing 67 recordings and used other four public datasets for evaluation. Compared with other existing sleep staging methods, our framework performs the best when solely using the EOG modality. Moreover, under our framework, EOG provides a comparable performance to EEG.

Asunto(s)

Algoritmos , Electroencefalografía , Electrooculografía , Polisomnografía , Fases del Sueño , Humanos , Electroencefalografía/métodos , Fases del Sueño/fisiología , Polisomnografía/métodos , Electrooculografía/métodos , Masculino , Adulto , Femenino , Adulto Joven

RESUMEN

BACKGROUND: Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME. METHODS: We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes. RESULTS: Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0-12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97-18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006). The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib. ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1ß.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy. CONCLUSIONS: In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Asunto(s)

Acrilamidas , Inhibidores de la Angiogénesis , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Pirimidinas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacología , Acrilamidas/uso terapéutico , Acrilamidas/farmacología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Masculino , Animales , Ratones , Persona de Mediana Edad , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Anciano , Microambiente Tumoral/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Indoles/uso terapéutico , Indoles/administración & dosificación

RESUMEN

To maximize the survival chances of society members, collective self-organization must balance individual interests with promoting the collective welfare. Although situations where group members have equal optimal values are clear, how varying optimal values impacts group dynamics remains unclear. To address this gap, we conducted a self-optimization study of a binary system incorporating communication-enabled active particles with distinct optimal values. We demonstrate that similar particles will spontaneously aggregate and separate from each other to maximize their individual benefits during the process of self-optimization. Our research shows that both types of particles can produce the optimal field values at low density. However, only one type of particle can achieve the optimal field values at medium density. At high densities, neither type of particle is effective in reaching the optimal field values. Interestingly, we observed that during the self-optimization process, the mixture demixed spontaneously under certain circumstances of mixed particles. Particles with higher optimal values developed into larger clusters, while particles with lower optimal values migrated outside of these clusters, resulting in the separation of the mixture. To achieve this separation, suitable noise intensity, particle density, and the significant difference in optimal values were necessary. Our results provide a more profound comprehension of the self-optimization of synthetic or biological agents' communication and provide valuable insight into separating binary species and mixtures.

RESUMEN

A key limitation of current dynamic contrast enhanced (DCE) MRI techniques is the requirement for full-dose gadolinium-based contrast agent (GBCA) administration. The purpose of this feasibility study was to develop and assess a new low GBCA dose protocol for deriving high-spatial resolution kinetic parameters from brain DCE-MRI. Nineteen patients with intracranial skull base tumours were prospectively imaged at 1.5 T using a single-injection, fixed-volume low GBCA dose, dual temporal resolution interleaved DCE-MRI acquisition. The accuracy of kinetic parameters (ve, Ktrans, vp) derived using this new low GBCA dose technique was evaluated through both Monte-Carlo simulations (mean percent deviation, PD, of measured from true values) and an in vivo study incorporating comparison with a conventional full-dose GBCA protocol and correlation with histopathological data. The mean PD of data from the interleaved high-temporal-high-spatial resolution approach outperformed use of high-spatial, low temporal resolution datasets alone (p < 0.0001, t-test). Kinetic parameters derived using the low-dose interleaved protocol correlated significantly with parameters derived from a full-dose acquisition (p < 0.001) and demonstrated a significant association with tissue markers of microvessel density (p < 0.05). Our results suggest accurate high-spatial resolution kinetic parameter mapping is feasible with significantly reduced GBCA dose.

Asunto(s)

Neoplasias Encefálicas , Medios de Contraste , Humanos , Estudios de Factibilidad , Imagen por Resonancia Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología

RESUMEN

BACKGROUND: Nursing interns often experience lots of challenges during their clinical nursing internships, which can adversely affect career decisions and result in a squandering of nursing education resources. Patient safety attitudes, professional identity and climate of caring may affect nursing interns' clinical experience. However, more evidence is requested to validate these relationships for nursing educators to develop effective education programs and facilitate interns' successful transition. METHODS: This was a cross-sectional study, which used a convenience sampling method to recruit 387 nursing interns during December 2022 to April 2023 in university affiliated hospital in Hunan province, China. Data were collected using standardized scales. Spearman correlation and multiple regression analysis were employed to examine the relationship between transition shock, patient safety attitudes, professional identity, and climate of caring. RESULTS: Nursing interns experienced transition shock at a moderate level and the highest levels of transition shock in response to overwhelming practicum workloads, with the second being related to the conflict between theory and practice. Transition shock was negatively correlated with patient safety attitudes, professional identity and climate of caring among nursing interns. CONCLUSIONS: Nursing managers and educators need to value the transition shock experienced by nursing interns. Our study suggests that developing a strong sense of professional identity and a positive attitude toward patient safety can be effective in reducing the level of transition shock among nursing interns. In addition, a caring climate within the nursing unit can significantly enhance the overall experience of nursing interns. This can be achieved by enhancing the support of clinical mentors, providing patient safety-focused education, and facilitating team communication among nurses.

RESUMEN

Multiplex fluorescence imaging plays a vital role in precision medicine for targeting complex diseases with diverse biomolecular signatures. Quantum dot (QD) probes with vibrant colors are promising candidates for multiplex imaging, but their stability and specificity are frequently compromised by the current tedious post-modification process. We have herein developed a robust and versatile host-guest peptide (HGP) toolbox for creating highly stable and specific QD-based peptide probes for imaging extracellular matrices and cells. The HGP system comprises a host peptide and a guest peptide with a shared sequence pattern of cysteine and negatively charged amino acids, allowing for QD stabilization and specificity towards targeted biomarkers. HGP has been demonstrated as a convenient one-step approach to construct hydrophilic QD-based peptide probes with superior stability under various conditions. Six multicolor HGP-modified QDs have been developed to specifically target extracellular matrix proteins such as collagen, laminin, and nidogen, as well as major cellular elements like the membrane, nucleus, and cytoplasm, providing an efficient tool for real-time monitoring of high-resolution interactions between cancer cells and the extracellular matrix. The HGP system represents a next-generation approach to developing QDs with unprecedented stability and specificity, holding great potential in multiplex imaging and precision medicine.

Asunto(s)

Puntos Cuánticos , Puntos Cuánticos/química , Péptidos/química , Imagen Óptica/métodos , Matriz Extracelular

RESUMEN

Major Depression Disorder (MDD) is a common yet destructive mental disorder that affects millions of people worldwide. Making early and accurate diagnosis of it is very meaningful. Recently, EEG, a non-invasive technique of recording spontaneous electrical activity of brains, has been widely used for MDD diagnosis. However, there are still some challenges in data quality and data size of EEG: (1) A large amount of noise is inevitable during EEG collection, making it difficult to extract discriminative features from raw EEG; (2) It is difficult to recruit a large number of subjects to collect sufficient and diverse data for model training. Both of the challenges cause the overfitting problem, especially for deep learning methods. In this paper, we propose DiffMDD, a diffusion-based deep learning framework for MDD diagnosis using EEG. Specifically, we extract more noise-irrelevant features to improve the model's robustness by designing the Forward Diffusion Noisy Training Module. Then we increase the size and diversity of data to help the model learn more generalized features by designing the Reverse Diffusion Data Augmentation Module. Finally, we re-train the classifier on the augmented dataset for MDD diagnosis. We conducted comprehensive experiments to test the overall performance and each module's effectiveness. The framework was validated on two public MDD diagnosis datasets, achieving the state-of-the-art performance.

Asunto(s)

Aprendizaje Profundo , Trastorno Depresivo Mayor , Humanos , Electroencefalografía/métodos , Trastorno Depresivo Mayor/diagnóstico , Encéfalo

RESUMEN

BACKGROUND: Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear. METHODS: We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed. RESULTS: The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D. CONCLUSIONS: KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D.

Asunto(s)

Linfoma Extranodal de Células NK-T , Humanos , Histona Metiltransferasas , Linfoma Extranodal de Células NK-T/patología , Carcinogénesis/genética , Proteína 1 Supresora de la Señalización de Citocinas

RESUMEN

Exosomes have been demonstrated to exert momentous roles in autism spectrum disorder (ASD). However, few studies have reported a correlation between exosomal microRNAs (miRNAs) and ASD. To date, our understanding of crucial competing endogenous RNA (ceRNA) networks in ASD remains limited. Herein, the exosomal miRNA profile in the peripheral blood of children with ASD and healthy controls was investigated and the level of immune cell infiltration in ASD was evaluated to determine the distribution of immune cell subtypes. Exosomes were isolated from the peripheral blood of ten children with ASD and ten healthy controls, and further identified using transmission electron microscopy and western blot analysis. RNA sequencing was conducted to investigate exosomal miRNA profiles in patients with ASD. The mRNA and circular RNA (circRNA) expression profiles were acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and circRNAs (DEcircRNAs) were identified and ceRNA regulatory networks were constructed. Furthermore, the immune cell infiltration levels in patients with ASD were evaluated. Exosomes were spherical, approximately 100 nm in size, and were confirmed via western blot analysis using exosome-associated markers CD9, CD63, and CD81. Thirty-five DEmRNAs, 63 DEmiRNAs, and 494 DEcircRNAs were identified in patients with ASD. CeRNA regulatory networks, including 6 DEmRNAs, 14 DEmiRNAs, and 86 DEcircRNAs, were established. Correlation analysis indicated that leucine-rich glioma inactivated protein 1 (LGI1) expression was significantly positively correlated with the content of CD8+ T cells. Our findings may be conducive to offering novel insights into this disease and providing further evidence of transcriptomic abnormalities in ASD.

Asunto(s)

Trastorno del Espectro Autista , MicroARNs , Niño , Humanos , Proyectos Piloto , ARN Endógeno Competitivo , ARN Circular , ARN Mensajero

RESUMEN

Chitinase plays a vital role in the efficient biotransformation of the chitin substrate. This study aimed to modify and elucidate the contribution of the relatively conserved residues in the active site architecture of a thermophilic chitinase SsChi18A from Streptomyces sp. F-3 in processive catalysis. The enzymatic activity on colloidal chitin increased to 151%, 135%, and 129% in variants Y286W, E287A, and K186A compared with the wild type (WT). Also, the apparent processive parameter G2/G1 was lower in the variants compared to the WT, indicating the essential role of Tyr-286, Glu-287, and Lys-186 in processive catalysis. Additionally, the enzymatic activity on the crystalline chitin of F48W and double mutants F48W/Y209F and F48W/Y286W increased by 35%, 16%, and 36% compared with that for WT. Molecular dynamics simulations revealed that the driving force of processive catalysis might be related to the changes in interaction energy. This study provided a rational design strategy targeting relatively conserved residues to enhance the catalytic activity of GH18 processive chitinases.

Asunto(s)

Quitinasas , Dominio Catalítico , Quitinasas/genética , Quitinasas/química , Quitinasas/metabolismo , Quitina/química , Simulación de Dinámica Molecular