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Metabolite-associated cell communications play critical roles in maintaining the normal biological function of human through coordinating cells, organs and physiological systems. Though substantial information of MACCs has been continuously reported, no relevant database has become available so far. To address this gap, we here developed the first knowledgebase (MACC), to comprehensively describe human metabolite-associated cell communications through curation of experimental literatures. MACC currently contains: (a) 4206 carefully curated metabolite-associated cell communications pairs involving 244 human endogenous metabolites and reported biological effects in vivo and in vitro; (b) 226 comprehensive cell subtypes and 296 disease states, such as cancers, autoimmune diseases, and pathogenic infections; (c) 4508 metabolite-related enzymes and transporters, involving 542 pathways; (d) an interactive tool with user-friendly interface to visualize networks of multiple metabolite-cell interactions. (e) overall expression landscape of metabolite-associated gene sets derived from over 1500 single-cell expression profiles to infer metabolites variations across different cells in the sample. Also, MACC enables cross-links to well-known databases, such as HMDB, DrugBank, TTD and PubMed etc. In complement to ligand-receptor databases, MACC may give new perspectives of alternative communication between cells via metabolite secretion and adsorption, together with the resulting biological functions. MACC is publicly accessible at: http://macc.badd-cao.net/.
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Comunicação Celular , Doença , Bases de Conhecimento , Metaboloma , HumanosRESUMO
AIMS: Gastrointestinal paresthesia and dysmotility are common side effects of vincristine (VCR) chemotherapy, which have become one of the factors for dose reduction, therapy delay or discontinuation. However, the mechanism is not entirely clear, whether it is related to autonomic nerves injury remains unknown. Therefore, we aimed to study whether VCR-induced gastrointestinal toxicity is related to changes in mesenteric afferent activity. METHODS: The effects of a single VCR stimulation and long-term systemic VCR treatment on mesenteric afferent activity were investigated by directly recording mesenteric afferent discharge in vitro. RESULTS: Our results showed that a single VCR (0.001-1 µmol/L) stimulation obviously increased the spontaneous, chemically evoked and mechanically evoked discharge of jejunal and colonic mesenteric afferents. This kind of hypersensitivity of VCR could be blocked by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. For the mice treated with VCR (0.1 mg/kg/d, i.p.) for 14 days, the abdominal withdrawal reflex and writhing response scores were reduced. Meanwhile, the spontaneous discharge of colonic mesenteric afferents and the afferent response to VCR was downregulated, and the afferent sensitivity to chemical and mechanical stimulation was reduced. Moreover, the expression of TRPV1 in colon was decreased. CONCLUSIONS: These results suggest that the direct stimulation by VCR increases the mesenteric afferent sensitivity by activating TRPV1, which may be the reason of VCR-induced abdominal pain; the long-term systemic treatment of VCR decreases mesenteric afferent sensitivity by reducing TRPV1, which may be the reason of VCR-induced constipation.
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Canais de Cátion TRPV , Camundongos , Animais , Vincristina/toxicidade , Regulação para Baixo , Canais de Cátion TRPV/metabolismoRESUMO
Light-matter interaction is crucial to both understanding fundamental phenomena and developing versatile applications. Strong coupling, robustness, and controllability are the three most important aspects in realizing light-matter interactions. Topological and non-Hermitian photonics have provided frameworks for robustness and control flexibility, respectively. How to engineer the properties of the edge state such as photonic density of state by using non-Hermiticity while ensuring topological protection has not been fully studied. Here we construct a parity-time-symmetric dimerized photonic lattice and probe the spontaneous PT-symmetry breaking of the edge states by utilizing the strong coupling between the photonic mode and a spin ensemble. Our Letter presents an accurate and almost noninvasive approach for investigating non-Hermitian topological states, while also offering methodologies for the implementation and manipulation of topological light-matter interactions.
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BACKGROUND: Endoscopic resection (ER) for jejunoileal lesions (JILs) has been technically challenging. We aimed to characterize the clinicopathologic characteristics, feasibility, and safety of ER for JILs. METHOD: We retrospectively investigated 52 patients with JILs who underwent ER from January 2012 to February 2022. We collected and analyzed clinicopathological characteristics, procedure-related parameters, outcomes, and follow-up data. RESULTS: The mean age was 49.4 years. Of the 52 JILs, 33 ileal tumors within 20 cm from the ileocecal valve were resected with colonoscopy, while 19 tumors in the jejunum or the ileum over 20 cm from the ileocecal valve received enteroscopy resection. The mean procedure duration was 49.0 min. The en bloc resection and en bloc with R0 resection rates were 86.5% and 84.6%, respectively. Adverse events (AEs) included one (1.9%) major AE (delayed bleeding) and five (9.6%) minor AEs. During a median follow-up of 36.5 months, two patients had local recurrence (3.8%), while none had metastases. The 5-year recurrence-free survival (RFS) and disease-specific survival (DSS) were 92.9% and 94.1%, respectively. Compared with the enteroscopy group, overall AEs were significantly lower in the colonoscopy group (P < 0.05), but no statistical differences were observed in RFS (P = 0.412) and DSS (P = 0.579). There were no significant differences in AEs, RFS, and DSS between the endoscopic submucosal dissection (ESD) and the endoscopic mucosal resection (EMR) group. CONCLUSIONS: ER of JILs has favorable short-term and long-term outcomes. Both ESD and EMR can safely and effectively resect JILs in appropriately selected cases.
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Colonoscopia , Ressecção Endoscópica de Mucosa , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos de Viabilidade , Colonoscopia/efeitos adversos , Endoscopia Gastrointestinal , Ressecção Endoscópica de Mucosa/efeitos adversos , Ressecção Endoscópica de Mucosa/métodos , Resultado do Tratamento , Recidiva Local de Neoplasia/patologia , Mucosa Intestinal/patologiaRESUMO
Theoretical prediction of vibrational Raman spectra enables a detailed interpretation of experimental spectra, and the advent of machine learning techniques makes it possible to predict Raman spectra while achieving a good balance between efficiency and accuracy. However, the transferability of machine learning models across different molecules remains poorly understood. This work proposed a new strategy whereby machine learning-based polarizability models were trained on similar but smaller alkane molecules to predict spectra of larger alkanes, avoiding extensive first-principles calculations on certain systems. Results showed that the developed polarizability model for alkanes with a maximum of nine carbon atoms can exhibit high accuracy in the predictions of polarizabilities and Raman spectra for the n-undecane molecule (11 carbon atoms), validating its reasonable extrapolation capability. Additionally, a descriptor space analysis method was further introduced to evaluate the transferability, demonstrating potentials for accurate and efficient Raman predictions of large molecules using limited training data labeled for smaller molecules.
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OBJECTIVE: Preeclampsia (PE) is a pregnancy-related multi-organ disease and a significant cause of incidence rate and mortality of pregnant women and newborns worldwide. Delivery remains the only available treatment for PE. This study aims to establish a dynamic prediction model for PE. METHODS: A total of 737 patients who visited our hospital from January 2021 to June 2022 were identified according to the inclusion and exclusion criteria, forming the primary dataset. Additionally, 176 singleton pregnant women who visited our hospital from July 2022 to November 2022 comprised the verification set. We investigated different gestational weeks of sFlt-1/PLGF (soluble FMS-like tyrosine kinase-1, placental growth factor) ratio combined with maternal characteristics and routine prenatal laboratory results in order to predict PE in each trimester. Multivariate logistic regression was used to establish the prediction model for PE at different gestational weeks. The discrimination, calibration, and clinical validity were utilized to evaluate predictive models as well as models in external validation queues. RESULTS: At 20-24 weeks, the obtained prediction model for PE yielded an area under the curve of 0.568 (95% confidence interval, 0.479-0.657). At 25-29 weeks, the obtained prediction model for PE yielded an area under the curve of 0.773 (95% confidence interval, 0.703-0.842)and 0.731 (95% confidence interval, 0.653-0.809) at 30-34 weeks. After adding maternal factors, uterine artery pulsation index(Ut-IP), and other laboratory indicators to the sFlt-1/PLGF ratio, the predicted performance of PE improved. It found that the AUC improved to 0.826(95% confidence interval, 0.748 â¼ 0.904) at 20-24 weeks, 0.879 (95% confidence interval, 0.823 â¼ 0.935) at 25-29 weeks, and 0.862(95% confidence interval, 0.799 â¼ 0.925) at 30-34 weeks.The calibration plot of the prediction model indicates good predictive accuracy between the predicted probability of PE and the observed probability. Furthermore, decision-curve analysis showed an excellent clinical application value of the models. CONCLUSION: Using the sFlt-1/PLGF ratio combined with multiple factors at 25-29 weeks can effectively predict PE, but the significance of re-examination in late pregnancy is not significant.
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Biomarcadores , Fator de Crescimento Placentário , Pré-Eclâmpsia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Gravidez , Feminino , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Fator de Crescimento Placentário/sangue , Adulto , Biomarcadores/sangue , Valor Preditivo dos Testes , Idade Gestacional , Modelos Logísticos , Estudos RetrospectivosRESUMO
OBJECTIVES: To assess and compare the effectiveness of various treatment approaches for laryngeal contact granulomas (LCG). METHODS: A retrospective analysis was conducted on a cohort of 45 patients diagnosed with LCG at the Second Affiliated Hospital of Xi'an Jiaotong University from October 2017 to May 2023. Based on the treatment modalities administered, patients were categorized into three groups: acid suppression alone, hormone injection combined with acid suppression, and surgery combined with acid suppression. Subsequently, the study compared differences in treatment efficacy and average healing time among these three groups, using various indicators. RESULTS: The findings indicate that the granuloma size in LCG patients with hoarseness (0.126, 95% CI 0.087-0.288) was significantly greater compared to LCG patients without hoarseness (0.047, 95% CI 0.014-0.083) (P = 0.001). However, there were no significant variations in age, morphology (unlobulated/lobulated), laterality ratio (left/right), sex ratio (male/female), history of tracheal intubation (non-intubation/intubation), and RFS score (RFS > 7/RFS ≤ 7) (P > 0.05), regardless of the presence of hoarseness symptoms. At the treatment observation endpoint of 3 months, the curative ratio in the group receiving hormone injection combined with acid suppression was found to be significantly higher compared to the group receiving acid suppression alone (P = 0.018). In addition, the average healing time of patients in the hormone injection combined with acid suppression group was notably shorter than that of the acid suppression alone group (P = 0.007). CONCLUSIONS: The combination of hormonal injections and acid suppression may enhance the curative ratio and expedite the healing time of LCG.
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Granuloma Laríngeo , Rouquidão , Humanos , Masculino , Feminino , Estudos Retrospectivos , Rouquidão/etiologia , Rouquidão/terapia , Granuloma Laríngeo/cirurgia , Granuloma , HormôniosRESUMO
Genome-wide association study (GWAS) by measuring the joint effect of multiple loci on multiple traits, has recently attracted interest, due to the decreased costs of high-throughput genotyping and phenotyping technologies. Previous studies mainly focused on either multilocus models that identify associations with a single trait or multitrait models that scan a single marker at a time. Since these types of models cannot fully utilize the association information, the powers of the tests are usually low. To potentially address this problem, we present here a multitrait multilocus (MTML) modeling framework that implements in three steps: (1) simplify the complex calculation; (2) reduce the model dimension; (3) integrate the joint contribution of single markers to multiple traits by Cauchy combination. The performances of MTML are evaluated and compared with other three published methods by Monte Carlo simulations. Simulation results show that MTML is more powerful for quantitative trait nucleotide detection and robust for various numbers of traits. In the meanwhile, MTML can effectively control type I error rate at a reasonable level. Real data analysis of Arabidopsis thaliana shows that MTML identifies more pleiotropic genetic associations. Therefore, we conclude that MTML is an efficient GWAS method for joint analysis of multiple quantitative traits. The R package MTML, which facilitates the implementation of the proposed method, is publicly available on GitHub https://github.com/Guohongping/MTML.
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Arabidopsis , Estudo de Associação Genômica Ampla , Estudo de Associação Genômica Ampla/métodos , Arabidopsis/genética , Biometria/métodos , Locos de Características Quantitativas , Modelos Genéticos , Método de Monte CarloRESUMO
Structural maintenance of chromosomes (SMC), including cohesin, condensin and the SMC5/6 complex, are protein complexes which maintain the higher structure and dynamic stability of chromatin. Such circular complexes, with similar structures, play pivotal roles in chromatid cohesion, chromosomal condensation, DNA replication and repair, as well as gene transcription. Despite extensive research on the functions of the SMCs, our understanding of the SMC5/6 complex has remained limited compared with the other two complexes. This article has reviewed the architecture and crucial physiological roles of the SMCs, and explored the associated phenotypes resulting from mutations of the SMC components such as Cornelia de Lange syndrome (CdLS) and microcephaly, with an aim to provide insights into their functions in eukaryotic cells and implications for human diseases.
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Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Humanos , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ciclo Celular/genética , Coesinas , Complexos Multiproteicos/genética , Proteínas de Ligação a DNA/genética , Adenosina Trifosfatases/genética , Animais , Síndrome de Cornélia de Lange/genética , MutaçãoRESUMO
Overall photocatalytic conversion of CO2 and pure H2 O driven by solar irradiation into methanol provides a sustainable approach for extraterrestrial synthesis. However, few photocatalysts exhibit efficient production of CH3 OH. Here, BiOBr nanosheets supporting atomic Cu catalysts for CO2 reduction are reported. The investigation of charge dynamics demonstrates a strong built-in electric field established by isolated Cu sites as electron traps to facilitate charge transfer and stabilize charge carriers. As result, the catalysts exhibit a substantially high catalytic performance with methanol productivity of 627.66 µmol gcatal -1 h-1 and selectivity of ≈90% with an apparent quantum efficiency of 12.23%. Mechanism studies reveal that the high selectivity of methanol can be ascribed to energy-favorable hydrogenation of *CO intermediate giving rise to *CHO. The unfavorable adsorption on Cu1 @BiOBr prevents methanol from being oxidized by photogenerated holes. This work highlights the great potential of single-atom photocatalysts in chemical transformation and energy storage reactions.
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Optical vortex beams, with phase singularity characterized by a topological charge (TC), introduces a new dimension for optical communication, quantum information, and optical light manipulation. However, the evaluation of TCs after beam propagation remains a substantial challenge, impeding practical applications. Here, we introduce vortices in lateral arrays (VOILA), a novel spatial multiplexing approach that enables simultaneous transmission of a lateral array of multiple vortices. Leveraging advanced learning techniques, VOILA effectively decodes TCs, even in the presence of strong optical nonlinearities simulated experimentally. Notably, our approach achieves substantial improvements in single-shot bandwidth, surpassing single-vortex scheme by several orders of magnitude. Furthermore, our system exhibits precise fractional TC recognition in both linear and nonlinear regimes, providing possibilities for high-bandwidth communication. The capabilities of VOILA promise transformative contributions to optical information processing and structured light research, with significant potential for advancements in diverse fields.
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Quantum illumination has been proposed and demonstrated to improve the signal-to-noise ratio (SNR) in light detection and ranging (LiDAR). When relying on coincidence detection alone, such a quantum LiDAR is limited by the timing jitter of the detector and suffers from jamming noise. Inspired by the Zou-Wang-Mandel experiment, we design, construct, and validate a quantum induced coherence (QuIC) LiDAR which is inherently immune to ambient and jamming noises. In traditional LiDAR the direct detection of the reflected probe photons suffers from deteriorating SNR for increasing background noise. In QuIC LiDAR we circumvent this obstacle by only detecting the entangled reference photons, whose single-photon interference fringes are used to obtain the distance of the object, while the reflected probe photons are used to erase path information of the reference photons. In consequence, the noise accompanying the reflected probe light has no effect on the detected signal. We demonstrate such noise resilience with both LED and laser light to mimic the background and jamming noise. The proposed method paves a new way of battling noise in precise quantum electromagnetic sensing and ranging.
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Nonclassical quantum states are the pivotal features of a quantum system that differs from its classical counterpart. However, the generation and coherent control of quantum states in a macroscopic spin system remain an outstanding challenge. Here we experimentally demonstrate the quantum control of a single magnon in a macroscopic spin system (i.e., 1 mm-diameter yttrium-iron-garnet sphere) coupled to a superconducting qubit via a microwave cavity. By tuning the qubit frequency in situ via the Autler-Townes effect, we manipulate this single magnon to generate its nonclassical quantum states, including the single-magnon state and the superposition of single-magnon state and vacuum (zero magnon) state. Moreover, we confirm the deterministic generation of these nonclassical states by Wigner tomography. Our experiment offers the first reported deterministic generation of the nonclassical quantum states in a macroscopic spin system and paves a way to explore its promising applications in quantum engineering.
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BACKGROUND AND AIMS: Stenosis after esophageal endoscopic submucosal dissection (ESD) has a high incidence, and muscular injury is an important risk factor for esophageal stenosis. Hence, this study aimed to classify muscular injury degrees and investigate their association with postoperative stenosis. METHODS: This retrospective study included 1033 patients with esophageal mucosal lesions treated with ESD between August 2015 and March 2021. Demographic and clinical parameters were analyzed, and stenosis risk factors were identified using multivariate logistic regression. A novel muscular injury classification system was proposed and used to investigate the association between different muscular injury degrees and postoperative stenosis. Finally, a scoring system was established to predict muscular injury. RESULTS: Of 1033 patients, 118 (11.4%) had esophageal stenosis. The multivariate analysis demonstrated that the history of endoscopic esophageal treatment, circumferential range, and muscular injury were significant risk factors for esophageal stenosis. Patients with type II muscular injuries tended to develop complex stenosis (n = 13 [36.1%], P < .05), and type II muscular injuries were more likely to predispose patients to severe stenosis than type I (73.3% and 92.3%, respectively). The scoring system showed that patients with high scores (3-6) were more likely to have muscular injury. The score model presented good discriminatory power in the internal validation (area under the receiver-operating characteristic curve, .706; 95% confidence interval, .645-.767) and goodness-of-fit in the Hosmer-Lemeshow test (P = .865). CONCLUSIONS: Muscular injury was an independent risk factor for esophageal stenosis. The scoring system demonstrated good performance in predicting muscular injury during ESD.
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Carcinoma de Células Escamosas , Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Estenose Esofágica , Humanos , Estenose Esofágica/epidemiologia , Estenose Esofágica/etiologia , Constrição Patológica , Ressecção Endoscópica de Mucosa/efeitos adversos , Estudos Retrospectivos , Neoplasias Esofágicas/cirurgia , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Reintervention modalities after myotomy failure in achalasia patients have yet to be established. The efficacy and safety of salvage peroral endoscopic myotomy (POEM) for treatment of achalasia after myotomy failure were evaluated in the study. METHODS: Between August 2011 and August 2021 at the Endoscopy Center of Zhongshan Hospital, 219 achalasia patients who had previously undergone a myotomy underwent a salvage POEM and were thus retrospectively enrolled in this study. After propensity score matching (PSM), operation-related parameters were compared between the salvage POEM group and the naïve POEM group. Subgroup analysis was performed between patients with previous Heller myotomy (HM) and patients with previous POEM. RESULTS: With similar baseline characteristics between both groups after PSM, the salvage POEM group presented with shorter tunnel length (11.8 ± 2.2 cm vs 12.8 ± .9 cm, P < .0001) and myotomy length (9.8 ± 2.0 cm vs 10.4 ± 1.0 cm, P < .0001) than the naïve POEM group. No significant differences were found in procedure-related adverse events between patients of salvage POEM and naïve POEM. The primary outcome of treatment success occurred in 175 of 193 patients (90.7%) in the salvage POEM group versus 362 of 374 patients (96.8%) in the naïve POEM group (P = .0046). At a 2- and 5-year follow-up, significantly higher rates of clinical failures were observed in the previous HM subgroup than in the previous POEM subgroup (P = .0433 and P = .0230, respectively). CONCLUSIONS: Salvage POEM after a previous myotomy failure, especially after a POEM failure, is a promising treatment option because it has a durable clinical relief rate.
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Procedimentos Cirúrgicos do Sistema Digestório , Acalasia Esofágica , Miotomia de Heller , Miotomia , Humanos , Acalasia Esofágica/cirurgia , Estudos RetrospectivosRESUMO
OBJECTIVES: Delayed bleeding is a rare but important major adverse event (mAE) after endoscopic submucosal tunneling procedures (ESTP), which is scarcely reported. We aimed to characterize the clinical characteristics of delayed bleeding and provide better management of this mAE. METHOD: From August 2010 to October 2022, we reviewed 3852 patients with achalasia receiving peroral endoscopic myotomy (POEM) and 1937 patients with upper gastrointestinal tumors receiving submucosal tunneling endoscopic resection (STER). Among these, records of 22 patients (15 POEM, 7 STER) with delayed bleeding were collected. Clinical characteristics, treatment, and outcomes of delayed bleeding were analyzed. RESULTS: The mean age was 43.6 years. Ten patients (45.5%) were intratunnel bleeding, seven (31.8%) were intratunnel bleeding accompanied by mucosal bleeding, and five (22.7%) were mucosal bleeding. The most common accompanied symptoms were hematemesis, fever, and melena. The most common accompanied mAEs were fistula, pulmonary inflammation, and pleural effusion with atelectasis. The mean duration from ESTP to endoscopic intervention was 5.3 ± 4.9 days. Active bleeding was identified in 21 patients (95.5%). The bleeding was successfully controlled by electrocoagulation (19 cases), endoscopic clipping (six cases), and Sengstaken-Blakemore tube insertion (three cases), and no patient required surgical intervention. The mean hemostatic procedure duration was 61.8 ± 45.8 min. The mean post-bleeding hospital stay was 10.0 ± 6.2 days. A brief meta-analysis of previous studies showed the pooled estimate delayed bleeding rate after POEM, STER, and G-POEM was 0.4%. CONCLUSIONS: Delayed bleeding is uncommon and could be effectively managed by timely emergency endoscopic procedures without requiring subsequent surgical interventions.
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Ressecção Endoscópica de Mucosa , Acalasia Esofágica , Humanos , Adulto , Estudos Retrospectivos , Resultado do Tratamento , Acalasia Esofágica/cirurgia , Endoscopia , Ressecção Endoscópica de Mucosa/efeitos adversos , Ressecção Endoscópica de Mucosa/métodosRESUMO
BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) is a promising endoscopic technique for achalasia. We aimed to establish a regression model and develop a simple nomogram to predict the technical difficulty of POEM in a single center with large volume cases. METHODS: 3385 achalasia patients treated with POEM were included, and the technical difficulty was systemically evaluated. All of them were randomized into the training cohort (n = 1693) or internal validation cohort (n = 1692). Then, the prediction model and nomogram were proposed based on multivariate logistic regression analysis in the training cohort and assessed in the validation cohort. RESULTS: Of 3385 patients, technical difficulty happened in 417 (12.32%) cases. In the training stage, six factors were weighted based on the ß coefficient from the regression model, including age, disease duration, sigmoid esophagus, mucosal edema, submucosal fibrosis, and tunnel length. The patients were categorized into low-risk (< 0.1), medium-risk (0.1-0.25), and high-risk (> = 0.25) groups. Our score model performed satisfying discrimination with the areas under the receiver-operating characteristic curve (AUC) of 0.743 (95% confidence interval (CI), 0.701-0.785) and calibration with goodness of fit in the Hosmer-Lemeshow test (P = 0.088) in internal validation. CONCLUSIONS: The prediction model and nomogram demonstrated good performance in predicting the technical difficulty of POEM.
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Procedimentos Cirúrgicos do Sistema Digestório , Acalasia Esofágica , Miotomia , Humanos , Colo Sigmoide , Acalasia Esofágica/cirurgia , NomogramasRESUMO
The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Here we investigate the presence and possible roles of aberrant splicing and splicing-dependent RNA-fusion transcripts in neuroblastoma. In addition, we attend to establish whether the spliceosome can be targeted to treat neuroblastoma. Through analysis of RNA-sequenced neuroblastoma we show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, producing a truncated BAG2-protein which inhibited retinoic acid induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism generating altered gene products in neuroblastoma and show that the spliceosome is a potential target for clinical intervention.
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Chaperonas Moleculares/genética , Proteínas Mutantes Quiméricas/genética , Neuroblastoma/genética , Splicing de RNA , Spliceossomos/efeitos dos fármacos , Aminoaciltransferases/metabolismo , Animais , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Fusão Gênica , Proteínas de Choque Térmico HSC70/metabolismo , Humanos , Camundongos Nus , Chaperonas Moleculares/metabolismo , Proteínas Mutantes Quiméricas/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Deleção de Sequência , Fatores de Transcrição/metabolismo , Proteínas tau/metabolismoRESUMO
Experiments for simultaneous elimination and detoxification of microgram level of As(â ¢) in the presence of micromolar H2O2 and Fe(â ¡) which are frequently encountered in natural water were conducted. The results showed that the molar ratio of oxidant to As(III) plays important role in As(III) oxidation under the experimental conditions. The extent of As(â ¢) oxidation with single H2O2 or Fe(â ¡) ranged from 7.9 % to 60.3 % and 22.2-46.6 %, respectively. Treatments with H2O2/As(â ¢) molar ratios in the range 150: 1-750: 1 or Fe(â ¡)/As(â ¢) molar ratios in the range 37.5: 1-375: 1 were more favor for As(â ¢) oxidation respectively, and increasing oxidant concentration did not result in complete As(â ¢) oxidation. As(â ¢) was completely oxidized and eliminated following the precipitation of ferric hydroxides in 5 reaction minutes when H2O2 and Fe(â ¡) coexisted in the reaction system. The interface characterization for the reacted precipitates after the experiment were conducted by using a high-resolution field emission scanning electron microscopy (SEM) coupled with an EX-350 energy dispersive X-ray spectrometer (EDX) and X-ray photoelectron spectroscopy (XPS), respectively. The results showed that As(â ¤) was the merely arsenic species and As oxide primary situated in the subsurface layer of the reacted precipitates, whereas Fe was more concentrated in the outermost surface layer. Our research showed that H2O2 and Fe(â ¡) at natural level may exert significant influence on arsenic mobilization in natural water. Considering the much more toxic of As(â ¢) than that of As(â ¤), the research also provide us an environmental friendly choice in the elimination and detoxification of microgram As(â ¢) in drinking water.
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Arsênio , Arsenitos , Poluentes Químicos da Água , Peróxido de Hidrogênio/química , Arsênio/química , Compostos Férricos/química , Oxirredução , Oxidantes , Água , Poluentes Químicos da Água/análise , Compostos Ferrosos/químicaRESUMO
UDP-glycosyltransferase (UGT) is the major detoxification enzymes of phase II involved in xenobiotics metabolism, which potentially mediates the formation of insect resistance. Previous transcriptome sequencing studies have found that several UGT genes were upregulated in indoxacarb resistant strains of Spodoptera litura, but whether these UGT genes were involved in indoxacarb resistance and their functions in resistance were unclear. In this study, the UGTs inhibitor, 5-nitrouracil, enhanced the toxicity of indoxacarb against S. litura, preliminarily suggesting that UGTs were participated in indoxacarb resistance. Two UGT genes, UGT33J17 and UGT41D10 were upregulated in the resistant strains and could be induced by indoxacarb. Alignment of UGT protein sequences revealed two conserved donor-binding regions with several key residues that interact with catalytic sites and sugar donors. Further molecular modeling and docking analysis indicated that two UGT proteins were able to stably bind indoxacarb and N-decarbomethoxylated metabolite (DCJW). Furthermore, knockdown of UGT33J17 and UGT41D10 decreased viability of Spli-221 cells and enhanced susceptibility of larvae to indoxacarb. Transgenic overexpression of these genes reduced the toxicity of indoxacarb in Drosophila melanogaster. This work revealed that upregulation of UGT genes significantly contributes to indoxacarb resistance in S. litura, and is of great significance for the development of integrated and sustainable management strategies for resistant pests in the field.