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Extensive research has made significant progress in exploring the potential application of extracellular vesicles (EV) in the diagnosis and treatment of osteoarthritis (OA). However, there is current a lack of study on bibliometrics. In this study, we completed a novel bibliometric analysis of EV research in OA over the past two decades. Specifically, we identified a total of 354 relevant publications obtained between January 1, 2003 and December 31, 2022. We also provided a description of the distribution information regarding the countries or regions of publication, institutions involved, journals, authors, citations, and keywords. The primary research focuses encompassed the role of extracellular vesicles in the diagnosis of OA, delivery of active ingredients, treatment strategies, and cartilage repair. These findings highlight the latest research frontiers and emerging areas, providing valuable insights for further investigations on the application of extracellular vesicles in the context of osteoarthritis.
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The dorsal root ganglia (DRG), housing primary sensory neurons, transmit somatosensory and visceral afferent inputs to the dorsal horn of the spinal cord. They play a pivotal role in both physiological and pathological states, including neuropathic and visceral pain. In vivo calcium imaging of DRG enables real-time observation of calcium transients in single units or neuron ensembles. Accumulating evidence indicates that DRG neuronal activities induced by somatic stimulation significantly affect autonomic and visceral functions. While lumbar DRG calcium imaging has been extensively studied, thoracic segment DRG calcium imaging has been less explored due to surgical exposure and stereotaxic fixation challenges. Here, we utilized in vivo calcium imaging at the thoracic1 dorsal root ganglion (T1-DRG) to investigate changes in neuronal activity resulting from somatic stimulations of the forelimb. This approach is crucial for understanding the somato-cardiac reflex triggered by peripheral nerve stimulations (PENS), such as acupuncture. Notably, synchronization of cardiac function was observed and measured by electrocardiogram (ECG), with T-DRG neuronal activities, potentially establishing a novel paradigm for somato-visceral reflex in the thoracic segments.
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Calcio , Electrocardiografía , Ganglios Espinales , Animales , Ganglios Espinales/fisiología , Calcio/metabolismo , Calcio/análisis , Electrocardiografía/métodos , Ratones , Nervios Periféricos/fisiología , Miembro Anterior/inervación , Miembro Anterior/fisiologíaRESUMEN
In the original publication [...].
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The rapid variation of influenza challenges vaccines and treatments, which makes an urgent task to develop the high-efficiency and low-toxicity new anti-influenza virus drugs. Selenium is one of the essential trace elements for the human body that possesses a good antiviral activity. In this study, we assessed anti-influenza A virus (H1N1) activity of polyethylene glycol (PEG)-modified gray selenium nanoparticles (PEG-SeNPs) on Madin-Darby Canine Kidney (MDCK) cells in vitro. CCK-8 assay showed that PEG-SeNPs had a protective effect on H1N1-infected MDCK cells. Moreover, PEG-SeNPs significantly reduced the mRNA level of H1N1. TUNEL-DAPI test showed that DNA damage reached a high level but effectively prevented after PEG-SeNPs treatment. Meanwhile, JC-1, Annexin V-FITC and cell cycle assay demonstrated the apoptosis induced by H1N1 was reduced greatly when treated with PEG-SeNPs. Furthermore, the downregulation of p-ATM, p-ATR and P53 protein, along with the upregualation of AKT protein indicated that PEG-SeNPs could inhibit H1N1-induced cell apoptosis through reactive oxygen species (ROS)-mediated related signaling pathways. Finally, Cytokine detection demonstrated PEG-SeNPs inhibited the production of pro-inflammatory factors after infection, including IL-1ß, IL-5, IL-6, and TNF-α. To sum up, PEG-SeNPs might become a new potential anti-H1N1 influenza virus drug due to its antiviral and anti-inflammatory activity.
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Apoptosis , Subtipo H1N1 del Virus de la Influenza A , Polietilenglicoles , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Perros , Células de Riñón Canino Madin Darby , Polietilenglicoles/química , Polietilenglicoles/farmacología , Inflamación/tratamiento farmacológico , Antivirales/farmacología , Selenio/farmacología , Selenio/química , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Humanos , Daño del ADN/efectos de los fármacosRESUMEN
In this study, a simple in situ technique followed by hydrothermal method is used to synthesize a novel tremella-like structure of ZIF-67Co(OH)F@Co3O4/CC metal-organic framework (MOF) derived from zeolite imidazole. The in situ synthesis of metal-organic frameworks (MOFs) increases their conductivity and produces more active sites for ion insertion. Their unique, scalable design not only provides more space to accommodate volume change but also facilitates electrolyte penetration into the electrode resulting in more active materials being utilized and ion-electron transfer occurring faster during the cycle. As a result, the binder-free ZIF-67Co(OH)F@Co3O4/CC supercapacitor electrode exhibits typical pseudo-capacitance behaviour, with a specific capacitance of 442 F g-1 and excellent long-term cycling stability of 90% after 5000 cycles at 10 A g-1.
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In mammals, global passive demethylation contributes to epigenetic reprogramming during early embryonic development. At this stage, the majority of DNA-methyltransferase 1 (DNMT1) protein is excluded from nucleus, which is considered the primary cause. However, whether the remaining nuclear activity of DNMT1 is regulated by additional mechanisms is unclear. Here, we report that nuclear DNMT1 abundance is finetuned through proteasomal degradation in mouse zygotes. We identify a maternal factor, Pramel15, which targets DNMT1 for degradation via Cullin-RING E3 ligases. Loss of Pramel15 elevates DNMT1 levels in the zygote pronuclei, impairs zygotic DNA demethylation, and causes a stochastic gain of DNA methylation in early embryos. Thus, Pramel15 can modulate the residual level of DNMT1 in the nucleus during zygotic DNA replication, thereby ensuring efficient DNA methylation reprogramming in early embryos.
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Núcleo Celular , ADN (Citosina-5-)-Metiltransferasa 1 , Desmetilación del ADN , Cigoto , Animales , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , Cigoto/metabolismo , Ratones , Núcleo Celular/metabolismo , Femenino , Metilación de ADN , Proteolisis , Desarrollo Embrionario/genética , Masculino , Embrión de Mamíferos/metabolismo , Ratones Noqueados , Regulación del Desarrollo de la Expresión Génica , Replicación del ADNRESUMEN
Wound healing is a complex, dynamic process involving the coordinated interaction of diverse cell types, growth factors, cytokines, and extracellular matrix components. Despite emerging evidence highlighting their importance, dermal sheath cells remain a largely overlooked aspect of wound healing research. This review explores the multifunctional roles of dermal sheath cells in various phases of wound healing, including modulating inflammation, aiding in proliferation, and contributing to extracellular matrix remodelling. Special attention is devoted to the paracrine effects of dermal sheath cells and their role in fibrosis, highlighting their potential in improving healing outcomes, especially in differentiating between hairy and non-hairy skin sites. By drawing connections between dermal sheath cells activity and wound healing outcomes, this work proposes new insights into the mechanisms of tissue regeneration and repair, marking a step forward in our understanding of wound healing processes.
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The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.
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Encéfalo , Canfanos , Lípidos , Nanopartículas , Rociadores Nasales , Ratas Sprague-Dawley , Animales , Nanopartículas/química , Ratas , Lípidos/química , Encéfalo/metabolismo , Canfanos/química , Canfanos/administración & dosificación , Canfanos/farmacología , Masculino , Administración Intranasal , Sistemas de Liberación de Medicamentos , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Tamaño de la PartículaRESUMEN
The Pedestrian Collision Avoidance System (PCAS) of Intelligent Vehicle (IV) can be effective in preventing the occurrence of traffic accidents. However, the complicated operation environments introduce great challenges to the camera used by the PCAS. Therefore, the camera based PCAS should be fully tested and evaluated before deployment. The traditional simulation test for the camera based PCAS attempted to use geometric or physical simulation models, which have low reality and are suitable for the primary stage of the PCAS development. Camera-in-the-Loop (CIL) test is one of Hardware-in-the-Loop methods that embeds the real camera hardware into the virtual simulation system to test the camera. CIL can utilize the real hardware response while overcoming the common simulation weakness of fidelity. In this paper, we construct a CIL test platform, and propose the CIL based test scenarios generation and scenario parameter impact evaluation method for PCAS. First, we construct the CIL test platform whose image quality and functional confidence are both validated to prove CIL credibility. Second, the PCAS under the test is analyzed and the corresponding test scenario parameters are designed. In order to accelerate the test scenario generation, a Greedy Based Combination test method (GBC) based on the CIL is proposed. The Chi-square analysis and two-factor of variance analysis verification methods are used to analyze the influence of individual and multiple scenario parameters on the PCAS performance. The experiment results show that the GBC improves the test speed by 12 times compared to the traversal test, and the frequency ratio of each scenario parameter is no more than 3% different from that of the traversal test. Also, GBC has an equivalent ability to find the PCAS collision scenarios parameter combination to the traversal test.
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Accidentes de Tránsito , Peatones , Humanos , Accidentes de Tránsito/prevención & control , Simulación por Computador , Automóviles , Fotograbar/instrumentaciónRESUMEN
Precise forecasting of satellite clock bias is crucial for ensuring service quality and enhancing the efficiency of real-time precise point positioning (PPP).The grey model with many benefits is an excellent choice for predicting real-time clock bias. However, the absolute prediction error of a small number of satellites is very high in actual forecasting process. In order to address this issue, a non-homogeneous white exponential law grey model has been constructed specifically for predicting clock bias sequences with non-homogeneous class ratio approximating constants. Considering that any model is difficult to apply to different kinds of satellite clocks and clock bias signals, an adaptive selection strategy for forecast model is proposed to ensure more excellent prediction accuracy. Afterwards, a prediction scenario based on the observed products of the BeiDou satellite navigation system (BDS) is created to demonstrate the effectiveness of the approach described in this article. The outcomes of the method are then compared with those of a single grey model and the ultra-rapid predicted products. The outcomes demonstrate that this strategy's prediction accuracy is less than 1 ns/day and that its prediction uncertainty is much decreased, which may improve data selection for real-time applications like real-time kinematics (RTK) and PPP.
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A total of 254 elderly OS patients diagnosed and treated in our hospital during May 2019 to April 2022 was randomly picked, of which 100 patients were finally enrolled. Patients were divided into OS fracture group and non-fracture group according to whether they had OS fracture. The contents of bone mineral density (BMD) and bone metabolism biochemical indexes, including Dickkopf1 (DKK-1), sclerostin (SOST), osteoprotegerin (OPG), osteopontin (OPN), osteocalcin (BGP) and 25 hydroxyvitamin D (25 (OH) D) were detected in lumbar L2c4 and left femoral greater trochanter. The correlation between bone metabolism and BMD was evaluated using Pearson analysis. The risk factors of OS fracture were analyzed using Multivariate logistic regression analysis. The predictive value of biochemical indexes of bone metabolism on the risk of OS fracture was analyzed using ROC curve.
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The epithelial-mesenchymal transition (EMT) is a genetic reprogramming that tumor cells utilize for metastasis. Epsin-3 (EPN3) is an endocytic adapter protein involved in clathrin-mediated endocytosis and had been previously linked to EMT in breast cancer and glioma metastasis. In this study, identified the role of epsin-3 in lung adenocarcinoma and metastasis and epsin-3 levels identified using an expression profile analysis of patient data indicated the protein was abnormally overexpressed in lung adenocarcinoma patients and this was directly linked to disease severity. Gene knockdowns of EPN3 in human adenocarcinoma cell line A549 and the non-small cell lung carcinoma cell line H1299 decreased the levels of mesenchymal markers, including vimentin (VIM), N-cadherin (NCAD) and embryonic transcription factors like zinc finger E-box binding homeobox 1(ZEB1), snail, and the key molecules of Wnt pathway such as ß-catenin and resulted in increased expression of the epithelial marker E-cadherin (ECAD). Our data links EPN3 to the EMT process in lung cancer and inhibition of its expression reduced the metastatic and invasive ability of lung adenocarcinoma cells by inhibiting the EMT process.
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Proteínas Adaptadoras del Transporte Vesicular , Adenocarcinoma del Pulmón , Movimiento Celular , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Invasividad Neoplásica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células A549 , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/genética , beta Catenina/metabolismo , Cadherinas/metabolismo , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Vía de Señalización WntRESUMEN
Protecting human health and ensuring food security require the swift and accurate detection of sulfonamides (SAs) residues in foods. Herein, we proposed an Eu-postfunctionalized bimetallic porphyrin metal-organic framework (PCN-221(Zr/Ce)@Eu-DPA-H4btec) synthesized solvothermally for fluorescence sensing. The PCN-221(Zr/Ce)@Eu-DPA-H4btec fluorescent sensor demonstrated excellent stability and high selectivity to SAs, and the detection limits of sulfamethazine (SM2), sulfamerazine (SMR), and sulfamethoxydiazine (SMD) were as low as 56 nmol/L, 45 nmol/L, and 56 nmol/L, respectively. The PCN-221(Zr/Ce)@Eu-DPA-H4btec fluorescent sensor was successfully applied for the detection of SM2, SMR, and SMD in real pork and milk samples, with satisfactory recoveries (81.2-118.3%) and high precisions (RSDs <8.2, n = 3). Combining the optical properties of the nanohybrids, PCN-221(Zr/Ce)@Eu-DPA-H4btec integrated fluorescent hydrogels were innovatively prepared for visual sensing of SM2, SMR, and SMD. This study provides an uncomplicated and sensitive method for SAs detection in food matrices.
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Europio , Contaminación de Alimentos , Hidrogeles , Estructuras Metalorgánicas , Leche , Porfirinas , Espectrometría de Fluorescencia , Sulfonamidas , Estructuras Metalorgánicas/química , Contaminación de Alimentos/análisis , Europio/química , Leche/química , Animales , Sulfonamidas/química , Sulfonamidas/análisis , Porfirinas/química , Hidrogeles/química , Porcinos , Fluorescencia , Límite de Detección , Colorantes Fluorescentes/químicaRESUMEN
This paper aims to study the spectrum-effect relationship between the fingerprints before and after salt processing of Dipsacus asper and the efficacy of warming and tonifying kidney Yang and find the main active components against kidney Yang deficiency before and after salt processing of D. asper, so as to provide the basis for clarifying the effect of salt processing on kidney Yang deficiency. The HPLC fingerprint before and after salt processing of D. asper was established by the HPLC-DAD. 15 common peaks were obtained, and 11 components were identified. The content changes of various components in rat serum were detected, and the difference in efficacy before and after salt processing was compared. The results of pharmacological experiments showed that salt processing of D. asper could enhance the kidney index. At the same dose, there was a significant difference between the raw D. asper and D. asper after salt processing groups. Compared with the model group, the contents of ACTH, cAMP, CORT, E_2, GH, Na~+-K~+-ATPase, T, and T4 in the serum of rats in the administration group increased to a certain extent, and the contents of cGMP and TNF-α decreased to a certain extent. Among them, there were significant differences in the above indexes in the serum of rats in the high-dose group of raw D. asper, middle-dose group of D. asper after salt processing, high-dose group of D. asper after salt processing, and the positive drug group. The overall results showed that D. asper after salt processing was more effective than raw D. asper in preventing kidney yang deficiency. The efficacy of D. asper was evaluated by grey correlation analysis, entropy method, and Pearson correlation analysis, and the components of D. asper after salt processing against kidney yang deficiency were screened out. According to the results of correlation degree ranking, the components with increased ranking before and after salt processing of D. asper were loganin, chlorogenic acid, dipsacoside A, asperosaponin â ¥, caffeic acid, and isochlorogenic acid B. It was preliminarily speculated that these compounds may be the potential pharmacodynamic components for the treatment of kidney yang deficiency before and after salt processing of D. asper. The changing components before and after the salt processing of D. asper were determined, which proved that D. asper after salt processing was superior to D. asper in the treatment of kidney yang deficiency. The spectrum-effect relationship between the efficacy of D. asper before and after salt processing and the treatment of kidney yang deficiency was established, which laid a foundation for the subsequent study on the pharmacodynamic components and molecular mechanism of salt processing of D. asper.
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Dipsacaceae , Medicamentos Herbarios Chinos , Riñón , Deficiencia Yang , Animales , Ratas , Dipsacaceae/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/administración & dosificación , Masculino , Deficiencia Yang/tratamiento farmacológico , Deficiencia Yang/fisiopatología , Riñón/efectos de los fármacos , Ratas Sprague-Dawley , Cromatografía Líquida de Alta Presión , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/fisiopatologíaRESUMEN
Pericentric heterochromatin is a critical component of chromosomes marked by histone H3 K9 (H3K9) methylation1-3. However, what recruits H3K9-specific histone methyltransferases to pericentric regions in vertebrates remains unclear4, as does why pericentric regions in different species share the same H3K9 methylation mark despite lacking highly conserved DNA sequences2,5. Here we show that zinc-finger proteins ZNF512 and ZNF512B specifically localize at pericentric regions through direct DNA binding. Notably, both ZNF512 and ZNF512B are sufficient to initiate de novo heterochromatin formation at ectopically targeted repetitive regions and pericentric regions, as they directly recruit SUV39H1 and SUV39H2 (SUV39H) to catalyse H3K9 methylation. SUV39H2 makes a greater contribution to H3K9 trimethylation, whereas SUV39H1 seems to contribute more to silencing, probably owing to its preferential association with HP1 proteins. ZNF512 and ZNF512B from different species can specifically target pericentric regions of other vertebrates, because the atypical long linker residues between the zinc-fingers of ZNF512 and ZNF512B offer flexibility in recognition of non-consecutively organized three-nucleotide triplets targeted by each zinc-finger. This study addresses two long-standing questions: how constitutive heterochromatin is initiated and how seemingly variable pericentric sequences are targeted by the same set of conserved machinery in vertebrates.
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Centrómero , Evolución Molecular , Heterocromatina , N-Metiltransferasa de Histona-Lisina , Histonas , Motivos de Nucleótidos , Animales , Humanos , Ratones , Centrómero/genética , Centrómero/metabolismo , Pollos , Homólogo de la Proteína Chromobox 5 , Silenciador del Gen , Heterocromatina/metabolismo , Heterocromatina/química , Heterocromatina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/química , Histonas/metabolismo , Histonas/química , Anfioxos , Metilación , Petromyzon , Proteínas Represoras/metabolismo , Proteínas Represoras/química , Proteínas Represoras/genética , Serpientes , Xenopus laevis , Pez Cebra , Dedos de ZincRESUMEN
Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection, and the study of anti-adenoviral drugs has far-reaching clinical implications. Elemental selenium can play a specific role as an antioxidant in the human immune cycle by non-specifically binding to the amino acid methionine in body proteins. Methods: The antiviral mechanism of selenomethionine was explored by measuring cell membrane status, intracellular DNA status, cytokine secretion, mitochondrial membrane potential, and ROS production. Conclusions: Selenomethionine improved the regulation of ROS-mediated apoptosis by modulating the expression of Jak1/2, STAT3, and BCL-XL, which led to the inhibition of apoptosis. It is anticipated that selenomethionine will offer a new anti-adenoviral therapeutic alternative.
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Apoptosis , Especies Reactivas de Oxígeno , Selenometionina , Transducción de Señal , Humanos , Células A549 , Antivirales/farmacología , Apoptosis/efectos de los fármacos , Quinasas Janus/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Selenometionina/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: As one of the leading causes of child mortality, deaths due to congenital anomalies (CAs) have been a prominent obstacle to meet Sustainable Development Goal 3.2. OBJECTIVE: We conducted this study to understand the death burden and trend of under-5 CA mortality (CAMR) in Zhejiang, one of the provinces with the best medical services and public health foundations in Eastern China. METHODS: We used data retrieved from the under-5 mortality surveillance system in Zhejiang from 2012 to 2021. CAMR by sex, residence, and age group for each year was calculated and standardized according to 2020 National Population Census sex- and residence-specific live birth data in China. Poisson regression models were used to estimate the annual average change rate (AACR) of CAMR and to obtain the rate ratio between subgroups after adjusting for sex, residence, and age group when appropriate. RESULTS: From 2012 to 2021, a total of 1753 children died from CAs, and the standardized CAMR declined from 121.2 to 62.6 per 100,000 live births with an AACR of -9% (95% CI -10.7% to -7.2%; P<.001). The declining trend was also observed in female and male children, urban and rural children, and neonates and older infants, and the AACRs were -9.7%, -8.5%, -8.5%, -9.2%, -12%, and -6.3%, respectively (all P<.001). However, no significant reduction was observed in children aged 1-4 years (P=.22). Generally, the CAMR rate ratios for male versus female children, rural versus urban children, older infants versus neonates, and older children versus neonates were 1.18 (95% CI 1.08-1.30; P<.001), 1.20 (95% CI 1.08-1.32; P=.001), 0.66 (95% CI 0.59-0.73; P<.001), and 0.20 (95% CI 0.17-0.24; P<.001), respectively. Among all broad CA groups, circulatory system malformations, mainly deaths caused by congenital heart diseases, accounted for 49.4% (866/1753) of deaths and ranked first across all years, although it declined yearly with an AACR of -9.8% (P<.001). Deaths due to chromosomal abnormalities tended to grow in recent years, although the AACR was not significant (P=.90). CONCLUSIONS: CAMR reduced annually, with cardiovascular malformations ranking first across all years in Zhejiang, China. Future research and practices should focus more on the prevention, early detection, long-term management of CAs and comprehensive support for families with children with CAs to improve their survival chances.
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Mortalidad del Niño , Anomalías Congénitas , Humanos , China/epidemiología , Masculino , Anomalías Congénitas/mortalidad , Anomalías Congénitas/epidemiología , Femenino , Lactante , Preescolar , Recién Nacido , Mortalidad del Niño/tendencias , Vigilancia de la Población/métodos , Análisis de DatosRESUMEN
Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.