Developing Hypoxia-Sensitive System via Designing Tumor-Targeted Fullerene-Based Photosensitizer for Multimodal Therapy of Deep Tumor.

Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C70 ) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C70 consuming O2 for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C70 -mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.

Causal relationship from heart failure to kidney function and CKD: A bidirectional two-sample mendelian randomization study.

BACKGROUND: Heart Failure (HF) is a widespread condition that affects millions of people, and it is caused by issues with the heart and blood vessels. Even though we know hypertension, coronary artery disease, obesity, diabetes, and genetics can increase the risk of HF and Chronic Kidney Disease (CKD), the exact cause of these conditions remains a mystery. To bridge this gap, we adopted Mendelian Randomization (MR), which relies on genetic variants as proxies. METHODS: We used data from European populations for our Bidirectional Two-Sample MR Study, which included 930,014 controls and 47,309 cases of HF from the HERMES consortium, as well as 736,396 controls and 51,256 cases of CKD. We also employed several MR variations, including MR-Egger, Inverse Variance Weighted (IVW), and Weighted Median Estimator (WME), to guarantee the results were accurate and comprehensive.). RESULTS: In this study, the MR analysis found that individuals with a genetic predisposition for HF have an elevated risk of CKD. Our study revealed a significant association between the genetic prediction of HF and the risk of CKD, as evidenced by the IVW method [with an odds ratio (OR) of 1.12 (95% CI, 1.03-1.21), p = 0.009] and the WME [with an OR of 1.14 (95% CI, 1.03-1.26), p = 0.008]. This causal relationship remained robust even after conducting MR analysis while adjusting for the effects of diabetes and hypertension, yielding ORs of 1.13 (IVW:95% CI, 1.03-1.23), 1.12 (MR-Egger: 95% CI, 0.85-1.48), and 1.15 (WME:95% CI, 1.04-1.27) (p = 0.008). However, in the reverse analysis aiming to explore CKD and renal function as exposures and HF as the outcome, we did not observe a statistically significant causal link between CKD and HF. CONCLUSION: Our study demonstrates the significance of HF in CKD progression, thus having meaningful implications for treatment and the potential for discovering new therapies. To better understand the relationship between HF and CKD, we need to conduct research in a variety of populations.

[Research trends and hot spots of Chuanxiong Rhizoma from 2010 to 2023].

This study aims to objectively and quantitatively analyze the research status and hot spots of Chuanxiong Rhizoma and provide guidance for further research and clinical application of this herbal medicine. Firstly, the research articles involving Chuanxiong Rhizoma from 2010 to 2023 were retrieved from seven databases including Web of Science, PubMed, Medline, CNKI, VIP, Wanfang, and SinoMed. Then, NoteExpress and manual reading were employed to complete the de-duplication and screening of the articles, and the annual number of publications and journals was analyzed. Finally, CiteSpace was used for systematic analysis of the research institutions, authors, and keywords, and the corresponding knowledge maps were established. After screening, 1 137 articles in Chinese and 433 articles in English were included, and the annual number of publications showed an increasing trend. Chinese Journal of Experimental Traditional Medical Formulae and Journal of Ethnopharmacology were the top Chinese and English journal in the number of publications. Chengdu University of Traditional Chinese Medicine and Nanjing University of Chinese Medicine published the most articles in Chinese and English, respectively. PENG Cheng and FENG Yi were the authors published more articles in Chinese and English. Ferulic acid, signaling pathway, mechanism, headache, ligustrazine, and apoptosis were frequent keywords. A total of 20 clusters and 30 bursts were generated. The comprehensive analysis showed that the research trends and hot spots in this field mainly focused on pharmacological components and isolation, pharmacological effects and mechanism, clinical application and efficacy, compatibility and efficacy of drug pairs, quality evaluation and control, and cultivation and germplasm improvement.

Effect of Danhong injection on heart failure in rats evaluated by metabolomics.

Background: Heart failure (HF) is characterized by reduced ventricular filling or ejection function due to organic or non-organic cardiovascular diseases. Danhong injection (DHI) is a medicinal material used clinically to treat HF for many years in China. Although prior research has shown that Danhong injection can improve cardiac function and structure, the biological mechanism has yet to be determined. Methods: Serum metabolic analysis was conducted via ultra-high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry (UHPLC-QE/MS) to explore underlying protective mechanisms of DHI in the transverse aortic constriction (TAC)-induced heart failure. Multivariate statistical techniques were used in the research, such as unsupervised principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). MetaboAnalyst and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to pinpoint pertinent metabolic pathways. Results: After DHI treatment, cardiac morphology and function as well as the metabolism in model rats were improved. We identified 17 differential metabolites and six metabolic pathways. Two biomarkers, PC(18:3(6Z,9Z,12Z)/24:0) and L-Phenylalanine, were identified for the first time as strong indicators for the significant effect of DHI. Conclusion: This study revealed that DHI could regulate potential biomarkers and correlated metabolic pathway, which highlighted therapeutic potential of DHI in managing HF.

A bibliometric and visual analysis of research trends and hotspots of myocardial apoptosis: A review.

BACKGROUND: Recent studies have found that cardiomyocyte apoptosis is closely associated with the pathophysiological development of various cardiovascular diseases, for example chronic heart failure and myocardial infarction. At present, there are many researches in this field, such as pharmacological research, traditional Chinese medicine intervention research and pathway research. However, the relevant research is fragmented, with few comprehensive analysis and systematic combing. METHODS: The relevant literature on cardiomyocyte apoptosis was downloaded from the Web of Science Core Collection (WoSCC) and PubMed databases. Citespace 6.1.R2 software Microsoft Excel 2019 and VOSviewer1.6.18.0 were used for bibliometric and visual analysis of publication volume, countries, institutions, journals, authors, keywords. RESULTS: Since 1996, there are 1881 research articles and reviews related to cardiomyocyte apoptosis published by 10,313 researchers from 1648 institutions in 58 countries or regions were included. The number of annual publications showed an upward trend, especially in recent years. Countries participating in this research area include China, the United States, and Japan. Capital Medical University, Harbin Medical University are the key research institution, and other institutions also have substantial contribution on the project as to cardiomyocyte apoptosis. The journal EUR REV MED PHARMACO has a large number of publications, whereas CIRCULATION has the highest number of co-citations. Keywords analysis showed that apoptosis, expression and oxidative stress had higher frequencies, leading to 8 clusters. CONCLUSIONS: Cardiomyocyte apoptosis is a hot research field in recent years. Through visualization and bibliometric analysis, it is found that this field focus on hotspots like clinical manifestations including heart failure or myocardial infarction, and microscopic mechanisms such as oxidative stress and inflammation.

Strength and Deformation Characteristics of Fiber and Cement-Modified Waste Slurry.

Using fiber and cement to modify waste slurry and apply it to roads is an effective way to recycle waste slurry. A new type of road material, fiber-cement-modified waste slurry (FRCS), was prepared in this study. The static and dynamic characteristics of the cement soil were studied using an unconfined compressive strength test and dynamic triaxial test. The results show that the optimum fiber content of FRCS is 0.75%. In the unconfined compressive strength test, under this fiber content, the unconfined compressive strength (UCS) of the FRCS is the largest, and the elastic modulus and modulus strength ratio are both the smallest, indicating that the tensile properties of the cement slurry have been enhanced. In the dynamic triaxial test, the hysteretic curve of the FRCS tends to be stable with the increase in the number of cycles, the dynamic elastic modulus of the FRCS decreases first and then increases with the increase in the dosage, while the damping ratio becomes stable after a rapid decline, and the fiber incorporation increases the cumulative strain of the soil-cement under low-stress cycles, indicating that the ductility of the FRCS is improved. In addition, a cumulative strain prediction model of the FRCS is established in this paper, which can provide a reference for the resource application of waste slurry in road engineering.

Risk factors associated with contrast-associated acute kidney injury in ST-segment elevation myocardial infarction patients: a systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the risk factors for contrast-associated acute kidney injury (CA-AKI) in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched the databases of PubMed, Embase and Ovid, up to February 2022, for observational studies that investigated the association between risk factors and CA-AKI. RESULTS: A total of 21 studies were included in the meta-analysis. Of the total 22 015 participants, 2728 developed CA-AKI. Pooled incidence was 11.91% (95% CI 9.69%, 14.14%). Patients with CA-AKI were more likely to be older, female, also had comorbidities (hypertension, diabetes, previous heart failure). Smoking (OR: 0.60; 95% CI 0.52, 0.69) and family history of CAD (coronary artery disease) (OR: 0.76; 95% CI 0.60, 0.95) were associated with lower risk of CA-AKI. Left anterior descending (LAD) artery occlusion (OR: 1.39; 95% CI 1.21, 1.59), left main disease (OR: 4.62; 95% CI 2.24, 9.53) and multivessel coronary disease (OR: 1.33; 95% CI 1.11, 1.60) were risk factors for CA-AKI. Contrast volume (weighted mean difference: 20.40; 95% CI 11.02, 29.79) was associated with increased risk in patients receiving iso-osmolar or low-osmolar non-ionic contrast. CONCLUSIONS: In addition to the known risk factors, LAD artery infarction, left main disease and multivessel disease are risk factors for CA-AKI. The unexpected favourable association between smoking, as well as family history of CAD, and CA-AKI requires further investigation. PROSPERO REGISTRATION NUMBER: CRD42021289868.

Machine Learning Advances in Predicting Peptide/Protein-Protein Interactions Based on Sequence Information for Lead Peptides Discovery.

Peptides have shown increasing advantages and significant clinical value in drug discovery and development. With the development of high-throughput technologies and artificial intelligence (AI), machine learning (ML) methods for discovering new lead peptides have been expanded and incorporated into rational drug design. Predictions of peptide-protein interactions (PepPIs) and protein-protein interactions (PPIs) are both opportunities and challenges in computational biology, which will help to better understand the mechanisms of disease and provide the impetus for the discovery of lead peptides. This paper comprehensively reviews computational models for PepPI and PPI predictions. It begins with an introduction of various databases of peptide ligands and target proteins. Then it discusses data formats and feature representations for proteins and peptides. Furthermore, classical ML methods and emerging deep learning (DL) methods that can be used to train prediction models of PepPI and PPI are classified into four categories, and their advantages and disadvantages are analyzed. To assess the relative performance of different models, different validation protocols and evaluation indexes are discussed. The goal of this review is to help researchers quickly get started to develop computational frameworks using these integrated resources and eventually promote the discovery of lead peptides.

Regional specialization of the tongue revealed by gustatory ganglion imaging.

Gustatory information is relayed from the anterior tongue by geniculate ganglion neurons and from the posterior tongue by neurons of the petrosal portion of the jugular/nodose/petrosal ganglion complex. Here, we use in vivo calcium imaging in mice to compare the encoding of taste information in the geniculate and petrosal ganglia, at single-neuron resolution. Our data support an anterior/posterior specialization of taste information coding from the tongue to the ganglia, with petrosal neurons more responsive to umami or bitter and less responsive to sweet or salty stimuli than geniculate neurons. We found that umami (50 mM MPG + 1 mM IMP) promotes salivation when applied to the posterior, but not anterior, tongue. This suggests a functional taste map of the mammalian tongue where the anterior and posterior taste pathways are differentially responsive to specific taste qualities, and differentially regulate downstream physiological functions of taste, such as promoting salivation.

Turn-On Fluorescence Chemical Sensing through Transformation of Self-Trapped Exciton States at Room Temperature.

Most of the current fluorescence sensing materials belong to the turn-off type, which make it hard to detect toxic substances such as benzene, toluene, and xylene (BTX) due to the lack of active chemical sites, thereby limiting their development and practical use. Herein, we show a guest-host mechanism stemming from the confined emitter's self-trapped exciton (STE) states or electron-phonon coupling to achieve turn-on fluorescence. We designed a luminescent guest@metal-organic framework (LG@MOF) composite material, termed perylene@MIL-68(In), and established its E-type excimeric emission properties in the solid state. Upon exposure to BTX, especially xylene, we show that the E-excimer readily converts into the Y-excimer due to nanoconfinement of the MOF structure. Such a transformation elevates the fluorescence intensity, thus realizing a turn-on type fluorescent sensor for detecting BTX solvents. Our results further demonstrate that controlling the STE states of perylene at room temperature (vs the previous report of <50 K) is possible via nanoscale confinement, paving the way to enabling turn-on type luminescent sensors for engineering practical applications.

Exploring the Molecular Mechanism of Action of Yinchen Wuling Powder for the Treatment of Hyperlipidemia, Using Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

BACKGROUND: Yinchen Wuling powder is often used to treat clinical hyperlipidemia, although its mechanism of action remains unclear. In this study, we aimed to investigate the active ingredients found in Yinchen Wuling powder and find its mechanism of action when treating hyperlipidemia, using a combination of network pharmacology, molecular docking, and molecular dynamics simulation approaches. METHODS: The TCMSP database was used to obtain the principle active ingredients found in Yinchen Wuling powder and the NCBI and DisGeNet databases were used to obtain the main target genes involved in hyperlipidemia, and the intersectional targets were obtained by EXCEL. We also used Cytoscape 3.7.2 software to construct a "Traditional Chinese Medicine-Active Ingredient-Target" network and use STRING platform to conduct "protein-protein interactional" (PPI) analyses on the intersection targets. Bioconductor software and RX 64 4.0.0 software were then used to perform GO functional enrichment analysis and KEGG pathway enrichment analysis on the targets. Molecular docking of core protein-ligand interactions was modeled using AutoDock Vina software. A simulation of molecular dynamics was conducted for the optimal core protein-ligand obtained by molecular docking using Amber18 software. RESULTS: A total of 63 active ingredients were found in Yinchen Wuling powder, corresponding to 175 targets, 508 hyperlipidemia targets, and 55 intersection targets in total. Cytoscape 3.7.2 showed that the key active ingredients were quercetin, isorhamnetin, taxifolin, demethoxycapillarisin, and artepillin A. The PPI network showed that the key proteins involved were AKT1, IL6, VEGFA, and PTGS2. GO enrichment analysis found that genes were enriched primarily in response to oxygen levels and nutrient levels of the vesicular lumen and were associated with membrane rafts. These were mainly enriched in AGE-RAGE (advanced glycation end products-receptor for advanced glycation end products) signaling pathway in diabetic complications, fluid shear stress, and atherosclerosis, as well as other pathways. The molecular docking results indicated key binding activity between PTGS2-quercetin, PTGS2-isorhamnetin, and PTGS2-taxifolin. Results from molecular dynamics simulations showed that PTGS2-quercetin, PTGS2-isorhamnetin, and PTGS2-taxifolin bound more stably, and their binding free energies were PTGS2-quercetin -29.5 kcal/mol, PTGS2-isorhamnetin -32 kcal/mol, and PTGS2-taxifolin -32.9 kcal/mol. CONCLUSION: This study is based on network pharmacology and reveals the potential molecular mechanisms involved in the treatment of hyperlipidemia by Yinchen Wuling powder.

DeepEBV: a deep learning model to predict Epstein-Barr virus (EBV) integration sites.

MOTIVATION: Epstein-Barr virus (EBV) is one of the most prevalent DNA oncogenic viruses. The integration of EBV into the host genome has been reported to play an important role in cancer development. The preference of EBV integration showed strong dependence on the local genomic environment, which enables the prediction of EBV integration sites. RESULTS: An attention-based deep learning model, DeepEBV, was developed to predict EBV integration sites by learning local genomic features automatically. First, DeepEBV was trained and tested using the data from the dsVIS database. The results showed that DeepEBV with EBV integration sequences plus Repeat peaks and 2-fold data augmentation performed the best on the training dataset. Furthermore, the performance of the model was validated in an independent dataset. In addition, the motifs of DNA-binding proteins could influence the selection preference of viral insertional mutagenesis. Furthermore, the results showed that DeepEBV can predict EBV integration hotspot genes accurately. In summary, DeepEBV is a robust, accurate and explainable deep learning model, providing novel insights into EBV integration preferences and mechanisms. AVAILABILITYAND IMPLEMENTATION: DeepEBV is available as open-source software and can be downloaded from https://github.com/JiuxingLiang/DeepEBV.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Physiological and gene expression analysis of the Manila clam Ruditapes philippinarum in response to cold acclimation.

Overwinter mortality of the Manila clam (Ruditapes philippinarum) is a major impediment to the aquaculture industry in China. Cold tolerance ability has a tremendous impact on the survivability of R. philippinarum during the overwintering season. In this study, we evaluated the effects of acute and chronic cold stress on the expression of Cold Shock Domain-containing E1 (CSDE1) and Antifreeze protein type II (AFPII) genes and the activities of lysozyme (LZM), catalase (CAT), and superoxide dismutase (SOD) in three cultivated strains (zebra, white, and white zebra) and two wild populations (northern and southern) of R. philippinarum. Under acute and chronic cold stress, the expression levels of CSDE1 and AFPII mRNA in the gills and hepatopancreas were significantly increased in all populations, but the increase varied among different strains and populations. Under acute cold stress, SOD activity significantly decreased in the two wild populations and the white zebra strain. LZM activity significantly decreased but CAT activity significantly increased in selected strains and populations after acute low temperature stress (P < 0.05). Under chronic cold stress, SOD activity significantly increased in the northern population and white zebra strain, while CAT activity significantly increased in the southern population and the white and zebra strains. These results provide useful information about the Manila clam response to cold stress that may be applied to improve the low temperature resistance of Manila clams in aquaculture environments.

Construction of Cu2O/In2O3 Hybrids with p-n Heterojunctions for Enhanced Photocatalytic Performance.

Fabrication of p-n heterojunction materials is an efficient strategy for improving the photocatalytic activity by suppressing the recombination of photogenerated electrons and holes. In this study, a p-n heterojunction consisting of Cu2O and In2O3 was synthesized using the hydrothermal in situ deposition method. The Cu2O/In2O3 hybrid exhibited enhanced performance in the photocatalytic hydrogen evolution reaction and degradation of organic pollutants compared with pure Cu2O and In2O3. The sensitization of In2O3 by Cu2O considerably enhanced the light response of the Cu2O/In2O3 hybrid, and the close contact between In2O3 and Cu2O led to the generation of the p-n heterojunction. The photoelectrochemical properties test proved that the successful fabrication of the p-n heterojunction in the Cu2O/In2O3 hybrid promoted the transfer of photoinduced electrons and holes and inhibited the recombination of photogenerated carriers efficiently. The present strategy provides an efficient approach to improve the performance of photocatalysts through the fabrication of p-n heterojunctions.

Cell-type specific parallel circuits in the bed nucleus of the stria terminalis and the central nucleus of the amygdala of the mouse.

The central extended amygdala (EAc) is a forebrain macrosystem which has been widely implicated in reward, fear, anxiety, and pain. Its two key structures, the lateral bed nucleus of the stria terminalis (BSTL) and the central nucleus of the amygdala (CeA), share similar mesoscale connectivity. However, it is not known whether they also share similar cell-specific neuronal circuits. We addressed this question using tract-tracing and immunofluorescence to reveal the EAc microcircuits involving two neuronal populations expressing either protein kinase C delta (PKCδ) or somatostatin (SOM). PKCδ and SOM are expressed predominantly in the dorsal BSTL (BSTLD) and in the lateral/capsular parts of CeA (CeL/C). We found that, in both BSTLD and CeL/C, PKCδ+ cells are the main recipient of extra-EAc inputs from the lateral parabrachial nucleus (LPB), while SOM+ cells constitute the main source of long-range projections to extra-EAc targets, including LPB and periaqueductal gray. PKCδ+ cells can also integrate inputs from the basolateral nucleus of the amygdala or insular cortex. Within EAc, PKCδ+, but not SOM+ neurons, serve as the major source of inputs to the ventral BSTL and to the medial part of CeA. However, both cell types can be involved in mutual connections between BSTLD and CeL/C. These results unveil the pivotal positions of PKCδ+ and SOM+ neurons in organizing parallel cell-specific neuronal circuits within CeA and BSTL, but also between them, which further reinforce the notion of EAc as a structural and functional macrosystem.

Interventions for Treating 3- or 4-part proximal humeral fractures in elderly patient: A network meta-analysis of randomized controlled trials.

BACKGROUND: The fractures of proximal humerus have a high incidence in elderly patients, especially 3- or 4-part fracture. There are 4 main treatments including nonoperation, open reduction and internal fixation(ORIF), hemiarthroplasty(HA) and reverse shoulder arthroplasty(RSA). However, which one is the optimal choice remains a controversial topic. METHODS: Through the search of three electronic databases (PubMed, Embase, and Cochrane), the randomized controlled trials of 3- or 4-part proximal humeral fracture, until the end of July 2017, which is concerned with the elderly patients, were identified. The quality evaluation of each study was evaluated, Constant score and reoperation rates were extracted and analyzed. We used R(R i386 3.3.2) and the package of gemtc to perform our network meta-analysis. RESULTS: Seven randomized controlled experiments with a total number of 347 patients were brought into our network meta-analysis. The rank probability plot of Constant score showed that the RSA had significantly the highest Constant score and lower reoperation than other treatments. The other way around, the efficacy of ORIF was the poorest. The rank for the Constant score was: RSA, HA, nonoperation and ORIF. The rank for the reduction in total reoperation rates was: RSA, nonoperation, HA and ORIF. CONCLUSIONS: The statistical result suggested that RSA has become a beneficial choice to treat displaced 3-or 4-part fracture in elderly patients, that might result in more favorable clinical outcomes and reduction of reoperation rates than other methods performed for the same indication. But the ORIF is the worst.

A comprehensive model for sub-10 nm electron-beam patterning through the short-time and cold development.

In this study, we propose a set of single-spot experiment to construct a comprehensive model of electron-beam lithography to describe the relation among the incident electrons, resist, and the development conditions such as durations and temperatures. Through the experiments, small feature can be achieved by performing a short-time development due to the high acceleration voltage and large depth of focus of electron-beam system. The singular point in the beginning of the development is also observed in our model and supported by the experimental data. In addition, we verify the characteristic region of each incident spot induced by the point spread function of the electron-beam system. We further fabricate the single line with narrow groove width by utilizing the results from single-spot experiment at low developing temperatures. The line is formed by arranging a series of incident points with a distance close to the characteristic radius. This method can eliminate the proximity effect effectively and thus the groove width is scaled down to 8 nm. By adopting the successful experience in the single line formation, dense array with narrow linewidth is also demonstrated under well suppression of the proximity effect. The minimum groove width of 9 nm with 30 nm pitch is achieved with 5 s development time at -10 °C. Finally, the exceptional capability of pattern transfer is presented due to the high aspect ratio of the resist.

The Angelman syndrome protein Ube3a is required for polarized dendrite morphogenesis in pyramidal neurons.

Pyramidal neurons have a highly polarized dendritic morphology, characterized by one long apical dendrite and multiple short basal dendrites. They function as the primary excitatory cells of the mammalian prefrontal cortex and the corticospinal tract. However, the molecular mechanisms underlying the development of polarized dendrite morphology in pyramidal neurons remain poorly understood. Here, we report that the Angelman syndrome (AS) protein ubiquitin-protein ligase E3A (Ube3a) plays an important role in specifying the polarization of pyramidal neuron dendritic arbors in mice. shRNA-mediated downregulation of Ube3a selectively inhibited apical dendrite outgrowth and resulted in impaired dendrite polarity, which could be rescued by coexpressing mouse Ube3a isoform 2, but not isoform 1 or 3. Ube3a knockdown also disrupted the polarized distribution of the Golgi apparatus, a well established cellular mechanism for asymmetric dendritic growth in pyramidal neurons. Furthermore, downregulation of Ube3a completely blocked Reelin-induced rapid deployment of Golgi into dendrite. Consistently, we also observed selective inhibition of apical dendrite outgrowth in pyramidal neurons in a mouse model of AS. Overall, these results show that Ube3a is required for the specification of the apical dendrites and dendrite polarization in pyramidal neurons, and suggest a novel pathological mechanism for AS.