NudC L279P Mutation Destabilizes Filamin A by Inhibiting the Hsp90 Chaperoning Pathway and Suppresses Cell Migration

Filamin A, the first discovered non-muscle actin filament cross-linking protein, plays a crucial role in regulating cell migration that participates in diverse cellular and developmental processes. However, the regulatory mechanism of filamin A stability remains unclear. Here, we find that nuclear distribution gene C (NudC), a cochaperone of heat shock protein 90 (Hsp90), is required to stabilize filamin A in mammalian cells. Immunoprecipitation-mass spectrometry and western blotting analyses reveal that NudC interacts with filamin A. Overexpression of human NudC-L279P (an evolutionarily conserved mutation in NudC that impairs its chaperone activity) not only decreases the protein level of filamin A but also results in actin disorganization and the suppression of cell migration. Ectopic expression of filamin A is able to reverse these defects induced by the overexpression of NudC-L279P. Furthermore, Hsp90 forms a complex with filamin A. The inhibition of Hsp90 ATPase activity by either geldanamycin or radicicol decreases the protein stability of filamin A. In addition, ectopic expression of Hsp90 efficiently restores NudC-L279P overexpression-induced protein stability and functional defects of filamin A. Taken together, these data suggest NudC L279P mutation destabilizes filamin A by inhibiting the Hsp90 chaperoning pathway and suppresses cell migration

Event-driven Real-time Retrieval in Web Search

Information retrieval in real-time search presents unique challenges distinct from those encountered in classical web search. These challenges are particularly pronounced due to the rapid change of user search intent, which is influenced by the occurrence and evolution of breaking news events, such as earthquakes, elections, and wars. Previous dense retrieval methods, which primarily focused on static semantic representation, lack the capacity to capture immediate search intent, leading to inferior performance in retrieving the most recent event-related documents in time-sensitive scenarios. To address this issue, this paper expands the query with event information that represents real-time search intent. The Event information is then integrated with the query through a cross-attention mechanism, resulting in a time-context query representation. We further enhance the model's capacity for event representation through multi-task training. Since publicly available datasets such as MS-MARCO do not contain any event information on the query side and have few time-sensitive queries, we design an automatic data collection and annotation pipeline to address this issue, which includes ModelZoo-based Coarse Annotation and LLM-driven Fine Annotation processes. In addition, we share the training tricks such as two-stage training and hard negative sampling. Finally, we conduct a set of offline experiments on a million-scale production dataset to evaluate our approach and deploy an A/B testing in a real online system to verify the performance. Extensive experimental results demonstrate that our proposed approach significantly outperforms existing state-of-the-art baseline methods

Event-Centric Query Expansion in Web Search

In search engines, query expansion (QE) is a crucial technique to improve search experience. Previous studies often rely on long-term search log mining, which leads to slow updates and is sub-optimal for time-sensitive news searches. In this work, we present Event-Centric Query Expansion (EQE), a novel QE system that addresses these issues by mining the best expansion from a significant amount of potential events rapidly and accurately. This system consists of four stages, i.e., event collection, event reformulation, semantic retrieval and online ranking. Specifically, we first collect and filter news headlines from websites. Then we propose a generation model that incorporates contrastive learning and prompt-tuning techniques to reformulate these headlines to concise candidates. Additionally, we fine-tune a dual-tower semantic model to function as an encoder for event retrieval and explore a two-stage contrastive training approach to enhance the accuracy of event retrieval. Finally, we rank the retrieved events and select the optimal one as QE, which is then used to improve the retrieval of event-related documents. Through offline analysis and online A/B testing, we observe that the EQE system significantly improves many metrics compared to the baseline. The system has been deployed in Tencent QQ Browser Search and served hundreds of millions of users. The dataset and baseline codes are available at https://open-event-hub.github.io/eqe .Comment: ACL 2023 Industry Trac

Altered dynamic functional connectivity of motor cerebellum with sensorimotor network and default mode network in juvenile myoclonic epilepsy

ObjectiveTo investigate whether changes occur in the dynamic functional connectivity (dFC) of motor cerebellum with cerebral cortex in juvenile myoclonic epilepsy (JME).MethodsWe adopted resting-state electroencephalography—functional magnetic resonance imaging (EEG-fMRI) and a sliding-window approach to explore the dFC of motor cerebellum with cortex in 36 JME patients compared with 30 and age-matched health controls (HCs). The motor cerebellum was divided into five lobules (I–V, VI, VIIb, VIIIa, and VIIIb). Additionally, correlation analyses were conducted between the variability of dFC and clinical variables in the Juvenile Myoclonic Epilepsy (JME) group, such as disease duration, age at disease onset, and frequency score of myoclonic seizures.ResultsCompared to HCs, the JME group presented increased dFC between the motor cerebellum with SMN and DMN. Specifically, connectivity between lobule VIIb and left precentral gyrus and right inferior parietal lobule (IPL); between lobule VIIIa and right inferior frontal gyrus (IFG) and left IPL; and between lobule VIIIb and left middle frontal gyrus (MFG), bilateral superior parietal gyrus (SPG), and left precuneus. In addition, within the JME group, the strength of dFC between lobule VIIIb and left precuneus was negatively (r = −0.424, p = 0.025, Bonferroni correction) related with the frequency score of myoclonic seizures.ConclusionIn patients with JME, there is a functional dysregulation between the motor cerebellum with DMN and SMN, and the variability of dynamic functional connectivity may be closely associated with the occurrence of motor symptoms in JME

Title2Event: Benchmarking Open Event Extraction with a Large-scale Chinese Title Dataset

Event extraction (EE) is crucial to downstream tasks such as new aggregation and event knowledge graph construction. Most existing EE datasets manually define fixed event types and design specific schema for each of them, failing to cover diverse events emerging from the online text. Moreover, news titles, an important source of event mentions, have not gained enough attention in current EE research. In this paper, We present Title2Event, a large-scale sentence-level dataset benchmarking Open Event Extraction without restricting event types. Title2Event contains more than 42,000 news titles in 34 topics collected from Chinese web pages. To the best of our knowledge, it is currently the largest manually-annotated Chinese dataset for open event extraction. We further conduct experiments on Title2Event with different models and show that the characteristics of titles make it challenging for event extraction, addressing the significance of advanced study on this problem. The dataset and baseline codes are available at https://open-event-hub.github.io/title2event.Comment: EMNLP 202

PKD1 Phosphorylation-Dependent Degradation of SNAIL by SCF-FBXO11 Regulates Epithelial-Mesenchymal Transition and Metastasis

SummaryMetastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics such as invasion, metastasis, and stemness. To better understand the posttranslational regulation of SNAIL, we performed a luciferase-based, genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 that targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of posttranslational regulation of EMT and cancer metastasis